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Drugs of the ANS

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					                                                                                                             RICHARD DUNHAM


                                                            CHOLINERGIC DRUGS
  Drug type           Drug                    Mechanism                            Clinical Use                         Side Effects
CHOLINERGIC    These are direct acting agonists (do not require nerve inervation).
AGONIST          Methacholine        -Agonist of muscarine           CV                                        -Salivation, Miosis,
                                     receptor (M>N)                  -Lowers BP & HR                           Lacrimation, Urination,
(Muscarinic)
                                                                     -Slows conduction thru AV node            Defacation, Sweating, -
                                                                     -Only used in dx of bronchial             Bronchoconstriction,
                                                                     reactivity                                Bradychardia
                                                                                                               NOTE: Sweating is the only
                                                                                                               Sympathetic action here
                                                                                                               *Relaxation of blood vessel
                                                                                                               BP reflex HR
                    Carbechol         -Direct stimulant of             RARE USE THERAPEUTICALLY                same
                                      muscarine & nicotinic            Eye
                                      receptor                         -Potent & long duration
                                      -NOT degraded by ACh-            -Relieve glaucoma
                                      esterase                         -After cataract surgery
                  Bethanechol         -Muscarinic only                 GU                                      same
                                      -Not degraded by ACh-            -Stimulate atonic bladder (urinate)
                                      esterase                         GI
                                                                       -Increase motility
                                                                       -Esophageal reflux relief
                                                                       -Post-op ileus tx

                   Pilocarpine        -3’ amine, partial agonist at   ** Intraocular pressure in open         -Aggravates ulcers
                                      M receptor                      angle glaucoma tx (DOC before
                                      -Crosses the BBB                timolol)
                                                                      -Closed angle glaucoma (used w/
                                                                      other drugs)
                                                                      -Xerostomia tx – post radiation tx
                                                                      etc.
                                                                      -Selective for sweat, salivary,
                                                                      lacrimal, bronchial glands & iris
                                                                      smooth muscle (weak effects on GI
                                                                      smmoth muscle and heart)
                    Cevimeline         M1 & M3 agonist                Tx of Sjogren syndrome                   Similar to pilocarpine
AChE-          AChE Inhbitors are indirect acting cholinomimetics (requires nerve innervation for effects so no effect on blood
INHIBITORS     vessels). Since ACh is released onto nicotinic (N) and muscarinic (M) receptors. You would see nicotinic sitmulation (unlike
               bethanecol) and muscarinic stimulation. Increasing ACh in the synapse would compete away competetive muscarinic
               antagonists (e.g. atropine overdose) and competetive nicotinic antatonists (curare). IF you have desensitized muscle
               receptors causing paralysis, should you use an agonist to stimulate? If you use an agonist, it will only make it worse by
               further desensitization. Should you use an antagonist? No, the efficacy of a blocker is zero.
                   Edrophonium         -Similar to neostigmine,       -Used in dx of myasthenia gravis         -Generalized ACh stimulation
                                       duration of 2-10 min           -MG tests: better =MG crisis             Cholinergic crisis – antidote is
                                                                      worse= cholinergic crisis                Atropine
                  Physostigmine        -Indirect acting 3’ amine      -GI/GU motility                         -CNS convulsion (@dose)
                                       -Periphery & INTO CNS          -Miosis (constriction)                   -Paralysis of skeletal muscle
                                       (lipid sol)                    -Tx of Glaucoma (ocular pressure)       (too much ACh)
                                                                      -Antidote for OD of muscarinic           -Potentially fatal arrhythmias
                                       -Reversible inhibition of      antagonists (Atropine,                   from AV block
                                       ACh-esterase                   phenothiazine, TCA)                      -Aggravation of asthma
                   Neostigmine         -Reversibly inhibits ACh-      -Stimulates GI/GU motility               -Potentially fatal arrhythmias
                                       esterase                       -Tx for myasthenia gravis (b/c no        from AV block
                                       -4’ amine; does NOT into       CNS effects & long life)                 -aggravation of asthma
                                       CNS                                                                     -NO Pupil constriction
                                       -Orally active                 -Antidote for tubocurarine

                                                                                                                                1
                Pyridostigmine       Same as neostigmine            Tx. Myasthenia gravis
                 Ambenonium
                 Demecarium          Same as neostigmine            Tx. glaucoma
              Organophosphates       “Irreversible” & lipid         -Glaucoma only in very very dilute     CNS
              DFP/Echothiphaate      soluble (CNS effects)          solutions                              -Excessive muscarinic/
                                                                    -Tounge Fasiculations                  nicotinic effects: confusion,
                Slow Reversible      Covalently binds to ACh-                                              ataxia, slurred speech, loss of
                   Malathion,        esterase                       Antidote  Pralidoxime &               reflexes, sweating, salivation,
               parathion, soman,     -Nerve gas & insecticides      ATROPINE                               convulsions, coma, respiratory
                  tabun, sarin                                                                             paralysis, death
                                     -These compounds               *CHRONIC toxicity is different         -Organophosphates (except
                                     phosphorylate the esteratic    from acute toxicity, and causes        echothiophate) are
                                     site on AChE at serine         demyelination motor/sensory           distributed to all parts of the
                                     hydroxyl groups                impairment (think of a farmer)         body including the CNS
                   Tacrine           -Only used for the CNS         Symptomatic Tx of Alzheimer’s          -Many side effects of Ach in
                  Donepezil          muscarinic effects ACh                                              periphery on M and N
                 Rivastigmine        in brain                                                              receptors (unwanted effects)
                 Galantamine                                                                               -N receptor paralysis
                                     Given Orally                                                          (desensitized muscle) may
                                                                                                           cause respiratory paralysis of
                                                                                                           diaphragm
                                                                                                           -AV block in elderly
OXIMES            Pralidoxime        Binds to ACh-esterasee         Antidote for acute                     -Only effective in short time
                   (2-PAM)           inhibitor to pull it from      organophosphate exposure               period after AchE conversion.
                                     enzyme (breaks P-bond)         NOT chronic exposure                   New nerve gases have very
                                     (NO CNS effects)                                                      short window of opportunity.
                     DAM                                             -Must use oxime before aging          *DAM not available in USA
                                     DAM has CNS effects             (aging for serine is 2-3 min)
              Antimuscarinic drugs are always contraindicated in patients with benign prostatic hypertrophy because of aggravation of
CHOLINERGIC
              symptoms. They are also contraindicated in glaucoma because of the mydriasis and cycloplegia effects of the drug. Blocking
ANTAGONIST
              ciliary muscle contraction blocks the outflow of vitreous humor, may lead to blindness.
                     Atropine        Competitive antagonist to       Eye                                  Low dose:
                                     muscarinic receptor             -Cycloplegic & myadriatic (near      -Bradycardia
                                                                     accommodation/dilation)              -Sedation
                                     Effects (in order of dose):     -Antispasmodic in GI/GU              Higher doses
                                        All secretions shut down    -Antidote for organophosphates       -Tachycardia (may 
                                        Mydriasis, cycloplegia      -Tx of incontinence (must use        ventricular arrhythmias)
                                        Hyperthermia (w/            doses, & would see many SE, so     -CNS hyperexcitation
                                         resulting vasodilation)     not really used)                     -Delerium
                                        Tachycardia                 -Antisecretory for surgery           -Hallucinations
                                        Sedation                    -Tx ulcer (stops secretion of H+)    -Seizures
                                        Urinary retention &         Anesthetic – decreases secretions
                                         constipation                -Tx of parkinsons                    -Dry mouth (no salivation)
                                        Behavioral excitation &                                          -Blurred vision (Pupil dilation +
                                         hallucination                                                    loss of accommodation)
                                                                                                          -Flushing of skin
                                                                                                          -Hot (no sweat i.e. no
                                                                                                          thermoregulation)

                                                                                                           CI: glaucoma, BPH
                 Scopolamine         -Competitive blocker of        DOC- Motion Sickness
                                     muscarin receptors             (prophylactic)
                                     -Greater action in CNS,
                                     longer duration
                 Tropicamide         Competitive antagonist to      Eye exam                               -SE only last a few hours
                                     muscarinic receptor            -Cycloplegic& myadriatic
                                     -Topical use
                  Ipatropium         Competitive antagonist to      -Anti-asthmatic, esp. in COPD          Generally considered safer
                  Tiotropium         muscarinic receptor            w/ vagal componenets & elderly         than giving a -agonist for

                                                                                                                            2
                 Thiotropium         -Does not change mucous          patients                                asthma b/c the agonist will
                                     viscosity, overal mucous        -DOC in bronchospasms                   definitely have an effect
                                     volume                           associated w/ -blockers in drugs       elsewhere, antaonist has no
                                     -Thio = inhalant w/ much         used in asthmatics                      efficacy
                                     longer half life
                  Pirenzepine        Selective M1 receptor            Ulcer tx                                Central effects not seen
                                     antagonist
                 Benztropine         -Penetrates CNS                  Parkinson’s Disease (central
               Trihexyphenidyl                                        effects)…will Tx the tremor &
                                                                      rigidity (caused by too much ACh)




                                 CHOLINERGIC ANTAGOINIST (Classified by structure)
  3’ Amines       Atropine
                 Scopolamine
                 Pirenzepine
                  Flavoxate
                 Oxybutynin
                 Tolterodine
                 Oxybutynin        Anticholinergic,              Tx of hyper-reflexic bladder
                                   antispasmotic
                 Homatropine                                     -Opthamology (preferred to
                Cyclopentolate                                   atropine b/c shorter duration)
                 Tropicamide
                 Benztropine       -enter CNS                    -Tx parkinsonism
                  mesylate                                       -Tx extrapyramidal effects of
                                                                 antipsychotic drugs
               Trihexyphenidyl
               hydrocholoride
                 Dicyclomine                                     -Tx irritable bowel syndrome

                Solifenacin        Selective M3 receptor         -Tx overactive bladder
                Darifenacin        antagonist
  4’ Amines     Ipratropium
                 Tiotropium
              Methscopolamine
                  Trospium
               Propantheline                                     -Antispasmodic, rhinitis, urinary     -Neuromuscular blocking b/c
                                                                 incontinence, Tx of ulcers            nicotinic effects (high doses)
                Glycopyrrolate                                   -used orally to inhibit GI motility
                                                                 -used parenterally to prevent
                                                                 bradycardia during surgical
                                                                 procedures




                                GANGLIONIC & NEUROMUSCULAR DRUGS
   Class              Drug                           Mechanism                            Clincal Use                    Side Effects
Ganglionic    The effects of ganglionic blockers will cause the dominant system (symp or para) at the tissue to be blocked.
 blockers             Arterioles (symp)  vasodilatoin; veins (Symp) dilation, venous return, CO
                      Heart (para) tachycardia. Does the tachycardia result from excess sympathetics after blocking parasympathetic?
                       No, all autonomic output is blocked. The intrinsic heart rate is faster than normal heart rate. If you put this person on
                       a treadmill, will their HR ? No, all autonomic output blocked.
                      Iris (para) mydriasis. So is this do to excess sympathetic tone on the iris? No, it is because the normal tone is

                                                                                                                              3
                          dilated (think of a person in a coma). If you flashed a pin light in the eye, would you see miosis? No, fixed pupils.
                         Ciliary muscle (para) cycloplegia
                         GI tract (para) tone and motility, constipation; Bladder (para)urinary retention
                         Salivary glands (para) xerostomia; Sweat glands (symp)  anhydrosis
                 These are important (only on board exams) for preventing baroreceptor reflex changes in heart rate orthostatic hypotension
                  Trimetaphan (given      -Short-acting blocker                        -Reduces HTN &               -All effects listed above
                          IV)                                                          prevents reflex
                                                                                       tachycardia
                                                                                       -Good for treating a
                                                                                       HTN patient w/ acute
                                                                                       aortic dissecting
                 Mecamylamine (given      2’ amine, so better absorption from GI       Same as trimetaphan          -WILL cross BBB (unlike
                        orally)                                                                                     trimetaphan)
                                                                                                                    -SE: sedation, tremor,
                                                                                                                    choreiform movements & mental
                                                                                                                    aberrations
                      Tetraethyl-         1st ganglionic blocker                       No longer used
                   ammoniium (TEA)        very short acting
                                          4’ ammonium
                    Hexamethonium         4’ ammonium                                  Experimental only,
                                                                                       hypertension
                    Decamethonium         Neuromuscular depolarizing blocking
                                          agent
  Ganglionic         Tetramethyl-         Stimulation is not followed by               Experimental only
  stimulants           ammonium           ganglionic blockade

                    Dimethylphenyl
                     piperazinium
                      Varenicline         Partial agonist at N receptor            -used to stop smoking
 Ganglionic &          Nicotine           -Preferentially stimulate Nn                                        Higher doses cause ganglionic
NMJ stimulants         Lobeline           (ganglionic)                                                        block
                                          -3’ amines
NM BLOCKERS      The nicotinic receptors have 2yd structures. ACh binds to the  subunit, thus 2 ACh must bind to a receptor for activation.
                 There are no cardiac or smooth muscle side effects because those tissues do not have the receptors. Make sure to add a CNS
                 depressant so that patient does not remember.
                     Tubocurarine         Low dose: Competitive blocker by         -Flaccid paralysis – 30-   *Low dose action can be
                                          binding nicotinic Receptor               60 min                     overcome by increasing [Ach]
                                          NONdepolarizing                                                     (AChE inhib)
                                                                                                              -Progressive paralysis (face,
                                          High dose: block ion channels of end                                limbs, respiratory muscles
                                          plate                                                               must intubate
                                                                                                              -NO effects on cardiac & SM
                                                                                                              -NO CNS effects (non-
                                                                                                              responding, but still aware)
                      Mivacurium          Very short duration, metabolized by      -Emergency                 -Not short duration in slow
                                          plasma cholinesterases (genotypically                               metabolizer (could antagonize
                                          determined)                                                         long duration w/ AChE-I)
                      Atracurium          Ester hydrolysis, Hofmann elimination;   -Safe in hepatic or        -HR/BP changes
                                          Onset – 2-3min; moderate duration;       renal impairment (b/c      -Bronchospasm
                                          Rapid recovery                           not metab)                 -Laudanosine toxicity
                                          -Not metab spontaneous inactivation -Not used                      seizures
                                          to laudanosine
                    CisAtracurium         1 of 10 stereoisomers                    -People like it            -No CV or Autonomic SE
                                          Hofmann Elimination                                                 -Predictable elimination
                                          Stable BP w/ dosing
                                          Onset in 2-3min Moderate duration
                     Pancuronium
                      Vecuronium
                      Rocuronium

                                                                                                                             4
          Succinylcholine        -Nicotinic receptor agonist (analog of     -Initial fasciculations      -Malignant hyperthermia (due
                                 AChhas efficacy)                          -Short acting:               to excessive release of Ca from
                                 -DEPOLARIZING, noncompetitive              deactivated by butyryl       the SR) Tx = dantrolene (blocks
                                 -IV b/c very short duration                ChE in serum                 release of Ca from SR)
                                 -Rapidly hydrolyzed by                     -Useful for rapid            -NO ganglionic block unless in
                                 pseudocholinesterase                       endotracheal intubation      doses
                                                                            and during ECT               -No antidotes b/c AChE-I would
                                 Two phases:                                                             worsen b/c no breakdown, and
                                  1. Phase I: depolarization,                                            agonist would only worsen depol
                                     fasciculation, prolong                                              block
                                     depolarization, flaccid paralysis                                   CI: atypical
                                  2. Phase II: desensitization (thus no                                  pseudocholinesterase,
                                     impulses through)                                                   hyperkalemia (risk of prolonged
                                                                                                         depolarization of tissue)




NM Blockers                Short acting         Intermediate acting       Long Acting                 AE: autonomic effects, some
NON-depolarizing           Mivacurium           Atracurium                Tubocurarine                (pancuronium) block M
                                                Cisatracurium             Metocurine                  receptors;
                                                Rocuronium*               Doxacurium                  Histamine Release-
(*Steroid derivatives)                          Vecuronium*               Pancuronium*                tubocurarine and metocurine;
                                                                          Pipecuronium*               and possibly with atracurium
                                                                                                      and mivacurium
  Neuromuscular Blockers:
           Two Types:

                     I.         Non-depolarizing-Competitively inhibits the NMJ receptors by binding without
                                activation of pre and postsynaptic sites. These cannot enter CNS due the charge of
                                the ammonium ions.

                                a.   Presynaptic inhibition- Release of Ach diminishes and contraction ―fades‖

                                b.   Postsynaptic inhibition- Blocks Ach at receptor. This is a competitive block
                                     therefore increased Ach can reverse this.

                     II.        Depolarizing-Competitive agonist that binds to and activates the NMJ receptor but
                                inactivates it by keeping the ion channel open (IE the receptor is prevented from
                                cycling back to it’s closed state).




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                                                        ADRENERGIC DRUGS
Beta-receptors are usually more sensitive to activators. So, beta responses are dominant at low doses. At higher doses, the alpha responses
will predominate. (pp=pulse pressure, later)
1
      Radial muscle of eye mydriasis
      Arterioles & veins vasoconstriction
      Liver glycogenolysis
      Kidney renin
2
      Autoregulation (presynaptic inhibition
      Pancreas insulin (remember that insulin is regulated by cAMP, that’s why it can’t be 1 receptor mediated, which causes Ca++)
      Platelets aggregation (since platelets are not innervated, this effect is caused by circulating epinephrine)
1
      Heart contractility, HR, conduction velocity
      Kidney renin
2 (mostly not innervated)
      Vasodilation
      Uterus Relaxation
      Liver gluconeogenesis, glycogenolysis,  lipolysis (& in adipose)
      Skeletal muscle glycogenolysis (for muscle contraction)
      Pancreas insulin secretion (if you are running away from the alligator, you have to be able to use the glucose) lipoprotein lipase
      Lung bronchodilation
      Drug type                 Drug                    Mechanism                          Clinical Use                       Side Effects
Epinephrine             (1, 1, 2)                                          DOC – bronchospasm &                   -CNS – anxiety, fear, tension,
                        *Note: only epinephrine interacts w/ 2               anaphylaxis (2)                       h/a, tremor
                        receptors                                             -Glaucoma – pressure via              -Cerebral hemorrhage via
                        -Since  receptors are more sensivitve, these         vasoconstriction of ciliary blood      BP
                        effects would be seen at low dose epinephrine         vessels                                -Pulmonary edema
                                                                              -Duration of local anesthetics
                        LOW dose: (like isoproterenol)                        via vasoconstriction (1) to limit     -Cardiac arrhythmia – esp. in
                          1: HR, SV, CO, pp                             abs & distribution                     digitalis pt.
                          2: TPR, BP, pp                                 -Tx cardiac arrest
                         Slightly lower BP, systolic BP, diastolic BP
                                                                              HINTS (Is it Epi or NE):
                        MEDIUM dose:                                          2 effects = epi
                          1: HR, SV, CO, pp                             If bronchodilate = Epi
                          2:TPR, BP, pp                                  If prevent premature labor= Epi
                          1: TPR, BP                                      If metabolic effects = Epi
                         So, maintains BP, while CO & perfusion
                         pressure                                             **At dose epinephrine: if give
                                                                              an 1 blocker, only have 1, 2
                         HIGH dose: (like NE)                                 effects and the previous
                          1: TPR, BP, potential reflex HR                hypertension (1)  hypotension
                          1: HR, SV, CO, pp                             b/c unmasked 2 = EPINEPHRINE
                          2:TPR, BP                                       REVERSAL
                          BP, vasoconstrict & in shock this would          *Clinically, if titrating doses of
                         perfusion more hypoxia, infarction, necrosis       epi into emergency patient in
                         HR via reflex perfusion even more                shock, and pt goes into
                                                                              hypertension, giving 1 blocker
                                                                              can be lifesaving
   Norepinephrine       (1, 1)                                              Shock –powerful vasoconstrictor
                        -Less pulmonary action than w/ epi                    -Not good enough for
                        NE can NEVER drop BP (no 2 activty)                  bronchodilation
 AGONIST               These will cause a decrease in blood pressure (2) and an increase in heart rate (1). Pulse pressure also increases.
nonselective              Isoproterenol       2 > 1 >>>a                    -Tx bronchospasms (bronchodilat)       -Flushing (vasodilat) (2)
                                                                              -Tx heart block &                      -HR arrhythmias (1)
                                                                              bradyarrhythmias (by conduct)
                                                                              Decreases peripheral resistance        -Discontinued from due to
                                                                              b/c no association w/ alpha            deaths from CV involvement

                                                                                                                                   6
                                                                              receptor
1 AGONIST               Dobutamine         B1 selective agonist              -Tx acute CHF  CO w/ little           Use w/ caution in A-fib
                                            (1 > 2)                         change in HR
                                                                              -Shock/resucitation – increases         Dobutamine - Tx
                                                                              force more than rate                    NORMOTENSIVE
                                                                              *Chronic CHF would have
                                                                              desensitization of those                Dopamine – Tx
                                                                              receptors, so cannot use dobutam        HYPOTENSIVE
2 AGONISTS           These will cause a decrease in blood pressure (2) and a reflexive increase in heart rate (causing palpitations). These
                      are not anti-inflammatory, so you would need to address the inflammatory effects if you were treating asthma. Common
Short acting (4hrs)   complaints of those using 2 agonists are anxiety & insomnia (think that 2 is part of fight/fright, so CNS stimulating).
Albuterol             Also, 2 prepares muscles for fight/flight (glycogenolysis, perfusion), so may see muscle tremors. Glucose levels
Levabuterol           would also increase because liver gluconeogenesis and glycogenolysis are stimulated. So don’t give to diabetics.
Pirbuterol              Metaproterenol        -Little effect on heart         -Acute Bronchodilator – asthma          2-Muscle tremor,
Terbutaline                                   -Resistant to COMT              -Relaxes uterus to prevent              restlessness, death rate in
Metaproterenol                                methylation/degradation         childbirth                              asthmatics
                                                                                                                      1- tachycardia, arrhythmia,
Long acting (>12hr)                                                                                                   pulmonary edema in
Salmeterol                                                                                                            pregnancy, high dose
Formoterol                                                                                                            continuous use hypokalemia
                          Terbutaline         -More selective for 2 than     SAME
                           Albuterol          metaproterenol                  -Prevent premature labor (give IV
                                                                              albuterol)
                          Salmeterol          -Slow PK, onset in 30-45min     -Only used for prophylaxis, may
                                                                              nighttime attacks
                           Ritodrine          Same                            -Primarily against premature labor -Hyperglycemia in mother &
                                                                                                                      reactive hypoglycemia in
                                                                                                                      newborn
                                                                                                                      -Risky – CV effects
                      Blocking 2 may precipitate (not cause) bronchospasms and vasospastic diseases. Also, since 2 increases lipolysis,
1/2 BLOCKER
                      glycogenolysis, then with a blocker you may expect hyperlipidemia and fasting hypoglycemia. 2 typically increase
nonselective
                      insulin, so blocking insulin release would not cause fasting hypoglycemia (insulin has little role between meals), but
                      rather it would cause HYPERglycemia after a meal, when insulin is required for glucose uptake. So obviously, B-
                      blockers would always be bad to diabetics (epinephrine’s effects are good via 1 and 2 to help alert to hypoglycemia, &
                      if blocked they would not know they are hypoglycemic)
                           Propanolol         Don’t give B-blockers:          MAJOR USE:                              -CI in acute CHF b/c
                                               1. Diabetics                   -Essential Hypertension,                cannot give drug to CO
                                               2. CHF                         arrhythmia,                             -Rebound tachycardia if
                                               3. Asthmatics                  -Migraines – blocks catechlamine        suddenly removed
                                                                              induced vasodilation in brain           CNS depressive!!!!
                                                                              -Anxiety                                CI: ASTHMA
                                                                              -Hypethyroidism – decrese               -Exercise intolerance – can’t
                                                                              sympathetic stimulation & blocks        increase CO
                                                                              periphera conversin of T4 to T3         -Decreased HR
                                                                              -Angina pectoris – reduction of         -Exacerbate CHF
                                                                              O2 requirement of heart                 -Conduction slowing
                                                                              -MI-reinfarct protection                -Incease TAGS (LDL)
                                                                              -Glaucoma                               -Sexual dysfxn
                                                                                                                      -Delays response to
                                                                                                                      hypoglycemics
                                                                                                                      -Arrhythmics
                             Naldol           Longer acting pure
                                              antagonist
                                              -No CNS involvement
                             Timolol                                          Glaucoma – reduced ciliary              -Watch for systemic effects
                                                                              epithelial humour production            -Sedating
                            Pindolol          Partial agonist (have                                                   No effect on blood lipids
                                              intrinsic symp activity)                                                (due to ISA)
                             Sotalol          K+ channel blocker & B-         -Antiarrhythmic (class III)

                                                                                                                                   7
                                       blocker
                 In the heart, 1 block would case a decrease in CO, SV, and HR. In the kidney, 1 block would allow 1 predominance,
1 BLOCKER
                 leading to a suppressed rennin release. In general, a drop in blood pressure would cause a reflex tachycardia (1) and in
                 a few days an increase in rennin (1). Both of these effects are blocked. 1 blocker also decreases aqueous humor
                 production. Blockers A  M are 1 selective, NZ are nonselective
                       Atenolol                                        Anti hypertension/ sympathetic        Atenolol does not cause
                                                                       cardiac overstimulation               sedation (too water soluble
                                                                       -Pt. on antidepressants w/ HTN,       to cross BBB)
                                                                       atenolol good b/c no sedation
                      Acebutolol       Partial agonist (have                                                 No effect on blood lipids
                                       intrinsic symp activity)                                              (due to ISA)
                                                                                                             -Sedating
                       Esmolol         -Very short t1/2                -Use in ill pt.s where risk of
                                                                       hypotension or heart failure is
                                                                       great
                                                                       -If they start to die, fine…. just
                                                                       stop giving the med
                     Metaprolol                                        Used in pregnancy
1/2 BLOCKER         Labetalol        1/2 BLOCKER                   Hypertension – peripheral             Orthostatic hypotension
nonselective &       Carvediolol       nonselective &                  vasodilator. Decrease BP w/o          Dizziness
1 Blocker                             1 Blocker                      altering TAG or glucose
                                                                       concentration
                                                                       -Antihypertensive w/o reflex
                                                                       tachycardia
DA                    Dopamine         Precursor ofr NE                Tx of shock –CO (1 on heart),       -Same SE as sympathetics
                                       DA > 1 > 1                    enhances perfusion to renal (D1),     -DA metabolized (MOA or
                                                                       splanchnic & coronary arteries        COMT) HVA Nausea,
                                       *DA = NE w/out the OH           -But at DA TPR (bad)             hypertension, arrhythmia
                                       group                           aggravating the ischemic/necrosis
                                                                       potential and possible reflex HR
                                                                       *Think about DA w/ 1 blocker!
1 AGONISTS         Phenylephrine      1 > 2                         Tx of mydriasis & hypotension
                    Methoxamine        -Slow metabolism w/ little      -Nasal decongestant
                     Metaraminol       CNS penetratin                  -Eye drops –  redness via
                                       -Likely to be used topically    vasoconstriction
                                       to cuase vasoconstriction       -End paroxysmal atrial
                                                                       tachycardia (via vagal reflex)
                       Midorine        1 agonist                      Tx of postural hypotension
                                       Prodrug desglymidodrine
                 In gerneral, antagonists have zero efficacy. so blocking  does not CAUSE vasodilation. Blocking  prevents
 BLOCKER
                 vasoconstriction. Lowering blood pressure can cause reflex tachycardias (via 1), but you can block with B-blockers.
nonselective
                 Phenoxybenzamine -IRREVERSIBLY blocks 1              Decrease BP                           Only mechanism to overcome
                                       & 2 (slightly 1 selective)    -Tx for pheochromocytoma-             is by making new adreno-
                                                                       induced hypertension.                 recptors, which takes approx
                                       -Also blocks H1, muscarinic     -Dx of pheochromocytoma               24 hrs
                                       & 5HT receptors, & inhibits     -Frostbite                            -MPR reflex tachycardia
                                       NE reuptake                     -Clonidine w/drawal                   -Reflex CO from blocked
                                                                       -Raynaud’s phenomena                  2 1 system overrides
                                                                       -Preoperative tx to help control      -Postural hypotension, nasal
                                                                       hypertension & sweating               stuffiness, nausea, vomiting
                                                                                                             -Ejaculation problems
                                                                                                             (shooting blanks)
                 Phentolamine          Nonselective, REVERSIBLE        -Same as Phenox but reversible        -Can trigger arrhythmias and
                                       -Blocks 1 & 2                 -Prevention of dermal necrosis        anginal pain
                                       -Blocks 5HT                     after the inadvertent
                                       -Agonist at muscarinic, H1,     extravasation ofNE                    CI: patients w/ coronary
                                       H2 receptors                                                          perfusion
1 BLOCKER       Prazosin              Highly 1 selective             Decreases BP w/ no reflex             Orthostatic hypotension (u’ll
                                                                       tachycardia                           get suPRAZed when u stand

                                                                                                                           8
                                                                              Antihypertensive                    up)
                                                                                                                  -Vertigo
                                                                                                                  -Nasal congestion
                                                                                                                  -Drowsiness
                          Terazosin            1 selective                   Tx of BPH-associated urinary
                                                                              retention
                                                                              -Relaxes SM of prostate
                          Tamsulosin           -1a selective antagonist      Tx BPH                                 Incidence of orthostatic
                                               (GU sm musc)                                                         hypotension
                          The effect of an 2 agonist is never immediate because enzyme activity (tyrosine hydroxylase) is changed by
   2 AGONIST
                          decreased synthesis. So, these are not likely to have effects on the blood pressure tracings seen on board exams. You
                          may see a transient hypertension initially.
                               Clonidine       -Decreases central NE            -Tx of mild hypertension            Sedation
                                                                                -Minimize sx from w/d from          -Orthostatic hypotension
                                                                                opiates, cigarettes & BDZ’s         w/d sx include hi BP, h/a,
                                                                                -Rx’s heroin’s anti-adrenergic      tremors, sweating,
                                                                                effects                             tachycardia
                                                                                CNS
                                                                                -Decreases sympathetic activity
                             Methyldopa        Prodrug
   2 BLOCKER                 Yohimbine        Increased release of NE,         -Erectile dysfunction               Replaced by PDE 5 inhibitors
                                               stimulating cardiac 1 &         -Reverse Clonidine effects
                                               vascular 1
                          Since these drugs are indirect, the de-inervated tissues will be nonresponsive. Indirect acting agonists will displace
   INDIRECT
                          norepinephrine from mobile pool. Drug interactions include MOA-a inhibitors.
   ACTING
                              1. MOA-a breaks down catecholamines (ACh, NE, serotonin), but NOT dopamine
   AGONISTS
                              2. MOA-b breaks down dopamine
                              Tyramine         -Released from cheese and red wine, normally oral bioavailability    CI: MAO-a inibitors
                                               is limited by MOA-a metabolism of tyramine in the gut & liver.
                                               With MOA-a inhibition, there is bioavailability
                            Amphetamine        -Promote NE release (DA,         Used to be used for ADHD            CI: MAO-a inibitors
                               Ritaline        5HT release also)
                                               -CNS target
                              Ephedrine        -Same as above                   -Included in many cold medicines    CI: MAO-a inibitors
                                               -CNS is side effect
   REUPTAKE                   Reserpine        -Prevents cytosolic              -Reduces reuptake of NE             -Side effects limited by
   INHIBITORS                                  reuptake of NE into vesicles -Effective, cheap                       using low dose (Depression)
                                                                                antihypertensive
                               Cocaine         Block reuptake of NE             -Used socially
                                               -Amplifies any adrenergic
                                               neurotransmission
                                               peripheral or central




                                                               GLAUCOMA
There are two types of glaucoma. The angel refers to the irido-corneal angel, where the aqueous humor drains
    1.    Open Angel glaucoma – degenerative changes in the canal of Schlemm to drain causes slowly increasing pressure, pressing the back of the
         eye. GOAL: decrease production of aqueous humor by blocking 1
    2.    Closed Angel glaucoma – the angel is narrowed. It could be because the iris is obstructing the canal of Schlemm, or it could be from
         genetics. A drug that causes constriction of the radial muscle may cause a mechanical blockage of the canal (1 agonist drugs). GOAL:
         stretch the iris via miosis, or constrict the ciliary muscles to allow the iris to bow backwards and allow drainage
       Class                     Drug                           Mechanism                              Clincal Use                  Side Effects
  Cholinomimetic             Pilocarpine          M agonist                                  DOC for emergency closed
                                                                                             angel or open angel glaucoma
                           Echothiophate          AChE inhibitor (organophosphate)           Same, longer duration

                                                                                                                                 9
    -Blocker               Timolol           Block actions of NE at ciliary
   nonselective                               epithelium and  aqueous humor
                                              formation
Carbonic anhydrase
     inhibitor




                                                              AUTOCOIDS
    Class                   Drug                  Mechanism                     Clinical Use                        Side Effects

    Histamine        H1 receptor:
    (H1) BLOCKER       Gq coupled
                      Found on the endothelium Ca NO synthesis diffuses to smooth muscle relaxation
                       Increases capillary permeability (associated w/ contraction of endothelial cells)
                       Found on bronchioles bronchoconstriction
                       Increases activation of peripheral nociceptors (PAIN & pruritus)
                       Involved in inflammatory and allegic reactions
                       Via Gi coupling, will decrease AV nodal conduction
                     H2 receptor:
                      Gs coupled (cAMP)
                      In stomach, causes increased gastric acid secretion from parietal cells ulcers
                      In the heart, causes increased SA nodal conduction
                      Also found on mast cells & in the CNS
                     Diphenhydramine       -Competetive blockers at    -Allergic rhinitis/urticaria     -Sedation, antimuscarinic,
                     Chlorpheniramine      H1 receptors                -Motion sickness                 antagonize serotonin
                        Hydroxyzine                                    (scopolamine is better)          -Dry mouth
                          Meclizine        1st Generation              -Sedation (side effect)          -Drug induced parkinson’s
                       Promethazine        -Also antagonize ACh,       -Sleep induction                 Potentiates effects of other CNS
                                           NE, Serotonin in CNS        -Parkinson’s disease (b/c        depressants (alcohol etc)
                                           **Not used in               antimuscarinic)                  Loss of appetite, nausea, distress,
                                           bronchospasm**              -Diphyd – also good local        constipation or diarrhea
                                                                       anesthetic that reverses
                                                                       effect of phenothiazines
                       Fexofenadine        -Competetive blockers at    Allergic rhinitis (daytime       PVC’s – tachycardia
                         Larotidine        H1 receptors                benefits) ―non sedative‖        Prolonged QT interval
                        Terfenadine*                                                                    Liver dysfxn
                         Astemizole*       2nd generation                                               Substrates for P-glycoprotein
                     (*Taken off market)
                                           -No sedation (do NOT                                         transp.
                                           cross BBB)
    Histamine            Cimetidine        -Inhibit gastric acid       -Gastric ulcer                   Mainly Cimetidine:
    (H2)                                   secretion                   -Zollinger-ellison syndrome      -Inhibits P450**
    BLOCKER                                -See GI drugs               -GERD (PPI are better)           Anti-androgenic Gynecomastia,
                                                                       -Hiatal hernia                   low sperm count, galactorrhea
                         Ranitidine        -Do NOT inhibit P450 -      -Same                            -VERY safe drugs
                         Famotidine        Longer acting                                                -Headache, dizzy, diarrhea,
                         Nizatidine                                                                     Less side effects than cimetidine
    Serotonin          Methysergide        -Congener of LSD which      -Migraine – prophylactically     -Toxic effects limit use
    antagonist                             antagonizes 5-HT            Carcinoid sndrome                -Leads to fatal pulmonary/cardiac
    Nonselective                           receptor                                                     fibrosis if used chronically
    HT2 BLOCKER      HT2 (a-c):
                      Gq coupled IP3/DAG
                      In CNS excitatory

                                                                                                                                10
                   In PERIPHERY  vasodilation, GI contraction, bronchial contraction, uterine SM contract, platelet aggregation
                  Cyproheptidine     -Also blocks H1               -Post gastric dumping           Sedating due to H1 Block
                                                                   syndrome
                                                                   -Vasospastic disease- trials
                                                                   -May be used as
                                                                   antihistamine
                                                                   -Allergic rhinitis, vasomotor
                                                                   rhinitis
                                                                   -Tx of smooth muscle
                                                                   manifest of carcinoid synd.
                    Olanzapine       Blocks HT-2a receptors in     -Tx of schizophrenia
                                     CNS                           (atypical antipsychotic)
                    Ketanserin       -Highly selective             Hypertension – trials
                                     -Also blocks 1 receptors     Vasospastic disease – trials
HT3 BLOCKER   HT3:
               Found in area postrema, peripheral sensory and enteric nerves
               Opens ion channels (only 5HT ion channel)
                Ondansetron                                      Adjunct in cancer
                Granisetron                                      chemotherapy:
                Palonosetron                                     -Anti-emetic
                 Dolasetron                                      -Prevents nausea/vomiting
                                                                 (esp from cisplatin)
                 (―setron‖)
HT4           HT4:
AGONIST        Coupled through Gs cAMP
               Found in GI SM
                 Cisapride        HT4 agonist in GI             Tx constipation in IBS            Serious cardiac effects, no longer
                 Tegaserod        prokinetic                     GERD?                             used in USA
               Metoclopramide     HT4 agonist in GI              Prokinetic (aka constipation)

HT1           HT1 (a-f):
AGONIST        Usually coupled through Gi cAMP (sometimes       Gs coupled)
               Found in CNS
                 Busipirone        HT-1a partial agonist,          Anxiolytic                      Non-addicting
                                   DA2, HT2 blocker                                                No cross tolerance w/ alcohol
                Sumatriptan        HT1d agonist                    Migraine acute tx (b/c          -Tingling/flushing @ injection site
                 (―triptan‖)                                       vasoconstriction effect)        -Chest tightness, angina in CAD
                                                                   Cost                            -CI patients at risk for coronary
                                                                   -More effective than ergots     heart disease b/c of the drug’s
                                                                   (ergonovine,                    vasoconstriction
                                                                   methylergonivine, ergotamine
                                                                   –used in postpartum
                                                                   bleeding)

SSRI               Fluoxetime        Inhibits reuptake of 5HT      Depression                      Weight loss
                    (Prozac)          5HT levels                                                 Insomnia
                                                                                                   Flushing, sweating
                                                                                                   GI disturbances
Ergot              Ergotamine        Partial agonist at  and      Tx of acute migraine            -GI distress
Alkaloids                            5HT-2 receptors in the        attacks                         -Prolonged vasoconstriction
                                     vasculature & maybe CNS                                       ischemia & gangrene, abortion
                                                                                                   near term
              dihydroergotamine      Bind -adrenoceptors,         Tx of acute migraine            Avoid over use (rebound migraine)
                                     dopamine recpt, 5-HT          attacks
                  Bromocriptine                                    Tx of hyperprolactinemia
                   Cabergoline                                     (Cabergoline more potent)
                   Ergonovine        Same                          -Tx of postpartum
                   maleate IM        -Uterine SM                   hemorrhage (usually use
                                     contractioncan stimulate     oxytocin)

                                                                                                                         11
                                   labor                          -Diagnosis of variant angina
                                   -Causes constriction of        by inducing coronary
                                   vascular smooth muscle by      vasospasm
                                   stimulating both adrenergic
                                   and serotonergic receptors




Adenosine           Adenosine      Inhibits all excitable cells   Paroxysmal Supraventricular       -Receptors through out body
                                   -Esp. AV node                  tachycardia                       -Anginal pain – vasodilation
                                   -Involved in autoregulation    -DOC after failure of             -Asystole (watch dose)
                                                                  valsalva type maneuvers            --Luckily short acting drug
                                                                  -Diagnostic & curative            -Contraindicated in pt. on
                                                                  Adenosine stress test – for       dipyridamol – potentiates affects
                                                                  those unable to jump on the       (theophylline is antidote)
                                                                  stairmaster
Adenosine        Methylxanthines   -Intereferes w/ Ca++           CNS Stimulant                     Anxiety, agitation
Antagonists       (Theophylline,   binding by SR                  HR & CO                         Insomnia
                    caffeine,      -Inhibits                                                        -CVS: catecholamine release,
                  theobromine)     phosphodiesterase                                               Arrhythmias
                                   prevents cAMP & cGMP
                   Theophylline    -Bronchodilation via           Asthma –(controversial)           -Many PK drug interactions
                                   inhibition of PDE cAMP                                         -CVS: catecholamine release,
                                   & also by antagonism of                                          Arrhythmias
                                   adenosine (a
                                   bronchoconstrictor)
                                   -Induction of histone
                                   deacetylases to suppress
                                   inflammatory gene
                                   expression
                                   -Promotes corticoid action
Adenosine          Dipyramidole    -Blocks adensine reuptake      -Tx angina pectoris               Do not give adenosine while on
agonists                           -i.e. increases levels         -Inhibit emboli from              this drug b/c pt. may arrest
                                   -Vasodilator (increases        prosthetic valve
                                   cAMP)
Prostaglandins      Misoprostol    PGE1 analog – mucosal         -GI protection from NSAID-        -Diarrhea, cramping abdominal
                                   resistance to injury           induce ulcers only in high risk   pain
                                   -Inhibits secretion of HCl     patients b/c of high adverse      -Stimulates uterine contractions
                                   in stomach & inhibit           SE and need for multiple
                                   gastric acid & gastrin         dosing (give PPI instead)         CI: pregnancy
                                   secretion                      -Opens Ductus arteriosus
                                                                  -Ripen cervix before
                                                                  induction of labor
                                                                  -Used w/ methotrexate (or
                                                                  mifepristone) in terminating
                                                                  pregnancy in 1st trimester
                    Alprostadil    PGE1                           -Keeps open ductus
                                   Given IV                       arteriosus
                                                                  -Male impotence (old use)
                   Dinoprostone    PGE2 causes uterine           -Ripen cervix before
                                   contraction                    induction of labor w/
                                                                  oxytocin
                 Epoprostenol      Analog of PGI2                -Used in severe pulmonary
                                   peripheral, pulmonary &       hypertension
                                   coronary resistance            -Prevents platelet
                                                                  aggregation in dialysis


                                                                                                                         12
                 Latanoprost           PGF2 (aqueous humor          -Glaucoma
                 Bimatoprost           production)
                 Travoprost
                 Unoprostone
Leukotriene      Zileuton              Inhibits 5-lipoxygenase        Asthma Tx
inhibitor                              (inhibits leuktn snth)         -Cold, NSAID, exercise
                                                                      induced
                 Zafirlukast           Blocks receptor for LTD4       Same
                 Montelukast
Corticosteroid   Inhalants:            Inhibit phospholipase A2       ASTHMA                          Inhalants: Local- oral/esophageal
                 Beclomethasone                                       *Inhalants: tx of asthma        candidiasis, hoarseness;
                 Budesonide                                           (mild-moderate), decrease       Systemic-minor AE b/c little
                 Fluticasone                                          hyperreactivity, improve        bioavailability
                                                                      epithelial function;
                 Systemic:                                            *Oral: used w/ long acting 2
                 Prednisone                                           agonist (and theophylline) in
                 Dexamethasone                                        severe persistent asthma
                 Cortisol              Same                           -Tx of adrenal crises           -Na retention, EC volume
                 Prednisone                                           -Immunosuppres, antinflamm      expansion, hypokalemia, alkalosis
                 Triamcinolone         -Withdraw drug slowly          -Preterm labor to stimulate     -Iatrogenic cushings
                 Betamethasone                                        fetal lung maturation           -Osteoporosis
                 Dexamethasone         *Avoid in diabetics                                           -GI acid & pepsin release
                                       plasma glucose                *Lack of cortisol associated    -Glaucoma, cataracts (via
                 (Listed in                                           w/ hypotension b/c              sorbitol)
                 increasing potency)   *Avoid in CHF b/c Na           permissive effects              -Wound healing, infections
                                       retention                                                      DRUG toxicities:
                                                                                                      -Cardiac glycosidehypokalemia
                                                                                                      -Loop diuretics, thiazides K
                                                                                                      loss
                                                                                                      -NSAIDs – peptic ulcers,  GI
                                                                                                      bleed
                                                                                                      -ACE-I - risk of blood dyscrasias
                                                                                                      -Chloroquine/mefloquine- risk of
                                                                                                      myopathy, cardiomyopathy
                                                                                                      -Anticholinergics - intraoc Pres
                 Aldosterone           Stimulates                     -Fludro= also has some anti-
                 Fludrocortisone       mineralocorticoid R            inflamm
Cortisol         Metyrapone            Blocks 11-OH, inhibit          -Diagnose adrenal
Blocker                                synthesis of adrenal           deficiencies
                                       steroids (Cortisol)            -Tx Cushings
Mast cell        Cromolyn              Inhibit early/late mast cell   Topical aerosol for             Cough & airway irritation
stabilizers      Nedocromil            histamine release              prophylaxis in asthma           CI: acute episodes
                                       (prevents degranulation)
Anti-IgE         Omalizumab            Inhibits IgE binding to        Tx asthma                       Very expensive, little info
antibodies                             FceR
Mucolytic        Acetylcysteine        Disrupts S-S bonds in          -Asthma (Facilitate             -Mechanical airway irritation, GI
                                       mucoproteins                   expectoration)                  disturbances
                                                                                                      CAUTION: in severe asthma or
                                                                                                      gastric ulcer patients (mucous is
                                                                                                      protective)
Progestin        Mifepristone          Blocks glucocorticoid &        -Abortion (esp. when given w/   Uterine bleeding, malaise, GI, skin
Antagonist                             progestin recptrs              PGE1 or PGF or misoprostol)     rashes
                                       -Give during mid-luteal        -Postcoital contraception       CI: ectopic preg; COPD,
                                       phase when progesterone        (w/in 72 hours)                 renal/hepatic dysfunction, adrenal
                                       is normally high               -Interferes w/                  failure, steroid therapy
                                                                      glucocorticoid for Cushing
                                                                      syndrome
                                                                      -Tx of progesterone dep
                                                                      meningiomas

                                                                                                                            13
                                                  NSAIDS
                    Drug                    Mechanism                     Clinical Use                        Side Effects

 Nonselective      Aspirin       Irreversible acetylation of   -Analgesia– not visceral pain,      -GI bleed
COX Inhibitor                    COX                           prevents sensitization of pain      -Risk of gout, competes w/
                                 -Prevents formation of        receptrs to mechanical & chemical   excretion/reabs of uric acid
                                 PGE, TXA2, Prostacyclin       stimuli (blocks PGE2)               -Reyes syndrome
                                 -Deacetylation  salicylate   -Reduce fever                       -Liver toxicity
                                 which is anti-inflammatory    -Reduce inflammation                -Acute Interstitial Nephritis –
                   OTHERS:
                                 -Analgesic at low doses and   -Anti-platelet coagulation (more    type 1 HS rxn acute renal
                Azapropazone**
                                 anti-inflamm at doses       later)                              failure
                   Carprofen
                                 (45mg/kg/day)                 - Survival post-MI                 -Analgesic Nephropathy renal
                   Diclofenac
                                 PK: Elimination follows 1st   -Some evidence that aspirin         papillary necrosis aftr many yrs
                    Diflunisal
                                 order kinetics at low doses   incidence of colon cancer          -Bronchoconstriction (b/c blocked
                    Etodolac
                                 (half life=3.5 hr); 0 order                                       COX  leukotrienes)
                  Fenoprofen                                   --------
                                 kinetics at doses                                               -Salicylism (at chronic doses)–
                 Flurbiprofen*                                 Overdose stimulate resp centr
                                                                                                   reversible tinnitus, dizziness, h/a,
                   Ibuprofen                                   hyperventilation Respiratory
                                                                                                   confusion
                 Indomethacin                                  alkalosis
                                                                                                   -PGE2 (normally renal vasodilator
                  Ketoprofen*                                  Metabolic acidosis
                                                                                                   that maintains renal perfusion)
                    Ketorolac                                    1. Salicylates are a weak acids
                                                                                                   can Na and water retention
                Meclofenamate                                    2. Impairs renal function
                                                                                                   -PGI2 (normal renal vasodil) may
                Mefenamic acid                                      accumult of sulfuric and
                                                                                                    hyperkalemia, acute renal
                 Nabumetone                                         phosphor acid
                                                                                                   failure
                   Naproxen                                      3. Uncoupled oxidat phosph
                                                                                                   BT (antiplatelet at low dose)
                   Oxaprozin                                        CO2 product glycolysis
                                                                                                   PT (anticoagulant at high dose)
                Phenylbutazone                                      glycogenolysis, gluconeo,
                   Piroxicam*                                       lipolysis, FA ox ketones
                                                                                                   Overdose tx --- fluid, glucose,
                    Sulindac                                     4. Inhibited dehydrogenases in
                                                                                                   HCO3-, K+, cooling, diuresis
                   Tenoxicam                                        Krebs cycle lactic acidosis
                                                                                                   (enhance renal excretion by
                   Tiaprofen                                   *Patient presents w/ mixed resp
                                                                                                   alkaline urine – CAI), lavage,
                    Tolmetin                                   alk & metab acid but after
                                                                                                   charcoal
                                                               doses/prolonged exposure
                                                               depress medullaresp paralysis
                                                                                                   *High risk of GI side effects
                                                               resp acidosis mixed acidosis
                                                               resp & met (bicarb, Pco2)
                  Ibuprofen      -Same potency as aspirin      Inflammatory diseases               GI disturbances
                                 -hi analgesia & antipyretic   Dysmenorrhea                        Tinnitus
                                 properties                                                        Rashes
                                 -Reversible inhibition of                                         H/a
                                 cyclo-oxygenase                                                   Interstitial nephritis
                  Naproxen       Longer-acting derivative of
                                 ibuprofen
                 Indomethacin    More potent cyclo-                                                Serious hematologic rxns
                                                               Closes ductus arteriosis
                                 oxygenase inhibitor
                                 -No bleeding time            Only effective in Hodgkin’s fever   Aplastic anemia
                                                               Ankylosing spondylitis              Acute renal failure
                                                                                                   N/V h/a
                                                               Gouty arthritis                     Acute pancreatitis
                                                               Pre-term uterine-contraction
                                                               reduction
                Phenylbutazone                                 No longer used                      Bad SE (aplastic anemia)

                   Tolmetin      Long t ½                      More potent than aspirin            <than aspirin

                                                                                                                         14
               Piroxicam

                Sulindac       Pro-drug (hepatic             Gouty arthritis                     Agranulocytosis
                              activation)                    Pre-term labor
                                                             Decreases adenomas w/ FAP
                                                             RA/Osteoarthritis
                                                             Ankylosing spondylitis
               Keterolac      Injectible form                                                    Same as other NSAIDS
                                                             Post-op pain –visceral
                              Like opiates w/o CNS side
                              effets                         Allergic conjunctivitis
  COX-2        Celecoxib                                     -Coxibs used primarily for          -Fewer GI SE than nonselective
 Selective                                                   inflammatory disorders              COX inhibitors
 Inhibitor                                                                                       -Renal toxicities similar to
                                                                                                 nonselective COX inhib
                                                                                                 -HS rxns (it is a sulfonamide)
                                                                                                 -COX-1 not blocked  plateltes
                                                                                                 make TXA2 thrombotic state
               Rofecoxib                                     Withdrawn from US market            Associated w/ thrombotic events
               Valdecoxib
               Etoricoxib     2nd generation, highest        Not approved in US
                              select,
               Meloxicam      Preferentially inhibits COX-
                              2, but not as selective as
                              coxibs
Non-NSAID    Accetominophen   NO anti-inflammatory           Analgesia                           -Does not affect uric acid levels
                              NO antiplatlet                 Fever                               -Hepatotoxic @ doses
                              -Weak COX-1,2 inibitor in      Good for pt. on probenecid &
                              peripheral tissues             uricosuric for gout b/c no X-       ANTIDOTE: Acetylcystein is
                              -May inhibits COX-3 in CNS     tolerence                           antidote (sometimes cimetidine)
               Phenacetin     Toxic prodrug is metabolized   Still available in some countries
                              to acetaminophen




                                                                                                                    15
                                                         GI Drugs

                 Drug                 Mechanism                         Clinical Use                       Side Effects

H2 Receptor    Cimetidine    MOA: Blocks gastric mucosal      -Tx of Zollinger-Ellison            -Many drug interactions
 Antagonist                  histamine (H2) receptor         syndrome                            -Decrease hepatic blood flow
                             gastric acid production (by     -Tx GERD                            -Inhibit P450
                             90%) & decrease pepsin           -Tx peptic ulcers & prevent         -Anti-androgenic effects
                             formation                        recurrence                          (gynecomastia in males and
                             -Must take before eating         -Prophylaxis in ICU against         galactorrhea)
                                                              stress ulcers                       -Infertility, libido
                             PK: usually given PO, in         -Preoperative prevents             -Skin rash
                             emergencies give IV              aspiration pneumonia                -Immunosuppression
                                                              -Tx of Tylenol O.D.                 -IV dose hallucination,
                                                              -Hiatal hernia                      delirium, restlessness,
                                                                                                  dizziness, somnolence
                                                                                                  -Absorption of weak acids
                                                                                                  CI: pregnancy
               Ranitidine    More potent than cimetidine,     same                                -No anti-androgen effects
               Famotidine    longer duration                                                      -No CNS effects
               Nizatidine                                                                         -No P450 inhibition
                                                                                                  -Absorption of weak acids
Muscarinic    Prienzepine    -Selective M3 receptor           -Adjuncts to histamine receptor     -Same as atropine
Antagonists                  blocker                          blocker tx                          -Dryness of mouth, blurred
                             -Atropine-like compound have     -Tx peptic ulcer                    vision, tachycardia, urinary
                             only small ability to decrease   -Not currently used                 retention, constipatin (higher
                             gastric acid                                                         doses)
                             -Little ability to cross CNS                                         -More side effects than benefit
              Dicyclomine    -Inhibits vagal stimulation of   -Tx of IBS                          same
                             acid secretion
 PROTON        Omeprazole    -Prodrugsulfenamide             DOC Z-E Syndrome (or MEN)          -Very safe at low doses
  PUMP        Lansoprazole   MOA: Covalently                  DOC peptic ulcers                  -H/a, dizzy, nausea
INHIBITOR     Esomeprazole   (irreversibly) binds H/K         -Tx histamine resistant ulcers      -Abdominal Pain
  S (PPI)     Pantoprazole   ATPase on mucosal side of        -Tx GERD                            -Long term use may be
              Rabeprazole    parietal cell suppresses H+     -H. pylori infection                carcinogenic due to hi gastrin
                             secretion (18hrs); they          -Tx of hemorrhagic ulcers           levels
                             support platelet aggregation     -Tx systemic mastocytosis           -Hyperplasia of oxyntic mucosal
                             maintain clot integrity          (mast cells histamine)           cells
                             PK: effects in 1 hour                                                -Absorption of weak acids
                                                              H. pylori triple therapy (7-14      -Acid environment is required
                                                              days):                              for absorption of Ketoconazole/
                                                              PPI + Clarithromycin +             itraconazole (impairs abs)
                                                              Amoxicillin
                                                              PPI + Clarithromycin +
                                                              Metronidazole (give if penicillin
                                                              allergic)
                                                              PPI + Tetracycline +
                                                              Metronidazole + bismuth
                                                              subsalicylate
                                                              *But continue PPI or H2-R block
                                                              for 4-6 weeks
 MUCOSAL      Misoprostol    PGE1 receptor agonist           -Prevent NSAID-induced ulcer        -Diarrhea
PROTECTIVE                   inhibits basal & stimulated      only in high risk patients b/c of   -Uterine contraction
  AGENTS                     gastric acid secrtion (Gi       high adverse SE and need for        -Abdominal pain
                             cAMP)                           multiple dosing (give PPI
                             -Enhances mucosal barrier by     instead)                            CI: pregnancy
                             increasing mucus & NaHCO3        -Abortiion w/ (MTX)
               Sucralfate    -At pH < 4 extensive            -GI ulcers & erosions               No major side effects

                                                                                                                  16
                                       polymyerizationsticky gel       -Stimulate PGE production           -Alterss bioavailability of other
                                       adheres strongly to base        -Promotes healing (increase         drugs
                                       of ulcer crater (physical        cell#)                              -―Large Pill‖ compliance
                                       barrier (                                                            -Constipation
                                       -Coats for >5 hrs                                                    CI: other anti-ulcer meds (b/c
                                                                                                            this drug needs an acid pH)
                       Bismuth          e.g. peptobismol                 -Said to have some antibacterial
                                        -Not a prodrug                   action against H. pylori 
                                        -Forms into white precipitate combined w/ metronidazole +
                                        at pH <3.5 coats ulcer          tetracyclines
                                        crater & acts as a diffusion
                                        barrier to H+/pepsin
 ANTACIDS         The carbonanates will alkalinize (remember carbonate is an endogenous buffer). The hydroxides work as a bze to
                  neutralize the acid. Antacids will increase oral absorption of weak bases (e.g. quinidine), decrease oral absorption of
                  weak acid (e.g. warfarin), and decrease absorption of tetracyclines (via chelation).
                   Na-bicarbonate       Immediate onset                  -ANTACIDS Symptomatic               -Belching
                                        -Short duration                  (not curative) relief of             -GAS!!!
                                        -May increase gastric pH to      dyspepsia associated w/ GERD,        -Alkalosis
                                        alkaline level which increases   gastritis, peptic ulcers             -Sodium retention
                                        HCl secretion
                    Ca Carbonate        Rapid onset                      -Same                                -Nephrolithiasis
                                        -Think: carbonates alkalinize    -Can be given as an adjuvant in      -Hypercalcemia
                                                                         osteoporosis                         -Alkalosis
                                                                                                              -Gastric acid rebound
                                                                                                              -Dense stools (constipation)
                                                                                                              -chleated by tetracylcines
                    Mg hydroxide        Mg(OH)2 – milk of magnesia       Same                                 -Osmotic diarrhea
                                        Relatively insoluble (poorly                                          -Hypermagnesemia
                                        abs)  slows removal from                                             -Belching
                                        stomach                                                               -Abs of digoxin & tetracyclins
                                                                                                              -Gastric acid rebound
                                                                                                              Mgloss of DTR & respiratory
                                                                                                              paralysis
                    Al3+ Hydroxide      Least potent                     Used in combo w/ other antacids -Reacts w/ HCl AlCl3
                                        Think: hydroxides neutralize                                          constipation
                                                                                                              -Long term use hypophosphat
                                                                                                              -NO Gastric acid rebound
PRO-EMETIC               Ipecac         Stimulate CTZ/gastric            Tx of accidental poisonings
                     Apomorphine        mucosal irritation
  ANTI-           The sources of afferent input to the Chemotactic Trigger Zone (CTZ):
  EMETIC               1. CTZ has D2 receptors, 5HT-3 receptors, neurokinin1 (NK1) receptors, and opiod receptors stimuli = emesis
                       2. Vestibular system (CN VIII) motion sickness  emesis
                       3. Irritation of the pharynx, innervated by the vagus (CN X) gag reflex         (note: vagus = muscarinic R)
                       4. Vagal and spinal afferent nerves from the GI tract are rich in 5HT-3 receptors  irritation of GI mucosa from
                           chemo, radiation, or distention release of serotoninvagus stimulationemesis
                       5. CNS psychological  emesis (e.g. vomiting prior to chemo)
                     Ondansetron         5HT-3 receptor blocker          -Tx emesis from cancer               Well tolerated & very safe
5HT-3 Recptor         Granisetron        centrally at CTZ and            chemotherapy (esp. w/                -H/a, dizziness, constipation,
  blockers             Dolasetron        peripherally at GI              cisplatin); give 30 prior chemo      Diarrhea
                     Palonosetron        PK: PO, IV; Palonnewer         -Give + corticosteroid for
                                         drug, more specific for         prevention of delayed n/v            -Small prolongation of QT
                                         5HT-3 & longer ½ life (40       -Radiation-inducd vomiting           interval
                                         hrs)                            -Post-op N/V
                                         -Others have short ½ life
                                         (4-9hrs)
                                         -Hepatic metabolism
                    Dexamethasone        Unknown mechanism for           -Enhance efficacy of 5HT-3
Corticosteroids
                  Methylprednisolone antiemesis                          recptr blockers


                                                                                                                            17
                   Aprepitant       NK1 receptor blocker (this      -Used w/ 5HT-3 blocker for           -Fatigue, dizziness, diarrhea
NK1 Recptor                         is the receptor to              prevention of acut/delayed n/v       -Metab by CPY3A4 & would
  Blocker
                                    substance P)                                                         inhibit other drugs from metab
               Dopamine receptors (D1) are also found on the lower esophageal shpincter, causing it to contract better
 D2 receptor     Phenothiazines      -Blocks DA receptors in        Cisplatin induced N/V               Sedation
   Blocker      Prochlorperazine     chemoreceptor zone             Poisons & visceral afferent pain    Extrapyramidal dyskinesias
                  Promethazine       -Blocks muscarinic                                                 (dystonias)
                                     receptors
                                     -Antihistamine sedation
                Metoclopramide       D2-receptor blocker            -Anti-emetic                        -Fatigue
                                     HT3-receptor blocker           -GERD                               -Insomnia
                                     HT4-receptor agonist           -Uremia                             -Hyperprolactinemia, infertility
                                     -ACh agonist w/in GI          -Diabetic gastroperesis             -Extrapyramidal symptoms
                                     GI motility                                                       (dystonias, restlessness,
                                                                                                        parkinsonian)
                Diphenhydramine      -Antihistamine (Blocks H1)     Motion sickness                     Sedation
 H1 blocker                          See antihistamines             Allergic rhinits/urticaria          Don’t give w/ other CNS
                                                                    Sedation                            depressants
                Dimenhydrinate       -Antihistamine (Blocks H1)     Motion sickness (inner ear)         Sedation
                   Meclizine         -Blocks muscarinic receptrs    Vestibular inflammation
                                     (Remember 1st generation
                                     H1 blockers)
  M blocker         Hyoscine         -Antimuscarinic
                  Scopolamine
                    Nabilone         Canabanoids (THC)              -Tx n/v associated w/ chemo         Hi abuse potential
 Canabanoid        Dronabinol        Unknown mechanism              -Tx wasting syndrome in AIDs &      Drowsiness
                                     -Works in higher centers in    certain cancers                     Ataxia
                                     brain                          -Tx glaucoma                        Inability to concentrate
                                                                                                        Disorientation
                                     Dronabinol not really used                                        Anxiety
                                     b/c bioavailability                                               Psychosis
                                                                                                        Laughter (that horrible stuff….)
                   Lorazepam         Benzodiazepinesreduce
                    Diazepam         anticipatory vomiting
PROKINETIC          Cisapride        -Release Ach in myenteric      -Tx GERD                            -Long QT syndrome
                                     plexus                         -Tx diabetic gastroparesis          (predisposes to arrhythmias w/
                                     -Muscle tone in the                                               erythromycin or ketoconazole)
                                     esophageal sphincter                                               -Diarrhea
                                     -Gastric empyting in
                                     people w/ diabetic
                                     gastroparesis
                Metoclopramide       See above                      See above                           See above
                                     The prokinetic is via
                                     muscarinic activity
LAXATIVES            Bran            BULK FORMING AGENTS            -Tx Constipation                    Virtually safe & effective
                     Agar                                           -Pre-op or pre-radiological exam
                 Methylcellulose     -Indigestible, hydrophilic,    -Maintain insulin control           -If not taken w/ H2O, then may
                    Psyllium         absorb water form bulky       -Cholesterol                       cause obstruction/impaction
                                     geldistends colon,            -Colon cancer risk                 -Dehydration, electrolyte
                                     promotes peristalsis                                               imbalance
                                                                                                        -Cramping, constipation
                                                                                                        -Nutritional def of calories,
                    Lactulose        OSMOTIC LAXATIVE               -Tx constipation                    vitamins, & minerals
                     Sorbitol        Soluble, non-abs salts        -Tx systemic encephalopathy
                    Mg oxide         hold water in stool by         -Tx IBS-constipation (lac/sorb)
                                     osmosis                        -Don’t use -Mg oxide for long       CI: bowel obstruction,
                                     -Lactulose also a substrate    time in renal disease b/c hyper-    undiagnosed acute abdomen
                                     for gut bacteria lactic     Mg                                  *Stimulants avoided in
                                     acid pH of gut (NH3                                            pregnancy

                                                                                                                        18
                                  NH4+, now not absorbed        -Flatulence & gas & cramping w/
                                  from gut)                     lactulose
            Polyethylene Glycol   OSMOTIC LAXATIVE              -Preop GI cleaning
                   (PEG)          Nonabs sugar w/ other         -IBS-constipation
                                  saltsno signif fluid or
                                  electrolyte shifts            NO bowel cramps
                 Docusate         STOOL SOFTENER                -Tx painful defecation or
                                  -Soften stool, permitting     constipation
                                  water and lipids to
                                  penetrate
                Mineral oil       STOOL SOFTENER                -Prevent/Tx fecal impaction in
                                  Lubricates fecal material,    young children and debilitated
                                  retarding water absorption    -Used for constipat of morphine
                Caster oil        STIMULANT LAXATIVES           Caster oilpotent (seldom used)   -May develop cathartic colon?
                 Bisacodyl        -Induce bowel movement                                          Fluid/electrolyte deficit
              Phenolphthalein                                   Ex-lax removed from market       Allergic rxn
                 (Ex-Lax)                                       (carcinogenic)                    Turns urine/feces pink
                    Aloe          STIMULANT LAXATIVES           Produce bowel movement in 6-12    Chronic use brown
                   Senna          Occur naturally in plants     hrs                               pigmentation of the colon
                 Cascara                                                                          (melanosis coli)
                                                                                                  -May turn urine red?
ANTI-         Diphenoxylate       OPIATE w/ little CNS          -General diarrhea                 -Habit forming
DIARRHEAL                         action                        -AIDS associated diarrhea         -Not too addicting b/c they are
                                  -Produces bowel relaxation    -Tx IBS-diarrhea                  relatively insoluble
                                  & peristalsis                                                  -Promotes ulcer formation
                                  -Onset in 1hr                                                   -Antimuscdry skin, dry mouth,
                                  -Atropine is added to                                           tachycardia, arrhythmias
                                  discourage abuse. Atrope is
                                  an antispasmodic & would                                        CI: don’t give to kids
                                  help in the constipating
               Loperamide         OPIATE, much lower abuse      -Much more effective on GI
                (Imodium)         potential b/c ability to     -Tx IBS-diarrhea
                                  cross CNS                     -Over the counter
               Hyoscyamine        Block ACh receptors to        Diarrhea                          Only produce the atropine-like
               Dicyclomine        decrease parasympathetic                                        side effects @ hi doses
                                  tone & motility of GI tract
                                  -Antispasmodic action
                 Bismuth-         Coats intestinal epithelium   H. pylori diarrhea
               subsalicylate      & irritation
              (Pepto Bismol)
                Octreotide        -Somatostatin derivative      -Tx diarrhea associat w/
                                  (Somatostn normally used in   metastatic carcinoid &
                                  Tx acromegallyinhib GH)      VIPomas

              Sulfasalazine       Have anti-inflamm effect      -Used in ulcerative colitis &
                                                                crohn’s disease
                Infliximab        Monoclonal antibody to TNF    -Tx IBS & RA

                Tegaserod         Selective 5HT-4 agonist       Relieve Irritable Bowel
                                                                Syndrome – constipation
                 Alosetron        Selective 5HT-3 blocker       Relieve Irritable Bowel
                Cilansetron                                     Syndrome – diarrhea
                   SSRIs          Serotonergic effect           Would seem to help IBS
                  Kaolin          Adsorbants absorb water
                  Pectin          to form better stools


                                                            GOUT


                                                                                                                   19
Acute                Colchicine         Binds to tubulin microtubul     Acute attach of gout
episodes                                polymerization, LTB4,           (rarely used anwymore,
                                                                          give NSAIDS)
Prophylaxis          Allopurinol        Prodrug converted by             Prevents the synthesis        GI distress, peripheral neuropathy
                                        xanthine oxidase inhibit the                                   -Rash, vasculitis
                                        enzmze purine metab                                          -Stone formation
                                        uric acid                                                      -Inhibits 6-mercaptopurine
                     Probenecid         Inhibits PCT reabsorption of      -Do urinanalysis, and if      -Crystallization if high excretion of
                                        uric acid                         see high concentration of     uric acid
                                                                          uric acid crystals (do        -Inhibits the secrtion of many acidic
                                                                          NOT use probenecid ,          drugs (e.g. penicillins,
                                                                          give allopurinol if patient   cephalosporins)
                                                                          is a high excretor)




                                                              Duretics
   ―Diuretic should be interpreted as ―loss of salt‖, not lose of fluids. Many of these drugs have sulfa allergies associated with
   them. A quick screening is that many white wines have sulfites in them, so ask if patient can drink white wines.
       Class                Drug                      Mechanisms                                                     Side Effects
                                                                                       Clincal Use

      Carbonic      Intracellular carbonic anhydrase generates H+ and HCO3-. The H+ leaves via the NHE. The H+ combines with
     anhydrase      filtered HC03 to form H2C03, which is broken down by luminal membrane CA into water and CO2 (both
      inhibitor     permeable).
                        Acetazolamide        -Related to                 -Short term tx of             -Bicarbonaturia
                         Dorzolamide         dichlorphenamide            glaucoma aqueous hum        -Hyperchloremic
                         (―-zolamide‖)                                   (dorzol topical, acetazol in  -ACIDOSIS
                                             MOA:                        emergency)                    -HYPOKALEMIA
                                             1. H+ formed in PCT by CA  -Urinary alkalinisation      -Renal stones (b/c
                                             (Carb Anhydrase blocked)    excretion of weak acids       bicarb in urine, Ca++,
                                             2. Na+/H+ antiport (NHE)   (e.g. ASA Overdose)           Phophate precipitate)
                                             3. Na & bicarb in lumen    -CSF production              -Sulfa allergies
                                             4. Diuresis                -Tx of metabolic alkalosis
                                                                         -Acute mountain sickness      CI – cirrhosis  NH4+
                                             -K+ secretion distally in  (altitude hypervent         usually trapped in acidic
                                             exchange for Na             resp alk, which is compens urine but reversed on
                                             -Cl b/c Na absorbed in    by metab acidosis; also drug  alkaliniztion  hepatic
                                             DCT via NCCT                prevents hypoxic vasoconstr encephalopathy (NH4+)
                                             ACIDazolamide = ACIDosis    in lungedema)
      Osmotic               Mannitol         -Excreted in glomerular     -Acute diuresis               -H/a, n/v
      diuretic                               filtrate w/in 30 min        -Maintain tubular flow/flush -Acute hypovolemia
                                             -Mannitol is not            debris                        -Dehydration,
                                             reabsorbed Retains H2O     -Intracranial/intraocular    hypernatremia
                                             in tubule                   pressure                       (mannitol 1st causes
                                             *Work on entire tubule, but -Tx of Rhabdomyolysis         fluid retention in
                                             considered to have greatest                               vascular b/for kidney
                                             action at PCT b/c PCT =                                   preload = bad)
                                             most active                                               CI: anuric states, CHF




                                                                                                                             20
Loop diuretic       Furosemide          -Duration 2-3 hours             -Tx acute pulmonary             -Ototoxic  esp. w/
                    Bumetanide          -Given IV, instant onset        edema                           aminoglycoside
                    Torsemide           -Direct effects on blood        -Fored diuresis esp. in acute   -Hypokalemic
                                        flow (renal/ pulmonary)         renal failure                   -ALKALOSIS
                                                                        -Tx anion overdose              -HYPOCALCEMIA
                                        1. Block NKCC of TAL            -Tx hypercalcemia,              -Hypomagnesemia
                                        2. Intracell K in TAL          hyperkalemia                    -Hyperuricemia (loops =
                                        3. Back diffusion of K into    -Tx of HTN                      weak acids, which would
                                        lumen                                                           compete w/ uric acid for
                                        4. Lose (+) lumen potential     HTN, CHF – 2nd line tx          secrtion)
                                        5. Mg, Ca reabsporption        (thiazides #1)                  -Nephritis
                                        6. Reabsorption of Na+
                                        7.  Diuresis                   -Patient w/ sulpha allergies    Drug interactions: digoxin
                                                                        use ethacrynic acid (NOT        (from the hypo-Mg)
                                        *Loops = potent vasodilators    furosemide)
                                        by prostaglandins (prostag                                     CI: GOUT,
                                        blocked by NSAIDS)
                  Ethacrynic acid                                       -Pt w/ sulfa allergies          NO sulfa allergy
                                                                                                        OTOTOXIC!!!!!!
  Thiazide      There is a basolateral Na/Ca pump (Na in, Ca out). So if the NCCT blocked, then there is less Na inside the cell,
                so more will be pumped in via the Na/Ca (thus, more Ca exported into blood). The only way the Ca gets into the
                tubule cell is via a Ca channel, which is PTH regulated. The effect of hypercalcemia has never proven beneficial
                for osteoporosis because the calcium entery can only occur if PTH is there (which is only stimulated by low Ca).
                There is NO change in blood/urine Ca or phosphate in osteoporosis anyways.
                Hydrochlorothiazide -Excreted by organic acid             -HTN                          Hypokalemic metabolic
                                          secretory system                -CHF                          alkalosis
                                          1. Block NCCT in DCT            -Tx of kidney stones (if Ca   Hyperglycemia*
                                          2. Luminal Na & Cl             stones) due to idiopathic     Hyperlipidemia *
                                          3. Diuresis                    hypercalciuria Ca does not Hyperuricemia
                                          *Hypocalcemia (+) PTH, (Gs      build up in renal tubule      HYPERCALCEMIA
                                          coupled) phorylates lumen      -DOC in nephrogenic           ALKALOSIS
                                          Ca+ channel to Ca uptake       diabetes insipidus loss of   *From insulin release
                                                                          Na at DCL will cause          (K channel open
                                          *Thiazides = potent             Na/water at CD                hyperpol of islets)
                                          vasodilators via ATP dep-K+                                   -Avoid use in diabetics or
                                          channel opening (remember       *Note ―thio‖ means sulfur in hyperlipidemias
                                          minoxidil or dizoxide)          the drug (think sulfa         Drug interactions: digoxin
                                                                          allergy)                      (toxicity from
                                                                                                        electrolyte disturb)
                                                                                                        Sulfa-Allergies
                     Indapamide           Same                            Same                          No hyperlipidemia
                    Metolazone          Similar to thiazides             BUT unlike thiazides, also
                                                                         effective at GFR < 30mL
 K+ sparing     K+ sparing diuretics will not enhance diuresis much because they act at the very end of the system, after most
                of Na reabsorption has already occurred. Aldosterone inserts ENaC into the luminal membrane, causing passive
                Na diffusion on luminal side. For each Na coming in, a K+ leaves the cell into the urine.
                    Triamterene           Triamterene hepatic           -Adjunct to K+ wasting           HYPERKALEMIA esp w/
                      Amiloride           metab & renal excretion        diuretics                        B-blockers, ACE-I
                                          Amiloride only renal          -Lithium induced DI              -ACIDOSIS
                                          excretion
                                                                                                          Triamterene – acute renal
                                          *Block Na/K or Na/H                                             failure (+indomethacin),
                                          antiporters in principle cells                                  kidney stones
                                          of CD
                   Spironolactone         Aldosterone receptor           -Adjunct to K+ wasting           -Same
                                          antagonist                     diuretics                        -Antiandrogen: Female
                                                                         -Only used in aldosterone       hirsuitism, male
                                                                         states (remember blockers        gynecomastia
                                                                         have zero efficacy) so no

                                                                                                                        21
                                                                               effect in Addison’s disease
                                                                               (b/c no aldosterone)
                            Eplerenone        Aldosterone receptor             Same                            -Same
                                              antagonist (Kidney specific)                                     -NO antiandrogen
        Natriuretic         Nesirtide         1. Activates guanylyl            -CHF
         peptide                              cyclasevascular SM              B-type natriuretic peptide
                                              relaxation                       in cardiac ventricles
                                              2.tubular Na reabs & GFR       released b/c of distension




                                                                   UTERINE DRUGS
    Drug type               Drug                      Mechanism                           Clinical Use                    Side Effects
                        Mifeprestone       -PGE-1 analog                        -Induction of labor upto 7wk.s      Uterine bleeding, malaise,
                         (RU 486)                                               -The morning after (72 hr)          rash

                                                                                                                    CI: ectopic, COPD,
                                                                                                                    renal/hepatic, adrenal
                                                                                                                    failure, steroid therapy
                        PGE2/PGF2a         Cause uterine contractions           Induce abortion/labor               -GI-nausea, vomiting,
                                                                                Topical – ripen cervix              diarrhea
                                                                                                                    -Hypotension-PGE2
                                                                                                                    -Hyperthermia
                                                                                                                    -Bronchospasm

                                                                                                                    CI: asthma, COPD, CAVD
                          Oxytocin         -Milk ejection                       -Lactation – nasal spray            Rare
                                           -Contraction in gravid uterus –      -Induce/maintain labor
                                           efficacy increases near term         Antidote: fenoterol                 CI:
                                           -Weak antidiuretic                   -Control hemorrhage                 -Fetal distress
                                                                                (contraction)                       -Premature
                                                                                -Test fetoplacental circulatory     -Cephalopelvic
                                                                                reserve                             misproportion
                                                                                                                    -
                         Engonovine        -a-adrenergic, dopaminergic,         DOC: induce p.p. contraction        N/ abd pain
                                           serotoninergic                       (hemorrhage control)                H/a
                                           -Lo dose – contract gravid uterus    -Prophylaxis                        Dizziness
                                           (promote labor/stop                  -Uterine atony (prolonged           Tinnitus
                                           hemorrhage)                          labor/big uterus)                   Hypertension
                                                                                                                    Bradycardia
                                                                                                                    Dyspnea
                                                                                                                    Toxicity
                                                                                                                    Ergotism – necrosis of
                                                                                                                    extremities
                                                                                                                    MI
                                                                                                                    Convulsions
Tocolytics            Tocolytics inhibit uterine contraction.
                          Ritodrine         B2 agonist-high cAMP to relax       -Prevention of premature labor      -Maternal tachycardia
                                            smooth muscle of the uterus         -Relaxes SM in uterus/resp.         -h/a, vertigo
                                            -3-6 hr. onset                      tract                               -Constipation
                                                                                                                    -Fetal tachycardia
                                           Tocolytic indication: uterine                                            -Hypoglycemia in fetus
                                           bleeding, cramping (<20wk.),                                             CI:
                                           premature labor w/ dilation (36                                          -
                                           wk.)
                        Mg++ sulfate       -Prolonged distribution in deep      -Tx pre-eclampsia seizure           -Bradycardia, delayed AV
                                           compartments                         -Hypomagnesemia – prevent fetal     conduction


                                                                                                                             22
                                             -Similar efficacy to B-             hypotrophy                          -Hypotension
                                             sympathomimetics                    -Adjunct tx of MI                   -Must monitor, BP, fetal
                                             -Mg++ antagonizes Ca++              -Osmotic laxative                   HR, reflexes
                                                                                 -Antacid
                                                                                                                     Ca++ gluconate - antidote
                                                                                 Toxicity: ECG changes  resp.
                                                                                 depression  loss of corneal        CI:
                                                                                 reflex                              -Renal failure,
                                                                                                                     myasthenia, AV block,
                                                                                                                     before delivery




                                                            ANTIHYPERTENSIVE DRUGS
Any drug that lowers blood pressure will cause a reflex tachycardia. Over a few days, the kideys will retain fluids via rennin secretion, which
may lead to edema. These side effects must be addressed when trying to treat hypertension. Also, any of the drugs affecting the
sympathetics will causes CNS depression and as well as many parasympathetic side effects.
     Drug type                Drug                 Mechanism                      Clinical Use                         Side Effects
Diuretics                  Thiazides       See diuretic section         -1st line against               -Hyper-GLUC
                                                                        hypertension                    -Hypokalemia – add K+ sparing if this is
                                                                        -CHF –shows the greatest        a problem
                                                                        effect to dec. ventricular
                                                                        hypertrophy, morbidity, and
                                                                        mortality
                                                                        -GFR < 30mL use
                                                                        Metolazone
                       Loop & K Sparing    See diuretic section         -K+- sparing is 2nd line
                                                                        -GFR < 30mL use loops
Presynaptic                Reserpine       Destroys vesicles CO,      -Not used clinically anymore    Denervation of sympathetics
blocking                                   TPR (b/c NE in                                             -60-80%  nasal congestion
                                           periphery) (inhibit                                          -Hypersecretion
                                           VMAT?)                                                       -Bronchoconstriction
                                                                                                        GI secretion, incontinence
                                                                                                        -Mental depression, may promote
                                                                                                        suicide
                                                                                                        -Parkinsonism, ulcers
                          Guanethidine     Accumulated into nerve                                       Drug interactions: TCA or cocaine
                                           ending by reuptake pump,                                     (TCA block reuptake pump block
                                           binds vesicles, preventing                                   action of guanethedine)
                                           release of NE from                                           -Diarrhea, edema
                                           vesicles
                       Stimulation of 2 causes a decrease of sympathetics outflow. This means there is a decrease TPR (symp on 1) and
2 AGONIST             also a decrease HR (less NE on 1). No reflex tachycardias.
                            Clonidine      Central acting               -2nd line tx for HTN            -Dry mouth
                                           -CO                         -Tx withdrawl symptoms in       -Sedation
                                           - Peripheral resistance     alcohol/heroin/benzodiazepi -Orthostatic Hypotension
                                           w/ maintanence of renal      en                              -Bradycardia
                                           blood flow                   -Alcoholic delirium             -AV block
                                           -Relaxation of veins         -Postmenopausal syndrome        -Would never see rebound tachycardia
                                                                        -Refractory diarrhea            b/c sympath outflow
                                                                                                        -w/drawal symptoms: Rebound
                                                                                                        (High BP, headache, tremor, sweathing,
                                                                                                        tachycardia)

                                                                                                                               23
                        Methyldopa        -Similar to clonidine        -Tx of HTN in pregnancy         -Coombs test (+) receptors become
                                          -Centrally acting            b/c highly protein pound        antigenic when bound to methyldopa
                                          -ProdrugmethylNE                                            (b/c similar to endogenous compnds)
                                                                                                       -Perfusion pressure of kidney
                                                                                                       renin  edema, so give w/ diuretic
                                                                                                       Drug interactions: TCA (block re-
                                                                                                       uptake, NE)
1 BLOCKER                Prazosin        -Competitively bocks a1      -Mild HTN                       -1st-dose Phenomenon weakness &
                         (t½ 3-4hr)       receptors w/out a reflex     -Low TPR                        syncope w/in 1hr. after 1st dose.
                                          tachycardia                  -Low BP by relaxing arterial    -Postural hypotension
                         Terazosin        -No effect on A2             and venous smooth muscle        -Dizziness, h/a
                         (t½ 12hr)                                     -HTN                            -Reflex tachycardia
                                          *Good effect on lipid        -BPH                            -Tests for antinuclear factor (ANF)
                         Doxazosin        profile: LDL & HDL                                         may turn (+)
                         (t½ 22hr)                                                                     -Urinary incontinence under strain
                                                                                                       b/c relaxed sphincters
-BLOCKER                 Propanolol      -LDL, TAGs, & HDL         -Do not use in asthma,          CI of nonselective BB: pregnancy,
                           Atenolol                                    COPD, CHF, SA or AV node        IDDM, (Blocks sympathetic response
                         Metoprolol                                    abnormalities                   to hypoglycemia therefore pt could
                            Pindolol                                                                   drop dead due to hypoglycemia with no
                            Esmolol                                                                    symptoms)
                            Labetol
                          Carvedilol                                                                  *-Blockers also suppres renin
VASODILATORS          These drugs work by the Nitric Oxide (NO) pathway
(Direct acting)          Hydralazine      TPR via arteriole           -Use in moderate to severe     -Edema
                                          dilation                     HTN                            Reflex tachycardia
                                                                       -Blacks respond well           -Drug induced SLE-like syndrome
                        Nitroprusside     TPR via dilation of         -Use in HTN emergencies        -Cyanide toxicity (coadministered
                                          BOTH arterioles &            (only use acutely, 12-24h)     thiosulfate)
                                          venules
                      These drugs act by opening potassium channels, causing hyperpolarization of smooth muscle and dilation.
                           Minoxidil      -Opens K-channels           -Tx of SEVERE HTN              Hyperglycemia (insulin release)
                                          arteriolar vasodilation      -Topical minoxidil used to
                                          -NO?                         Tx baldness
                          Diazoxide       -Given IV                    HTN emergencies                -Hyperglycemia (from insulin)
                                          -Opens K channels
                                          arteriolar vasodilation
Ca Channel Blockers   CCBs block the L-type of Ca channel (found in Heart & blood vessels). All CCBs vasodilate arterioles, but not all go into
                      the heart and decrease CO. All CCBs will be used for angina and hypertension treatment.
                          Verapamil       Cause CO & vasodilate       -Antiarrhythmic due to         -No reflex tachycardia
                           Diltiazem      arterioles                   nodal conductivity            -Constipation (Verapamil)
                                          -Verapamil most potent
                                          on heart.
                          ―--dipines‖     Vasodilate (especially                                      -Hypotension reflex tachycardia
                                          coronary)  TPR                                            -Gingival hyperplasia (remember…
                                          -very little effect on AV                                   phenytoin & cyclosporin)
                                          conduction
                      Fast onset/short Long acting, slow onset         Long acting &  vascular        potency:
                          Verapamil       Amlodipine                   selectivity:                   Isradipine
                           Diltiazem      Felodipine                   Nisoldipine
                          Nifedipine
Diuretics                  Thiazides      See diuretic section         -1st line for HTN              -Hyper-GLUC
                                                                       -CHF –shows the greatest       -Hypokalemia – add K+ sparing if this is
                                                                       effect to ventricular         a problem
                                                                       hypertrophy, morbidity, and
                                                                       mortality
                                                                       -GFR < 30mL use
                                                                       Metolazone

                                                                                                                              24
                       Loop & K Sparing      See diuretic section        -K+- sparing is 2nd line
                                                                         -GFR < 30mL use loops
Angiotensin-II (AT-II) has two receptors, AT-1 and AT-2. The AT-1 receptors are found on blood vessels and are sitmulated through Gq
coupling, causing vasoconstriction. AT-1 receptors are also found the zona glomerulosa of the adrenal cortex and their stimulation results in
aldosterone secretion. The vasoconstriction raises TPR and increases the blood pressure back to normal. Angiotensin II causes EFFERENT
vasoconstriction at renal arterioles. Aldosterone causes the DCT or collecting duct to retain Na and water. These drugs will not need the
coadministration of diuretics
ACE-I                       Captopril       See CHF                      -Protective of diabetic        -Dry cough (bradykinin)
                                            -Blocks formation of AT-     nephropathy                    -Hyperkalemia (due to aldosterone)
                                            II,                          -CHF                           -Angioedema
                                                                                                        -Acute renal failure in renal art sten
ARB                         Losartan        AT-1 receptor antagonist     Same                           No cough
                                                                         *NOT approved for CHF
Pulmonary Hypertension may result from left heart failure or may be a consequence of fibrousing diseases of the lungs. Conversely, it may be
a consequence of shunts, or it may simply be idiopathic.
ET-A BLOCKER                Bosentan        Endothelin (ET-1) is a       Tx of pulmonary HTN            CI: pregnancy (Teratogenic)
                                            powerful vasoconstrictor
                                            through ET-A and ET-B
                                            receptors
                                            -Bosentan blocks ET-A
                                            receptors
PGI2 analogs              Epoprostenol      Anolog of prostacyclin       Tx of pulmonary HTN            CI: pregnancy (promotes aborption &
                                            (PGI2),                                                     contraction of myometrium)
                                            -Given via infusion pump
PDE-5 inhibitor            Sildenafil       Inhibit PDE-5 cGMP                                       CI: nitrates
                                            pulmon artery vasodilat




                                                          What if HTN and a comorbidity?
                                   Angina            Beta blocker, CCB
                                  Diabetes           ACE-I, ARB (avoid B-blocker + thiazide hyperglycemia)
                                Heart Failure        ACE-I, ARB (or B-blocker)
                                  Post-MI            Beta blocker
                                    BPH              Alpha blocker
                                Dyslipidemia         Alpha blockers, CCB, ACE-I, ARB (basically avoid B-blockers & thiazides)




                                                                             ANGINA
Angina is an ischemic heart disease. There are two basic categories: angina of exertion (coronary atherosclerosis) and Prinzmetal angina
(vasospastic). Angina and heart attack only differ at the histological level. In heart attack, the tissue has infracted and died. Effective
treatment of angina must address the development of atherosclerosis. Risk factors for angina: hypertension, diabetes, hyperlipidemia, and
smoking. Vasospastic angina does not typically involve hyperlipidemias.
The strategy of treatment:
     1.   Increase oxygen delivery to the heart by dilation of the coronaies. This should reduce vasospasms. (Nitrates and CCBs)
     2. Decrease oxygen requirement of the heart by TPR, CO, or both (Nitrates, CCBs, and Beta blockers)
     Drug type                Drug                       Mechanism                           Clinical Use                    Side Effects
     B-blockers            Propranolol       -Decrease severity/freq of             -Cardioprotective post-MI        CI: vasospastic angina
                            Atenolol         exertional angina                      (keep on for 2-3 yr.s)
                           Metoprolol        -Ineffective in unstable                                                Remember other CI:
                                             -(-) Inotropic effect                  Angina associated w/:            -Astham/COPD

                                                                                                                                25
                                               -(-) Chronotropic effect             -Exertional                      -CHF
                                               -Decreased sys BP w/ exercise                                         -Diabetes
                                               NET EFFECT: decrease heart
                                               O2 demand
  Ca Channel blockers         Nifedipine       Binds serum proteins                 -DOC for vasospastic angina      Dihydropyradines
                          (dihydropyridine)    -Hepatic metabolism, renal           (Nifedipine)                     -Dizzy, h/a, flush, digital
                                               secretion                                                             dyasthesia, peripheral
                                Verapamil      -Blocks L-type Ca++ receptors –      All CCBs can be used for         edema, constipation, reflex
                                Diltiazem      cardiopressant & vasodilation        angina, only nifed for vasosp    tachy
                                               -Decrease afterload
                                                                                    - risk of MI in HTN patient      Verapamil, diltiazem –
                                                                                                                      bradycardia, slow SA & AV
        Nitrates          In an endothelial cell, there is Nitric Oxide synthase, which is turned on by phosphorylating reactions when bradykinin,
                          serotonin, and ACh bind. Nitric Oxide synthase will produce NO, which will diffuse into the vascular smooth muscle.
                          Nitric Oxide will stimulate the production of cGMP leading to dephosphorylation of the myosin light chain (i.e.
                          relaxation). Nitroglycerin (R-O-N=O) require cellular cysteine to be metabolized to a nitrosothiol, which will donote
                          NO. Note: people with angina may have atherosclerosis and diabetes, both of which may decrease penile function. A
                          side effect of nitrates also causes some dysfunction, BUT sildenafil is contraindicated.
                          *Review the mechanism of smooth muscle contraction and relaxation and drugs affecting them (Kaplan 2008 p.109).
                          VERY complicated
                             Nitroglycerin       -Relax coronary arteries            -Tx of acute angina              -Flush, headache (vasodilat)
                                                 -Venodilate  preload of                                            -Orthostatic hypotension
                                                 heart less contractility needed                                     -Doses arterial vasodil
                                                  less work done by heart                                            reflex tachy & edema
                                                 *(Some arteriolar dilation at                                        -Methemoglobinemia
                                                 doses)                                                             -Tachphylaxis (repeated
                                                 -Decreased myocardial demand                                         use uses sulfhydryl groups)
                                                 PK: Buccal, IV, transdermal,                                         -Dizziness, weakness,
                                                 sublingual                                                           cerebral ischemia
                                                 -Decrease preload
                                                                                                                      CI: Sildenafil
                                                                                                                      (cardiovascular toxicity)
                              Isosorbide         PK: only PO, extended release       Chronic management of
                               dinitrate                                             angina (preventive)
                           (& mononitrate)
                             Amyl Nitrites       Extremely volatile at room temp     No longer used for angina        Methemoglobinemia
                                                                                     -Tx of CN- poisoning             Abuse




                                                  CONGESTIVE HEART FAILURE
DIURETICS               Loops                                                    Tx CHFassociated backward
                                                                                 failure & pulmonary edema
                   Spirinolactone     Improves survival                         Remodeling in CHF
ANF analog           Nesiritide       Recombinant ANF (recombinant human         Tx acutely decompensated CHF
                                      B-type natriuretic peptide (rh BNP)
                                      cGMP vasodilation
ACE-inhibitors       Captopril        -Renal elmination                          -1st line drug—Hypertension        -Hypotension
                                      -Angiotensin II Antagonist                 -CHF – decrease sudden death,      -Dry cough/bronchospasm
                                      -Decreased vasoconstriction, NE,           progression, morbidity,            (bradykinin)
                                      aldosterone                                -MI – if started in preinfarct     -Angioedema
                                       Bradykinin  vasodilation                period                             -Hyperkalemia
                                      -No, Reflex tachy, no change in CO, No     -Progressive renal disease         -Proteinuria
                                      Na/H2O retention                                                              -Dysgeusia (taste)
                                       sympathetic tone                         -Less efficacious in Black         -Hypercalcemia

                                                                                                                                  26
                                     Vasodilates venous blood vessels to        Patients.                           CI – renal artery stenosis, renal
                                     decreased pre-load and aterioles to                                            failure, pregnancy fetal
                                     lower TPR. Decreased Na/fluid              -1st DOC-first line of choice in    hypoperfusino oligohydramnios),
                                     retention                                  the Rx of CHF w/ diuretics          hx of angioedema (COPD)
                                                                                                                    Toxicity – hypotension w/o
                                                                                                                    tachycardia
                                                                                                                    Interactions: NSAID (bradykinin
                                                                                                                    pthway), K+ spare/waste diuretic,
                                                                                                                    digoxin, lithium levels
                      Enalapril      -Enalapril is prodrug (hepatic             -More potent than captopril,
                    (enalaprilat)    conversion)                                slower onset, longer action
                      Fosinopril     -Enalaprilat – IV for HPT emergency
                      Moexipril      -Fosinopril, moexipril – only hepatic
INOTROPES        Diuretics are often on board in a patient with CHF. All diuretics will distrurb electrolytes. All diuretics (except K+ sparing) will
                 decrease K+, which increases digoxin toxicity. Loop diuretics can cause hypomagnesemia. Thiazides may cause hyper-Ca. Low Mg and
                 high Ca cause increased contractility, which may precipitate arrhythmias if on digoxin.
                       Digitalis     Inhibits cardiac Na/K ATPase              -CHF                                  -Arrhythmia (any type)
                       (Digoxin)     intracell Na+, Na/Ca exchange           -Tx arrythmias: supraventricul        -GI distress: anorexia, vomiting,
                                     intracell CaCa release from SR         tachycardia ( AV conduction)         diarrhea (abs of nutrients follows
                                     contraction force                         *Do NOT use in Wolf Parkinson         Na+ gradient, which is now blocked)
                                                                                White syndrome                        -Neurologic- seizures (also due to
                                     Indirect effect:                                                                 Na+ block), “digitalis delirium”
                                     -Inhibits neuronal Na/K ATPase            Non-indicated                         (headache, fatigue, neuralgia,
                                     results in vagal and sympath             -Myocarditis, cor pulmonale           hallucinations, and mental sx)
                                     stimulation                                -Uncontrolled HTN                     -Visual disturbances  halo’s,
                                     -Decrease AV conduction (prolong           -Bradyarrhythmias                     particularly everything yellow
                                     ERP)                                                                             -Gynecomastia – rare
                                                                                Tx of Digoxin toxicity:
                                     *Long half life need loading dose         - or withdraw drug                   Precipitating factors for toxicity
                                                                                -Monitor dig & K+ levels, EKG         -Hypokalemia
                                     ECG                                        -Correct electrolyte                  -Hypo Mg++, or hyper Ca++
                                     Atria- P changes                           -Arrhythmias lidocaine               -Quinidine & verapamil displace
                                     AV – PR prolonged                          (heart is more depol than             digoxin from binding sites
                                     Ventricles – short QT, depressed ST,       normal, & lidocain binds depol),      -Sympathomimetics may
                                     T                                                                                contractility arrythmias
                                                                                -Mg++, K+(take to normal hi),         -Resp. disease – increase digoxin
                                      Morbidity but no effect on mortality -Temporary pacemaker                      response
                                                                                -Digitalis Ab                         ->65, skinny, fever
                                                                                                                      -Acid base imbalance
                  Amrinone (AKA      Phosphodiesterase inhibitorscAMP -Like coffee it relaxes vascular              Milrinone has actually shown to
                     inamrinone)     which Ca current contractility…         and bronchial smooth muscle           have an mortality
                                     (Remember that NE on 1 causes                                                   -Never actually proved beneficial
                      Milrinone      cAMP)
                      Dopamine       Sympathomimetics cAMP PKA               -Acute CHF b/c chronic CHF           See autonomics
                    Dobutamine       phosphorylates Ca-channelsCa              recepters are desensitized          -Use with caution in atrial fib.
                                     current into heart contractility.        -Shock
                                     Also has some vasodilating effects         -BP up with perfusion to
                                                                                Kidneys,
ARB (AT-II             Losartan      Like ACE-I: decrease                       -Hypertension                         NO COUGH b/c there is no
Receptr Blckr)                       vasoconstriction, NE release,                                                    levels of bradykinin
                                     aldosterone secretion                                                            -It may be fetotoxic

                                     Unlike ACE-I: no affect on
                                     degradation of bradykinin




                                                                                                                                    27
                                            Antiarrhythmic Drugs
NOTE: these are some of the harder arrhythmias to understand:
 Atrial tachycardias are divided into those originating from the node and those that do not. If it comes from the
   node, use B-blocker or CCB to slow nodal conduction. If not from the node, use something that slows AV nodal
   conduction (e.g. adensine). Atrial tachycardias not from the SA node (but at other sites in atria) can be caused by
   CAD, COPD, increased catecholamines, alcohol and digoxin.
 Supraventricular tachycardias (PSVT) refer to those SVT that have a sudden almost immediate onset. A person
   experiencing PSVT may see their heart rate go from 90 to 180 beats per minute instantaneously. Because sinus
   tachycardias have a gradual (i.e. non-immediate) onset, they are excluded from the PSVT category. PSVTs are usually
   AV nodal reentrant tachycardias.
 AV nodal reentrant tachycardia (AVNRT) is also sometimes referred to as a junctional reciprocating tachycardia. It
   involves a reentry circuit forming just next to or within the AV node itself. The circuit most often involves two tiny
   pathways one faster than the other, within the AV node. Because the AV node is immediately between the atria and
   the ventricle the re-entry circuit often stimulates both, meaning that a retrogradely conducted p-wave is buried
   within or occurs just after the regular, narrow QRS complexes.
 Atrioventricular reentrant tachycardia also results from a reentry circuit, although one physically much larger than
   the AVNRT. One portion of the circuit is usually the AV node, and the other, an abnormal accessory pathway from the
   atria to the ventricle (e.g. Wolff-Parkinson-White syndrome with the Bundle of Kent).
Class           Drug                   Mechanism                    Indications                    Adverse Effects

     Na+ CHANNEL
      BLOCKERS
  Ia       Quinidine        -Binds to open, activated       *Tx of Atrial fib, need     Toxicity
                            Na-channels to prevent Na       prior digitalization        -Cinchonism (blurred vision,
                            influx & prolong APD            (digoxin slows AV nodal     ringing in ears, headache,
                            (prolong phase 0)               conduction counteracting    altered color perception, nausea,
                            -Block K+ channel (prolong      the antimuscarinic          vomiting, diarrheaall referr
                            AP & ERP)                       effects of quinidine)       to the drug’s autonomic effects)
                            -Antimuscarinic– (low doses)                                -Contractility
                            paradoxical AV conduction      -Supraventricular           -Proarrhthmic: block M symp
                            b/c  sympathetic control       arrhythmia                  control of heart HR
                            - Blocker (high                -DOC for Chronic
                            concentration) hypotens       Ventricular Tachycardia     ***Toxicity, wide QRS***
                            reflex tachycardia (arrhth)                                 -Wide QRS (b/c anti-M & more
                                                            -Depress automaticity       cells depolarized at a period of
                            *Quinidine = weak base, &       (ectopic pacemakers)        time)
                            antacids abs toxcity        -Depress conduction &       -Long QT & changed T
                                                            excitability (esp.          -Prolong PR intervaltorsade
                            *ANY DRUG prolonging            depolarized tissue)         d’pointes
                            depolarization will be a risk
                            for torsade d’pointes (this     -Antimalarial               Drug interactions: hyperkalemia,
                            includes all anti-M drugs)                                  quinidine displace digoxin from
                                                                                        tissue binding sites
          Procainamide      Similar to Quinidine            Procainamide – 2nd line     Procainamide
          Dysopyramide      -Ischemic tissue is more        acute MI-associated         -Drug induced SLE
                            depolarized than normal         vent. Arrhythmias           -Agranulocytosis,
                            tissue & closer to threshold    (lidocaine – 1st)           -Antimuscarinic: aggravate
                            -Prolongs the refractory                                    glaucoma, urinary retention
                            period                                                      -Mental confusion/ psychosis
                            -Block active Na+ channel
                            -Less antimuscarinic                                          Disopyramide
                            -1 block? (Kaplan says no)                                 -Negative inotropy,
                            -Acetylated  (NAPA)                                        -Cardiac failure w/o existing
                            (blocks K+ channels)                                        myocardial dysfxn
                                                                                        -Atropine-like systemic AE
  Ib        Lidocaine       -Block inactive/refractory      Suppression of arrhyth      -Exacerbation of arrhythmia
                            Na+ channels & shorten          assosociated w/             -SA stands still in pt. w/ MI

                                                                                                                   28
                         APD (phase 0) due to           depolarization:              -CNS toxicity @ high dose
                         block ―window‖ Na current       -DOC Post-MI
                         -Inactive channels more         -Open heart surgery          Interactions
                         likely to be found in           -Digoxin toxicity            -Agents enterfering w/ hepatic
                         ischemic tissue (since partly   -CNS toxicity                perfusion or P450-
                         depolarized) drug              -DOC for ventricular
                         preferentially goes to          tachycardia & fibrillation   Least cardiotoxic
                         ischemic tissue                 after cardio-conversion
                                                         -Not for long-term
                         EXTENSIVE 1ST PASS              prophylactic post MI
                         METABOLISM due to               *Not useful in atrial
                         metabolism by amidases          arrhythmias
                         (So only given IV)
       Tocainamide       Similar to lidocaine            Same as lidocaine            -Frequent @ therapeutic dose
        Mexilitine       Orally active (used in                                       -Neurologic: N, tremor, blurred
                         chronic dosing)                                              vision
                                                                                      -Allergic: rash, fever,
                                                                                      agranulocytosis
         Phenytoin
Ic       Flecainide        -Acts on ALL Na channels        -Life threatening           *MOST pro-arrhythmogenic
        Propafenone        conformations                   refractory ventricular      (15% of patients die)
         Moricizine        -NO effect on APD               arrhythmias ONLY            -Visual disturbances
                           -NO ANS effects                 -Use only orally for atrial -Increases mortality post-MI tx
                           -Slow dissociation from Na+     arrhythmias                 of PVC
                           channel in recovery             -Pretreat w/AVN blocker
II    -BLOCKERS: They are used to control supraventricular tachychardias like atrial fib and atrial flutter. Their
      mode of action is on NODAL tisussue.
         Propranolol       Decrease Phase 4                -Recovery from MI          Hypotension
       Acebutol (1)       -Depresses SA-node freq  prevent sudden death              Aggravation of CHF
        Esmolol (1)       sinus bradycardia               (post -MI prophylaxis)      Asystole
       Satolol (1,2)     - Automaticity of purkinje                                 Propanolol= very lipid soluble 
                           - Conduction AV-node           -Control SVT & A-fib        CNS depression
                           -Negative ionotrope the        (b/c class II affects
                           reason -blockers are good      nodal tissue, the atrial    CI – diabetes, vasospastic
                           prophylaxis post-MI,            beats must go thru AV)      disorders (e.g asthma,
                           prevent heart working too       -Exercise/stress induced    prinzmetal angina)
                           hard                            vent. Arrhythmias
                           -Suppress ectopic               -Ischemic HD/ angina
                           ventricular depolarization      -In ICU give esmolol
                           -Hemodynamic activity           (short t ½ IV)
         Metoprolol                                        DOC in pregnancy
III   K+ BLOCKERS: Used only with life threatening ventricular arrhythmias (i.e. wide QRS) that don’t respond well
      to class I, but all of this is debatable and changes often.
        Amiodarone         -Blocks K+ channels APD       -CHF w/ <30% EF             -Pulmonary Fibrosis up to 45%
                                                           -Low dose for atrial fib    of pts
                           -Blocks Na-channels (Ia)        -Supraventricular           -Photosensitivity
                                                           Arrhythmia                  -―Grey man syndrome‖
                           -Mostly effects                 -IV for acute ventricular   -Blue skin discolor (―smurf
                           purkinje/ventricular (long      tachycardia                 skin‖) b/c of iodine rxn w/
                           plateau)                        -Anti-anginal               starches in skin
                           t½ = 30-120 days steady                                    -Corneal depositis
                           state @ 8-10mo (use             *Amiodarone is a class Ia, -Hepatotoxicity
                           loading doses)                  II, III, IV, so no          -Hyperthyroidism
                                                           matter what arrhythmia      QT (but Torsade rare)
                           ―iod‖ in amiodarone means it    it should have an effect
                           has iodine                                                  Drug interaction – digoxin,
                                                                                       warfarin, quinidine, theophylline
          Ibutilide                                        Used for emergencies        QT (risk of Torsade)
                                                                                       CI: if K or QT

                                                                                                                  29
               Sotalol        Prolongs repol (phase 3)       Tx/prophylaxis severe         -Postural Hypotension
                              Nonselective 1-blocker        ventricular arrhythmias       -Proarrhythmic
                              (class II)                     esp those not responding      -Torsades des pointes
                              -Renal excretion               to class Ib                   -CNS depression
                              (unchanged)                    -Atrial arrhythmias           *Before starting sotolol, must
                                                                                           hospitalz for 72 hrs & make sure
                                                                                           patient not a fast responder
   IV      Ca+ CHANNEL BLOCKERS: The main clinical use will be that of supraventricular tachycardias (like B-blockers).
           Their mode of action is on NODAL tissue (the depolarization in nodal tissue is due to Ca entry).
             Verapamil        -Blocks L-type Ca++          DOC in atrial                   -Well tolerated
              Diltiazem       channels                     fibrillation/flutter            -Constipation
               Bepridil       -Lg effect on AV conduction                                  -AV block (esp w/ added AV
                              due to phase O of nodal     -Re-entry SVT                   block of B-block & digoxin)
                              conduction (also some        -SVT                            -Verapamil displaces digoxin
                              effect on phase 4)           -Ischemic heart disease         from tissue binding sitesmore
                                                           & HTN                           dig toxicity
                                                                                           -Negative inotropic effect

                                                                                       -CI: depressed cardiac function.
 Other   These are not classified as antiarrhythmics, but they have a role in management.
            Adenosine       Adenosine receptors in          -DOC for Tx of             -Flushing
                            heart nodal tissue are Gi       paroxysmal ventricular     -Bronchoconstriction (Gq)
                            coupled (cAMP)SA/AV          tachycardia (90%           dyspnea
                            nodal conduction                effective)  stops heart
                            -Enhance K+ conductance         for a second               -A-fib, V-fib
                            -Inhibits cAMP-mediated         -Potent vasodilator
                            influx  hyperpolarization      -Emergency management -Adenosine is antagonized by
                            (esp. AV node)                                             theophyline (so theophyline
                            -Degraded in seconds by                                    would  nodal conduction)
                            adenosine deaminase
             Atropine       Muscarinic antagonist           Brady-arrhythmias to
                                                            vagal tone
            Magnesium       -Functional Ca++ antagonist     Tx for torsades des
                            -K+ channel block               pointes
                                                            -Tx for digitalis induced
                                                            arrhythmia
                                                            -prophylaxis for
                                                            arrhythmias in acute MI
 Treatment of Torsades des pointes:                                                    Drugs causing Torsades:
        Correct hypokalemia                                                              K+ channel blockers (class
        Correct hypomagnesemia                                                             IA & III)
        Discontinue drugs that prolong the QT interval                                   Antipsychotics
        Attempt to shorten APD with drugs (e.g. isoproterenol) or electrical pacing        (thioridazine)
                                                                                          TCA’s




                                                   Things u shouldn’t do

Disease                                  Contraindicated                                Reason
COPD, asthma                             B-blockers                                     Induction of bronchospasm
                                         ACE-I                                          Induction of cough, use AT1
Bradycardia                              Clonidine                                      Aggravation, risk of Adams-Stokes
                                         B-blocker                                      syndrome
                                         Verapamil/diltiazem
Diabetes                                 Thiazides                                      Reduced glucose tolerance
                                         B-blockers                                     Blunt sx of hypoglycemia
Gout                                     Thiazides                                      Reduced excrfetion of uric acid
                                                                                                                    30
CAD                                       Hydralazine              Provocation of angina (reflex
                                          Prazosin                 tachycardia)
                                          Minoxidil
Peripheral artery occlusive disease       B-blockers               Aggravation/manifestation
CHF                                       Ca++ antagonist          Negative inotrope
                                          B-blockers
Renal failure                             Amiloride, Triamterene   May cause hyperkalemia
                                          Spironolactone
                                          ACE-I                    Plasma concentration up, side effects




                                  CHF
            Sx/problem                         Approach
      Fatigue                    Rest, + intotrope
      Edema                      Salt restriction
                                 Diuretic
                                 Digitalis (+ inotropre)
      Dyspnea                    Diuretic (thiazide, loop)
      Congestion                 Nitrovasodilator
      Poor cardiac               + Inotrope, digitalis
      contractility
       preload/afterload        ACE-I
                                 Ang-block
                                 Ven-vasodilators
      Cardiac tissue             ACE-I
      remodeling                 Ang-block
                                 B-block
                                 Spironolactone
      Irreversible heart         Transplant
      failure




                                                                                                   31
                                   ANTIBIOTIC CLASSIFICATION
                   Cell wall damage/syntheisis      Penicillin
                   inhibited                        Cephalosporins
                                                    Monobactams
                                                    Bacitracin
                                                    Vancomycin
                                                    Cycloserine
                   Cytoplasmic membrane damage      Polymyxins
                   or sythesis inhibited            Polyene antibiotics
                   Inhibit synthesis/metabolism     Quinolones (DNA Gyrase)
                   of nucleic acids                 Rifmapin
                                                    Nitrofuranotoin
                                                    Nitroimidazoles
                   Inhibit protein synthesis        30S
                                                    Tetracyclines
                                                    Spectinomycin
                                                    Aminoglycosides (e.g. Neomycin)

                                                    50S
                                                    Macrolides (e.g. Chloramphenicol, Erythromycin)
                                                    Clindamycin
                   Modify energy metabolism         Sulfonamide
                                                    Trimethoprim
                                                    Dapsone
                   Nucleic acid analogs             Zidovudine
                                                    Ganciclovir
                                                    Vidarabine
                                                    Acyclovir




                                                            ANTIBIOTICS
General principles:
        For seriously ill patients, use bactericidal drugs because their immune system cannot clear the organism
        For drugs that act by concentration dependent killing (aminoglycosides, fluoroquinolones, and carbapenems), once daily dosing can achieve
         the high levels.
        For drugs that act by time dependent killing (B-lactams, glycopeptides, macrolides, clindamycin, and linezolid), treatment should be via
         continuous infusion or multiple daily dosing.
        Class                     Drug                          Mechanism                           Clincal Use                      Side Effects
 SULFONAMIDES            Sulfonamides were the 1st drugs used to cure or prevent systemic infections, but since the penicillins they have become less
                         useful. Sulfonamides are derivates of PABA. They are BACTERIOSTATIC. Sulfonamides are acetylated by the liver (actually
                         become less water soluble) and then excreted by the kidneys. Drink a lot of water to avoid renal stones. Sulfonamdies inhibit
      RAPIDLY            dihydropteroate synthase. Generally, sulphonamides are DOC for PCP infections of AIDS. Sulfonamides inhibit gram (+) and (-),
    ABSORBED:            nocardia, chlamydia, and some protozoa. Ricketsiae are NOT inhibited but are actually stiulated in their growth.

                         PABA(Dihydropteroate synthase) DIHYDROFOLIC ACID (dihydrofolate reductase) THF  purines/DNA

                         Dont give sulphonamides to neonates (no conjugating rxns) & the drugs will displace bilirubin from albumin. Sulphonamides are
                         used for E. coli and are soluble enough to cross BBB  but don’t give for neonatal E. coli meningitis.
                             Sulfisoxazole         -Short acting (4-8h), rapidly  -Nocardia (immunocompromised)              -Hypersensitivity
    Short acting                                   absorbed                       Pneumonia/brain abcess                     (Stevens-johnson)
                                                                                  -Trachoma                                  -Crystalluria, hematuria
                                                                                  -Lympphogranuloma venereum                 -Hemolytic anemia (in G6PD
                                                                                  -Tx of UTI (sulfisoxazole +                def)
                                                                                  phenazopyridein)                           -Kernicterus
                                                                                  -1st line Tx against Toxoplasma            -High protein binding

                                                                                                                                  32
                                                                            (sulfisoxazole + pyrimethamine)         displacement of drugs from
                                                                                                                    binding sites (warfarin,
                                                                                                                    tolbutamide)
                                                                                                                    -Phototoxicity
                                                                                                                    -Drug interaction (292
                                                                                                                    lippencott)
                      Sulfadiazine         -Short acting, rapidly           Above
                                           absorbed                         - Tx of toxoplasma (sulfadiazine +
                                                                            pyrimethamine)
  Intermediate
                   Sulfamethoxoazole       -Intermediate acting (12-        Above + resp. infection in combo
                         (SMX)             18h)                             -Neisseria
                                                                            -Gram (–)
                                           SMX + trimethroprim =            BACTRIM’s spectrum:
                                           Bactrim for UTI/resp. tract      -DOC & prophylaxis of
                                                                            Pneumocystis carini
                                                                            -DOC for nocardia
                                                                            -Toxoplasma
                                                                            - Complicated UTI
                                                                            -TB (part of tx)
     Long              Sulfadoxine         -Long acting (7-9 days)          Prophylaxis for malaria
                                           -Used w/ pyrimethamine
POORLY ABSORBED       Sulfasalazine        -In the GI broken down to       -Tx IBD & RA                            -Reversible infertility
                                           5-aminosalicylate (anti-         Derivatives of 5-ASA:                   -Crystalluria (esp at acid pH)
                                           inflam) & sulfapyridine          1. Pentasa – controlled relase
                                                                               formulation delivering to entire
                                           POORLY absorbed                     GI tract including small bowel
                                                                            2. Asacol – delayed delivery to
                                                                               terminal ileum & beyond
                                                                            3. Olsalazine – new prodrug, coupled
                                                                               5-ASA split by intestinal bacteria
                                                                            4. Rowasa – Rectal enema and
                                                                               suppositories, used for
                                                                               proctosigmoiditis
 SPECIAL USES
                     Sulfacetamide                                          -Opthalmic infxns (e.g. trachoma)

                        Mafenide           Carbonic anhydrase               -Burns (topical) use for short          -Irritation
                                           Inhibitor                        period & only localized area            -Pain
                                                                                                                    -Acidosis (w/ extensive use)
                   Silver sulfadiazine                                      -Prevents infection of burnt            -Well tolerated (minimal SE)
                                                                            surfaces and chronic ulcers             -Rash, itch, allergy
                      Trimethoprim         Inhibits DHF reductase in        Used w/ sulfamethoxazole                BMS & enterocolitis
                                           bacteria                                                                 -Megaloblastic anemia
                        TMP-SMX            oral                             -PCP, most community acquired
                                                                            MRSA, toxoplasma
                     Pyrimethamine           Inhibits DHF reductase in                                              BMS & enterocolitis
                                             protozoa
   FLUORO-        Inhibit replication by inhibiting topoisomerase II & IV (block A subunit of DNA gyrase). DNA gyrase normally introduces
 QUINOLONES       negative supercoiles. Quinolones enter cells easily via porins and are used to treat INTRACELLULAR pathogens (e.g. legionella
                  or mycoplasma). Good against S.pneumo + atypicals so, great for pneumonia
                                             -Fe and Ca limit absorption due      -UTI                              -Articular damage (children)
                                             to chelation                         –Gram (–)’s                       -Tendonitis/tendon rupture
                                                                                  -STD’s/PID                        -Photosensitivity
                                                                                  -Cutaneous, soft tissue (except   -GI irritation
                                                                                  nalidixic acid) & bone infections -Rash
                                                                                  (osteomyelitis)                   -Convlsions, N/V
                                                                                  -Respiratory –) except nalidixic  -All quiniolones QT interval
                                                                                  acid)                             -May cause increase
                                                                                  -Bacterial enteritis              intracranial pressure in kids
                                                                                  -Diarrhea                         - [plasma] of theophylline

                                                                                                                            33
                                                                                                                     CI: pregnancy, kids
                     Nalixic acid         Narrow spectrum                       UTI
                      Norfloxacin
                     Ciprofloxacin                                              -Pseudomonas assoc. w/ cystic
                       Ofloxacin                                                fibrosis
                                                                                -Enterobacteriacea & other
                                                                                gram (–) bacilli
                                                                                -Synergistic w/ penicillins
                                                                                -Acute diarrrheal enteric
                                                                                pathogens (grm – rods)
                                                                                -Gonorrhea (2nd line after
                                                                                ceftriaxone)
                                                                                -UTI’s comp/uncomp
                     Lomefloxacin         -More gram (+)                        *Elminated via biliary               -Sparfloxacin may prolong
                     Gatifloxacin         -Some strains of MRSA &               -Sparflox taken off market?          QT interval, arrhythmias
                     Sparfloxacin         enterococci
                                          -Fewer gram (-)
                     Moxifloxacin         -Broadest spectrum                    *Elminated via biliary              -Trovafloxacin has
                     Trovafloxacin        -Anaerobes                                                                hepatotoxic potential
                                                                                                                    -Moxiflox risk of long QT
  OTHERS              Methenamine          -Liberates formaldehyde w/            UTI                                -Gastritis
                        mandelate          urinary pH <5.5                                                          -Chemical cystitis
                     (Methenamine +        -No affect at alkaline pH                                                -Hematuria
                      mandelic acid)       -Metabolite caustic to bugs in                                           -Painful/frequent micturition
                                           urinary system.                                                          -DO NOT GIVE W/
                                                                                                                    SULFONAMIDES – insoluble
                                                                                                                    complex (crystaluria)
                      Nitrofurantoin       -Bacteriostatic                       UTI’s – E. Coli                    -Interstitial pulmon fibrosis
                                           -U/k mechanism (reactive                                                 -Hemolytic anemia G6PD
                                           intermediates damage DNA)                                                def.
                                           -Turns urine brown                                                       -Peripheral neuritis
                                                                                                                    -Cholestatic jaundice
                                                                                                                    -GI irritation
                    Phenazopyridine        -Used along w/ urinary                -Urinary analgesic (takes care of  -Red/Orange urine
                                           antiseptics                           burning piss)                      -Overdosage can produce
                                           -No antibacterial effects                                                methemaglobinemia
 CELL WALL       Penicillins are BACTERICIDAL drugs that inhibit cell wall synthesis. They bind to penicillin binding proteins (PBP), which
INHIBITORS       inhibits transpeptidase enzymes (responsible for the linking/cross linking of peptidoglycans). This causes the activation of
                 autolytic enzymes. Penicillins are effective against actively growing microbes, but ineffective against microbes that do not
PENICILLINS      have a cell wall (e.g. mycoplasma). Betalactamase enzymes are bacterial enzymes that break the betalactam ring. Penicillins
                 cause TIME DEPENDENT killing, where drug is directly related to the time above MIC. B-lactams are synergistic with
                 aminoglycosides.

                  Generally, all penicillins are water soluble (exceptions: nafcillin, ampicillin), thus renal excretion and need dose reduction in
                 renal disease. Tubular secretion can be blocked by probenecid so that high concentrations can be achieved. Aquired
                 resistance to penicillins by plasmid transfer has become a serious problem. Most of the penicillins are incompletely absorbed
                 after oral administration, and they reach the intestine in sufficient amounts to affect the composition of the intestinal
                 flora. However, amoxicillin is almost completely absorbed. So, amoxicillin is NOT appropriate therapy for the treatment of
                 (for example) shigella or salmonella derived enteritis. Also, penetration for penicillins is generally good, although no
                 penetration into the CNS, unless inflammation has opened pores in the BBB.

                      Penicillin G        -Acid labile, so give IV or IM        Serious life threatening disease     Jarisch Herxheimer rxn
1st generation     (Benzyl penicillin)    -SHORT DURATION                       ACTIVE AGAINST:
                                          -Poor CNS effects (unless             -Strep pneumo (although
                                          meningitis)                           resistance)
                                          -90% excreted by renal                -Strep pyogenes
                                          secretion, 10% by glomerular          -Strep viridans
                                                                                -Bacillus anthracis
                                                                                -Corynebacterium diptheriae

                                                                                                                              34
                                                                                   -Syphillus (1’ and 2’)
                                                                                   -Neisseria gonorrhoeae
                                                                                   -Neisseria meningitides
                                                                                   -Clostridium perfringens
                        Penicillin V        Given PO b/c acid stable               Prophylaxis/mild infections          -Not used for Tx of
                                                                                                                        bacteremia b/c of its
                                                                                                                        minimum bactericidal
                                                                                                                        concentration
                    Procaine penicillin     Slo abs. Lasts 12-24 hr.s              Gonococcal infections
                   Benzathine penicillin    Abs. Very slow lasts 2 wk.s
                                            Usually suppository form
  2nd generation         Cloxacillin        Penicillinase resistant                -Very narrow spectrum                Interstitial nephritis
                          Oxacillin                                                -Tx penicillinase producing Staph    (Methicillin)
                          Nafcillin         Nafcillin is elimited primarily via
                        Dicloxacillin       the biliary route.                     ―Naf for Staph‖
                        Methicillin
  3rd generation        Amoxicillin         -Commonly given w/ Beta                -Broad spectrum                      -Pt. w/ mono will develop
                         Ampicillin         lactamase inhibitors (sulbactam        (Similar spectrum to penicillin G,   rash when given Ampicillin
                                            & clavulinic acid)                     but includes some gram -)            -Inactivation a problem b/c
                                                                                   -Widely used in Tx of                of plasmid mediated
                                            Not water soluble                      respiratory diseases                 penicilliniase (typically E.coli
                                                                                   -Amoxicillin is completely           and H.influenza)
                                                                                   absorbed from GI, so don’t tx GI
                                                                                   infections
                                                                                   Active against:
                                                                                     -Ecoli
                                                                                     -H.influenza
                                                                                     -Proteus
                                                                                     -Salmonella typhi
                                                                                   DOC for Listeria (Ampicillin)
  4th generation       Piperacillin                                                -Tx Pseudomonas infxn                Carbenicillin & Ticarcillin
                       Mezlocillin                                                 -Effective against many gram (-),    causes platelet dysfxn
                      Carbenicillin                                                but NOT Klebsiella
                        Azlocillin                                                 (constituative penicillinase)…add
                       Ticarcillin                                                 clavulanic acid
                   PMCAT                                                           ―Antipseudomonal penicillins‖

CEPHALOSPORINS     Most cephalosporins are eliminated through the kidney (a few exceptions). Cephalosporins have          ADVERSE EFFECTS:
                   been divided into 4 generations. As the generations progress, there is:                                -Cross sensitivity w/
                             Gram (+) coverage                                                                          penicillin in 10%
                            Gram (-) coverage                                                                           -Cefamandole, cefotetan,
                             CNS penetration                                                                            cefoperazone cause
                             Resistance to -lactamase                                                                  hypoprothrombinemia
                                                                                                                          (inhibit Vit K dep factors)
                   Cephalosporins are INEFFECTIVE against LAME:                                                           & disulfiram-like rxn (due
                   L= Listeria monocytogenes                                                                              to MTT side chain (―azol‖)
                   A= Atypicals (mycoplasma, legionella, C. pneumonia)                                                    -Nephrotoxicity (doses)
                   M= MRSA                                                                                                -Hemolytic anemia (rare)
  1st generation   E= Enterococci
                        PARENTERAL           Water soluble Don’t cross           -Good activity against gram (+)
                           Cefazolin         into CSF                             -Modest activity against Gram (-)
                         Cephalothin
                          Cephapirin                                              Active against PEcK:
                         Cephradine          *Note: ‖ph‖ in name = 1st            Proteus
                                             generation                           E. Coli
                            ORAL                                                  Klebsiella
                          Cephalexin         Cefazolin – long half life, used     Moraxella
                          Cefadroxil         in surgery prophylaxis
                         Cephadrine

                                                                                                                                 35
  2nd generation       PARENTERAL            gram (-), gram (+)               Active against HEN-PEcKS
                       Cefamandole*                                             -H. influenza
                         Cefotetan           None enter CSF EXCEPT:             -Enterobacter aerogenes
                         Cefonicid           -Cefuroxime                        -Neisseria
                     Cefuroxime sodium       -Cefaclor                          -Proteus mirabilis
                         Cefoxitin                                              -E. coli
                        Ceforanide           *Eliminated via biliary (for pts   -Klebsiella
                                             w/ renal problems)                 -Strep pneumo & pyogenes
                           ORAL                                                 -Tx B. fragilis (Cefoxitin, but has
                         Cefaclor                                               little activity against H. influenza)
                     Cefuroxime axetil
                       PARENTERAL            *Eliminated via biliary (for pts   -Often used w/ a macrolide to cover     -All penetrate CNS
                      Cefoperazone*          w/ renal problems), i.e. NOT       atypicals in community aquired          EXCEPT cefoperazone
  3rd generation       Ceftriaxone*          water soluble                      pneumonia                               (does not cross enough to
                        Ceftazidime                                             -DOC for Gonorrhea (IM                  fight meningitis)
                        Cefotaxime            CNS cefotAXime,                  Ceftriaxone single dose)
                        Ceftizoxime          ceftriAXone                        -DOC in meningitis (Cefotaxime,
                        Moxalactam           --Think of an AX to the head       Ceftriaxone)
                                             that chops meningitis.             - Tx B. fragilis (Cetizoxime)
                           ORAL                                                 -Ceftazidime has pseudomonas
                         Cefiximne                                              coverage
                         Cefepine            -Extended spetrum                  -Tx gram (–) resistant bacilli to
                                             - Stability to beta-              3rd generation cephalo’s
  4th Generation                             lactamases                         -Effective against pseudomonas
OTHER CELL WALL          Cycloserine         -Structural analog of D-           -Tx TB resistant to streptomycin,       -Psychoses
  SYNTHESIS                                  alanine competitively             isoniazid, PAS                          -Delirium
  INHIBITORS                                 inhibits conversion of L-          -Atypical mycobacterium (MAC,           -Confusion
                                             alanine to D-form and linkage      kansasii) often sensitive               -H/a
                                             (stage 1 of cell wall synth)       -2nd line in TB & CNS nocardia          -Convulsions
                                                                                (1st= sulfa)                            -Tremors
                         Bacitracin          Inhibitor of the isoprenyl         -Topical use only (ointment & drops)    -Toxic for systemic use
                                             phosphate (stage 2 of cell wall    -Tx furunculosis, impetigo,             -Nephrotoxicity
                                             synth)                             pyoderma, carbuncle, abscesses
                                                                                -Tx suppurative/infected corneal
                                                                                ulcers
                         Vancomycin          -Inhibits transglycosylase by      -Tx MRSA (IV Vanco)                     -Must be given slowly!!
                                             interfering w/ D-alanyl-D-         -Tx Enterococci                         -Red man syndrome (type-
                                             alanine cell wall precursor        -Backup for C. difficile                1 HS causing vasodilation
                                             units (stage 3 of cell wall        (pseudomembranous colitis) give        from histamine i.e.
                                             synth)                             Flagyl 1st                              extreme flushing)
                                                                                -SERIOUS staph infections               -Pain, chills, rash, fever
                                             -Does NOT enter CNS                                                        -Hypotension
                                             -Water soluble                     Resistance:                             -Nephrotoxic
                                                                                 1. Cytoplasmic protein that reduces
                                             -Systemic effects only when            the access of the drug to the       FONT
                                             given IV                               site of its action                  Flushing
                                             -Oral form is not absorbed          2. VRE use D-alanyl-D-lactate         Ototoxic
                                             from GI                                   as a precursor                   Nephrotoxic
                                                                                 Resistant VRSA & VRE give            Thrombophlebitis
                                                                                 Daptomycin &/or quinopristin/
                                                                                 dafopristin & linezolid
                         Teicoplanin         -Inhibits bacterial cell wall      -Similar spectrum to Vanco
  Monobactam                                 synthesis                          -Tx MRSA & E. Fecalis
                          Aztreonam          MOA: same as penicillins;          Tx of gram (-) rods only (give IV)     No cross-allergenicity w/
                                             resistant to -lactamases                                                 penicillins or cephalosporin
  Carbapenems      Carbapenems are resistant to -lactamases, active against most gram (-) and (+) including anaerobes (except MRSA and VRE).
                   They are NOT active against intracellular bacteria. They have a structure very similar to the penicillins, but they have sulfur
                   in the structure. Carbapenems are thus far the only antibiotic capable of inhibiting the L,D-Transpeptidases. They are
                   administered IV in the hospital for SEVERE infections.

                                                                                                                              36
                       Meropenem
                       Ertapenem
                        Imipenem           Cilastatin is not an antibiotic                                           Seizures (50% of pts)
                      (+ Cilastatin)       but a peptidase inhibitor that
                                           protects imipenem from renal
                                           breakdown
   MEMBRANE           Polymyxin B          -Competively replace Mg++ and
  INHIBITORS          Polymyxin E          Ca++ from negatively charged
                                           P groups on membrane lipids
                                           disrupts cell membrane


                                            PROTEIN SYNTHESIS INHIBITORS
AMINOGLYCOSIDE   Aminoglycosides are bactericidal, accumulated intracellularly via an oxygen-dependent uptake (do not work against
                 anaerobics). Use aminoglycosides to kill GRAM NEGATIVE RODS.
                      Concentration dependent killing & are bacteriocidal.
                      Inhibit the formation of initiation complex (30S)
                      Water-soluble (no surprise w/ glycoside, ie sugar), and they are excreted unchanged in the urine thus,
                       [aminoglycoside] in renal disease
                      Synergistic with -lactams
                      Poorly absorbed from the GI tract.
                      Limited penetration into CSF
                      Ototoxicity (esp when used w/ loop diuretics) & nephrotoxicity (esp when used w/ cephalosporins). Other side effects
                       include: 1) neuromuscular blockade from inhibiting the release of ACh (reverse w/ infusion of calcium gluconate or
                       neostigmine) and 2) contact dermatitis. Toxcity may be enhanced by loop diuretics
                      There is some partial cross-resistance among them. The main mode of resistance is the production of conjugating
                       enzymes.
                     Streptomycin                                            -Not very effective against gram (-)  -Optic nerve dysfunction
                                                                             -Tx of TB                             (chronic use)
                                                                             -Tx of Enterococcal infections
                                                                             (Penicillin G + streptomycin)
                                                                             -DOC for bubonic plague &
                                                                             tularemia
                       Neomycin            Used topically (very toxic);      Adjunct in hepatic encephalopathy     -Contact dermatitis
                                           can be used orally sometimes      to kill off gut bacteria systemic   -Found over the counter in
                                           not absorbed to kill gut         ammonia                               the triple antibiotic
                                           flora                                                                   ointment (e.g. Neosporin)

                        Amikacin           -Resistant to aminoglycoside      -Pseudomonas coverage
                                           inactivating enzymes
                       Netilmicin          -Resistant to aminoglycoside      -Reserved for organisms resistant
                                           inactivating enzymes              to other aminoglycosides
                      Tobramycin                                             -Pseudomonas coverage
                      Gentamicin                                             - NEVER use for respiratory
                      Daptomycin           Distinct MOA, disrupts            -Skin and soft tissue infections
                                           multiple aspects of bacterial     caused by Gram (+) infections
                                           cell membrane function &          -Staph aureus bacteraemia and
                                           appears to bind to the            right-sided S. aureus endocarditis.
                                           membrane & cause rapid            -Binds avidly to pulmonary
                                           depolarization loss of           surfactant, and therefore cannot be
                                           membrane potential               used in the treatment of pneumonia.
                                           inhibition of protein, DNA and    -Good against mutidrug resistant
                                           RNA synthesis, bacterial         staph (e.g. MRSA)
                                           cell death
                     Spectinomycin                                           Tx of resistant gonococcal infection
 TETRACYLCINE    -Broad spectrum (same spectrum as macrolide)                VACUUM THe Bed Room                    -Fanconi-like syndrome
                 -Bacteriostatic                                             -Vibrio cholerae                       -GI irritaton
                 -30s at A site prevents elongation                         -Acne (propionibacter)                 -Pain & phlebitis
                 -Impaired abs w/ milk & food                                -Chlamydia                             -Hepatotoxic (esp in
                 -Chelation w/ cations                                       -Ureaplasma Urealyticum                pregnant)
                                                                                                                           37
             -Concentrate in liver, spleen, skin, teeth                    -Mycoplasma (erythromycin also     -Photosensitivity
             -Gram + resistant                                             DOC)                               -Superinfection
             -Gonococci/meningococci respond                               -Tularemia                         -Hypersensitivity
             -Resistance b/c of of pumping drug out of cell                -H. pylori                         -Brown mottled teeth (Ca
             -Binds Ca in body in teeth and bone (so don’t give kids)      -Borellia burgdorferi              binding)
                                                                           -Rickettsia                        -Leucocytosis, thromboct
             -DON’T GIVE W/ PENICILLIN                                                                        purpura
                                                                           *Cannot be used for bone           CI: pregnant,& kids (<8yrs)
                                                                           infections
                                                                                                              Photosenstivity:
                                                                                                              -Sulfonamides
                                                                                                              -Quinolones
                                                                                                              -Tetracycline
                  Doxycycline           -Lipid sol biliary excretion      -Tx traveler’s diarrhea from       -Vestibular toxicity (balance
                                        (Good for renal problems)          ETEC                               not hearing, reversible)
                                        -Good penetration into tissues     -Good CNS penetration              -Food does not interfere w/
                                        -No food interruption              -DOC for Lyme’s disease            abs & poor Ca++ chelation
                                                                           -DOC for prostatitis
                   Minocycline          -Water sol distributes in         -Tx of asymptomatic                -Vestibular toxicity
                                        body fluids ( in saliva/tears)   meningococcal carrier state        -Food does not interfere w/
                                        -Enters CSF w/o inflamed           (rifampin same use)                abs & poor Ca++ chelation
                                        meninges                           -Tx nocardiosis (better combined
                                        -No food interruption              w/ sulfonamides)
                 Demeclocycline                                            Tx of SIADH                        Photosensitivity (also seen
                                                                                                              w/ sulphonamides, quinolones)
                                                                                                              Diabetes insipidus
                   Tigecycline          Derivatve of minocylcine           Active against gram (-) and (+),   -Don’t use in kidney
                                                                           anaerobes, chlamydiae,             infections
                                                                           mycobacteria, MRSA, VRE

                Chloramphenicol         -Lipid soluble                   -Meningitis (H. influenzae, N.       -Aplastic anemia
                                        -Broad spectrum, binds 50S       meningitides, S. pneumo) used in -Gray baby syndrome (baby
                                        -Inhibits peptide bond           babies in past before vaccinat       lacks UDP glucuronly trans)
                                        formation                        -Backup for Salmonella typhi, B.     -Superinfection
                                        -Inhibit peptidyl transferase    fragilis, Rickettsia                 -Hypersensitivity
                                        -Inhibits CYP 450                -DOC for Rickettsia in pregnancy     -Very toxic, not used often
                                                                         or in child
MACROLIDES   Macrolides inhibit protein synthesis by blocking transloctation (50S). They inhibit CYP450. They are probably safe in
             pregnancy, and may cause reversible deafness at high doses. Since macrolides are bacteriostatic and are used in HIV patients,
             you must use huge doses pay attention to the side effects. Resistance is usually by the production of methyltransferases.
             Macrolides increase serum concentrations of theophyllines & oral contraceptives.
                  Erythromycin          -Metabolized by liver &          -Gram (+), not MRSA                  -GI distress (from
                                        excreted in bile                 -Atypicals                           stimulating motilin receptors)
                                                                         -Legionella                          -Erythromycin estolate
                                                                         -Campylobacter                       cholestasis & obstructive
                                                                                                              jaundice
                  Azithromycin          -Metabolized by liver &          -Similar spectrum, more active in    -GI distress (from
                                        excreted in bile                 respiratory infections               stimulating motilin receptors)
                                        -DOES NOT inhibit CYP450         -Best macrolide to use in pregnant
                                                                         -Mycobacterium avium
                 Clarithromycin                                          Activity against M. avium &         LEAST GI distressing
                                                                         H.pylori
                   Clindamycin          -NOT a macrolide, same MOA       -Gram (+) (except enterococcus)      -1st known drug associated w/
                                        -Distributes to bone & stays     -Some ANAEROBES                      pseudomembranous colitis
                                        active
                                        -Does not cross CNS,             -Osteomyelitis
                                        eliminated via biliary
                    Linezolid           Inhibits the formation of the    -Tx VRSA & VRE (enterococcus         -BMS (platelets)
                                        initiation complex (50S)         faecium NOT faecalis) & other

                                                                                                                       38
                                             -No cross resistance w/ other   drug resistant Gram (+) cocci
                                             protein synthesis inhibit
STREPTOGRAMINS        Quinupristin +         -Given together 30:70           -VRSA
                       Dalfopristin          -Binds 50S preventing AA        -VRE (enterococus faecium AND
                                             incorporation at A site         fecalis)




                        Disulfiram-like Effects
                               Metronidazole                                     Tx of MRSA
                                Cefamandole                                           ORAL:
                                Cefoperazone                                        -TMP/SMX
                                 Cefotetan                                         -Clindamycin
                               Chlorpropamide                                        Linezolid
                                                                                   Doxycycline

                                                                                    OTHER:
                                                                                   Daptomycin
                                                                                   Vancomycin
                                                                                   Tigecycline




                                                      HIV ANTIVIRALS
   Class             Drug                         Mechanism                        Clinical Use                         Side Effects
   NRTI      Nucleoside Reverse Transcriptase Inhibitors (NRTIs) are components of most combination drug regimens. Commonly two NRTIs are
             used together with a protease inhibitor. They all lack a 3’ OH group, and once phosphorylated by cellular enzymes they are
             incorporated into viral DNA by reverse transcriptase. They inhibit elongation because cannot form a phosphodiester bond. The
             NRTIs are mostly renally excreted. Also, do not give the same nucleoside analogue. All the drugs put on the market after AZT are
             less BMS.
             HAART = 2 NRTIs + PPI
                   Zidovudine        The 1st drug for HIV infection      -Tx and prophylaxis of HIV     -BMS (esp at doses)
                     (AZT)           lots of different resistances                                       -Headache  don’t forget the added
                                                                          Resistance:                    toxicities from taking an antiinflamm (e.g.
                                     MOA: thymine analogue, requires      -Mutations in the genes        aspirin)
                                     triphosphorylation to be activated that code for RT                 -Hematotoxicity (dose limit) may
                                     PK: well abs PO (less w/ food),                                     require blood transfusion on starting tx
                                     crosses CNS, ½ life (1 hrs),                                        -Myalgia and myopathy (don’t take aspirin
                                     intracell ½ life (3 hrs)                                            family drugs kidney toxicity)
                                                                                                         -Peripheral neuropathy
                                                                                                         Rare, but potentially fatal lactic acidosis

                                                                                                         Drug Interact:
                                                                                                         -Azole antifungals, cimetidine inhibit
                                                                                                         CYP450s AZT (worse toxicity)
                                                                                                         -Indomethacin & probenecid they
                                                                                                         affect renal clearance
                                                                                                         -TMP-SMX additive BMS (used in
                                                                                                         pneumocystis carini)
                                                                                                         -Rifampin (induces P450) AZT
                                                                                                         -Stavudine & rivavirin activated by the
                                                                                                         same pathways
                    Abacavir           -Analog of guanosine              Resistance:                     GI, h/a, dizziness
                                       PK: NOT renally excreted, but     -May be cross-resistance        5% hypersensitivity rxn (1 or more: rash,
                                       metab by alcohol dehydrogenase    w/ strains resistant to AZT     GI, malaise, respiratory distress)
                                       and glucuronyl transferase        & 3TC                           0sensitized individuals should never be
                                                                                                         rechallenged (can be genetically screened)
                 Didanosine (DDI)      Inosine analogue (precursor for                                   Greater affinity for mito DNA
                                       guanosine/adenosine) ddATP in                                    polymerase peripheral neuropathy,

                                                                                                                           39
                              cell                                                                 lipoatrophy, pancreatitis (…remember
                              PK: Abs best in fasting state or                                     valproate)
                              w/ antacid, crosses CNS (less                                        -Less BMS than AZT
                              than AZT)                                                            CI: Zalcitabine, stavudine (similar
                                                                                                   toxicities)
          Lamivudine (3TC)    MOA: Cytosine analog that            -Tx of HIV                      -Least toxic of NRTIs (least potent)
                              terminates synthesis of proviral     -Acitive in hepatitis B         -Few significant SE
                              DNA chain & inhibits HIV & HBV       -Never used alone too
                              RT (does not affect mito DNA         weak (should not be used w/
                              synth or BM precursor cells          other cytosine analogs
                                                                   Resistance:
                                                                   -Mutation at viral codon 184
                                                                   (but restores sensitivity to
                                                                   AZT & tenofovir)
            Emtricitabine     -Fluoro-derivative of analog of      -Inhibits HIV and HBV RT        -Does not affect CYP450s, no significant
                              3TC                                                                  interactions w/ other drugs
                              -Taken once a day                                                    -Diarrhea, h/a, rash
                                                                                                   -Hyperpigmentation of the soles/palms
                                                                                                   -Lactic acidosis, fatty liver,
                                                                                                   hepatomegally
          Stavudine (D4T)     AZT analogue (thymidine alalog)     Tx HIV                          Greater affinity for mito DNA
                              binds same site                                                      polymerase peripheral neuropathy,
                              -Strong inhibitor of  and y DNA                                     pancreatitis, lipoatrophy
                              polymerases                                                          -Less BMS than AZT
                              PK: completely abs PO not                                            -DO NOT USE W/ AZT
                              affected by food, crosses CNS
             Zalcitabine      1st cytosine analog developed, but   Tx HIV                          -Peripheral neuropathy (dose limiting)
               (DDC)          removed from the market b/c of                                       -GI distress
                              toxicity                                                             -Pancreatitis, neutropenia, rash
                                                                                                   CI: Didanosine (similar toxicities)
              Tenofovir       MOA: nucleoTIDE (AMP) analog         Tx HIV                          GI (n/v/d, flatulence)
                              PK: take w/ food, long half life
                              once daily dosing                                                    CI: only NRTI w/ sig drug interactions
                                                                                                   (DDI, no longer recommended combined
                                                                                                   use & atazanavirso  by boosting w/
                                                                                                   ritonavir)



NNRTI   Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) are highly selective, noncompetitive inhibitors of HIV-1 RT do not
        require metabolic activation. They inhibit reverse transcriptase at a different site from the NRTIs. Since they can be added to
        the NRTIs, they are synergistic with NRTIs. They lack cross-resistance with NRTIs. These drugs have cross-resistance WITHIN
        the NNRTI class, drug interactions, and a high incidence of hypersensitivity rxns. These drugs are NOT myelosuppressive.
              Nevirapine      PK: well abs PO (not affected by        Used in combination         -Potential severe hepatotoxicity (don’t use
                (NVP)         food), crosses to CNS, excreted in      with other antiretroviral in women w/ CD4 < 250, male CD4 < 400)
                              the urine as metabolites (CYP3A4 +      drugs for HIV-1 tx in
                              CYP2B6)                                 adults and children         CI: induces CYP3A4 metab of PI’s (no
                                                                                                  dosage adjust needed), oral
                                                                      Resistance:                 contraceptives, ketoconazole,
                                                                      -Target site is HIV-1       methadone, metronidazole, quinidine,
                                                                      specific, not essential to theophyline, warfarin
                                                                      enzyme rapid resist
           Efavirenz (EFV)    Preferred NNRTI                                                     -Mostly CNS (50%) dizziness, h/a, vivid
                              PK: bioavail w/ fatty meal; well                                   dreams, loss of concentrationresolves
                              distrib after PO, 99% plasma                                        after few weeks
                              albumin bound, half life                                            -Rash (25%)
                              (>40hrs)once-a-day dosing
                                                                                                  CI: Pregnancy; potent inducer of CYP450
             Delavirdine
               Adefovir       Does not require phosphorylation

                                                                                                                     40
   Protease    Aspartate protease (pol gene encoded) is a viral enzyme that cleaves precursor polypeptides in HIV buds to form the proteins of the
  Inhibitors   mature virus core. The enzyme contains a dipeptide structure not seen in mammalian proteins (important for selectivity). PIs bind to
               this dipeptide, inhibiting the enzyme. Resistance occurs via specific point mutations in the pol gene, such that there is not complete
               cross-resistance b/w different PIs. Since PIs have nothing to do with DNA replication, they will NOT cause BMSthus, good for
               adding these drugs to the regimen!. Since they have a different MOA, they can only be synergistic with those drugs blocking
               replication. Most have poor bioavailablity. However, the biggest problem is the inhibition of CYP450s. They also cause disorded lipid
               and carbohydrate metabolism.
                     Saquinavir         Given w/ low dose RTV; high fat meals                                    H/A, fatigue, nausea, GI
                                        enhance absorption                                                       CI: drugs that enhance metabolism
                                        Half life = 7-12 hours                                                   (e.g. rifampin, rifabutin, nevirapine)
                      Indinavir         Given w/ RTV to increase absorption,                                     -Nephrolithiasis
                                        permit twice daily dosing                                                -Hyperbilirubinemia
                                        -Least protein bound, absorption decreaed                                -Fat redistribuation
                                        when taken w/ meals                                                      -GI distress
                                        -Half life = 1.8hours                                                    -Thrombocytopenia
                                                                                                                 -Inhibition of CYP3A4
                                                                                                                 CI: dosage should be reduced w/
                                                                                                                 hepatic insufficiency
                      Ritonavir         PK enhancer/ booster of other PI’s                                       -GI distress
                                        -Potent inhibitor of CYP3A4                                              -Asthenia & circumoral paresthesias
                                        -Half life = 3-5 hours                                                   -Major drug interactions: induces
                                                                                                                 CYP 1A2 & inhibit the major P450s
                                                                                                                 (3A4 & 2D6) thus limited use
                  Nelfinavir (NFV) Canot be boosted y RTV; metabol by several                                    Diarrhea (controlled by loperamide),
                                        CYPS; major metabolite (CYP2C19) has                                     nausea, flatulence
                                        antiviral activity equal to parent compound
                                        -half life = 5h                                                          CI: can inhibit metabolism of other
                                                                                                                 drugs
                   Fosamprenavir        Given w/ RTV; prodrug amprenavir                                        H/A, fatigue, nausea, vomiting,
                       (fAPV)                                                                                    paresthesias
                                                                                                                 CI: can inhibit metab of other drugs
                  Lopinavir (LPVr)      One of the preferred PIs; given with RTV                                 GI, hypertriglyceridemia, insulin
                                        -Poor intrinsic bioavailability                                          resistance
                                        -half life =1.8 hours                                                    CI: enzyme inducers (avoid St Johns
                                                                                                                 Wort), Oral solution contains EtOH
                                                                                                                 (ovoid disulfiram or metroniadazole)
                     Atazanavir         ATV + RTV = only once daily preferred PI;                                -Competitive inhibitor of glucuronyl
                        (ATZ)           structurally unrelated to other PIs; well                                transferase (benign hyperbilirubinemia
                                        absorbed orally (increased by food)                                      + jaundice)
                                        -Highly protein bound (86%)                                              -Prolongs PR intervale + slows HR
                                        -Half life = 7h                                                          CI: Metabolized by & inhibits
                                                                                                                 CYP3A4, proton pump inhibitors;
                                                                                                                 administration must by more than
                                                                                                                 12h apart from H2 blockers &
                                                                                                                 antacids
                  Tipranavir (TPV) Inhibits HIV protease resistant to other                                      Same as other PIs + severe and fatal
                                        PIs                                                                      hepatitis
                                        -Twice daily w/ RTV                                                      -Fatal/nonfatal intracranial
                                        -Well absorbed when taken with food; half                                hemorrhags
                                        life = 6h
                                                                                                                 CI:Inducer of CYP 450
                      Darunavir         Inhibits HIV protease resistant to other                                 Same as other PIs + RASH
                                        PIs; well absorbed when taken w/ food
                                        Half life = 15 h (w/ RTV)                                                CI: metabolized by & inhibits
                                                                                                                 CYP3A4
VIRAL                Enfurvitide        -Fusion inhibitor; structurally resembles      -Use for tx-              -Injection-related (3% discontinue)
ATTACHMENT                              gp41                                           experienced adults w/ $$$ (estimated at $20,000)
                                        MOA: Binds gp41 (recognizes chemokine          evidence of HIV
                                        receptrs) and inhibits fusion of HIV-1 to      replication

                                                                                                                              41
                                          CD4+
                                          (note: gp120  recognizes CD4+)
                                          -Has to be administered parenterally (twice
                                          daily subQ injections)
 VIRAL ENTRY             Maraviroc        Blocks CCR5 coreceptor that works w/                                    -Well tolerated
                                          gp41 to facilitate HIV entry through cell
                                          membrane (only CCR5 expressing virus can
                                          be treated w/ maraviroc
  INTEGRASE              Raltegravir      Specifically inhibts final step in integration   -Give w/ other         Well tolerated
  INHIBITOR                (RAL)          of viral DNA into host cell DNA                  retrovirals for tx-    Nausea, h/a
                                          -Half life = 9h twice daily dose                experienced patients   Diarrha
                                          -Metabol via UGT1A1-mediated                     w/ evidenc of viral
                                          glucuronidation no interactions w/              replication
                                          CYP450 inducers, inhibitors


                                                           OTHER ANTIVIRALS
Respiratory Virus        Oseltamivir      -Inhibits viral neuraminidase by acting as      -Effective against both    -GI discomfot & vomiting, so take
   infections             Zanamivir       a sialic aicd analog                            Influenza A and B          the drug w/ food (oselt)
                                          -Does not interfere w/ the immune               -Prevent infection (if     -Airway irritation (zana)
                                          response to influenza A                         given prior to exposure)
                                          -Oseltamivir (oral)                             -Modest effect if given    CI: severe reactive asthma (zana)
                                          -Zanamivir (inhaled/nasal spray)                w/in first 24-48h of
                                                                                          onset
                    Blocks the viral membrane matrix protein (M2), which functions as a channel for H+ (required for fusion of viral membrane w/ host
                    cell membrane). Does not impair immune response to Influenza A vaccine. Viral Uncoating Inhibitors
                          Amantadine      PK: Distributes well and penetrates CNS;      -Tx & prevention of          -Livedo reticularis
                                          NOT extensively metabolized, but              Influenza A infxns           -Nose/throat irrriation
                                          excreted in urine & may accumulate in                                      -Atropine-like SE
                                          renal failure                                 -Parkinson’s
                                          -Also antimuscarinic action
                          Rimantadine     Does NOT cross CNS; extensively
                                          metabolized by liver; metabolites and
                                          drug eliminated by kidney
                            Ribavirin     Synthetic guanosine analog                   Effective against a broad    Dose-dependent transient anemia
                                          phoshorylat then inhibits IMP                spectrum of RNA and          (hematotoxic)
                                          dehydrogenase as a triphosphate             DNA viruses (RSV,            -Upper airway irritation
                                          inhibits viral mRNA capping                   Influenza A & B, Lassa
                                                                                        fever, Hanta viruses)        CI: Pregnancy
                                                                                        -Adjunct to  INF in HCV
                          Palivizumab     Monoclonal antibody against RSV               -Given in premature
                                                                                        infants before start of
                                                                                        RSV season if <12mo old
  Anti-Herpes              Acyclovir      Guanosine analog that is 1st phosphorylated -Tx HSV-1,2 & VZV              -Will NOT cause BMS
     Drugs                                by viral thimidine kinase incorporates                                    -Minor SE w/ oral use
                                          into DNA & causes chain termination           Resistance: change or        -Crystaluria
                                                                                        absence (TK- strains) in
                                                                                        the thymidine kinase         -Cannot be used for CMV b/c
                                                                                                                     virus lacks thymidine kinase
                          Valacyclovir    Prodrug acyclovir; longer half life than
                                          acyclovir and more bioavail
                          Pencyclovir     Acivated by viral thymidine kinase &
                                          inhibits DNA pol, but does not cause chain
                                          termination
                          Famcyclovir     Prodrugpencyclovir                           -Gential herpes & herpes
                                          -Given Orally                                 zoster
                           Docosanol      Aliphatic alcohol that inhibits fusion        -Shortens healing time
                                          between HSV envelope and plasma
                                          membranes, preventing viral entry &

                                                                                                                                42
                                        subsequent replication
                                        -Used toppically
                       Ganciclovir      Guanine derivative that is                    -Prophylaxis & Tx of         Dose limiting BMS (a problem with
                                        phosphorGTP inhibits DNA pol of CMV         CMV retinitis and over       those already immunosuppressed)
                                        and HSV & causes chain termination;           CMV infections
                                        usually given IV; penetrates into CNS
                                        -Any kinase can turn on ganciclovir
                      Valganciclovir
                       Foscarnet        Not an antimetabolite; but still inhibits     -CMV                         Dose-limiting nephrotoxicity with
                                        DNA & RNA pol. Requires an IV infusion        -HSV resistant strains       acute tubular necrosis, electrolyte
                                        pump (so must be hospitalized)                (e.g. TK- strains)           imbalance with hypocalcemia
                                                                                                                   (tremors & seizures)
                                                                                                                   -NOT hematotoxic (so no BMS)
                                                                                                                   -Avoid pentamidine IV (used for
                                                                                                                   pneumocystis when bactrim not
                                                                                                                   working also nephrotoxicity)
HEPATITIS




                                                                     CHEMOTHERAPY
    Drug type                   Drug                       Mechanism                     Clinical Use                    Side Effects
Drugs that are cell cycle specific are more effective against actively growing tumors with high growth fractions (leukemias, lymphomas).
ANTI-                  Cell cycle specific (S phase) are easy to recognize because typically they have some type of nucleotide analog.
METABOLITES               5-Fluorouracil       MOA: 5-FU 5’ FUMP5-             -Topical for basal cell       -BMS, alopecia, anorexia, n/v/d
 1. Pyrimidine                                 FUDP 5-FdUMP, which              cancer and keratoses          -Severe ulceration of oral & GI
    Antagonists                                inhibits thymidylate              -Tx slowly growing solid      mucosa
                                               synthetase (dUMPdTMP)            tumors (e.g. colorectal,      -Hand/foot syndrome
                                               PK: IV, topical; rapidly metab    breast, ovarian, pancreatic,  (erythmatous desquamation of
                                               in liver, lug, kidneyfluoro--   gastric)                      palms & soles after extended
                                               alanine (urine) + CO2 (exhaled)                                 infusions)
                                               -Elevated levels of               *Usually given w/
                                               dihydropyrimidine                 Leucovorin
                                               dehydrogenase (DPD) = 5-FU       effectiveness of 5-FU
                                               breakdown
                           Capecitabine        MOA: Oral prodrug5-FU,           -Metastatic breast cancer     Similar to 5-FU
                                               but the final step is thymidine   (resistant to 1st line)       -GI toxicity
                                               phosphorylase (found in           -Colorectal cancer            -Carefully used in patients w/
                                               tumors)TUMOR SPECIFIC                                          renal or hepatic impairment
                                               PK: PO, well absorbed                                           CI: pregnancy, lactation,
                                                                                                               patients on coumarin
                                                                                                               anticoagulants or phenytoin
                            Cytarabine         Analog of 2’deoxy-cytidine        -AML 1st line (Cytarabine +   -N/V/D
                              (ara-C)          (arabinose instead of ribose)     6-TG + daunorubicin)          -Severe BMS
                                               MOA: Ara-c enters                                               -Hepatic dysfunction
                                               cellphosph by deoxycytidine                                    -High doses or IT injection
                                               kinase & other kinases ara-                                    leukoencephalopathy
                                               CTP (cytotoxic) inhibits
                                               DNA polymerase
                                               Inhibits DNA elongation

                                                                                                                               43
                                    PK: not effective orally
                                    (deaminated in intestine,
                                    liver); does NOT go into CNS
                   Gemcitabine      MOA: Analog of                    Locally advanced or           BMS (dose limited)
                                    deoxycytidine                    metastatic adenocarcinoma     -N/V, alopecia, rash, flu-like
                                    (deoxycytidine kinase) 2’,2’-    of pancreas (1st line)        syndrome
                                    difluorodeoxycytidine             -Non small cell lung cancer   -Transient elevation of serum
                                    triphosphate, which:                                            transaminases, proteinuria,
                                    Inhibits DNA synth                                             hematuria
                                    Inhibits ribonucleotide
                                    reductase
                                    PK: IV, eaminated to non-toxic
                                    metaboliteurine

                 6-Mercaptopurine   MOA: 6-MP  6-thioinosinic        -Acute lymphocytic            -BMS
                     (6-MP)         acid (TIMP, a thio analog of      leukemia (ALL)                -Hepatotox (jaundice, necrosis)
2. Purine                           hypoxanthine) by HGPRT,           -Immunosuppression            -
   Antagonists                      which adds a ribose-P:
                                    Blocks 1st step of de novo       Resistance:
                                    purine ring biosynth (via          1. Inability to
                                    glutamine phosphoribosyl              biotransform 6-MP to
                                    pyrophasphate                         the corresponding
                                    amidotransferase)                     nucelodite b/c of         When taking Allopurinol (inhibits
                                    Blocks IMP AMP & XMP                HGPRT (e.g. lesch        xanthine oxidase) reduce 6-MP
                                    TIMPTGMP to inhibit                 nyhan syndrome)           dose by 75% to avoid toxicities
                                    RNA                                2. Dephos
                                    PK: PO, erratic abs; metab in      3.  Metab of the drug to
                                    liver 6-methyl-MP or to              thiouric acid
                                    thiouric acid via xanthine
                                    oxidase)
                    Cladribine      -Similar rxns to fludarabine      -Hairy cell leukemia          Severe BMS
                                    -Incorporated At 3’ end of        -Non-hodgkin lymphoma         Fever
                                    DNAblocks elongation                                           Peripheral neuropathy
                                    -Also, blocks DNA repair and                                    Teratogenic
                                    inhibits ribonucleotide reducts
                                    PK: single continuous 7-day
                                    infusion; well distributes &
                                    into CNS
                   Fludarabine      5’ phosphate of 2-                -CLL*                         -BMS (dose limiting)
                                    fluoroadenine arabinoside         -Hairy cell leukemia          -Diarrhea, n/v
                                    MOA: prodrug loses Phos 2-       -Indolent Non-Hodgk Lymph     -Fever
                                    F-araA taken into cells &                                      -Edema,
                                    phosph incorporated into         *May replace chlorambucil     -Severe neuro toxicity -
                                    DNA & RNA (S-phase)                                             Progressive encephalopathy,
                                    PK: IV (if oralintest bacter                                   blindess & death at doses
                                    split off the sugar toxic)
                   Pentostatin      MOA: potent inhibitor of          -Hairy Cell Leukemia (good    BMS
                                    adenosine deaminase (ADA)         at causing complete           GI symptoms
                                    Blocks DNA synth                 remission)                    Skin rashes
                                    Blocks ribnucleotide             -CLL, CML, promyelocytic      Abnormal liver function results
                                    reductase                         leukemia cutaneous T cell     Immunosuppression (long lasting)
                                                                      lymphoma, non-Hodgkin         Renal/neuro complications
                                                                      lymphoma, Langerhans cell     (doses)
                                                                      histiocytosis
                                                                      -No sig affect on solid
                                                                      tumors or multiple myeloma    CI: given w/ fludarabine 
                                                                                                    severe/fatal pulmonary toxicity
                  6-Thioguanine     6-TG TGMP (6-thioguanylic        -AML (6-TG +                  BMS (dose dependent)
                     (6-TG)         acid) via HGPRTTGDP             Daunorubicin + Cytarabine)    Liver toxicity

                                                                                                                     44
                                 TGTP:
                                 Blocks purine synth               *Not recommended for          *Breakdown via thiopurine
                                 Blocks phosphorylation of         maintainance therapy or       methyltransferase (TPMT), must
                                 GMPGDP                            continuous for long term      screen patients before therapy
                                 TGTP incorporated into            (liver tox)                   (3% of whites/blacks have a
                                 DNA, blocking cell cycle                                         homozygous deletion of TPMT)
                                 PK: PO, abs erratic &                                            *Can give w/ Allopurinal w/out
                                 incomplete                                                       dose b/c 6-TG requires
                                                                                                  deamination before it is
                                                                                                  metabolize by xanthine oxidase
                                                                                                  (so if XO is inhib, already
                                                                                                  inactiv)

                  Methotrexate   MOA: Folate analogue             -ALL                           -Diarrhea, n/v, stomatitis, rash,
                                 enters cell via active            -Burkitt’s lymphoma            erythema, urticaria, alopecia
                                 transpor inhibits DHF            -Breast cancer                 -Crystalluria
                                 reductase (S phase)               -Choriocarcinoma               -Long use liver cirrhosis
                                                                   -Head and neck carcinomas      -Pulmonary toxicity (rare)
                                 Antidote = Leucovorin             -RA, psoriasis                 -Neurotoxicity
 3. Folate                       rescue (N5, N10-methylene         --Abortion when used w/        -BMS,
    antagonists                  FH4 DHFR not needed) b/c         misoprostol in 3rd term        CI: pregnancy
                                 healthy cells pick up the
                                 folate better than the
                                 cancer cells (can give before
                                 MTX)

                  Pemetrexed     -Folate analogue, transported     -Mesthelioma (+ cisplatin)     -BMS
                                 into cell same as MTX             -Second line therapy of non-   -Skin rash, mucositis, diarrhea,
                                 -Inhibits DHFR &                  small cell lung cancer         fatigue
                                 thymidylate synthase
ANTI-TUMOR         Bleomycin     G2 phose                          -Testicular cancers            -Pulmonary fibrosis
ANTIBIOTICS                      Copper/Fe chelating               (Bleomycin + etoposide +       -Pneumonitis
(CCS)                            Complexes w/ Fe and O2           cisplatin or vinblastine)      -Mucocutaneous rxns (blisters)
                                 Dna strand breaks                 -Squamous cell carcinomas      -Alopecia
                                 PK: bleomycin inactivating        -Lymphomas                     -Hypersensitivity
                                 enzyme is high in some                                           -BMS IS RARE
                                 tissues (liver, spleen), low in
                                 others (lung, skin)

Anthracycline      Doxorubicin   MOA: effective in S & G2          Broad spectrum:                -Irreversible cardiotxicity
                                 phases                            -Hematologic malignancies      dilated cardiomyopathy (co-
                                 Inibits topoisomerase II         -Solid tumors (e.g. lung,      admin w/ iron chelator
                                 Intercalation into DNA          ovarian, breat)                dextrazone to toxicity)
                                 inhibition of synth & DNA                                        -Transient BMS, stomatitis, GI
                                 strand breaks                     *One of the most widely used   disturbances
                                 Bind to cellular membranes,                                     -Severe Alopecia
                                 altering the fluidity/ion                                        -Increased skin pigmentation
                                 transport
                                 Generation of semiquinone                                       *Drugs are dark red veins may
                                 & oxygen free radicals                                           become visible and red urine
                                 (cardiotoxicity) by CYP450                                      *Extravasation of drug is a
                                 PK: IV, metab by liver                                           serious proglem tissue necrosis
Anthracycline     Daunorubicin   Same                              -Tx AML                        Same
                   Idarubicin
                  Mitoxantrone   MOA: resembles                    -Advanced, hormone             -BMS (dose limiting)
                                 anthracycline ring binds         refractory prostate cancer     -Blue discoloration of
                                 DNA strand breaks               -Low grade non-Hodgkin’s       fingernails, sclera & urine
                                 synth inhbiited                   lymphoma                       -Mild nausea, vomiting, mucositis,
                                                                   -Breast cancer                 alopecia

                                                                                                                   45
                                                                        -AML
                    Plicamycin         MOA: plasma calcium thu         -Testicular cancer
                                       actions on osteoclasts indep     -Hypercalcemia associated
                                       of action on tumors              w/ neoplasms
ANTI-TUMOR        Dactinomycin         MOA:                             -Wilm’s tumor (Surgury +          Highly toxic, older drug
ANTIBIOTICS      (Actinomycin D)        Intercalates into double       Dactinomycin + vincristine)       -BMS (dose limiting)
(CCNS)                                 helix stable complex                                              -Stomatitis, n/v/d, alopecia
                                       Also blocks RNA                 -Gestationl choriocarcinoma       -Sensitizes to radiation
                                       polymerase elongation &          (Dactinomycin + MTX)
                                       causes strand breaks
                    Mitomycin          MOA: Generates alkylating        -Squamous cell cancer of          -Hemolytic Uremic Syndrome
                                       agents (via reduction) that      the anus (Mitomycin + 5-FU
                                       cross link DNA                   + radiation)
                                       -Targets hypoxic tumor stem      -Squamous cell carcinomas
                                       cells (as environment is more    -Pancreatic cancer
                                       conducive to reduction)          -Superficial bladder cancer
                                                                        (intravesical tx)
EPIPODO-             Etoposide           Cell cycle specific            -Germ cell cancer (testicul)       Leukopenia (dose limiting)
PHYLLOTOXINS                              MOA: inibit late S-G2         -Gastic cancer
                                         phase; inhibits                -Lung cancer                       Note: ―topo‖ = topoisomerase
                                         topoisomerase II               -Lymphomas
                                         PK: water insoluble
                     Teniposide          -Same as etoposide               ALL                              Leukopenia (dose limiting)
                                         -Semisynthetic derivative of
                                         podophyllotoxin (mayapple
                                         root)
MICROTUBULE     Microtubule inhibitors are effective because the mitotic spindle is part of the cytoskeleton and is essential for equal
INHIBITORS:     partitioning of DNA. These compounds are NATURAL products that are cell cycle specific (CCS) at the M phase.
                     Paclitaxel          -From European Yew               -Ovarian cancer                  -Neutropenia
TAXANES                                  -Stabilize microtubules          -Metastatic breast cancer        -Hypersensitivity (premedicate
                                         PK: IV (not into CNS)            -Non small cell lung cancer      w/ dexamethasone +
                                                                          (Paclitaxel + cisplatin)         diphenhydramine)
                                                                                                           CI: patients w/ cardiac disease
                     Docetaxel           -Same as paclitaxel                                               -Fewer SE than paclitaxel
                                         -Semisynthetic                                                    -Neutropenia
                                                                                                           CI: patients w/ cardiac disease
VINCA               Vinblastine          -Block microtubule               -Metastatic testicular           BMS (dose limiting)
ALKALOIDS                                synthprevents cell prolif       cancer (Bleomycin +              GI, alopecia
                                         PK: rapid cytotoxicity           Cisplatin + Vinblastine)
                                                                          -Lymphomas
                     Vincristine         Same                             -ALL                             Peripheral neuropathy
                                                                          -Wilm’s tumor
                                                                          -Ewing’s sarcoma
                                                                          -Lymphomas
                     Vinrelbine          Same                             Non-small cell lung cancer       Granulocytopenia (dlose limiting)
CAMPTOTHECINS        Irinotecan          -Semisynthetic                   -Colon or rectal cancer (1st     -BMS (dose limiting)
                                         -Inhibit topoisomerase I         line) (Irinotecan + 5-FU +       -Thrombocytopenia
                                                                          leucovorin)                      -Anemia
                     Topotecan           Same as Irinotecan               -Ovarian Cancer (when            Same
                                                                          primary therapy fails)
ALKYLATING      Alkylating agents are Cell Cycle Non-Specific (CCNS) and do not differentiate b/w cycling and resting cells, although
AGENTS          they are most toxic to rapidly dividing cells. In addition to being cytotoxic, they are mutagenic and carcinogenic and can
                lead to 2’ malignacies, such as acute leukemia.
                  Mechlorethamine        -Alkylation of N7 Guanine on -Lymphatic cancers (mainly           -Severe n/v (can premedicate w/
                                         both strands of DNA              used for Hodgkin’s)              dexamethasone)
                                         (―bifunctional agent‖)           -Solid tumors                    -Severe BMS
                                         -Cross-linkage between                                            -Latent viral infxn
                                         chains & depurination                                            -Extravasation is serious (give
                                         strand breaks, miscoding         -Developed as a nitrogen         sodium thiosulfite to inactivate

                                                                                                                           46
                                     mutations                        mustard during WWII              drug)
                                     PK: very unstable, must be
                                     made just before using;
                                     powerful blistering agent
                                     (vesicant) so give IV
                  Cyclophosphamide   -Similar to mustard agents       -Many cancers (e.g. Burkitt’s,   -BMS
                                     Pro-Drug hydroxylation via      breast)                          -Mucositis
                                     CYP450 breaks down into                                          -HEMORHAGIC CYSTITIS 
                                     phosphoramide mustard +          -Nephrotic syndrome              Antidote = mesna
                                     acrolein (acroleinhem cy)       -Intractable RA                  -Hepatotoxicity (dose)
                                     -Phosph mustard rxn w/ DNA                                        -Veno-oclusive disease of the
                                     is cytotoxic, attaks DNA at                                       liver
                                     N7 guanine                                                        -Amenorrhea, testicular atrophy,
                                     PK: Oral (unlike most                                             sterility
                                     alkylating agents)
                    Ifosfamide       Similar to cyclophosphamide                                       -Neurotoxicity  probably
                                                                                                       related to the metabolite,
                                                                                                       chloroacetaldehyde
                     Carmustine      MOA: Alkylation that inhibits    Brain tumors (glioblastoma       -Delayed hematopoietic
Nitrosureas          Lomustine       replication, RNA, protein        multiforme)                      depression
                                     synthesis, target dividing                                        -Aplastic BM (prolonged use)
                                     cells                                                             -Renal toxicity
                                     PK: crosses CNS                                                   -Pulmonary fibrosis
                                     Carmustine = IV
                                     Lomustine = oral
                    Streptozocin     MOA: Alkylation that inhibits    Insulinomas                      -Diabetogenic
                                     replication, RNA, protein                                         -Minimal BM toxicity
Nitrosureas                          synthesis, target dividing
                                     cells
                                     -Specifically toxic to -cells
                                     of pancreas
                    Dacarbazine      Prodrug MTIC via CYP450         Melanoma                         -BMS, n/v
                                     forms methylcarbonium                                            -Hepatotoxicity
                                     ions that attack nucleophilic                                     Hepatic vascular occlusion
                                     gropus, cytotoxic by DNA
                                     methylation
                                     PK: IV
                   Temozolomide      MOA: prodrugMTIC (NOT           -Resistant gliomas               -BMS
                                     via CYP450) forms methyl-       -Anaplastic astrocytomas         -n/v
                                     carbonium ions that attack
                                     nucleophilic groups, cytotoxic
                                     via DNA methylatation
                                     -Also inhibits DNA repair
                                     enzyme 06-guanine DNA
                                     alkyltransferase
                                     PK: PO, crosses CNS (but to
                                     lesser extent than
                                     carm/lomustine)
                     Melphalan       -Bifunctional alkylating agent   -Multiple myeloma                Hematologic toxicities
                                     PK: PO                                                            -GI upset
                    Chlorambucil                                      CLL                              -Leukemogenic
                      Busulfan                                        CML                              -BMS & pulmonary fibrosis in old
                                                                                                       -Leukemogenic
HORMONAL          Glucocorticoids:   Bind to receptor to induce       -Induce remission in ALL         -Immunosuppresion
AGENTS:           Dexamethazone      production of specific           -Lymphomas                       -Hyperglycemia
                    Prednisone       proteins                                                          -Cataracts
Glucocorticoids   Hydrocortisone                                                                       -Glaucoma
                                                                                                       -Osteoporosis
                                                                                                       -Mood changes

                                                                                                                       47
                     SERMs interact at estrogen receptors but have different effects on different tissues. Tamoxifen is an estrogen
                     antagonist in breast cancer tissue, but can cause endometrial hyperplasia by acting as a partial agonist in the uterus
                          Tamoxifen         Estrogen antagonist (SERM)        -Estrogen receptor positive      -Similar to estrogen (hot
Selective Estrogen                           binds to estrogen               breast cancer                    flashes, n/v, rash, vaginal
Receptor                                    recepotors depletes              *Note: estrogen competes w/ bleeding)
Modulators (SERM)                           estrogen, estrogen receptrs,      tamoxifen, use w/ a GnRH         -Hypercalcemia
                                            & growth factors                  analog (e.g. leuprolide) in      -Endometrial cancer
                                                                              premenopausal
                         Toremifene         SERM, Similar to tamoxifen        -Advanced breast cancer
                                                                              (postmenopausal)
                                                                              -Prophylaxis in high risk
                                                                              women
                     AIs block aromatase in liver, fat, muscle, skin and breast tissue. Peripheral aromatization is an important estrogen
                     source postmenopausally
Aromatase            Aminoglutethemide      -AI                               Metastatic breast cancer         *Newer AI’s developed due to
inhibitors (AI’s)                           -Inhibits adrenal synth of                                         SE
                                            pregnenolone (precursor of         Usually taken w/
                                            estrogen)                         hydrocortisone
                                            -Inhibits hydrocortisone
                                            synth compensatory
                                            ACTH overrides drug
                         Exemestane         -Steroidal AI                     Breast cancer                    -Hot flashes, n/v
                                            -Metab by CYP450                                                   -Androgenic SE (acne, hair
                                                                                                               changes)
                         Anastrozole        -Non-steroidal AI                 -Breast cancer (2nd line to      -Do not predispose to
                          Letrosole         -More potent & selective          tamoxifen)                       endometrial cancer
                                            than aminoglutethemdie            Do not need to be given w/      -Do not have androgenic SE
                                                                              hydrocortisone
                     Prostate cancer is dependent upon hormonal stimulation with androgens
                          Leuprolide        GnRH agonist androgens          Prostate cancer                  -Impotence
Anti-Androgens
                                            & estrogens (castration level)                                     -Hot flashes
                                            PK: sustained release prep,                                        -Tumor flare (minimal compared
                                            SC, depot IM                                                       to estrogen tx)
                          Goserelin         GnRH agonist                      Prostate cancer                  Same
                                            PK: IM
                          Flutamide         Synthetic, non-steroidal          Prostate cancer                  Liver failure
                                            antiandrogen  competes w/        -Since it blocks inhibitory
                                            natural hormone for recetpor effects of testosterone on
                                            binding, preventing               GnRH LH, testosterone,
                                            translocation to nucleus          it is always given w/
                                            PK: PO                            leuprolide or goserelin
                         Nilutamide         Same                              Prostate cancer                  Visual problems

                      Ethinyl estradiol    Synthetic estrogens Block       Postatic cancer                  Thromboemboli, MI, strokes,
                     Diethylstilbesterol   production of LH                *Replaced by GnRH (SE)          hypercalcemia, gynecomastia,
                                           androgen synthesis in                                            impotence
                                           testes
Other
                        Megesterol-        -Progestins                      Breast
                         Acetate           *Replaced by AIs                 Endometrial cancer
PLATINUM                 Cisplatin         -Similar to alkylating agents,   -Solid tumors (e.g.              -Severe persistent vomiting
COORDINATION                               bind to DNA cross links        testicular cancer) (Cisplatin    (1hr-5days) (use ondansetron)
COMPLEXES                                  inhibit synthesis                + Bleomycin + etoposide)         -Nephrotoxicity (dose limiting)
                                           -Cell cycle nonspecific                                           tx w/ amifostine, also requires
                                           (CCNS)                           -Ovarian cancer                  aggressive hydration
                                                                            (Cyclophosphamide +              -Hypomagnesemia
                                           PK: IV, intraperitoneally for    Cisplatin)                       -Hypocalcemia
                                           ovarian cancer                                                    -Ototoxicity, tinnitus
                                                                            -Bladder cancer                  -NO BMS
                                                                                                             -Neurotoxicity (deafness)

                                                                                                                              48
                  Carboplatin     Same                             -When patients cannot be       -Mild n/v
                                                                   vigorously hydrated            -NO nephrotox
                                                                   -Switch to carboplatin when    -NO ototoxicity
                                                                   nephrotox on cisplatin         -NO neurotox
                                                                                                  -BMS (dose limiting)
                  Oxaliplatin     Same                             Advanced Colorectal Cancer
MONOCLONAL       Trastuzumab      Binds to HER2 sites in           Breast cancer                  CHF, fever, chills, h/a, dizziness,
ANTIBODIES                        breast cancer tissue                                            n/v
                  Rituximab       Binds to CD20 antigen on B       -Posttransplant lymphoma       -Hypotension, bronchospasm,
                                  cells                            -CLL                           -Angioedema
                                  PK: infuse slowly (fast can be                                  -Cardiac arrythmias,
                                  fatal)                                                          -Tumor lysis syndrome
                 Bevacizumab      Inhibits angiogenesis            Bevacizumab + 5-FU 
                                                                   colorectal cancer
                  Cetuximab       Targets EGF & interferes w/      Colorectal cancer              Difficulty breathing, low BP,
                                  cancer cell growth                                              interstitial lung disease, rash,
                                                                                                  fever, constipation
                 Gemtuzumab-                                       AML
                  ozogamicin
                 Alemtuzumab                                       B-cell CLL
               I131-tositumonab                                    Relapsed non-Hodgkin’s
                                                                   lymphoma
SIGNAL             Imatinib       Deregulates BCR-ABL              -CML in blast crisis           -Fluid retention, edema
TRANSDUCTION                      kinase prevents tyrosine        -GI stromal tumor              -Hepatotoxicity
INHIBITORS                        phosph inhibits proliferat                                     -Thrombocytopenia
                                                                                                  -N/V
                   Gefitinib      Targets EGF                      Non-small cell lung cancer     Acne, nausea, diarrhea,
                                                                   (when other therapy fails)     interstitial lung disease (rare)
                  Bortezomid      Proteasome inhibitor,                                           Few adverse SE
                                  induces growth inhibition &
                                  apoptosis
                   Sunitinib      Inhibits VEGFR-1, VEGFR-2,
                                  PDGFR
                  Sorafenib       Inhibits B-RAF, VEGFR-1,
                                  VEGFR-2, PDGFR
                 Vatalanaib       Inhibits VEGFR-1, VEGFR-2
                 Thalidomide      -Immunomodulatory drug
                                  -Inhibits angiogenesis,
                                  stimulates T-cells
                 Lenalidomide     Analogue of thalidomide
                 Procarbazine     Undergoes oxidative rxn         Hodgkin’s disease              -BMS, n/v/d
                                  cytotoxic                        *Inhibits MOA avoid           -Neurotoxic
                                                                   tyramine                       -Mutagenic & teratogenic
                L-Asparaginase    Breaks down asparagine           -ALL (L-asparginase +
                                  (tumor cells cannot              Vincristine + prednisone)
                                  synthesize asparagine)
INTERFERONS     Interferon 2                                      -Hiary cell Leukemia
                                                                   -CML
                                                                   -Aids relatd Kaposi sarcoma
                Interferon 2                                      -Hiary cell Leukemia
                                                                   -CML
                                                                   -Aids relatd Kaposi sarcoma
                                                                   -Follicular lymphoma
                 Hydroxyurea      Urea analog inhibits            -CML                           -BMS (dose limiting)
                                  ribonucleotide reductase        -Tx of blast crisis of AML     -Mucositis, diarrhea, h/a,
                                  inhibit DNA synth                -Adjunct therapy w/            lethargy
                                  -S phase                         radiation for head + neck ca   -Maculopapular rash
                                                                   (Also synth of HbFuse fo
                                                                   tx of sickle cell)
                                                                                                                    49
   Tretinoin       All trans-retinoic acid         -Acute promyelocytic          Vitamin A toxicity (h/a, fever,
                   (tretinoin) induces remission   leukmia                       dry skin & mucous membranes,
                   through induction of terminal                                 skin rash, pruritis,
                   differentiation, in which                                     conjunctivitis), CNS toxicity,
                   leukemic promyelocytes lose                                   weight gain
                   ability to proliferate                                        -Teratogenic
Arsenic Trioxide   Induces differentation &        -Acute promyelocytic          -Fatigue
                   apoptosis                       leukemia (induces remission   -QT elongation
                                                   in those w/ the t(15:17)      -Arrthymias
                                                                                 Teratogenic




                                                                                                  50
                                                             Immunosuppression
                 Immune activation cascade SIGNALS:
                      1. T-cell triggering at CD3-APC
                      2. Co-stimulation (CD80/86 of APC engage CD28 on T cell)
                                   Signals 1 and 2 activate several intracellular signal transduction pathways, one of which is the
                                    calcium-calcineurin pathway, which is targeted by cyclosporine and tacrolimus
                      3. Stimulus for T cell proliferation: IL-2 binds to CD25 (aka IL-2 receptor) on the surface of other T
                          cells to activate mammalian target of rapamycin (mTOR)
    Drug type           Drug                      Mechanism                          Clinical Use                  Side Effects
CORTICOSTEROID       Prednisone       MOA: unclear, but Tcells           -Suppress acute rejection of       -Diabetes
                 Methylprednisolon affected most                         organ allografts                   -Hypercholesterolemia
                                                                         -Tx chronic GVHD                   -Cataracts
                                                                         -Tx autoimmune conditions          -Osteoporosis
                                                                                                            -Hypertension
ANTIMETABOLITE     Azathioprine       Pro-drug interacts w/ sulfhydral -Immunosuppression after             N/V,
     (OLD)                            compounds (e.g. glutathione)      transplantation                    Skin rash
                                      6-mercaptopurinethioinosinic      -Inflammatory bowel disease        Hypersensitivity rxn
                                      acid (immunosupprssive             *Antimetabolites usually used      BMS
                                      nucleotide)                        w/ corticosteroids + calcineurin   Gi irritation
                                      -Lymphocytes mostly affected       inhibitors (CsA, TAC)
                                      by cytotoxicity due to their       *Little effect suppressing a       CI: pregnancy
                                      rapid proliferation & dependence   chronic immune response            *Allopurinol significantly
                                      on de novo synthesis of purines    *Has been replaced by MMF          metab of azathioprine
                   Methotrexate       MOA: Unknown                       -Tx rheumatoid arthritis,          Hepatic
                                      Particularly active against        psoriasis                          fibrosis/cirrhosis (not
                                      lymphoid cells                     -Prevent GVHD                      BM suppression)
                                      -See cancer chemotherapy                                              Abortion w/ misoprostol
                                      -Antinflamm but not cytotoxic                                         (PGE1 analog)
ANTIMETABOLITE    Mycophenolate-      MOA: inhibit purine synth;         -Heart, liver, kidney transplant   -Diarrhea, n/v,
    (NEW)         mofetil (MMF)       MMFmycophenolic acid (MPA),                                          -Abdominal pain
                                      a potent reversible inhib of IMP                                      -Leucopenia
                                      dehydrogenase (block the de                                           -Anemia
                                      novo formation of GMP b/c
                                      lymphocytes lack the salvage                                          CI: pregnancy
                                      pathway)
                                      PK: extensively bound to albumin,
                                      long ½ life (14-18days);
                                      -Prodrugactive metabolite
                                      -Antacids absorption
                    Leflunomide       -Blocks dihydroorotateorotate     Rheumatoid Arthritis               CI: pregnancy
                                      (drug inhibits dihydroorotate
                                      dehydrogenase)
ALKYLATING       Cyclophosphamide -2nd line to azothioprine              -Tx disorders of humoral           Leukopenia
AGENTS                                -Hi dose  tolerance to new        immunity (SLE)                     Cardiotoxicity
                                      antigen                                                               Alopecia
                                      PK: PO, Prodrug hydroxylatd-      Autoimmune                         Risk of bladder cancer
                                      intermedactive phosphoramide      -RBC hemolysis, Ab RBC             b/c of mutagenicity
                                      mustard & acrolein (phos must     dyscrasia, BM suppression          (acrolein)
                                      cytotoxic)                         BM transplant @ hi doses           BM suppression
                                                                                                            -Hemorrhagic cystitis
                                                                                                            (antidote = mesna)

                                                                                                             -Doesn’t cause side
                                                                                                             effects of steroids/anti
                                                                                                             ca drugs
CYTOKINE           Cyclosporin A      -Complexes w/ cyclophilin (an      -Organ transplants                  -Nephrotoxicity
INHIBITORS             (CsA)          immunophilin) binds calcineurin   -Severe RA (alternative to          -Hepatotoxic

                                                                                                                       51
                                        inhibits dephos of NFATc         methotrexate)                       -Viral infection common
                                        NFATc cannot enter nucleus to      -Recalcitrant psoriasis not         (CMV, herpes)
                                        promote rxns for cytokine synth    responding to other therapies       -Hypertension,
                                         IL-2 synthesis                  *Most effective w/                  -Hyperlipidemia
                                        PK: PO or IV, metab by CYP3A4      cortisteroids + antimetabolite      -Hyperkalemia, tremor
                                                                                                               -Glucose intolerance
                                                                                                               -Gum hyperplasia
                                                                                                               -Hirsutism
                                                                                                               -Lymphomas
                     Tacrolimus (TAC)   MOA: same as CsA (but binds        -Liver, kidney transplants (give    -Similar to Cyclosporin A
                                        immunophilin-FKBP-12 instead)      w/ corticostrds &/or antimetab)     (NO gingival hyperplasia,
                                        -Higher potency & fewer side       -Ointment prep for mod-severe       NO hirsutism)
                                        effects than CsA                   atopic dermatitis                   -Nephrotox, neurotox
                                        PK: PO or IV, oral abs variable,   *Preferred to CsA b/c doses        more common than CsA
                                        abs  w/ fatty meal, long half     of corticosteroids required         -Post transplant insulin
                                        life, metab by CYP3A4                                                  dependent diabetes (esp
                                                                                                               Black & Hispanic patients)
                                                                                                               -Avoid use w/ NSAID –
                                                                                                               interferes w/ renal blood
                                                                                                               flow
                        Sirolimus/      MOA: forms complex w/ FKBP-        -Prevent reject of renal            -CsA + SRL more
                     Rapamycin (SRL)    12binds MTOR (serine-             transplnt                           nephrotoxic than CsA
                                        threonine kinase)block            -SRL + CsA + corticosteroids        -Nausea, diarrhea, h/a
                                        progression of activated T cells   (allows lower doses)                -Leucopenia
                                        from G1S phase inhibit cell      -SRL-coated stents inhibit          -Thrombocytopenia
                                        proliferatinhibit cell response   restenosis of blood vessels         -Impaired wound healing
                                        to IL2 (NOT IL-2 synthesis)       (endothelial cell proliferation)   (esp diabetics & obese
                                        PK: Oral only, Abs w/ fatty                                           problem for transplantng)
                                        meal, long ½ life, metab by                                            -Hyperlipidemia
                                        CYP3A4,
                                        *SRL  [CsA], so don’t give at
                                        same time (separate 1-2 hrs)
TNF Inhibitors        Etanercept       TNF-receptor dimmer binds          -RA                                 Risk of reactivating
                                        both TNF and TNF                 -Chron’s disease                    latent TB must screen
                       Infliximab       Ab against TNF                    -Psoriasis
                       Adalimumab       IgG1 against TNF                  *Will improve symptoms but not
                                                                           reverse pathophys
IL-1 Inhibitors         Anakinra        Recombinant form of IL-1ra         -RA                                 Neutropenia
                                        (receptor antagonist)              -Modest effects on pain,            Susceptibility to
                                                                           swelling, but bony erosions       infeciton
ANTIBODIES           Antithymocyte-     Rxn against T-cell precursors      -Give at time of transplant to      Chills
                     Globulins (ATG)    (thymocytes); polyclonal           prevent early allograph             Fever
                                         PK: IV (very slow infusion, 1-    rejection                           Leukopenia
                                        2wk), half life 3-9 days           -Tx severe rejection episodes of    Thrombocytopenia
                                                                           corticosteroid resist acute         Infections
                                                                           reject                              Skin rashes
Note: Muro murine   Muromonab-CD3      Monoclonal antibody against        -Acute reject of renal allograph    -Anaphylactic rxns
antibodies               (OKT3)         CD3 of mature T-cell               -Corticosteroid resist acute        -Cytokine storm (initial
                                        -Depletes Tcells for 48 hrs        allograft reject (heart, liver)     binding of OKT3
                                        PK: IV                             -Depletes T-cells from donor BM     activation of Tcell)
                                                                           prior to transplant                 *Prevent cyto storm w/
                                                                                                               methylprednisolone+
                                                                                                               diphenhydramine +
                                                                                                               acetaminophen
Note: Chimeric         Basiliximab      Monoclonal anti-IL-2 receptor      -Acute rejection of renal           Well tolerated
antibodies ―xi‖       Daclizumab       (Anti-CD25)                        transplant (give w/ CsA +
                                        PK: IV,                            Corticosteroids)
                                        Dacilizumab: long ½ life
                                        (20days); give 5 doses (1@ 24hr

                                                                                                                        52
                                             before, 4@14 day intervals)
                                             *Basiliximab ½ life only 7 days,
                                             only 2 doses given (1@ 2hrs
                                             prior, 1@4days after
Note: Humanized            Alemtuzumab       Monoclonal Anti-CD52 (depletes       -Refractory B-cell CLL               -Cytokine storm
antibodies  ―zu‖                            T cells                                                                   -Neutropenia
                                                                                                                       -Anemia
                                                                                                                       -Pancytopenia (rare)
Note: anything              Alefacept        Anti-CD2 (inhibits T cells)          Chronic plaque psoriasis             CI: HIV patients (drug
binding to a receptor                                                                                                  depletes CD4, CD8 cells
 ends in ―cept‖                                                                                                        risk of infection)
                           Abataccept        Anti-B7 (down regulates Tcells)      Rheumatoid Arthritis                 -Exacerbations of
                                                                                                                       bronchitis
                                                                                                                       -Risk of infection
                            Efalizumab       Anti-LFA-1 (limits Tcell             Chronic plaque psoriasis             Immune-mediated
                                             adhesion, activation, & migration)                                        thrombocytopenia
                                                                                                                       -Hemolytic anemia
                                                                                                                       risk of infection
STEROIDS                    Prednisone       CANCER:                              Lymphomas                            Adrenal suppression
                                             General anti-lymphocytic effect      DOC for:                             Growth inhibition
                                             -Triggers apoptosis                  -ITP                                 Decreased muscle tone
                                             IMMUNOSUPPRESSION:                   -Autoimmune hemolytic anemia         Osteoporosis
                                             Toxic to some T-cell lines           -Acute glomerulonephritis            Cushing’s syndrome
                                             -Suppress immunity & inhibits        G vs. H disease                      Immune suppression
                                             production of mediators
                                             -Ameliorate drug
                                             toxicity/inflammation




                                                   ANTIHYPERLIPIDEMIC DRUGS
Hypercholesterolemia is associated with atherosclerosis. Liver synthesizes cholesterol-esters and package with TAGs to make a VLDL (B-100).
Loss of TAG via lipoprotein lipase (requires C2) from the VLDL produces IDL (mainly Chol-ester). The IDL collects more chol-esters from HDL.
The IDL becomes LDL. HDL picks up extra cholesterol from tissues (via LCAT & A2).
 Drug type            Drug                     Mechanism                         Clinical Use                          Side Effects

 STATIN           Lovastatin        ALL statins                     -Tx for hypercholesterolemia             Grapefruit juice inhibits CYP450
                 Simvastatin        1. Inhibit HMG CoA              (LDL-c)                                 3A4 aggravating statin toxicity
                 Atorvastatin       reductase block                -Tx for hypertrigleridemias (esp.        rhabdomyolysis
                                    cholesterol synthesis           mixed LDL, TAG diseases)
                                     Liver cholesterol,                                                     ALL STATINS:
                                     LDL-R expression              Rule of 6’s = 2x dose of statin         -Myalgia check CK regularly
                                     Plasma LDL                    6% cholesterol (use drug combos         -Rhabdomyolysis (risk w/
                                    2. VLDL synthesis             instead)                                 gemfibrozil) relased myoglobin
                                    triglyceridemia                                                         ATN kidney failure (give
                                                                                                             mannitolenhance mg excret)

                                                                                                                                53
                                 -PK: metabolized on P450                                                 -Hepatotoxicity (check liver function
                                 3A4                                                                      tests)
                Fluvastatin      PK: metabolized by               -Same                                   *Don’t give to homozyogos familial
                                 alternative P450’s                                                       hypercholest.  No LDL recptrs
               Pravastatin       PK: NOT metabolized by           -Same                                   CI: pregnancy, breast feeding, active
               Rosuvastatin      P450’s                           -Good for people on other drugs         liver disease, & may cause problems in
                                                                                                          kids
  Niacin          Niacin         -Inhibits lipolysis in adipose   -DOC for Tx of HDL                     -Cutaneous Flush (b/c of
              (Nicotinic Acid)   tissue TAG synthesis           -Use, when statin is CI                 prostaglandins tx w/ aspirin)
                Vitamin B3       requird for VLDL Blocks        -Tx of familial hyperlipidemias         -Hepatotoxicity (fatty liver b/c liver
                                 synthesis of VLDL                -Used w/ statins to treat severe        is forced to keep its fat)
                                                                  hypercholesterolemias                   -Impaired insulin sensitivity
                                 HDL, VLDL, LDL                                                        -Myopathy (if given w/ statinjust
                                 ApoA1 Clearnce (HDL)                                                   monitor closely)
                                                                                                          -Pruritius
                                                                                                          -Acute gouty attack
 Fibrates      Fenofibrate       Activate PPAR activates        Tx of hypertriglyceridemia              -Mild GI (less common w/ fenofibr)
               Gemfibrozil       lipoprotein lipase FA                                                  -Gall stones (risk b/c more free
                                 uptake plasma TAG                                                      fatty acids being excreted)
                                                                                                          -Myositis (renal patients at risk)
                                 VLDL, IDL                                                              -More breakdown of VLDL can cause
                                 Modest LDL                                                              production of LDL in some
                                 HDL in most
                                                                                                          Drug interacts: compete w/ warfarin
                                                                                                          for plasma binding sites
                                                                                                          CI: Statins; safety in pregnancy not
                                                                                                          known
 Bile acid    Cholestyramine     Prevents reabsorption of         -Tx of hypercholesterolemia (esp.       -Steatorrhea, constipation,
Sequestrant     Colestipol       bile acid synthsis uses         in young and pregnant women)            bloating, flatulence, nausea
                Colesvelam       cholest.  LDL-Recpt           -DOC for type IIa/b                     -Malabsorption of fat sol vitamins &
                                 LDL clearance                    hyperlipidemias                         oral lipid soluble drugs (digoxin,
                                                                  -Tx of pruritus (only                   warfain, & thiazides)
                                 -IF LDL the liver tries to      Cholestyramine) caused by               -Colesvelam has fewer GI SE
                                 make more VLDL and             accumulation of bile acid in            -VLDL & TAG
                                 TAG synthesis hyper-TAG         patients w/ biliary obstruction (e.g.
                                                                  in pancreatic cancer)                   CI: hypertriglyceridemia
Cholesterol      Ezetimibe       -Inhibits uptake of dietary      -Hypercholesterolemia (when             -Diarrhea, abdominal pain
Absorption     Plant sterols     cholesterol by blocking          statin CI) -Used w/ statins             -Headache
Inhibitors                       transporter (NPC1L1                                                      -Rash & angioedema (rare)
                                 receptr) in GI  forces liver
                                 to synth more cholesterol                                               CI: Breast feeding
                                 LDL
                                 -Inhibit VLDL prodct LDL
                                 PK: metabolized in SI & liver
                                 w/ biliary & renal exretion
               Omega 3-FA        TAG biosynthesis & FA          -Used if TAG >500mg/dL
                (fish oils)      oxidation




                                                                                                                               54
                                                     BLOOD DISORDERS
     Drug                                           Mechanism                             Clinical Use                      Side Effects
 THROMBOLYTIC      Streptokinase     -Acts on both bound & free                - IV in short term emergency         -Excessive bleeding, possible
    AGENTS                           plasminogen plasmin not clot            management of coronary               intracerebral hemorrhage
                                     specific deplete circulating             thrombus in MI, DVT, PE              -Hypersensitivity rxns &
                                     fibrinogen, & factors V, VIII             -EARLY ADMINISTRATION!!              hypotension
                                                                               -used in situations angioplasty is   -antigenic, s trep antibodies
                                                                               not readily available                may activity
                                                                                                                    Antidote: aminocaproic &
                                                                                                                    tranexainic acids
                     Urokinase       Human kidney cells                        Same
                                     Generates plasmin
                   Alteplase (tPA)   Recombinant                               Same, but also used in ischemic      -No allergy problems b/c
                      Reteplase      -Clot specific, acting mainly on fibrin   stroke                               human recombinant
                    Tenecteplase     bound plasminogen plasmin                                                     -Very $$ ($500/dose)

                    Anistreplase
  ANTI-    Block       Aspirin       -Irreversible acetylation of COX          -Prophylactic treatment of
           COX                       -Inhibits TXA2 (normally TXA2            transient cerebral ischemia
PLATELET
                                     platelets to degranulate & aggregate)     -Incidence of recurrent-MI
                                     -Increases bleeding time                  -Mortality in post-MI
                                     -Vascular COX is less sensitive to
                                     aspirin than platelet COX
           Block     Clopidogrel     -ADP Receptor Blocker                     - Ischemic events in patients       Clopifewer SE(preferred)
           ADP-R     Ticlopidine     -Irreversible inhibitors of P2Y12 (ADP    with ischemic stroke, MI, or         -Hemorrhage, leucopenia,
                                     receptor subtype on platelet              peripheral vascular disease          thrombocytopenic purpura
                                     surface)interfering w/ aggregation       (alternative to aspirin)             (making aspirin safer)
                                     and activation by preventing ADP-         -Used as antiplatetlet (instead
                                     induced expression of platelet GP2b/3a    of aspirin) if patient also has
                                                                               gastric ulceration
           Block    Dipyridamole     -Phosphodiesterase inhibitor cAMP       -Little effect by self
           PDE      (Percantine)     (which platelet sensitivity to           - Dipyridamole + warfarin
                                     activating stimuli)                       prevent thromboemboli in
                                                                               patients w/ artificial valves
                                     -and block uptake of adenosine (acts at   -Prophlaxis tx in angina
                                     A2 receptors to activate platelet         -Coronary vasodilator
                                     adenylyl cyclase)???                      -Aspirin + dipyridamole (extend
                                                                               release) 2’ prophylaxis of
                                                                               cerebrovascular disease
                     Cilostazol      -Phosphodiesterase inhibitor              -Tx of intermittent claudication
                                     -Promotes vasodiation and inhibition
                                     of platelet aggregation
           Block     Abciximab       -Monoclonal antibody against human        -Acute coronary syndromes
           GPIIb                     GP IIb/IIIa receptor                      -Post-angioplasty
           /IIIa
                                     - platelet aggregation by preventing
                                     the cross linking rxn
                    Eptifibatide     -cyclic peptide reversible antagonist     -Acute coronary syndromes
                                     of GP IIb/IIIa receptor                   -Post-angioplasty
                     Tirofiban       -Nonpeptide reversible antagonist of      -Acute coronary syndromes
                                     GP IIb/IIIa receptor                      -Post-angioplasty
ANTICOAGULANT         Heparin        Renal excretion                           -Good for emergency situations       -Bleeding  1st sign
                                     Structure: large polysaccharide, water    -DOC for anticoagulation in          -Hypersensitivity rxns
                                     soluble                                   pregnancy                            -High doses AT-III
                                     -Kinetics: give parenterally (IV, SC),                                         (sequestration) inactivat

                                                                                                                           55
               hepatic & RES elimination; no placental                                      of coagul factthrombosis
               access, half life = 2 hrs                                                    -Heparin induced
               -Mechanism: binds antithrombin III                                          thrombocytopenia (HIT)
                serine protease-inhibiting activity                                       type II (antibodies to
               fast inactivation of IIa, IXa, Xa, XIa,                                      complex of heparin and a
               XIIa (binding of heparin to ATIII                                            platelet protein, Platelet
               allows it to rapidly inhibt thrombin                                         Factor 4) platelet
               except that already bound to fibrin);                                        aggregation & degranulation
               works on active form of factors,                                             discontinue heparin & give
               inactivating intrinsic/common pathway                                        a DTI or fondaparinux
               (i.e. works in plasma & works fast)                                          -LMWH have longer half
               LMWH inhibit activated factor X but                                          lives, less thrombocytopenia
               have less effect on thrombin (II)                                            Antagonist: Protamine
               than UFH                                                                     sulfate chemical
               Monitoring: PTT (no LMWH monitor)                                            antagonism, fast
Enoxaparin     LMWH                                       DOC for unstable Angina
 (Lovenox)                                                DOC for MI
Danaparoid     -Mainly inhibits factor X, less            -Prophylaxis of deep vein         -Less immunogenic, safer in
               inhibition of thrombin                     thrombosis in hip replacement     hypersens rxns to heparin
               -LMWH-like from porcine gut mucosa         surgery
               -Contains heparin sulfate, dermatan        -Tx of HIT
               sulfate, chondroitin sulfate
Fondaparinux   -Selective factor X inhibitor              -Prevention & tx of DVT
               -Synthetic pentasaccharide, binds
               antithrombin III which leads to
               inhibiting of Xa;
               -Once daily SC injection
 Lepirudin     Direct Thrombin Inhibitors (DTIs)          Bivalirudin + aspirin tx of      -No antidote
 Desirudin     -Recombinant forms of hirudin (from        unstable angina when undergoing
Bivalirudin    leech)                                     percutaneous transluminal
Argatroban     -Directly bind to active site of           coronary angioplasty (PTCA)
               thrombin (independent of AT-III, thus
               can reach and inactivate fibrin-bound
               thrombin in thrombi)
               -Monitored by PTT, given parenterally
 Warfarin      Structure: small, lipid soluble            Prophylaxis use                   -Hemorrhage
(coumarins)    -Kinetics: lipid soluble ORAL, 98%                                          -Bleeding of fetus
               protein bound, half life = 30+ hours;      Drug interactions:                -Petechiae
               placenta access, slow hepatic metab        -Inhibitors of P450’s warfarin   -Adrenal insufficiency
 Dicumarol     -Mechanism: inhibits Vit K epoxide         activity (cimetidine macrolide,   -Low Therapeutic index
               reductase prevents -carboxy             azole antifungal)                 -Protein C deficiency
               liver synthesis of vit. K-dep. clotting   -Inducers of P450’s: warfarin    procoagulant effect in 1st
               factors (II, VII, IX, X, protein C); No    activity (barbituates,            few days & thus requires
               effect on factors already present (i.e.    carbamazine, rifampin)            heparinization of patient
               works on inactive forms of clot factors    -Warfarin is an acidic molecule   always before warfarin
               in liver), effect takes 8-12 hours,        abs by cholestyramine           Cutaneous necrosis (b/c
               inhibit extrinsic/common pathway           -Displacement from plasma         protein C)
               Monitoring: PT (need close monitoring)     proteins by other drugs free
               Antagonist: Vit K (slow onset), fresh      fraction anticoagulat           CI: pregnancy
               flozen plasma
   Vit. K      Causes synth. of clotting factors          For Warfarin overdose &           CI: Synthetic analogs
  SYNTH.                                                  newborns
  ANALOG       Menadione – H2O soluble                                                      Hemolysis – G6PD
Phytonadione                                                                                Kernicterus – newborn
 Menadione                                                                                  (hyperbilirubinemia)
  menadiol
                                                                                            Deficiency
                                                                                            -decrease prothrombin/
                                                                                            clotting factors

                                                                                                   56
                                                                                                                           -ecchymoses, bleeding
  PRO-CLOTTING                 VIII                                                   Hemophilia A
                                IX          From dried human plasma                   Hemophilia B (Christmas)
                                            Has several Vit. K-dep. factors
Plasminogen                 Tranexamic      Inhibit conversion of plasminogen to
Activation Inhibitors           acid        plasmin
                           Aminocaproic     Same                                      Post-tPA, urokinase,
                               acid                                                   streptokinase
                                                                                      i.e. bleeding due to fibrinolysis
                          Antihemophilic                                              hemophiliacs
                             Globulin
                            Thrombin        Clots fibrinogen                          Topical hemostat (capillary
                                                                                      bleeding)
       OTHER                Protamine       Heparin antagonist
                                            From fish sperm




                                                           ANTIPROTOZOALS
      Drug                                                 Mechanism                             Clincal Use                               Side Effects
    MALARIA             Liver forms of malaria are common in plasmodium vivax and ovale.
                            Chloroquine     MOA: Drug is concentrated in             -DOC for Tx of all malaria           Very well tolerated even w/
                                            organism’s food vacuolein the food      (except resistant falciparum)        long use
                                            vacule, the organism digets the host’s   -Chloroquine + primaquine              1. Short term – GI
                                            Hbrelease of toxic hemeorganism        Prophylaxis for all malaria                  disturbance
                                            protects itself by polymerizing the      -Chloroquine + primaquine Tx           2. Long-term – SIGHT,
                                            heme to hemozoinBUT chloroquine         of persistent liver stage                    HEARING DAMAGE
                                            binds to heme, preventing its            -Chloroquine + emetine              Toxicity: dizziness, blurred
                                            polymerization to hemozin pH,          Amebic liver abcess                  vision, retinal damage,
                                            heme = oxidative damage to              -Collagen disorders/autoimmune       headache, diarrhea, GI
                                            membranedeath of parasite and cell      like lupus & RA due to the anti-     irritation, epigastric pain,
                                            PK: given PO rapidly, completely abs;    inflammatory effect                  exfoliative dermatitis, rarely
                                            concentrates in erythrocytes, liver,                                          myocardia depression
                                            spleen, kidney, lung, crosses CNS        -Chloroquine resistant species       *Long term high dose for
                                                                                     can expel the drug via a             rheumatologic disease
                                            BLOOD SCHIZONTICIDE                      membrane P-glycoprotein pump         irreversible ototoxicity,
                                            (Erythrocytic phase)                                                          retinopathy, myopathy,
                                                                                     Safe in pregnancy if traveling       neuropathy
                                            -Gametocidal except for falciparum                                            *Causes EKG changes (b/c
                                                                                                                          quinidine like effect)
                                                                                                                          CI: psoriasis, porphyria
                           Primaquine       8-aminoquinolone                         -Tx exoerythrocytic forms of         -GI irritation, H/A
                                            -Liver phase of infxn                    recurring malarias (P. vivax and     -Agranulocytosis
                                            -Extensive metabolism (oxidation/        ovale)                               -Pruritis
                                            demethylation)                                                                -Methemaglobinemia
                                            TISSUE SCHIZONTICIDE                                                          -Hemolysis in G6PD def.
                                            Gametocidal                                                                   (primaquine is a cell oxidant)
                         Pyrimethamine      ANTIFOLATES!                             -Proguanil + Atorvaquone             -Pyrimethamine
                            Proguanil       -Pyrimeth, proguan cycloguanil         (malarone) prophylxis of            megaloblastic anemia (tx w/
                          Sulfadoxine*      inhibits DHF reductase of parasite (at   resist falciparum                    leucovorin)
                           Dapsone*         low concentrations)                      -Pyrimethamine + sulfadoxine         -GI distress
                                            *Oral route, urinary elimination         (fansidar) prophylaxis in           -Sulfas crystalluria,
                                                                                     chloroquine sensitive regions        hemolysis, Steven-Johnson
                                            Blood schizonticide & sporontocide-(in                                        syndrome
                                            mosquito’s gut)

                                                                                                                                   57
                          Quinine        -MOA: unknown…interfere w/ heme           -Reserved for the serious           -Cinchonism (h/a, tinnitus,
                                         polymerization death of erythrocytic     infections (IV dose)                vertigo blurred vision, GI
                                         form of parasite? Prevent DNA strand      -Tx chloroquine-resistant           distress)
                                         separation?                               falciparum (1st line therapy)       -Cardiac conduction
                                                                                   -Relieve leg cramps                 disturbances & hypotension w/
                                         -Quinidine can be used in place of        -Myotonia congenital                overdose
                                         quinine                                   -Sclerosing agent                   - Black water fever,
                                                                                   -Quinine + doxycycline or           (intravascular hemolysis)
                                         BLOOD SCHIZONTICDE                        clindamycin or pyrimethamine        -Hemolysis in G6PD patients
                                                                                    limits toxicity & shortens        -Avoid in psoriasis
                                                                                   therapy                             CI: pregnancy (X)
                          Mefloquine     -MOA: unknown                             -1st line for prophylaxis (Use      -Cardiac conduction
                                         -PK: Long half life (6 days)b/c of       doxycline instead??)                abnormalities
                                         enterohepatic circulaiton; ONLY given     -Tx for chloroquine resist          -Avoid in psychiatric
                                         orally b/c IM causes irritation; highly   falciparum (alternative)            disorders & seizures
                                         protein bound; 20% excreted               -Safe for pregnancies if            -Neurological abnormalities
                                         unchanged,                                traveling to chloroquine-           (people becoming vegetables)
                                         BLOOD SCHIZONTICDE                        resistant areas
                                                                                   -Not available on USA market
                         Amiodaquine     Similar to cloroquine                     Often used b/c of low cost,         -Agranulocytosis
                                                                                   limited toxicity, and sometimes     -Aplastic anemia
                                         BLOOD SCHIZONTICDE                        effective against falciparum        -Hepatotoxicity
                                                                                   Amiodaquine + artesunatetx         -Photosensitivity
                                                                                   falciparum (as an alternative)      -Dermatitis
                                                                                                                       -GI disturbances, H/A
                       Halofantrine      MOA: unknown                              -Tx all malarias (even resistant)   -Cardiotoxicity long QT
                                         -Effective in erythrocytic phases         -Not available in USA, but          -Embryotoxicity
                                                                                   approved by FDA                     -Limited use b/c of irregular
                                                                                                                       abs & cardiotoxicity
                        Doxycycline      ANTIBIOTIC                                Prophylaxis for chloroquine-
                                         Often used w/ quinine                     resistant & mefloquine-
                                                                                   resistant falcip
                        Artemether       MOA: metabolized in food vacuole          -Tx multi-drug resistant            Nausea, vomiting, diarrhea
                        Artesunate       PK: short half life (thus, not good       falciparum (acts very rapidly)
                                         prophylaxis), lipid soluble               -Only drugs reliably effective      Very $$, limited availability
                                         BLOOD SCHIZONTICDE                        against quinine resistant strains   (Not available in USA)
                        Atorvaquone      -Inhibits electron transport/ATP          No resistance seen
                                         synthesis;
                                                                 AMEBIASIS
                                             (Drug choice DEPENDS ON CLINCIAL PRESENTATION)
Asymptomatic Intestinal     Amebic Colitis metronidazole + luminal amebicide             Extraintestinal Infection metronidazole + luminal
 infection  give luminal                                                                 amebicide
        amebicide           TC + erythromycin (alternative) for moderate colitis         *10 day course of metronidazole cures 95% of
                            Dehydroemetine or emetine (alternative) for severe           uncomplicated liver abscesses (can follow w/ choloroquine)
                            infection, but usually avoided due to toxicities
                          Metronidazole     MOA: prodrug bioactivation           -DOC for all tissue infxns from    -Seizures
    AMEBIASIS              Tinidazole       (pyruvate:oxidoreducase – present in E. histolytica                      -Ataxia
                                            anerobic bacteria)  forms a          -DOC for Tx giardiasis             -Disulfiram-like effects
                                            cytotoxic product which binds to      -DOC for Tx urogenital             -N/V, diarrhea
                                            protein and DNAkills parasite        trichomoniasistx both partnr      -Dry mouth/stomatitis
                                            PK: PO, parenteral                    -Gardnerella vaginalis             -Insomnia
                                                                                  -Anaerobic infxn ―below the        -Weakness
                                                                                  diaphragm‖ esp B. fragilis &      -Potentiates coumarin drugs
                                            *It is elminated via hepatic          C. difficile (DOC for              -Urethral burning
                                            metabolism. Thus, any P450          Pseudomembranous colitis)          -Metallic taste
                                            drug                                 -Acute ulcerative gingivitis
                                                                                                                     Safety in pregnancy not
                                                                                  -Cancrum oris
                                                                                                                     established, teratogenic/
                                            TISSUE AMEBICIDAL                     -Ulcerative colitis
                                                                                                                     carcinogenic in animals
                                                                                  -Cutaneous leishmania

                                                                                                                                 58
                                                                                      -Decubitis ulcers
                                                                                      -Alternative for Tx H. pylori
                                                                                      (metronidazole + TC + PPI/H2X)
                             Emetine          MOA: Blocks ribosomal movement         -Severe intestinal & extra-      VERY TOXIC
                          Dehydroemetine      inhibting protein synthesis             intestinal amebiasis             Heartcloudy swelling &
                                              Only given to hospital patients         *Almost completely replaced by   necrosis, hypotension, CHF,
                                              Narrow therapeutic range                metronidazole                    arrhythmia, retrosternal pain
                                              PK: subcutaneously or IM,                                                -Urticaria/ pruritic eruption
                                              concentrated in liver, spleen,          -Balantidium coli                -N/V, diarrhea
                                              kidney heart; eliminated through        -Fasciiola hepatica              -Muscular weakness, pain,
                                              kidney                                  -Pargonimus westermani           abscess @ injxn site
                                              TISSUE AMEBICIAL                                                         -Fatigue, h/a, dizziness
                            Diloxanide-       MOA: unknown                            DOC asymptomatic carriers       Mild, mainly GI
                              furoate         PK Oralhydrolyzed in gut              of cysts                         -N/V, abdominal cramps
                                              diloxanide (amebicidal) & furoate       -Tx moderate/severe              -Esophagitis
                                              (abs from the gut, conjugated in        intestinal amebiasis             -Dry mouth
                                              liver & excreted in urine)              *Kills amebiasis in 80-90% of    -Pruritus
                                              -Oral, 90% absorbed, conjugated         patients w/ single course of     -Urticaria
                                              in liver, urine excretion               therapy                          -Proteinuria
                                              LUMINAL AMEBICDE
                             Iodoquinol       MOA: unknown                            -Alternate for tx asymptomatic   Infrequent SE:
                                                                                      carriers                         -Diarrhea, anorexia, N/V
                                              LUMINAL AMEBICDE                        -Alternate for Tx mild to        High dosessystemic:
                                                                                      severe intestinal amebiasis      -Nephrotoxicity
                                                                                                                       -Optic atrophy
                                                                                                                       -Peripheral neuropathy
                                                                                                                       -Thyroid enlargement
                                                                                                                       -Agranulocytosis
                                                                                                                       CI: thyroid, renal disease
                           Paramomycin        LUMINAL AMEBICDE                        -Some efficacy against
                                                                                      cryptosporidiosis in AIDs
                           Tetracycline       MOA: eliminates normal intestinal       *Ineffective used alone          CI: children under 8yrs &
                                              flora (ameba’s main food source)                                         pregnancy
                                              -Chelates Ca, Mg, Al forms into non-
                                              absorbable compounds
                            Chloroquine       Tissue amebicidal                       Used in combo for hepatic absc   See malaria
TRYPANOSOMIASIS             Nifurtimox                                                Tx of trypanosma cruzi (Chagas
                                                                                      disease)
                             Arsenicals                                               Tx of African trypanosma
                                                                                      (rhondiense, gambiense)
LEISHMANIASIS             Stibogluconate
TOXOPLASMOSIS            Pyrimethamine +
                           sulfadiazine
GIARDIASIS                Metronidazole
PNEUMOCYSTOSIS              TMP-SMX                                                   DOC
                           Pentamidine                                                Backups                          CI: foscarnet
                           Atovaquone         Interferes w/ electron transport        Backups                          Very toxic




                                                              ANITHELMINTHS
Typically, the treatment will be one large dose. So, the side effects generally are mild or not an issue.
       FOR                Mebendazole          -Inhibits microtubule synthesis          DOC: Nematodes                 GI irritation
  NEMATODES                                    -Depletes helminth energy stores           1. Whip worm (trichuris

                                                                                                                                 59
 (―roundworms‖)                        by decreasing glucose uptake                  trichuria); prolapsed        Use w/ caution: in cirrhosis, in
                                       -Affected parasites are expelled w/           rectum                       children under 2yrs
                                       feces                                      2. Pin worm (enterobius
                                       -Rapid metabolization, reduced abs            vermicularis)                CI: pregnancy
                                       w/ high fat meal                           3. Hookworms (Necator
                                                                                     americanus & Ancyclostoma
                                                                                     duodenale)
                                                                                  4. Roundworm (Ascaris
                                                                                     lumbricoides)
                    Thiabendazole      -Inhibits microtubules synthesis          1. Threadworm                    TOXIC
                                       Larvicidal & ovicidal                         (strongyloides)alternat     -CNS distorbances, n/v,
                                       Inactivated by liver hydroxylation            to ivermectin                dizziness, anorexia
                                       -Excreted urine/liver                     2. Trichinella (early stages)    - Rarely, Steven-Johnson
                                                                                 3. Cutaneous larva migrans       syndrome, erythema
                                                                                     (Ancyclostoma caninum, A.    multiforme, fatalities
                                                                                     braziliense) alternative
                                                                                     to ivermectin                CI: pregnancy, kidney/liver
                                                                                *Much more toxic than other       disease
                                                                                benzimidazoles/ivermectin, so
                                                                                other drugs are preferred
                   Ivermectin          MOA: GABA agonist, chloride influx       DOC:                              -Mazotti rxn: killing of
                                       is enhanced hyperpolarization           1.    Onchocerca volvulus        microfilaria (oncocerca)
                                       paralysis of worm                         2. Strongloidiasis               fever, h/a, dizziness,
                                       PK: doesn’t cross BBB                                                      somnolence, hypotension if
                                                                                -Tx scabies, lice, cutaneous      severe, given corticoids
                                                                                larva migrans w/ external use     CI: pregnancy, patients w/
                                                                                                                  meningitis
                  Diethylcarbamazine   MOA: not known                           DOC:                              Lacks serious toxicity
                                                                                 1.   Lymphatic filariasis
                                       PK: Take after meals                      2. Loa loa
                                                                                 3. Tropical eosinophilia
                                                                                *Replaced by ivermectin for tx
                                                                                of onchocerca
                  Pyrantel-pamoate     Depolarizing NM block spastic           Broad spectrum antihelmintic      Mild: n/v, diarrhea
                                       paralysis of worm expelled from         -Tx pinworm & Ascaris
                                       GI tract                                 (roundworm)
                                                                                -Moderately effective for Tx
                                       PK: poorly abs orally, exerts effects    of hookworm
                                       in GI
                     Doxycylcine       -Tetracycline                            Tx Wuchereria bancrofti
                                       MOA: indirectly acting by killing        -Also onchocerca
                                       Wolbachia (intracell symbiont of
                                       filarial parasites)
FOR                  Praziquantel      MOA: permeability of cell               DOC:                              -Drowsiness, dizziness,
TREMATODES                             membrane to Ca paralysis of              1.   ALL schistosomiasis         malaise, anorexia, GI upset
(flukes)                               parasite                                  2. Most trematodes               -Not recommended in
                                                                                 3. Most Cestode                  pregnancy
                                       PK: rapidly abs orally, goes into CSF,   *Cysticercosis albendazole       CI: ocular cysticercosis
                                       short ½ life                             preferred but prazi has similar   worm would blow up in
                                                                                efficacy                          eyeblindness (tx surgical)
                                                                                                                  Drug interact phenytoin,
                                                                                                                  dexamethasone,
                                                                                                                  carbamazepine, cimetidine
                                                                                                                  (prazi b/c inhibit P450s)
                       Bithionol       MOA: inihibit helminth’s electron        DOC for Tx of fasciolia           Common/mild, can be severe
                                       transport chain                          hepatica (sheep liver fluke)      -Diarrhea, abdominal cramps,
                                                                                -Tx pulmonary paragonimas         anorexia, n/v, dizziness, h/a,
                                       -Not available in USA                    westermani (alternate)            skin rashes
FOR CESTODES         Albendazole       MOA: Similar to mebendazole              DOC:                              -Few SE w/ 1-3 day use

                                                                                                                            60
(tapeworm)                                                              1.    Neurocystercosis (Taenia   -Long term use (hydatid
                                PK: erratically absorbed after PO,            solium) controversial     disease)GI distress, h/a,
                                abs enhanced by high fat meal; rapid    2. Hydatid disease               fever, fatigue, alopecia,
                                first pass                                    (Echinococcus)             pancytopenia
                                                                        3. Pinworm                       -Neurocyster tx
                                *Give on empty stomach for luminal     Also: Hookworm, strongyloides,    inflammatory responses
                                parasites                              trichuris                         *Follow blood count & liver
                                *Give w/ fatty meal for use against    *Glucocorticoids usually given    enzyms for long therapy
                                tissue parasites                       gefore therapy to SE from        CI: pregnancy, kids <2yrs
                                                                       dying cysticerci
               Niclosamide      -Salicylamide derivate                 2nd line Tx of most cestodes      Nausea
                                MOA: Inhibits parasit mitochondrial    -T. Solium (followed by purge)    Abd pain
                                anaerobic phosphorylation of ADP in    -T. saginata                      Pruruitis
                                -Lethal for cestode’s scolex &         -Diphyllobothrium (fish tape      Fever
                                segments of cestodes, but not          worm, B12 def)
                                against ova present in segments                                          *Avoid alcohol w/in 1 day of
                                -Give laxative prior purge bowl of    NO longer used in USA             Tx
                                all dead segments to prevent
                                digestion and liberation of the ova,
                                which could lead to cysticercosis.




                                                 ANTIFUNGALS
                  Drug                       Mechanism                          Clincal Use                       Side Effects
SUBCUTANEOUS   Amphotericin B   MOA: Binds ergosterol pores in        Broad spectrum                    ―Amphoterrible‖
  & SYSTEMIC                    membrane (increases permeability)                                        Cumulative toxicity:
 INFECTIONS                     -Low therapeutic index                 -DOC –for life threatening        -Nephrotoxic (dose
                                -Fungicidal or fungistatic depending   systemic mycoses                  dependent) tubular acidosis,
                                on organism                            (Candida, Histoplasma,            GFR, anemia
                                                                       Cocidioides, Blastomyces,         -Neurologic (intrathec neural
                                PK: Slow IV infusion; extensively      Aspergillus, cryptococcus)        damage/seizures)
                                bound to plasma proteins; little                                         -Anemia (from EPO)
                                goes into CSF give intrathecal in     -Fungal mening (Intrathecal)
                                meningitis (no inflamm effect on       -GI mycosis (Oral)                Infusion releated:
                                meninges)                              -Tx of mucormycosis               -Fever, chills, vomiting, h/a,
                                -Poorly absorbed from the GI, so                                         hypotension (sometime K+)
                                oral effective only on fngi within                                       -Histamine release
                                the lumen of the tract (not            Resistance:                       -Alleviated partly by pre-tx w/
                                systemic)                              -Fungi w/ low ergosterol in       NSAIDs, antihistamines
                                -Half life is > 2 weeks                their membranes
                                -Hepatic impairment, renal
                                impairment, and dialysis have little
                                impact on drug concentrations
                Amphotec®       New lipid formulations                 Used for those who cannot         Nephrotoxicity
                 Abelcet®                                              tolerate Amphotericin B           -$$$
                AmBisome®
                Flucytosine     MOA: Pro-Drug(fungal cytosine         -Tx systemic mycoses &            5-FU is an antineoplastic, so
                                deaminase) 5-fluorouracil (5-FU)      Cryptococcus meningitis           would see those side effects,
                                    1.  5-FU5fdUMPinhibits           (Flucytosine + Ampho B)           which ar significant b/c tx
                                        thymidylate synthase          -Tx Chromoblastomycosis           lasts 6-9 months
                                        inhibits DNA synthesis         (Flucytosine + itraconazole)      -BM depression (dose-
                                    2. 5-FUFUTP                      -Synergistic (Ampho B             depend)
                                        incorporates into RNA         flucytosine penetrance)          -Hepatic dysfunction


                                                                                                                     61
                                                  inhibit protein synthesis                                       -GI disturbances
                                        PK: well absorb orally, enters CSF                                        -Severe enterocolitis
   Azoles                                                                                                         *Flucytosine NOT used along
                                                                                                                  b/c synthesis of cytosine
                                                                                                                  resistance
                Imidazoles have two nitrogens on azol ring (ketoconazole, miconazole, clotrimazole). Triazoles have three nitrogens on the azol
                ring (intraconazole, fluconazole, voriconazole, posaconazole). They all block 14-sterol demethylase(CYP 450)block
                demethylation of lanosterol to ergosterol (blocks ergosterol synth). Generally, the imidazoles are less specific than the
                triazoles. Effective orally & will have problems with absorption. Absorption is decreased by food and antacids. Resistance via
                pumps.
                      Ketoconazole        -Less selective for fungalP450     -Rarely used to Tx systemic            -N/V, anorexia
                                          than newer azoles)                 mycoses b/c narrow spectrum &          -Allergic rash
                                          -Disrupts membrane,                adverse effects replaced by           -Inhibits steroid synthesis
                                          permeability                      itraconazole                           cortisol, testosterone
                                          -Also inhibits gonadal/adrenal     -Active against Histo, Blasto,         Antiandrogen effects
                                          steroid synthesis                  Candida, and Coccidiodies, but not     libido, gynecomastia
                                          PK: PO only; azoles = weak         aspergillus species.                   -Liver dysfxn (rare)
                                          acids abs w/ food or             -Still used for Tx of                  -Nephrotoxic
                                          antacids, (e.g. give w/ coke),     mucocutaneous candidiasis
                                          DOES NOT ENTER CNS                 -Tx Cushings Syndrome,                 INHIBTS CYP450’s  Many
                                                                             Testicular Ca (anti-androgen)          drug interactions

                                                                              Resistance seen esp in protracted     CI: pregnancy
                                                                              therapy w/ advanced HIV infxn
                     Itraconazole       PK: PO, metab in liver                Broad spectrum                        -N/V, rash, hypokalemia, h/a,
                                        (CYP3A4) major metabolite            -Azole of choice (DOC) for Tx:        edema, hypertension
                                        also antifungal                         1. Blastomycosis
                                        -Strong inhibitor of CYP3A4             2. Sporotrichosis                   ―Itra Blasts Sperm into Hot
                                        -Does NOT enter CSF                     3. Paracoccidiomycosis              People‖
                                                                                4. AIDs-Histoplasmosis
                      Fluconazole       -Enters CSF                           -Broad spectrum                       Least toxic azole
                                        -Slow metabolism, renal               -Azole of choice for Tx of            -NO endocrine effects
                                        excretion                             systemic funal infxn less toxic
                                        -No endocrine side effects            than amphoB and distributes to CNS    -Least effect of all azoles
                                        -High oral bioavailability, wide      -Tx & prophyalxis (azole of           on hepatic microsomal
                                        therapeutic index, NOT                choice, DOC?)                         enzymes
                                        dependent on gastric acidity            1. Cryptococal meningitis
                                        -Poorly metabolized                     2. Candidiasis
                                                                                3. Coccidoides
                                                                              -Prophylactic in bone marrow
                                                                              transplants & AIDs

                     Voriconazole       PK: PO, IV preps; metabolized         Broad spectrum                        *Many drug interactions b/c
                                        by multiple CYP450’s                  Tx serious infections from            metab by multiple P450’s
                                        -Goes into CSF                        scedosporium, apiospermum,            -Transiet visual
                                                                              fusarium species                      disturbances, resolves in
                                                                              -DOC invasive aspergillosis (seems    30min-1hr (>30% of users)
                                                                              to have replaced ampho B)
                     Posaconazole       PK: Oral only, CYP3A4 inhibitor       -Broad spectrum, similar to
                                        -Administer w/ full meal              itraconazole
Echinocandins                           -Goes into CSF                        -Tx Mucor and other zygomycetes
                      Caspofungin       MOA: inhibit (1,3) glucan            -Tx Aspergillus & Candida (2nd line   -Fever, rash, nausea,
                      Micafungin        synthesisinterfere w/ fungal         after ampho B                         phlebitis, flushing (histamine
                     Anidulafungin      cell wall synthesis cell lysis                                             release)
                                        PK: only IV, not CYP450’s
CUTANEOUS            Terbinafine        Inhibits squalene epoxidase          DOC for dermatophytoses (esp          -GI disturbances, h/a, rash
INFECTIONS                              synthesesis of ergosterol in         onychomycoses)                        -Taste & visual disturbances
                                        dermatophytes                         -Tx candida                           (rare)
                                        PK: PO, but for topical fungal                                              -Possilbe hepatotoxicity

                                                                                                                            62
                                             infxn; deposited in skin, nails,
                                             fat; long ½ life (200-400hrs)
                                             -Does NOT affect CYP450
                           Griseofulvin      -Accumulates in keratin             Tx Dermatophytes only (Replaced       -Barbiturates absorption
                                             containing tissues (keratin is in   by terbinafine)                       -Hepatotoxic  metab of
                                             hair, skin, nails) Disrupts        -Microsporum                          warfarin, contraceptives
                                             mitotic spindlesinhibits fungal    -Epidermophyton                       -H/a post-discontinuation
                                             mitosis                             -Trichophyton                         -Peripheral neuritis
                                             PK: PO, but for topical fungal                                            -Teratogenic /carcinogenic
                                             infxn active, must given w/         -Can be given IV to tx Candidas if    -Potentiates effects of
                                             fatty meal,                         allergic to ampho B                   alcohol
                                                                                                                       -Induces CYP450 (so avoid
                                             -Tx for 6-12mo                                                            w/ history of porphyrias)
                        Nystatin (topical)   MOA: Similar to Ampho B             Candidiasis                           Rare SE
                                             -Not well-absorbed from GI          -Vaginal                              –Lack of absorption
                                             -Too toxic for IV                   -Skin                                 -N/V
                                             -Never used parenterally, only      -Oral for topical tx of GI fungi
                                             given PO                            (thrush)
                           Micoconazole      MOA: same as ketoconazole           -DOC – topical Tx of candida          Rare SE
                           Clotrimazole      Topical only                                                              -Micoconpotent inhib of
                           Butoconazole                                                                                warfarin metabolism
                           Terconazole




                                                        OPIOD ANALGESICS
Headaches or mild/moderate pain is usually treated with an NSAID. Neurogenic pain responds best to anticonvulsants, TCA, or SSRI. However, for
severe or chroinic malignant pain, opiods are the drug of choice. Opiods interact with  (mu),  (kappa), and  (delta) receptors. The analgesic
properties are mainly mediated by the  receptors, but the with  receptors in the dorsal horn also contribute. The enkephalins interact more
selectively with the  receptors in the periphery. All the opiod receptors are Gi protein linked (cAMP). The respiratory depression of opiods is due
to suppression of the respiratory drive in response to high CO2 (opiods do NOT affect respiratory drive in response to low O2). The distribution of
receptors:
     1. Brainstem receptors influence respiration, cough, nausea, vomiting, blood pressure, papillary diameter, and control of stomach secretions
     2. Medial Thalamus receptors mediate deep pain that is poorly localized and emotionally influenced
     3. Spinal cord Receptors in the substantia gelantinosa receive incoming sensory information, leading to the attenuation of painful afferent
          stimuli.
     4. Hypothalamus receptors affect neuroendocrine function
     5. Limbic system greatest concentration of opiate receptors in the limbic system is in the amygdala. These do not exert analgesic action, but
          may influene mood.
     6. Periphery  Opiods bind to peripheral sensory nerve fibers and their terminals. As in the CNS, they inhibit calcium-dependent release of
          excitatory proinflammatory substances (e.g. substance P) from these nerve endings.
                   Longitudinal smooth muscle tends to relax
                   Circular smooth muscle tends to constrict
     7. Immune cells have a role in nociception (response to painful stimuli)

Tolerance is pharacodynamic (aka functional) because of a change in receptor sensitivity to drugs. Opiate receptors are Gi coupled, and tolerance
causes an cAMP production, escaping effects of opiates. Tolerance occurs in all CNS effects, but there is no tolerance in peripheral effects such as
miosis and constipation. Dependence is both physical and psychological.
Withdrawl syndrome (physical) yawning, lacrimation, rhinorrhea, salivation, t anxiety, sweating, goose bumps, muscle cramps, spasms, CNS originating
pain (mostly b/c excessive sympathetic response) (clonidine can be given for many symptoms, but the pain management must be centrally acting,
                                                                                                                                63
methadone is used because of its longer half life). Withdrawl lasts several weeks and is very PAINFUL. Withdrawl is also psychological, and craving
may be seen.

Why are opiods contraindicated in pregnancy? They are lipid soluble and would cross the placenta into the baby, causing respiratory depression.
Most likely the baby would be stillborn. Don’t forget that the baby cannat do glucuronidation. (Exception, you can give meperidine, not glucuronidated).
      Class                 Drug                          Mechanism                        Clincal Use                         Side Effects
   STRONG           These drugs show a high affinity for  receptors and varying affinities for the other receptors.
  AGONIST                  Morphine         MOA:                                 -Analgesia                       -Respiratory depression (most
                                            -Act at CNS receptors               -Tx diarrhea                     common cause of death in OD)
                                            hyperpolarize nerve inhibit         -Relief of cough (codeine or     -Pin point pupils (morphine excites
                                            firing                               dextromethorphan used now)       the Edinger-Westphal nucleus of the
                                            -Acts at k recptors in Lamina I/II -Tx acute pulmonary edema          oculomotor nerve  parasymp to
                                            of the dorsal horn release of                                       eye)
                                            substance P (modulates pain                                           -Emesis (morphine directly stimulates
                                            percept)                                                              the CTZ)
                                            -Inhibits the release of many                                         -GI symptoms ( circular SM tone,
                                            excitatory transmitters from                                          longitudinal SM relax constipat,
                                            noceceptive nerves                                                    cramping, biliary pressure,
                                                                                                                  -No major cardiovasc effects
                                            -Inhibits release of GnRH, CRH,                                       -Histamine releaseurticaria,
                                            LH, FSH, ACTH, -endorphin                                            sweating, vasodilation, & sometimes
                                            -GH, prolactin, ADH (causes                                        bronchoconstrict
                                            urinary retention)                                                    -Hormonal (can urinary retention,
                                                                                                                  but inhibit voiding, so may need a
                                            PK: abs slow, erratic; significant                                    catheter)
                                            1st pass in liver, only small amount                                  -Labor – may prolong the 2nd stage of
                                            crosses CNS, duration of 3-5hrs                                       labor b/c uterine contractions
                                            -Liver conjugation morphine-                                         -Enhances cerebral and spinal
                                            6-glucuronide (100X more potent)                                      ischemia
                                                                                                                  -Little effect on the heart

                                                                                                                 Drug interact: depressant actions
                                                                                                                 enhanced by phenothiazines, MOA-I,
                                                                                                                 TCA. Low doses of amphetamine or
                                                                                                                 hydroxyzine enhance analgesia
                                                                                                                 Caution: renal dysfunction
                                                                                                                 metabolite build uprespiratory
                                                                                                                 dysfunction
                                                                                                                 CI: Asthmatics, pregnancy (no
                                                                                                                 glucuronidation in newborn death
                          Meperidine       -Antimuscarinic                        -Analgesia                     -NO miosis (pupil dilation)
                                           MOA:                                    1. Biliary colic              -Tachycardia
                                           -IVDilates blood vessels,              2. Analgesia in pregnancy     -NO GI/GU/gallbladder spasm
                                           including cerebral vessels CSF           (Baby’s have CYP450s,      -Seizures (from serotonin)
                                           pressure                                   but main potential SE is   -Respiratory depression similar to
                                           -Contracts SM (lesser extent               still respiratory          morphine
                                           than morphine)                             depression)                -Antimuscarinic (e.g. dry mouth)
                                           PK: short acting; metabolized by
                                           CYP450normeperidine (SSRI)                                           Drug interactions: SSRI (too much
                                           Duration of 2-4hrs                                                    serotonin)
                          Methadone        Causes less euphoria                   -Withdrawl maintenenance of    -Biliary pressure
                                           PK: PO good abs, longer duration       opiate addicts                 -Constipation
                                           (25hrs),                                                              -Physical dependence
                           Fentanyl        PK: IV, epideral, intrathecal, rapid   -Anesthesia                    -Respiratory depression
                                           onset, short duration (15-             -Tx of cancer patients w/      CI: fentanyl patch in the
                                           30min) but half life terminal         breathrough pain who are       management of acute & postop pain
                                           (9hrs);                                tolerant to opiods (Fentanyl   (due to hypoventilation)
                                           100X potent as morphine; metab         patch used in chronic pain
                                           by CYP3A4                              managemnt)

                                                                                                                                   64
                                      Transdermal half life (17hrs)
                    Alfentanil        An ultra-short acting (5-10 min)      -Analgesia                       Stronger respiratory depression than
                                      derivative of fentanyl, but less                                       fentanyl
                                      potent
                   Sufentanil         A more potent (5-10X) derivative      -Heart surgury
                                      of fentanyl
                   Remifentanil       The shortest acting opiod w/          -Anesthesia
                                      rapid offset, even after prolonged
                                      infuss
                    Carfentanil       Derivative of fentanyl, but             -Veterinary medicine to
                                      10,000X more potent                     immobilize large animals
                                                                              (e.g.elephants)
                        Heroin         Produced by diacetylation of morphine 3x more potent and lipid -Not used clinically in USA
                                       solubility crosses CNS exaggerated euphoria                             -Used in the UK
                                       Heroin is converted to morphine in body, but lasts half as long           -most abused
                     Oxycodone         -Semisynthetic morphine                Tx. Severe pain                    -Abuse death
                                       derivative
  MIXED              Nalbuphine        k Agonist spinal cord analgesia,                                         -Little abuse potential
 AGONIST-            Pentazocine       dysphoria (as opposed to
ANTAGONIST                             euphoria)
                                        Antagonist precipitate
                                       withdrawl
  PARTIAL      Partial agonists can precipitate withdrawl if the patient is taking a full agonist (e.g. heroin or methadone). The ceiling effect is
  AGONIST      seen with the partial agonists. At some point after continuing to up the dose, there is no further analgesic effect, only further
               side effects. However, if you were using a full agonist (e.g. morphine) you cannot saturate the receptors and can continue to
               increase dosing with increasing analgesia
                       Codeine         Lower doses antitussive w/            -Cough suppressant (replaced by        -Rarely produces dependence
                                       little analgesic                       dextromethorphan)
                                                                              -Analgesia (due to conversion to
                                                                              morphine)
                                                                              -Used w/ NSAIDS
                      Tramadol         MOA: unknown, partial agonist??                                               Ceiling effect for respiratory
                                       -Centrally acting, binds                                                     depression
                                       receptors
                                       -Weakly inhibts reuptake of
                                       serotonin & NE
                   Buprenorphine       -Partial agonist at  receptors        -Opiate detox less severe             -Little sedation
                                       -Antagonist at k recptors              withdrawl symptom compared to          -Little respiratory depression
                                       PK: sublingual, parenteral, long       methadone                              (ceiling effect)
                                       half life (37hrs), OD hard to
                                       reverse b/c high binding affinity
ANTAGONIST            Naloxone         PK: IV, PO; duration (60-100min)       -Reversal for respiratory depression (IV)…can give for a relative
                                       Competitive antagonist at at ,        overdose and the patient can walk out of the room…will drift back into
                                       k,  receptors                         intox like an hour later
                     Naltrexone        Much longer acting (48hrs), PO         -Craving for alcohol (PO)
                                                                              -Tx of opiate addiction (PO) for ―painless withdrawl‖rich kid put
                                                                              on general anesthesia and muscle relaxants and given naltrexone to
                                                                              mediate the biochemical withdrawl within 48 hours instead of a
                                                                              week…and without seizures.
                      Alvimopan        Peripherally acting antagonist at      -Relief constipation from analgesic
                                        receptors, basically the “anti- therapy w/ chronic tx w/ opiods
                                       loperamide
ANTIDIARRHEA         Loperamide        Peripheral opiate receptor             Tx diarrhea
      L                                agonist, not abs stays in the gut
                   Tinctura opii       Basically pure opium                   -Given if loperamide isn’t enough, so
                                                                              this would stimulate all the opiate
                                                                              receptors
ANTITUSSIVE     Dextrometorphane       -no analgesia                          Tx of cough

                                                                                                                              65
                  Levopropoxyphene
                        Codeine
   Other             Apomorphine       -Dopaminergic agonist (D1,           -Adjunct tx of Parkinsons
                                       D2) centrally acting                -Powerful emetic (Used to be used
                                       -Morphine derivative, but does       for intoxications to cause emesis,
                                       not contain morphine or bind to     now used in torture)
                                       receptors                            -Alternative medicine, tx of
                                                                            addiction, ―vomiting therapy‖ for 2-
                                                                            3weeks…low relapse rates




                                                  ANTIMYCOBACTERIALS

1st line for TB    The treatment of TB is always multiple drugs, at minimum two drugs (both bacteriocidal). Most of these drugs will be used for
                   6mo-1yr for tx. Treatment is divided into two phases. The intensive phase lasts 2 months, and the Continuation phase is the
                   final four months of treatment. For example, the intial short course therapy for TB includes rifampin, isoniazid,
                   pyrazinamide, and ethambutol (RIPE) for 2 months. Then isoniazid and rifampin are given for the next 4 months.
                   Isoniazid and Rifampin will cure 95-98% in 9 mo. The other drugs are added to shorten duration of treatment.
                       Isoniazid (INH)      MOA: INH = prodrug, needs              -DOC in latent TB                 -Peripheral neuritis (20%)
                                            bacterial catalase (KatG) to be        Given 1 yr for PPD+ kids         from B6 exretion (give B6),
                                            turned on inhibits synthesis of       (<3yr)                            restlessness, muscle
                                            mycolic acid & cell wall effective -Prophylaxis:                        twitching, insomnia
                                            against intracell and extracellular      1. Immunosuppressed             -Hepatotoxicity (<2%) in
                                            organisms                                2. Infants of highly infx       elderly due to conversion of
                                            PK: well abs (not w/ antacids), Goes        parents (used for 6 weeks)   INH in the liver to hydrazine
                                            into CNS                                 3. Close contacts of active TB  (toxic metabolit) take
                                            -INH is acetylated (genetic            *INH is specific for TB,          baseline hepatic enzyme level
                                            variable), excreted through renal      effective against intracellular   -Sideroblastic anemia (no B6
                                                                                   bacteria                           used in transaminase rxn
                                            *INH is the most potent of TB                                            to detox amino groups from
                                            drugs, but never given alone.          Resistance:                       INH)
                                                                                   -Deletion of KatG gene            -SLE in slow acetylators
                                            *Bactericidal for rapidly growing,     -Deletion of inhA (codes for
                                            but bacteriostatic for bacilli in      the ―target‖ low Resistance)     Drug Interact:
                                            stationary phase;                                                        -Inhibits phenytoin &
                                                                                                                     warfarin metab
                                                                                                                     -MAO-I tyramine rxn
                            Rifampin        MOA: Inhibits RNA polymerase           -Broader spectrum;                -Hepatitis
                           (Rifabutin)      (by inhibiting rho factor)             -Rifabutin = DOC for TB           -Rash, n/v
                          (Rifapentine)     -Bactericidal against intracell &      infected HIV patients b/c less    -Induces many P450’s
                                            extracell mycobacterial strains        interaction w/ HAART drugs,       (elimination of steroid Oral
                                            (and other gram +/-)                   also better aginst MAC            contracept)
                                                                                   -Enhances effect of               -Red-orange metabolites
                                            -Rifapentine- longer half life,        amphotericin B in systemic        (desmethyl?) all biological
                                            permits weekly dosing;                 fungal infexn                     fluid turns red
                                                                                   -Tx of Brucellosis (Doxy +        -Flu-like syndrome
                                                                                   Rifampin)                         -Take baseline hepatic
                                                                                   *Resistance via change in         enzymes & CBC count
                                                                                   enzyme
                           Ethambutol       Inhibits synthesis of                  -Bacteriostatic, specific for TB  Dose-dep retrobulbar (optic)
                                                                                                                             66
                                           arabinogalactan (cell wall             and M. kansasii                      neuritis visual acuity and
                                           component)                                                                  red/green discrimination
                                                                                    -Restistance: mutation of emb      (Don’t give kids <5)
                                                                                    gene                               -Interferes w/ excretion of
                                                                                                                       uric acid
                                                                                                                       -Establish baseline visual
                                                                                                                       acuity and color vision
                         Streptomcin        -May be included as 2nd line, see       -One of the first drugs used to    Deafness, vestibular
                                            aminoglycosides                         tx TB,                             dysfunction, nephrotoxicity
                        Pyrazinamide        MOA: unknown, but metabolically         -Bactericidal to actively          Hepatitis, polyarthralgia,
                                            activated by bacteria (pncA             dividing TB                        myalgia, rash, hyperuricemia,
                                            gene) strains lacking the                                                 photosensitivity, porphyrin
                                            bioactivating enzyme are resistanc      Resistance  lack of pncA gene synthesis (porphyria)
                                                                                                                       -Take baseline hepatic
                                                                                                                       enzymes and uric acid
2nd line for TB   The 2nd line drugs are either less effective, more toxic, or have not been studied as extensively. They are useful in patients who
                  cannot tolerate the first line drugs or who are infected with mycobacteria that are reistant to the 1st line agents.
                         Capreomycin        Inhibits protein synthesis              -Reserved for tx of multidrug      -Nephrotoxicity
                                                                                    resistant TB                       -Ototoxicity
                         Ethionamide        Structural analog of Capreomycin,                                          -Gastric irritation
                                            but different MOA                                                          -Hepatotoxicity
                                            MOA: inhibits acetylation of                                               -Peripheral neuropathies
                                            isoniazid                                                                  -Optic neuritis
                                                                                                                       -Mental disturub, impotence
                         Cycloserine        Bacteriostatic, inhibits bacterial                                         -CNS disturbances
                                            cell wall synthesis involving D-                                           (psychosis)
                                            alanine (alanine racemase)                                                 -Peripheral neuropathy
                                                                                                                       CI: Epileptic patients
                         Para-Amino-        -Blocks dinhdropteroate                 -Alternative for ethabutol in      -Hypersensitivity rxns
                     Salicylic Acid (PAS) synthase)                                 kids < 5 yrs                       -Renal, thyroid, liver
                                            -Does not go into CNS                                                      dysfunctions
                        Ciprofloxacin       Fluoroquinolones                        Tx of multidrug resistant TB &
                          Ofloxacin                                                 some atypical strains
                         Sparfloxacin
                        Azithromycin        Macrolides, use doses                 -Azithgood prophylactic for
                       Clarithromycin                                               M. avium in AIDs
                                            Azithromycin – long ½ life (4 days)     -Part of the regimen that
                                            Clarithromycin – short ½ life           includes ethambutol and
                                                                                    rifabutin
                                                                                    -Tx of M. avium intracellulare
LEPROSY DRUGS     Mycobacterium leprae (leprosy) does not grow on artificial media (obligate intracellular). Droplets from sneezes and nasal
                  mucosa are heavily infected. M. Leprae shows a predilection for peripheral nerves, skin, and mucosa of upper respiratory tract,
                  and it appears to grow in cooler areas of the body. Severeity depends on host immunity. Primary resistance is due to acquiring
                  infection from patients harboring resistant organisms. Secondary resistance develops during treatment from noncompliant or
                  subtherapeutic dosing.
                  TUBERCULOUS LEPROSY: Rifampin + Dapsone (for 6 months)
                  LEPROMATOUS LEPROSY: Rifampin + Dapsone + clofazimine (for 12 months)
                           Dapsone          -Structurally & MOA like to             -DOC for leprosy (daspone +        -Hemolysis (esp in G6PD)
                                            sulfonamides & inhibits folate          rifampin)                          -Methemoglobinemia
                                            synthesis                               -Tx pnuemocystis jiroveci          -Peripheral neuropathy
                                            -Short acting                           pneumonia                          -Drug induced SLE
                                            -Bacteriostatic for M. leprae                                              -Lepra Rxn Erythemia
                                                                                                                       nodosum leprosum (like
                                                                                                                       Jarisch Herxheimer rxn)
                                                                                                                       tx w/ clofazimine
                         Acedapsone         Repository from of dapsone; longer
                                            duration
                         Clofazimine        -Structurally related to dapsone,       -Tx of dapsone-resist leprosy      -Eosinophilic enteritis, GI
                                            but no cross resistance                -Tx of Lepra Rxn                   irritation

                                                                                                                              67
                                                                                      -Tx of leprosy in those not        -Skin discoloration (red-
                                                                                      tolerating dapsone                 brown)
                             Amithiozone                                              -Alternative to dapsone
                                                                                      -Used in combination




                                 Disease Modifying Anti-Rheumatid Drugs (DMARD)
Rheumatoid arthritis appears to be an autoimmune disease driven primaryily by activated T cells (IL-1, TNF). NSAIDS offer mainly symptomatic
relief. They reduce inflammation and the pain it causes and often preserve function, but they have little effect on the progression of bone and
cartilage destruction. . The DMARDs have the potential to reduce or prevent joint damage, but the effects of therapy may take 6 weeks to 6 months
to become evident. You can start the patient on an NSAID in this window period. Combination therapy generally more effective: give weekly MTX and
add other agents (note: leflunomide + MTX increases the risk of hepatotoxicity, so monitor closely; Anakinra & TNF inhibitors increase the risk of
neutropenia and infections, so don’t use)
         Class                   Drug                          Mechanism                          Clincal Use                     Side Effects
                             Methotrexate        MOA: competitively inhibits AICAR       -DOC for Tx of RA               -Nausea
                                                 transformylase (the last step in de                                     -Mucosal ulcers
                                                 novo purine synthesisIMP), causes                                      -Hepatotoxicity (dose related)
                                                 AICAR levels which inhbits ADA                                         -Hypersensitivty (rare)
                                                 andd AMP deaminase (no degradation                                      -Pseudolymphomatous rxn
                                                 of AMPIMP). AMP is extracell                                           (rare)
                                                 converted to adenosine by the ecto-
                                                 5’nucleotidase                                                          Antidote = leucovorin
                                                 -Adenosine is a potent anti-                                            (toxicity)
                                                 inflammatory mediator (acts on A2b
                                                 receptors)suppresses NFkB
                                                 activation induced by TNF
                                   Gold          -IM formulations contain 50%            -Used infrequently b/c of
                            Aurothiomalate       elemental -gold; PO contain 29% gold    toxicity
                                  (IM)           MOA: gold salts taken up by
                            Aurothioglucose      macrophages and suppress
                                  (IM)           phaocytosis and lysosomal enzyme
                             Auranofin(PO)       activity
     CYTOTOXIC                 Chlorambucil      -Probably phenylacetic acid mustard
       AGENTS:                                   (a metabolite) cross links
   Alkylating agents                             DNApreventing cell replication
                           Cyclophosphamide      -Phosphoramide mustard cross links      -PO for tx of RA (not           -Infertility (dose limiting)
                                                 DNAprevents cell replication           effective IV)                   -BMS
                                                 -Suppresses T/B cell function by 30-    -Tx SLE                         -Hemorrhagic cystitis
                                                 40%
    Antimetabolites            Azathioprine      Purine antimetabolite 6-                                               -BMS
                                                 MPsuppresses B/T cell function                                         -GI disturbances
                                                 -Xanthine oxidase degrades it 6-                                       -infexns & malignancies
                                                 thiouric acid prior to excretion via                                    -Dose if given w/ allopurinol
                                                 urine
                               Leflunomide       -Undergoes rpaid conversion to active -Patients not responding to       -Diarrhea & elevation of liver
                                                 metabolite A77-1726inhibits            MTX, give MTX +                 enzymes
                                                 dihydroorotate dehydrogenase de       leflunomide
                                                 novo orate synth UMP p53
                                                 translocates to nucleus
                                                 -Lymphocytes arrested in G1 phase
                              Mycophenolate      See immunosuppress; IMP
                                 mofetil         dehydrogenase inhibitor (isoform 2,


                                                                                                                                  68
                                       the one expressed in lymphocytes)
 IMMUNOPHILIN         Cyclosporine     MOA: see immunosuppress; also
   LIGANDS                             increases expression of TGF-B, a
                                       potent inhibitor of IL-2 stimulated T
                                       cell proliferation and generation of
                                       CTL lymphs
 ANTIMALARIAL        Chloroquine       MOA: mechanism of anti-inflamm            -Often used as adjuvants to     -Irreversible retinal damage
    DRUGS          Hydrochloroquine    unclear                                   NSAIDs                          (never gonna see the malaria
                                                                                 -Often given to those who       comin’) less w/
                                                                                 have not responded              hydrochloroquine
                                                                                 optimally to salicylates and
                                                                                 NSAIDS
                     D-penicillamine   Analog of AA cysteine                     -Tx RA (after use of gold       -Dermatologic problems
                                       MOA: unknown                              salts has failed but before     -Nephritis
                                                                                 use of corticosteroids)         -Aplastic anemia
                      Sulfasalzine     drug 5-aminosalicylic (5-ASA) +          -Tx ulcerative colitis          -Rash
                                       sulfapyridine; metabolized by GI          -Tx RA (5-ASA)                  -Dizziness, n/v & h/a
                                       bacteria                                  -Tx juvenil arthritis           -Occasionally leukopenia
                                                                                 -TX ankylosing spondylitis
 ANTI-CYTOKINE        Adalimumab       Human IgG1 anti-TNF antibody
     DRUGS                             binds TNF-prevents interaction
                                       w/ p55 & p75 cell surface
                                       receptors downregulation of
                                       macrophage & T cell function
                       Infliximab      Chimeric monoclonal antibody that         -Tx RA, ankylosing              -B/c it is a chimeric therapy,
                                       binds w/ affinity/specificity to         spondylitis, Crohn’s disease,   can  formation of human
                                       TNF                                      psoriatic arthritis             antichimeric antibodies
                                       -Given IV                                                                 (HACA) give MTX to 
                                                                                                                 prevalence
                                                                                                                 -ANA antibodies & anti-double
                                                                                                                 stranded DNA found, but only
                                                                                                                 very rarely drug induce SLE
                       Etanercept      Recombinant fusion receptor; has two                                      -Injection site reactions
                                       soluble TNF p75 receptor moieties                                         erythema, local pain, swelling,
                                       linked to the Fc portion of human                                         itching (20-40% of patients)
                                       IgG1 binds TNF and also inhibits                                        -ANA antibodies & anti-double
                                       lymphotoxin-                                                             stranded DNA found, but not
                                       ―cept‖ = receptor analog                                                  documented SLE
ANTI-INTERLEUKIN        Anakinra       IL-1 receptor antagonist
      DRUGS
  INHIBITORS OF        Abatacept       -Fusion protein composed of an
 COSTIMULATION                         immunoglobulin fused to the extracell
                                       domain of CTLA-4 (can bind B7)
                                       -Inhibits activation of T-cells
                       Rituximab       -Chimeric monoclonal antibody             -Targets CD20 positive B
                                       -Anti-CD20                                lymphocytes
GLUCOCORTICOIDS                        -Inhibit phospholipase A2                 -Can slow down the              -Fractures, infections,
                                       -Also selectively inhibit expression of   appearance of new bone          cataracts
                                       COX-2                                     erosions                        -Diabetes, hypertension,
                                                                                 -Alleviate pain (intra-         accelerated atherosclerotic
                                                                                 articular glucocort)            heart disease




                                                                                                                          69
                                                 ANTI-DIABETIC DRUGS
     Class                 Drug                           Mechanism                         Clincal Use                     Side Effects
   INSULIN        Insulins may be in suspensions, the thicker the suspension (i.e more complexing agent), the slower the kinetic. Insulin will be
   ANALOGS        used to treat type 1 DM, life-threatening hyperkalemias, and stress induced hyperglycemia.
                          Lispro           Not suspension, IV solution
  Rapid Acting                             Onset: 0.3-0.5h
                                           Peak effect: 1-2h
                                           Duration: 3-4h
                          Aspart           Rapid & short acting
                           Glulisine

                     Regular Insulin       Not suspension, IV solution
  Short Acting      (Regular Humulin)      Onset: 0.5-1h
                                           Peak effect: 2-4h
                                           Duration: 5-7h
                                           Short acting, soluble, crystalline zinc insulin, usually given SC
                          Lente            Suspension (30% semilente, 70% ultralente), given only SC
 Intermediate                              Onset: 2-4h
    acting                                 Peak effect: 8-12h
                                           Duration: 18-24h
                    Semilente Insulin      Amorphous precipitate of insulin with zinc ion in acetate buffer;
                       suspension          not suitable for IV (only SC)
                   Neutral protamine       -Suspension of crystalline zinc insuoin combined at neutral pH
                    Hagedorn (NPH)         with protamine (positively charged polypeptide) (only given SC)
                  (AKA isophane insulin
                      suspension)
                       Ultralente          Suspension                                -Used to have a baseline
  Long Acting
                                           Onset: 3-4h                               insulin level in a diabetic
                                           Peak effect: 8-16h (LONG ACTING)          patient
                                           Duration: 18-24h
                          Glargine         LONG ACTING
                          Detemir          LONG ACTING
     ORAL         Tachyphylaxis is a term describing a rapid decrease in response to the drug after repeated doses over a short period of time.
SECRETOGOGUES     This may be due to change in drug metabolism, progression of B cell failure, change in dietary compliance, misdiagnosis of slow
                  onset type 1 DM. Most of these patients will eventually require insulin. Since some of these drugs are cleared by liver or
                  kidney, drug interactions will cause hypoglycemia. Cimetidine (inhibit p450) for the liver metab or acetylacetates (kidney).
                  Long term administration of oral secretogogues reduces serum glucagon levels, which may contribute to the hypoglycemic effect
                  of the drugs.
                     SULFONYLUREAS         MOA: Block (bind SUR1 subunit) the        -Used in Type 2             -Hypoglycemia
                                           ATP-dep K+ channels on B-cells (like      diabetics                   -Weight gain
                                           ATP)  insulin release, glucagon                                   -Hypersensitivity (possible cross-
                                           release, insulin receptor sensitivity                                allergy w/ sulfonamides
                                                                                                                 -Tachyphylaxis
                                                                                                                 Drug interactions:
                                                                                                                 -Mainly w/ first generation
                                                                                                                 drugs hypoglycemia w/
 1st generation                                                                                                  cimetidine insulin, salicylates,
 Sulfonylureas                                                                                                   sulfonamides
                       Tobutamide          -Short duration of action, rapidly        Appropriate in renal
                                           metabolized by the liver                  dysfunction
                                                                                     -Safest sulfonylurea
                                                                                     for use in elderly
                                                                                     diabetics
                       Chlorpropamide      Long acting, slowly metabolized by                                    -SIADH (drug potentiates action
                                           the liver                                                             of ADH)
                                                                                                                 -Transient hematologic toxicity
                                                                                                                 (leucopenia, thrombocytopenia)
                                                                                                                 -Disulfiram rxns

                                                                                                                                70
                                                                                                                       CI: elderly patients
                         Acetohexamide          Active metabolites, cleared by kidney
                                                dose in renal dysfunction
                      Second generation sulfonlyreas have increased potency by weight compared to the first generation. They have decreased side
  2nd generation      effects and are more expensive. They should be used with caution in patients with cardiovascular disease.
  Sulfonylureas              Glipizide          Shortest half life (2-4h), metaboliz        -Safe to use in elderly    CI: hepatic impairment & renal
                                                by liver                                    (little hypoglycemia)      insufficiency
                                                -Absoption delayed w/ food (take
                                                30min before breakfast)
                            Glyburide           Metabolized in liver, longer acting                                    -Causes hypoglycemia in 20-30%
                                                                                                                       CI: hepatic impairment & renal
                                                                                                                       insufficiency
                             Glimepiride        Long duration & most potent once                                      -Hypoglycemia in only 2-4%
                                                daily dosing & improves compliance;
                                                metabolized by liver
                                                -Sometimes called 3rd generation
                             Repaglinide        MOA: like sulfonlyureas, stimulate          -Postprandial glucose      -Do not use w/ sulfonlyureas
                                                insulin release by binding to SUR1 and      regulators (b/c so rapid) -No sulfur in the structure
Meglitinide analogs                             inhibiting ATP-dep K+ channel               -Used in Type 2
                                                PK: rapid onset (peak at 1hr), short        diabetics w/ sulfa         Drugs interactions:
                                                duration (5-8hr), metab by CYP3A4           allergy                    -Drugs that inhibit CYP3A4
                                                -Take just before each meal                                            enhance glucose lowering effect
                                                *Not as effective as sulfonlyureas in                                  -Drugs that induce CYP3A4 lower
                                                reducing FPG and HbA1c levels                                          effects
                            Nateglinide         -Newer drug, SAME as repaglinide            SAME                        SAME
                                                -Also partially restores initial insulin    -Safe in patients w/
                                                release in response to glucose (lost in     renal function
                                                type 2 DM                                   -In contrast to other
                                                -Cleared by CYP2C9 and 3A4                  oral secretogogues, dose
                                                -Duration is less than 4 hrs                titration not required
   INSULIN            Two classes of agents, the biguanides and thiazolidinediones, improve insulin action. These agents lower blood sugar by improving
 SENSITIZERS          target cell response to insulin (thus require insulin for action) without increasing pancreatic insulin secretion. These drugs are
                      euglycemic
    Biguanides               Metformin          MOA: Inhibits hepatic                       -Newly diagnosed Type      -Risk for hypoglycemia is very low
                                                gluconeogenesis hepatic glucose           2 DM (1st line)            -GI distress (anorexia, n/v/d)
                                                output; also slows intestinal abs of        -Tx of polycystic ovary    -Small risk of potentially fatal
                                                sugars & improves peripheral glucose        disease                    lactic acidosis (impairment of
                                                uptake & utilization                        -Decreases body weight     liver gluconeoblocks liver
                                                -NOT metabolized, excreted as an            -Only hypoglycemia         metabolism of lactic acid)
                                                active compound by kidneys                  agent shown to             -Absorption of B12 (long term
                                                -Hyperlipidemia (LDL & VLDL)               macrovascular events      use) annually screen B12 levels
                                                cholesterol &HDL, (plasma TAGs by in Type 2 DM
                                                15-20%)                                                                CI: Renal or hepatic disease,
                                                *Equivalent efficacy to sulfonylureas                                  alcoholism, acute MI, severe
                                                in FPG and HBA1c                                                      infection, or diabetic
                                                                                                                       ketoacidosis due to risk of
                                                                                                                       lactic acidosis
                      Thiazolidinediones have ―thio‖ in the name, noting that they have sulfur in their structure and may cause hypersensitivity. Since
Thiazolidinediones    another thiazolidinedione (troglitazone) was withdrawn from the market because of hepatic toxicity, liver function enzymes are
                      routinely monitored.
                           Pioglitazone         MOA: ligand of PPARy, a nuclear             Mortality &               -Hepatotoxicity (watch liver enz)
                                                receptor (promotes glucose                  macrovascular events       -Less hypoglycemia than
                                                uptake/use, modulates synthesis of                                     sulfonylureas
                                                lipid hormones or cytokines,                -Prevention of Type 2      -Weight gain
                                                adiponectin?, adiopcyte production        diabetes                   -Fluid retention (presents as mild
                                                & secretion of FA) insulin                                           anemia w/ peripheral edema)
                                                sensitivity/resistance in adipose
                                                tissue, liver, & skeletal muscle                                       Drug interactions: oral
                                                -Also has PPAR- effects                                               contraceptives

                                                                                                                                   71
                                               -Metabolized by 2C8 & 3A4 to active                                   -CI: pregnancy, heart failure, liver
                                               metabolites                                                           disease
                            Rosiglitazone      Ligand of PPARy, less TAG effects                                    Same, but no significant drug
                                               -Metabolized mainly by 2C8 and 2C9                                    interactions
                                               to active metabolites
-GLUCOSIDASE                 Acarbose         Competitive e inhibitors of the          Used as monotherapy in       -Gas, diarrhea, abdominal pain
  INHIBITOR                                    intestinal  glucosidases               type 2 DM or in              -Hypoglycemia if combined w/
                                               postprandial hyperglycemia              combinations                 sulphonureas must tx w/ glucose
                               Miglitol        Same effects, different structure,                                    (dextrose) NOT sucrose
                                               much more potent                                                      (breakdown blocked
                                                                                                                     CI: renal impairment or IBD
DPP-4 INHIBITOR              Sitagliptin       Inhibitor of dipeptidyl peptidase-4      -Potentiation of glucose
                                               (DPP-4), the enzyme that degrades        mediated insulin
                                               GLP-1 and other GLP-1-like               secretion, suppression
                                                                                        of postprandial glucagon
  INCRETIN                   Exenatide         Synthetic analog of GLP-1                                             N/V/D
   ANALOG
AMYLIN ANALOG                Pramlintide       Amyli is a small polypeptide released by the -cells of pancreas at
                                               the same time as insulin. Amylin is also deficient in diabetics. It
                                               slows gastric emptying and promotes satiety glucose in
                                               blood. It is used as an ajunct in both type 1 & 2 DM




                                                HYPOTHALAMIC & PITUITARY
Drugs that mimic or block the effects of hypothalamic and pituitary hormones have three primary applications:
    1. Replacement therapy for hormone deficiency states
    2. Antagonists for diseases that result from excess production of pituitary hormones
    3. Diagnostic tools for identifying endocrine abnormalities
       Class                   Drug                     Mechanism                            Clincal Use                         Side Effects
    GROWTH             GH (somatotropin) secretion varies throughout life. Secretion is high in childhood, reaches maximum levels during adolexcence &
 HORMONE (GH)          decreases as the age advances. Amplitude of GH secretory pulses is maximal at night, shortly after the onset of deep sleep. GH
                       release is stimulated by 5HT, clonidine, & HYPOGLYCEMIA. GH release is suppressed by IGF-1, free fatty acids, &
                       hyperglycemia
                           Somatropin         Recombinant human GH             -Tx of GH-dep growth retardation        KIDS:
                            Somatrem          (rhGH)                           (symmetrical pituitary dwarfism)        -Intracranial hypertension
                                              PK: given SC or IM 3X/week,      -Improves muscle or bone strength       (rare)
                                              onset=2-4h, duration =36h        -Tx AIDs associated wasting             -Scoliosis from rapid growth
                                                                               syndrome                                -Hypothyroidism
                                                                               -Tx of growth failure in Prader Willi   ADULTS:
                                                                               Syndrome                                -Tend to have more AE
                                                                               -Tx of Turner syndrome (increase        -Peripheral edema, myalgias,
                                                                               height)                                 arthralgias (esp hands/wrist)
                                                                                                                       CI: patients w/ malignancies
                           Mecasermin         Recombinant IGF-1 (& IGF         -Tx of GH insensitivity (Laron          -Hypoglycemia (eat a snack
                                              binding protein-3)               dwarfism)                               20min before or after drug)
                                                                               -GH deficiency & anti-GH antibodies
GH ANTAGONIST               Octreotide        Somatostatin analog (45X         -Tx small GH-secreting ademonas         Very $$$
                            Lanreotide        more potent in inhibiting GH,    (whichgigantism/acromegally)           -Gall stones & pancreatitis w/
                                              2X potent in inhibiting insulin  -Tx many hormone secreting              long term use
                                              secretion) reduces GH           tumors (e.g. Carcinoid syndrome,        -n/v/d, abdominal cramps,
                                              product                          gastrinoma, glucagonoma)                flatulence, steatorrhea
                                              -Long duration
                          Bromocriptine       Dopamine receptor agonist        Tx acromegally
                                              reduces GH production

                                                                                                                                   72
                          Pegvisomant        Prevents GH from activating       Tx acromegally
                                             its receptor
      GHRH                 Sermorelin        GHRH analog                        -Used to test for GH secretion
                                                                                -Stimulate GH (for short people)
GONADOTROPINS are used to induce ovulation in women with anovulation due to hypogonadotropic hypogonadism, polycystic ovarian syndrome,
obesity, & other causes. Because of the high cost of gonadotropins and the need for close monitoring during their administration, gonadotropins are
generally reserved for anovulatory women who fail to respond to other less complicated forms of treatment (e.g. clomiphene, AI, metformin). The two
most serious complications in women treated with gonadotropins and hCG are the ovarian hyperstimulation syndrome (0.5% of pateints ovarian
enlargement, ascites, hydrothorax, hypovolemia, sometimes shock) and multiple pregnancies (risk at 15-20%).
                       Menotropins (hMG) Extracted from the urine of            -Used in hypogonadal states of men
                                               postmenopausal women (FSH-       & women
                                               like and LH-like & hCG?)
        FSH                Urofolitropin       Purified preparation of human    -Stimulates gametogenesis & follicle
                              (uFSH)           FSH extraceted from the          development in women &
                                               urine of post-menopuasal         spermatogenesis in men
                                               women                            -Tx infertility
                                                                                -Tx hypogonadotropic hypogonadism
                                                                                & associated oligospermia
                          Folitropin alfa      Recombinant forms of FSH
                          Folitropin beta      (rFSH), shorter half life than
                                               ones from urine
         LH            LH is a major stimulant of gonadal steroid production. It regulates follicular development and ovulation. No pure preparation of
                       LH is available for use. Drugs may produce ovarian hyperstimulation or familial ovarian hyperstimulation, causing multiple
                       pregnancies (Rx. Ganirelix)
                             Lutropin          Recombinant hman LH (rLH),       -Stimulates follicular development in
                                               given SC, half life of 10h       infertile women w/ profound LH def
                                                                                (Lutropin + Folitropin alfa)
                                hCG            -Purified hCG from the urine     -Used in infertility
                                               -LH agonist
                       Choriogonadotropin      Recombinant hCG (rhCG)
                                alfa
       GnRH                 Leuprolide         -Given in pulsatile doses,       Long acting agonists                    -Gonadotroph suppression
                             Histrelin         resembling physiological         -Tx prostate cancer                     does not occur immediately
                                               cycling                          -Endometriosis (tx up to 6mo)           (transient flare up initially)
                                               -Continuous dosing would LH     -Precocious puberty                     -Less likely than gonadotropins
                                               & FSH                           -Uterine leiomyoma (tx 3-6mo)           to cause multiple pregnancies
                                               -First 7-10 days causes ―flare‖                                          & ovarian hyperstimulation
                                               & afterwards suppresses          Pulsatile:                              syndrome
                                               PK: injected once daily          -Amenorrhea, infertility
                             Goserelin         PK: depot injection 1x/mo        -Cryptorchism
                           Nafarelin         PK: Nasal spray, longer lasting
     GnRH                   Ganirelix        When gonadotropins are used       -Used in controlled ovarian             -These produce an immediate
  ANTAGONIST               Cetrorelix        to stimulate follicle develop    hyperstimulation until the              effect (as opposed to GnRH
                                             risk of premature endogenous      apprapriate follicular maturation has   agonists), so don’t need to use
                                             surge in LH b/c of rapidly        occurred, then drug discontinued        until day 6-7 of cycle
                                             changing hormones the LH                                                 -Lower risk of ovarian
                                             surge could prematurely                                                   hyperstimulation syndrome
                                             stimulate ovulation                                                       -Adherence is critical b/c
                                                                                                                       effects reverse very quickly
                          Abarelix                                             Palliative prostate cancer
   PROLACTIN        Prolactin is responsible for lactation (milk production). Hyperprolactinemia inhibits GnRH release causing hypogonadism and
                    infertility. Also seen with high prolactin levels are amenorrhea, galactorrhea in women, & loss of libido & infertility in men.
                          Prolactin                                            -No therapeutic value
   PROLACTIN           Bromocriptine        Dopamine agonist, affinity        -Suppresses prolactin release           -Light headedness, h/a, nausea
  ANTAGONIST             Cabergoline        for D2 receptor                    -Shrink pituitary prolactin secretg     -Orthostatic hypotension
                          Pergolide         -Bromocriptine ½ life = 7h         tumors & restore ovulation in many      -Fatigue
                                            -Pergolide ½ life = 20h            -Acromegally                            -Psychiatric manifestations
                                            -Cabergoline ½ life = 65h                                                  -Erythromelalgia (rare)
CORTISOL is bound to plasma Corticosteroid binding globulin (CBG), an 2 globulin synthesized by the liver that binds about 90% of the circulating

                                                                                                                                  73
hormone. The remainder is free (5-10%) or loosely bound to albumin (5%). CBG is in pregnancy due to estrogen and hypothyroidism
       CRH                   CRH            CRH stimulates the release of     -CRH can be used in the diagnosis of
                                            ACTH from the anterior pituit ACTH secretion by pituitary
                                                                              adenoma, adrenal & ectopic tumors
      ACTH                  ACTH                                              -Only used in diagnostic purposes in
                                                                              adrenal insufficiency
                          Cosyntropin       Synthetic analog of ACTH          -DOC in infantile spasms
                       Tetracosactide

Signs of hyperthyroidism: 1) Marie’s sign- tremors of the body or extremity seen especially in outstretched hands, 2) Dalrymaple sign– staring look, 3)
Ballet sign– loss of voluntary movements of the eye, 4) Stellwag’s sign– infrequent blinking.

Steps in synthesis of THYROID hormones:
    1. TSH stimulates the thyroid to uptake Iodide (I-) via the sodium/iodide symporter (NIS). This can be inhibited by thiocyanate (SCN-),
          pertechnetate and perchlorate & radioactive iodide.
    2. Oxidation to iodine (I2) by thyroid peroxidase at the apical membrane. Thyroidal peroxidase is transiently blocked by high levels of
          intrathyroidal iodide and blocked more persistently by thioamide drugs
    3. Then tyrosine residues on the thyroglobulin molecule are rapidly iodinated to form MIT & DIT in a process called iodide organification (occurs
          in the colloid)…blocked by thioamide drugs
    4. Condensation of two DITs produces T4 (still attached to thyroglobulin)…blocked by thioamide drugs.
    5. Thyroglobulin is endocytosed back into the cell
    6. T3 & T4 are cleaved from thyroglobulin via the lysosome and secreted into the plasma. Inhibited by Ipodate
    7. Peripheral deiodination of T4 produces T3. Deiodination may occur in the inner ring, producing rT3, which is metabolically inactive.
          Amiodarone, iodinated contrast media, B-blockers, corticosteroids, severe illness, or starvation inhibit the 5’ deiodinase necessary for
          the conversion of T4 to T3, resulting in low T3 and high rT3 in the serum.

Goitrogenic: cabbage (contain thiocyanate), sulfodimethoxine, & cassave (contains carbohydrates and thiocyanate)

Severeal drugs may provoke autoimmune or destructive inflammatory thyroiditis hypothyroidism:
    1. Amiodarone, structurally similar to thyroid hormone
    2. Lithium, increased levels in thyroid gland inhibit release of hormones
    3. Interferon Alfa & interleukin-2
       TRH                 Protirelin         -TRH stimulates TSH and         -Test the anterior pituitary’s
                                              prolactin secretion             ability to secrete TSH
    THYROID                T3 & T4            T3 is fast acting, has short    -Tx Myxedema                          -T4 sensitizes myocardium to the
   HORMONES                                   half life and more $$$                                                effects of sympathetics
                                                                                                                    Arrhythmias
                                                                                                                    -Thyrotoxicosis
                                                                                                                    -Osteoporosis?
                                                                                                                    -Borderline adrenal insuff
                                                                                                                    patient adrenal insufficiency
  THIOAMIDES              Methimazole        -Block thyroid peroxidase        -Tx of thyrotoxicosis                 -Nausea, GI distress
                                             -Block iodination of tyrosine    (preferred drug b/c less serious      -Altered sense of taste or smell
                                             residue on TG                    SE)                                   (only methim)
                                             -Block coupling rxns                                                   -Maculopapular pruritic rash
                                             -Methimazole does not            *Note, since the synthesis rather     -Arthralgia
                                             inhibit conversion from T4 to    than the release of hormones is       Rare:
                                             T3 (& antagonizes PTU)           affected, the onset of these          -Agranulocytosis
                                             -Methimazole is 10X as           agents is slow, often requiring 3-4   -Hepatotoxicity
                                             potent as PTU                    weeks before stores of T4 are         -Vasculitis (manifests as lupus)
                                             PK: given 1x/day, PO             depleted.
                                                                                                                    -Cross placental barrier and are
                                                                                                                    concentrated by the fetal thyroid
                                                                                                                    (Category D in preg risk of fetal
                                                                                                                    hypothyroidism
                         Propylthiouracil    Same, but also blocks            -Tx of thyrotoxicosis                 -Same AE as Meth, but is more
                                             5’deiodinase in peripheral       -Preferable in pregnancy              highly protein boundless cross
                                             tissue                           -Preferred in thyroid storm due       placenta, so preferable in
                                             PK: given 3x/day, PO             to ability to block T4 to T3          pregnancy

                                                                                                                                  74
                                                                                                                -More serous AE
                                                                                                                -Hypoprothrombinemia
    IODIDES          Wolff-Chaikoff effect - large doses of iodides initially causes hypothyroidism for 10-14 days, but they the effect ―escapes‖
                     and thyroid hormone production resumes.
                     Iodine/Iodide salts -Inhibit organification            -Used prior to introduction of      -Jodbase-dow phenomenon
                                          -Block hormone release            thioamides in 1940’s, now rarely    (hyperthyroidism in susceptible
                                          -The size & vascularity of       used as sole therapy                people)
                                          the hyperplastic gland            -Improvement in thyrotoxic in 2-    -Intraglandular stores of iodine
                                                                            7d (valuable in thyroid storm)      (may delay onset of thioamide tx or
                                          *Do NOT use alone b/c gland       - Useful in preoperative prep       prevent use of radioactive iodine)
                                          will escape from iodide block     -Thyrotoxic crisis (Iodides +       -Avoid chronic use in preg (fetal
                                          in 2-8 wksmay exacerbate         PTU + B-blockers)                   goiter)
                                          thyrotoxicosis                                                        -Iodide intoxication (iodism)
                                                                                                                -Anaphylactoid rxn (angioedem)
                                                                                                                -Brassy taste, burning of
                       Lugols solution    A mixture of iodine &                                                 teeth/gums
                                          potassium iodide                                                      -Enlargement of parotid and
                     Saturated solution   Potassium iodide                                                      maxillary glands
    ANION              K+ Perchlorate      Competitive block of iodide     -Patients w/ iodide induced          Aplastic anemia
  INHIBITORS           Pertechnetate       uptake                          hyperthyroidism
                        Thiocyanate        *Effects can be overcome by     *Rarely used today b/c of SE
                                           large doses of iodides, so
                                           effectiveness is somewhat
                                           unpredictable
Iodinated Contrast       Diatrizoate       MOA: Rapidly inhibit            -Tx of hyperthyroidism (offlabel     Relatively nontoxic
      Media                                converstion of T4T3            use)
                                           PK: PO

                          Ipodate          MOA: same, may also inhibit
                                           hormone release from
                                           thyroid gland
                           Iohexol         MOA: same                       same
                                           PK: PO, IV
 RADIOACTIVE             131-Iodine        Emits  rays that destroy       -Only isotope used in Tx of          No risk of cancer
   IODINE                                  thyroid after a few weeks       thyrotoxicosis                       NO pain
                                                                           -Tx of refractory Grave’s disease    Hypothyroidism
                                                                                                                CI: pregnancy, nursing
   B-Blockers              Esmolol         Improve symptoms, but do        -Tx tachycardia, tremors,
                                           not alter thyroid hormone       sweating from thyrotoxicosis
                                           levels
  ANDROGENS
                        Oxandrolone        Synthetic androgens             -Replacement therapy in              -Over-masculinization
                         Stanozolol                                        hypogonadism, osteoporosis, and      -Hirsutism (in women)
                      Fluoxymesterone                                      could be used in growth              -Depression of menses
                       Oxymetholone                                        stimulation (muscle mass, RBC)     -Acne
                         Nandrolone                                                                             -Clitoral enlargment
                       Phenpropionate                                                                           -Rarely causes hepatic adenomas
                                                                                                                and carcinomas
                                                                                                                -Cholestatic jaundice & prostatic
                                                                                                                hypertrophy
                                                                                                                -Premature closure of epiphysis
                                                                                                                -May lead to dependence
                                                                                                                CI: pregnancy
  ANDROGEN               Leuprolide        GnRH analog @ continuous        -Tx of prostatic cancer
 ANTAGONIST              Gonadorelin       dose
                          Flutamide        Receptor inhibitors             -Tx of hirsuitism (cypro or
                        Cyproterone                                        spironolac)
                       Spironolactone
                        Ketoconazole       Steroid synthesis inhibitors    -Tx of Cushing’s disease

                                                                                                                              75
                 Metyrapone           Synthesis inhibitor (blocks
                                      11-hydroxylation)
                   Finasteride        5- reductase inhibitor        -Tx of benign prostatic
                                      reduces production of DHT       hyperplasia
                  Mifepristone        Blocks Glucocorticoid &         -Abortion
                                      progestin receptors
ESTROGENS     Estradiol is the major natural estrogen. Conjugated equine estrogen is purified from pregnant mare’s urine. The most common
              synthetic froms are ethinyl estradiol and mestranol. Diethylstilbestrol is a nonsteroidal estrogen.
              ESTROGEN                  Regulates growth &           -Tx of hypogonadism in girls          -Hypertension
                                          maturation of reprod        -Oral Contraceptive Pills (+          -Thromboembolism
                                          tract                       Progestins)                           -Hepatic adenoma
                                        Stimulates endomet           -Postmenopausal HRT                   -Breast & endometrial cancer
                                          growth                      -Tx prostate cancer, acne,            -Procoagulant (ATIII, & @
                                        Bone resorption &           dysmenorrheal, DUB                    dosesfactors II, VII, IX, X)
                                          maintain normal structure                                         -Endometrial hyperplasia, breast
                                          of the skin & blood                                               tenderness, migraine,
                                          vessels                                                           cholestastasis
                                        Thyroxin binding globulin                                         CI: Hx of thromboembol,
                                        HDL and TAG levels                                                Pregnancy, Liver disease, Breast
                                        LDL levels                                                        cancer
                                        Promotes coagulation
                    Estradiol
                   Conjugated
                    estrogen
               Ethinyl estradiol
                   Quinestrol
                   Clomiphene         -Estrogen antagonist                                                  Multiple births, ovarian
                                      (hypothal & anterior pit)                                             enlargment, hot flashes, visual
                                      -Estrogen Agonist (ovary)                                             disturbances
 PROGESTIN    Progestin is normally not used, only the synthetic compounds. Progesterone is a progestin, but also androgenic and
              antiestrogenic.
              Medroxyprogestero
                   ne acetate
                Norethindrone
                Norethindrone
                     acetate
                  Desogestrel                                                                               -NO androgenic effects
                                                                                                            -NO anti-estrogenic effects
 PROGESTIN        Mifepristone
 INHIBITOR          (RU 486)
    Other            Danazol          Partial agonist at              -Used to tx endometriosis (anti-      -Weight gain
                                      progesterone, glucocorticoid    proliferative effect by negative      -Edema
                                      and androgen receptors          feedback)                             -Acne
                                                                                                            -HDL levels
                    Oxytocin          Synthesized in                 1. A uterine stimulant, used to        -Hypertensive epidosdes (b/c of
                     (Pitocin)        paraventricular nuclei of the     induce or enhance labor             contraction of blood vessels)
                  (Syntocinon)        hypothalamus                   2. Contracts myoepithelial cells of    -Uterine rupture
                                                                        breast & cuase milk letdown
                                                                     3. Can control postpartal and
                                                                        postabortal bleeding
ADH ANALOGS   ADH is Synthesized in the supraoptic nuclei of the hypothalamus. Adverse effects generally include: hypertension, headache,
              abdominal cramps, and nausea. Too much ADH think SIADH  hyponatremia, dizziness, volume contraction
              ADH Receptors:
                1. V1 in the arterioles vasoconstriction
                2. V2 insertion of aquaporin channels in kidney
                 Desmopressin         -Synthetic, long acting ADH     -Tx diabetes insipidus from           No effect on V1, so will not
                                      analog at V2 only, not V1       surgery or trauma or cranial          affect blood pressure (no
                                      -Nasal spray                    radiotherapy for lymphocytic          hypertension)
                                                                      leukemia
                                                                                                                        76
                           Vasopressin        Boosts factor VIII               -Used in mild to moderate
                                                                               hemophilia
                                                                               -Used in bleeding from varices,
                                                                               prior to definitive tx of portal
                                                                               hypertension
        PTH               Teriparatide        PTH analog, use once daily       -Promotes osteoblastic activity
                                              -Continuous PTH promotes         new bone formation
                                              osteoclastic activity

   Calcium Salts           Ca chloride        IV preparations                  -Used in severe cases of               -Peripheral vasodilation
                          Ca gluconate                                         hypocalcemia                           -Transient tingling
                                                                                                                      -Cardiac arrhythmias (if rapid
                                                                                                                      infusion)
                          Ca carbonate        Oral preparations                -Preventive measures against
                           Ca citrate                                          osteoporosis
                         Ca phosphate                                          -Tx mild cases of hypocalcemia
                           Ca Lactate
     Vitamin D              Calcitriol        Active form of Vit D             Used in:                               -Vascular calcification
                         Cholecalciferol      Vitamin D3                       -Osteoporosis                          -Nephrocalcinosis
                         Ergocalciferol       Vitamin D2                       -Chronic renal failure                 -Soft tissue calcification
                           Calcifediol        25-(OH) Vit D                    -Nutritional rickets                   -HYPERCALCEMIA (typically
                                                                                                                      asymptomatic)
 Bisphosphonates       Etidronate (IV, PO)    Inhibit osteoclastic activity    -Tx malignancy associated              -Erosive esophagitis (alendronate)
                        Pamidronate (IV)      by disrupting mevalonate         hypercalcemia                          -GI distress (gas)
                           Alendronate        pathway ( osteoclast H+         -Tx paget’s disease of bone
                                              ATPase)                          -Tx osteoporosis (esp                  -Osteomalacia if taken > 12 mo
                            ―-dronate‖        -Reduce resorption and helps     corticosteroid induced)                (etidronate & pamidronate)
                                              formation of hydroxyapatite
                                              -Structural analog of
                                              pyrophosphate                                                           Patient should stand for 30 min
                                              -Very poorly absorbed (<1%)                                             afterwards (reflux = caustic to
                                              after oral administration, so                                           esophagus)
                                              must be given in fasting
                                              state with




                                                         ANTICONVULSANTS
        Class                    Drug                           Mechanism                             Clincal Use                     Side Effects
Very rarely there is a single drug of choice. More likely, the drug will be chosen based on the side effects. Generally, anticonvulsants are additive with
other CNS depressants. You should avoid abrupt withdrawal, which may precipitate seizures. There is decreased efficacy of oral contraceptives via
induction of cytochrome P450. Note, a person with seizures may want to avoid pregnancy since many of the drugs cannot be taken, but remind patients
that oral contraceptives are metabolized quicker potentially causing an unwanted pregnancy. Phenobarbital is considered safest during pregnancy.
  The mechanisms of action:
     1. Decrease axonal conduction by preventing Na influx through fast Na channels (blocks the propagation of seizures, does not prevent)
     2. Increasing inhibitory tone by facilitation of GABA-mediated hyperpolarization
     3. Decrease the excitatory effects of glutamate
     4. Decrease the presynaptic Ca influx through type T channels in the thalamic neurons
   Na CHANNEL                 Phenytoin          Blocks axonal Na channels in their        -Blocks the propagation of -Induction of CYP 450
    BLOCKERS                                     inactivated state                         seizures                      -CNS depression
                                                 -Non-linear kinetics ([blood] faster     -Tx of any seizure except     -Gingival hyperplasia
                                                 than expected)                            absence seizures              (…remember dihydropyridines)
                                                 -Zero order elimination kinetics                                        -Hirsutism
                                                                                                                         -Osteomalacia (Vit D)
                                                                                                                         -Megaloblastic anemia (folate)
                                                                                                                         -Aplastic anemia (check CBCs)
                                                                                                                                    77
                                                                                                      -Teratogenic (cleft lip/palate)
              Carbamazepine        Same as phenytoin                       Same                       -CNS depression
                                   -Induces its own metabolism             -DOC for trigeminal        -Exfoliative dermatitis (SJS)
                                                                           neuralgia                  -Osteomalacia (Vit D)
                                                                                                      -ADH secretion
                                                                                                      -Megaloblastic andemia (folate)
                                                                                                      -Aplastic anemia (check CBCs)
                                                                                                      -Teratogenic (cleft lip/palate/
                                                                                                      spina bifida)
                Lamotrigine        -Block Na channels                      Newer, used in seizure     -SJS rashes
                                   -Block glutamate receptor (AMPA)        states
                Felbamate          -Block Na channels                      same                       -Hepatotoxicity
                                   -Block glutamate receptor (NMDA)                                   -Aplastic anemia
                Zonisamide         Same as phenytoin
T-Type Ca      Ethosuximide        Blocks T-type Ca channels mainly in     DOC for Absence            Blood toxicities
CHANNEL                            thalamus                                seizures
BLOCKERS        Valproate          -Like phenytoin (block Na channel)      -Any seizure state (even   -Inhibits CYP 450
                                   -Inhibits GABA transaminase (blocks     absence seizure)           -Hepatotoxicity
                                   degradation of GABA GABA)             -Tx of mania in bipolar    -Thrombocytopenia
                                   -Block T-Type Ca Channels (thalamus)    -Tx of migraines           -Pancreatitis (rare)
                                                                                                      -Alopecia
                                                                                                      -Teratogenic (spina bifida)
GABAergic     Benzodiazepines      Act POSTsynaptically
               Barbiturates
                Topiramate
                 Tiagabine         Act PREsynaptically, inhibit
                                   reuptake of GABA
                Viagabatrin        Act PREsynaptically, inhibit
                                   degradation of GABA (inhibits
                                   GABA aminotransferase)
                Gabapentin         GABA effects
                 Pregabalin
 INHIBIT       Phenobarbital       Act POSTsynaptically Block
GLUTAMATE       Topiramate         glutamate receptors (and also help
                                   GABA)
                Gabapentin         Glutamate release by blocking          -Tx neruopathic pain
                Pregabalin         PREsynaptic voltage gated Ca
                                   channels (also GABA, but not major
                                   mechanism)




                                SEIZURE                               DOC
                                Partial seizure (simple or complex)   Valproate, phenytoin,
                                                                      carbamazepine
                                General-tonic clonic                  Valproate, phenytoin,
                                                                      carbamazepine
                                General- Absence                      Ethosuximide
                                Status epilepticus                    Lorazepam (IV), diazepam,
                                                                      phenytoin, or fosphenytoin




   NEUROTRANSMITTER    RECEPTOR       EFFECT                                            AGONIST         ANTAGONIST
   GABA                GABA-A         INHIBITORY: When two molecules of GABA            Muscimol        Picrotoxin

                                                                                                                  78
                                                  bind receptor, the ion gate is opened and influx                     Bucuculline
                                                  of Cl. Found throughout CNS, generates fast
                                                  IPSP
                                   GABA-B         INHIBITORY: GABA binds receptor and elicits
                                                  action through AC pathway (cAMP levels +
                                                  opens a K+ channel so that K+ flows out of the
                                                  cell hyperpolarization + closes Ca channel) 
                                                  slow IPSP
        Glutamate                  NMDA           STIMULATORY: When Glutamate + glycine                                Amantadine
                                                  (cofactor) bind NMDA receptor, the ion gate                          Memantine
                                                  opens with influx of Na and Ca and efflux of K.                      Ketamine
                                                  Stimulatory. A voltage dependent membrane                            PCP
                                                  depolarization is also required to open the gate                     Dizocilpine
                                                  b/c NMDA is plugged by extracellular Mg.
                                   AMPA           STIMULATORY: When Glutamate bind AMPA
                                                  receptor, the ion gate opens with influx of Na
                                                  and Ca and efflux of K. May play a role in
                                                  excitotoxicity in neuronal cell death
        Glycine                    Glycine        INHIBITORY: Glycine binds receptors found in
                                   Receptors      spinal cord causing ion channel to open and influx
                                                  of Cl
        Dopamine                   D1             STIMULATORY: dopamine binds D1 receptor             Pergolide
                                                  activates AC pathway (cAMP) and PLc pathway
                                                  (IP3 + DAG). Found in the CNS
                                   D2             INHIBITORY: dopamine binds D2 receptor              Bromocriptine
                                                  AC pathway (cAMP + opens K channel so efflux        Pergolide
                                                  of K)  hyperpolarization                            Pramipexole
                                                                                                       Ropinirole
        Histamine                  H1             PLC pathway
                                   H2             AC pathway                                                           Diphenhydramine
                                                                                                                       Cimetidine




                                                     GENERAL ANESTHETICS
The stages of anesthesia (1-4):
    1. Stage of analgesia: The patient initially experiences analgesia without amnesia. Later in Stage I, both analgesia and amnesia are produced
    2. Stage of excitement: During this stage, the patient often appears to be delirious and may vocalize but is definitely amnesic. Respiration is
         irregular both in volume and rate, and retching and vomiting may occur if the patient is stimulated. For these reasons, efforts mre made to
         limit the duration and severity of this stage, which ends with the reestablishment of regular breathing.
    3. Stage of surgical anesthesia: This stage begins with the recurrence of regular respiration and extends to complete cessation of
         spontaneous respiration (apnea). The most reliable indication that stage III has been achieved is loss of responsiveness to noxious stimuli
         and reestablishment of a regular respiratory pattern.
    4. Stage of medullary depression: This deep stage of anesthesia includes severe depression of the vasomotor center in the medulla, as well as
         the respiratory center. Without circulatory and respiratory support, death rapidly ensues.

     Class                    Drug                       Mechanism                         Clincal Use                       Side Effects
IV ANESTHETICS        Many IV drugs have an onset of anesthetic action faster than the most rapid inhaled agents (desflurane, sevoflurane).
                      Adjunctive use of potent opiods (fentanyl) contributes cardiovascular stability, enhanced sedation, and profound perioperative
                      analgesia. Benzodiazepines have a slower onset and slower recovery than the barbiturates or propofol and are rarely used for
                      induction of anesthesia. However, preanesthetic administration of benzodiazepines can be used to provide anxiolysis, sedation,
                      and amnesia when used in conjunction with other anesthetic agents
    Hypnotics               Propofol       Short acting hypnotic                   -Induction &                  -Patients feel better in the
                           (Diprivan)      -Alkylphenol/10% lipid (made from       mantainance anesthesia        immediate post-op b/c post-op n/v
                       ‖milk of amnesia‖   soy/egg)                                (most popular)                -Cardiovas/resp depression

                                                                                                                                 79
                                       MOA: GABA & NMDA                        -DOC for ambulatory          -Hypertriglyceridemia
                                                                               surgery                      -Severe acidosis in kids w/
                                        PK: half life = 15-20min; rapid        -Given w/ adjuvant           respiratory infection
                                        hepatic clearance (10x faster than     antimicrobials (infections   Drug of abuse
                                        thiopental)                            from bacterial               -Burning at injection site (90%) b/c
                                        Blood pressure during induction      contamination of             drug is a direct irritant to blood
                                        through peripheral arterial           emulsion)                    vessel (pain if lipids in emulsion)
                                        resistance                             -Antiemetic                  Cerebral metabolic rate
                                                                                                            Cerebral blood flow,  ICP
                      Etomidate         -Short acting hypnotic                  Cardiovascular stability    -Less Cardiovas/resp depression
                                        -Imidazole (only dextro isomer w/                                   (NO histamine release)
                                        anesthetic properties)                                              -Burning at injection site
                                        MOA: GABA?                                                          -Cerebral metab rate
                                        Half life = 3-6 min; hepatic                                        -Cerebral blood flow
                                        clearance                                                           -ICP
                                                                                                            -Myoclonic jerks
                                                                                                            -Inhibition of adrenocortical
                                                                                                            synthesis (8-24h)
                                                                                                            -Proemetic
                       Ketamine         -Moderately rapid action hypnotic       -Bronchodilator             -Oral secretions
                     (―Special K‖)      -Dissociative anesthetic                -Good in elderly w/ CV      -Night terrors
                                        -Acrylcyclohexilamine (PCP-like, S-     disase                      -CVS stable (slight stimulant), slight
                                        isomer >>>> R)                          -Induction                  BP
                                        MOA: NMDA                                                           -ICP, cerebral blood flow,
                                        PK: Half life = 5 min; liver clearance                              cerebral metabolic rate
                                        (hepatic active metabolite 30%-                                     -Seizure activation
                                        norketamine)                                                        -Emergent delirium, hallucinations
                                                                                                            (emergent rxns impair recovery)
                                                                                                            CI: intracranial surgery
  Barbiturate     Barbiturates reduce hepatic blood flow and glomerular filtration rate, but these drugs produce no adverse effects on hepatic or
                  renal function. Barbiturates can exacerbate acute intermittent porphyria by inducing the production of hepatic ALA synthase.
                      Thiopental        -Moderate duration thiobarbituarte      -Tx seizure                 -People complain of ―hangover‖
                                        -Rapid onset and rapid recovery         -Given when operating on    -Cardiovas/resp depression
                                        (bolus dose); slow recovery following   aortic arch to lower        -Cerebral metab rate (55% w/
                                        infusion                                cerebral meatab rate        isoelectric EEG)
                                        -Rapidly diffuses out of brain & is     while blood flow is         -Bronchoconstriction (histamine)
                                        redistributed to muscle/fat             stopped                     -Precipitation & porphyria
                                        MOA: GABA agonist                       -Standard induction
                                        Half life = 11min; hepatic clearance,   agent                       CI: porphyrias
                                        long elmination time                    -Used on patients w/
                                        -30% dose in elderly                   cerebral swelling (b/c no
                                                                                ICP from drug)
                    Methohexital        Short duration oxybarbiturate           -Used for ECT sedation      -Mild cardiovas/resp depression
                                        MOA: GABA                               (poor antiseizure med)      -Can Cerebral metab rate (55%
                                        PK: half life = 4 min, hepatic          -Neurosurg ablation of      w/ isoelectric EEGbut doesn’t
                                        clearance (faster than thiopental)      sezure foci (b/c drug can   change the seizure threshold)
                                                                                cause central excitatory    -Hiccoughing
                                                                                activity)                   Non-malignant hypertherm trigger
    Opiods             Fentanyl                                                 -Analgesia                  -Significant depression of
                   Hydromorphone                                                -Blunt sympathetics         hypercarbic respiratory drive
                  Benzodiazepines are primarily used as premediation before anesthesia b/c of sedative, anxiolytic, amnestic properties.
Benzodiazepines   Compared with the IV barbiturates, benzodiazepines produce a slower onset of central nervous system depressant effects
                  which reach a plateau at a depth of sedation that is inadequate for surgical anesthesia
                      Midazolam         PK: more rapid, shorter elimination     -Used in balanced           -AMNESIA
                                        half life (2-4h); steep dose response anesthesia & conscious        Flumazenil reversal available
                                        curve;                                  sedation, cardiovascular
                                        -Water soluble                          stability
                                                                                -DOC for parenteral
                                                                                admin

                                                                                                                             80
                 Lorazepam          Not water soluble
                  Diazepam          Not water soluble
              Dexmedetomidate       -2 agonist (central > peripheral)       -Atypical sedative           -Little RR effects
                                    PK: half life = 6min, but  w/ renal &   (cardiac surgical            -Twilight state
 2 Agonist                         hepatic dysfunction                      indication, ICU & OR        -Hypertension & bradycardia
                                                                             use)’                        -Low BP & bradycardia
                                                                             -Used for people on
                                                                             drugs?

  INHALED     Volatile anesthetic = liquid at room temp, but evaporate easily   (Halothane, Isoflurane, Desflurane, Enflurane, Sevoflurane)
ANESTHETICS
              Uptake & Distribution of Inhaled anesthetics
               1. Solubility – The blood:gas partition coefficient is a useful index of solubility and defines the relative affinity of an
                  anesthetic for the blood compared with that of inspired gas. So, low coefficients mean a relatively insoluble drug in the
                  blood (desflurane, nitrous oxide). When an anesthetic with low blood solubility diffuses from the lung into the arterial blood,
                  relatively few molecules are required to raise its partial pressure, and so arterial tension rises rapidly. If high arterial
                  tensions are reached rapidly, then there is a rapid equilibration with the brain and a fast onset of action. Conversely, for
                  anesthetics with moderate to high solubility (halothane, isoflurane), more molecules dissolve before partial pressure changes
                  significantly.
               2. Anesthetic concentration in the inspired air – has direct effects on both the maximum tension that can be achieved in the
                  alveoli and the rate of increase in its tension in arterial blood. Increases in the inspired anesthetic concentration increase
                  the rate of induction of anesthesia by increasing the rate of transfer into the blood.
               3. Pulmonary ventilation – the rate of rise of anesthetic gas tension in arterial blood is directly dependent on both the rate
                  and depth of ventilation (magnitude of effect related to the blood:gas partition coefficient). An increase in pulmonary
                  ventilation is accompanied by only a slight increase in arterial tension of an anesthetic with low blood solubility or low
                  coefficient but can significantly increase tension of agents with moderate to high blood solubility. THUS, hyperventilation
                  increases the speed of induction of anesthesia with inhaled anesthetics that would normally have a slow onset.
               4. Pulmonary blood flow – An increase in pulmonary blood flow (ie increased CO) slows the rate of rise in arterial tension,
                  particularly for those anesthetics with moderate to high blood solubility. Increased pulmonary blood flow exposes a larger
                  volume of blood to the anesthetic. In persons with circulatory shock, the combined effects of decreased cardiac output
                  (resulting in decreased pulmonary flow) and increased ventilation will accelerate induction of anesthesia with halothane.
               5. AV concentration gradient – dependent mainly on uptake of the anesthetic by the tissues

              EFFECTS OF INHALED ANESTHETICS
                      All inhaled anesthetics tend to increase right atrial pressure in a dose-related fashion, which reflects depression of
                       myocardial function. (Enflurane, Halothane more so)
                      Inhaled anesthetics decrease the metabolic rate of the brain.
                      The more soluble volatile agents increase cerebral blood flow because they decrease cerebral vascular resistance.
                       The increase in cerebral blood flow (thus ICP) is not wanted in patients who already have increased intracranial
                       pressure. At low concentrations, all of the halogenated agents increase cerebral blood fow, but at higher
                       concentrations, the increase in cerebral blood flow is less with the more insoluble agents.
                      All volatile anesthetics are respiratory depressants and also depress mucociliary function in the airway. Prolonged
                       anesthesia may lead to pooling of mucus and then result in atelactasis and postoperative respiratory infections.
                      Solubility: Halothane > Enflurane > Isoflurane > Nitrous Oxide
                      Nitrous oxide has little effect on uterine muscle, but the halogenated anesthetics are potent uterine muscle relaxants
                       (concentration dependent)
                      Minimum Alveolar Concentration (MAC) = concentration (as a % of inspired gas) to prevent movement in 50% of
                       people to a surgical incision
                      Malignant Hyperthermia – hypermetabolic state in muscle tissue & dysfunctional Ryr1 receptor; seen in 1:15000 kids &
                       1 in 40000 adults; triggers include inhalation anesthetics and succinylcholine. The signs of MH include increased
                       ETCO2, trunk or total body rigidity, masseter spasm or trismus, tachycardia, tachypnea, acidosis, increased
                       temperature may be a late sign
                Nitrous oxide        PK; true gas, not metab (no            -May be a better inducer      -B12 inactivation
               (―Laughing gas‖)      hetapotox), sweet smelling             for those w/ CV disease       -Spontaneous abortions
                                     LOW SOLUBILITY                         than halothane                -PostOperative Nausea Vomiting
                                     -MAC = 104, low potency                                              (30%)
                                     -Cerebral metab rate                                                -Minimal CV effects
                                                                                                          -Least likely to cerebral blood flow
                                     Note:                                                                of inhaled anesthetics

                                                                                                                           81
                 Nitric Oxide = NO                                                 -Expanding gas (75% N20 for 10 min
                 Nitrous Oxide = N2O                                               = 2X size of pneumothorax b/c N20
                                                                                   is 20X more soluble than N2?)
                                                                                   -Diffusional hypoxia
  Desflurane     Fluorinated methyl ethyl ether        -Ambulatory patients        -Expensive
                 -Isoflurane w/ a F- instead of Cl-    (rapid anesthesia, rapid    -Caustic smell (too much too quickly
                 PK:                                   off)                        causes bronchospasms/coughing &
                 MAC = 6.1, low potency                                            sympathomimetic SE)
                 LOW SOLUBILITY                                                    -Carbon Monoxide production
                 -MAP in direct proportion to their                               -Little hepatitis risk
                 alveolar concentration due to                                    -Low volatility  need special
                 systemic vascular resistance                                      vaporizer
 Sevoflurane     Fluorinated methyl isopropyl ethyl    Cardiac stable:             -[Compound A] renal damage
                 PK: degraded by contact with the      -Ischemic preconditioning   -Expensive
                 carbond dioxide absorbent in          (via K-ATP channels)        -NO hepatitis risk
                 anesthesia machines to vinyl ether
                 called ―Compound A‖                   -Pediatric anesthesia
                 MAC = 2.1, medium potency             -Ambulatory patients
                 LOW SOLUBILITY                        (rapid anesthesia, rapid
                 -MAP in direct proportion to their   off)
                 alveolar concentration due to 
                 systemic vascular resistance
                 -Bronchodilation
  Isoflurane     -Halogenated methyl ethyl ether       -Mainstay anesthetic        -Respiratory depression
                 -MAC = 1.2, medium potency                                        -Possible coronary steal
                 Medium solubility                     Cardiac stable:
                 -MAP in direct proportion to their   -Ischemic preconditioning
                 alveolar concentration due to        (via K-ATP channels,  w/
                 systemic vascular resistance          sulfonylurea &
                 -Depressant effect on the EEG         hyperglycemia)
  Enflurane      Halogenated methyl ethyl ether        -precursor to Isoflurane    -Mild generalized muscle twitching
                 -MAP in direct proportion to their                               (myoclonic) @ doses
                 alveolar concentration due to CO                                 -Respiratory depression
                 -Depressant effect on the EEG                                     -Seizures
                                                                                   -Renal complications
  Halothane      Halogenated ethane                    -One of the most widely     -Halothane hepatitis (cumulative, so
                 PK: 40% metab by liver (highest),     used internationally, not   if used halothane in past, risk)
                 -HIGH SOLUBILITY                      used in the USA             -Intracranial pressure (ICP)
                 -MAP in direct proportion to their   -Cheap                      -Sensitizes the myocardium to
                 alveolar concentration due to CO     -Still used in pediatric    circulating catecholamines
                 (bradycardia w/ kids)                 anesthesia (being           (epinephrine) may cause ventricular
                 MAC = 0.75, High potency              replaced by sevoflurane)    arrhythmias
                 -Depressant effect on the EEG                                     -Malignant hyperthermia (give
                 -Bronchodilation                                                  dantrolene)
                 -Pleasant smell
Methoxyflurane   70% metab by liver release                                       -Nephrotoxicity
                 fluoride ions nephrotox                                          -VERY slow onset and recovery
                 HIGH SOLUBILITY
    Xenon        Inert gas, ―ideal agent‖              -CV stable                  EXTREMELY EXPENSIVE
                 MAC: High 70                          -non-smelly
                 VERY INSOLUBLE




                                                                                                   82
                                             SEDATIVE-HYPNOTIC-ANXIOLYTIC
GABA-A receptor activation opens Cl- channels. GABA-B receptors allow K+ effux. Both receptors cause hyperpolarization. Benzodiazepines and
barbiturates act only on the GABA-A receptors. Benzodiazepines use the y (gamma) binding site. Barbiturates bind at the  site.
       Class                   Drug                         Mechanism                           Clincal Use                        Side Effects
  Benzodiazepines      Benzodiazepines are used in insomnia, anxiety, and as anticonvulsants. Benzodiazepines potentiate the action of GABA. They
                       have zero efficacy. Most of the benzodiazepines are very similar and really only differ in their pharmacokinetics. These drugs
                       are liver metabolized to active compounds (except for oxazepam, temazepam, and lorazepam). Because of all the active
                       metabolites, half-life of the drug does not correspond to duration of action. The onset of action is related to the relative
                       degree of lipid solubility. BZs that are highly lipid soluble (midazolam, triazolam, diazepam, flurazepam) have a more rapid
                       onset of action. Longer acting drugs will be used for anxiety, while the short acting will be used for insomnia. Just a few points
                       to remember…Do not treat pain with a benzodiazepine & benzodiazepines are NOT antipsychotics.
                           Midazolam          Ultra-short acting (3-8h)                -Use for uncomfortable           -Drowsiness, sedation, confus
                            Triazolam                                                  procedures (Preop sedation,      -Ataxis (vertigo, slurr speech)
                                                                                       Anesthesia)                      -Resp depression (very dose)
                           Temazepam          Short acting, No active metabolites Sleep disorder                        -Amnesia (retrograde &
                           Oxazepam                                                    Anxiety (oxazepam)               anterograde)
                           Alprazolam         Short duration of action                 Anxiety, panic attacks,          -Floppy infant syndrome if taken
                             (Xanex)                                                   phobias                          in the perinatal period
                           Lorazepam          Short-medium duration (10-20h)           Anxiety, preop sedation,         - Libido
                                              IV, no active metabolites                status epilepticus (IV)          -Enhanced sedation w/ many
                            Diazepam          -Very long duration (1-3 days) due to Anxiety, preop sedation,            other drugs
                                             many active metabolites                 muscle relaxation, withdrawl
                                             -Given IV                               states                           Long term:
                                                                                                                      -Sleep disturbances (REM is
                           Clonazepam         Very long duration (1-3 days)           Tx of epilepsy                  suppressed)
                                                                                                                      -Withdrawl syndrome (rebound
                                                                                                                      insomnia, anxiety)
                          Flurazaepam         Short onset, long duration              Acute Tx of insominia           risk of falls in elderly
                           Flumazenil         BZ receptor antagonist (BZ-1 & BZ-      -Reverse the CNS                -Will NOT reverse CNS
                                              2)                                      depressant effect of BZ         depression of barbiturates or
                                                                                      overdose                        alcohols
   Barbiturates        Barbiturates increase the duration of Cl channel opening (allow GABA to stay on there longer), but they also have GAGAmimetic
                       activity at high doses. Barbiturates also inhbit complex 1 of the electron transport chain. Barbiturates are general inducers of
                       CYP450. Barbiturates induce metabolism of most lipid-soluble drugs, such as oral contraceptives, carbamazepine, phenytoin,
                       warfarin, ect.
                           Thiopental         Ultra-short acting; extremely lipid     Induce anesthesia (IV)          -Sulfa allergies (thiopent)
                                              soluble (half life = 3-10h)                                             -Withdrawl (anxiety, agitation,
                         Pentobarbital        Half life = 15-50 hours                 ER management of seizures       life threatening seizures)
                         Phenobarbital        Long acting (half life = 80-120 h)      Tx seizures                     CI: porphyrias
   Non-BZ drugs             Zolpidem         These are NOT benzodiazepines. They do not share the benzodiazepine stucture, but they bind to the
                            Zaleplon         BZ-1 receptor specifically
                                             BZ-1 receptor agonist               Tx of insomnia                 -Less tolerance & abuse potential
                                                                                 -OD reversed by flumazenil
                           Buspirone         No effect on GABA,                  Used for generalized anxiety   -Nonsedative anxiolytic (as
                                             5HT-1a portial agonist (modulates   disorders                      opposed to BZ)
                                             serotonin transmission)                                            -Pupillary constriction
                                             -Takes 1-2 weeks to have an effect                                 -Nervousness, restlessness,
                                                                                                                dysphoria, tachycardia




                                                         LOCAL ANESTHETICS
       Class                    Drug                          Mechanism                              Clincal Use                     Side Effects



                                                                                                                                    83
                                              DOPAMINE: Parkinson’s & Psychosis
Dopamine receptors are classifed into D1 and D2:
         D1Gs coupled
         D2Gi coupled. These receptors are the most sensitive (by about 1000x compared to D1)
             o   D2A = nigrostriatal pathway (cell bodies in substantia nigra project to the striatum, where they release DA, which inhibits
                 GABAergic neurons. In Parkinson disease, the loss of DA neurons in this tract leads to excessive ACh activity  extrapyramidal
                 dysfunction)
             o   D2C= mesolimbic pathway (cell bodies in the midbrain project to the cerebrocortical and limbic structures  functions include
                 regulation of affect, reinforcement (addiction), cognitive functions, and sensory perception. Psychotic disorders and addition are
                 partly explained by DA in these pathways… and drugs that DA functions reinforcemtn and at high doses may cause psychoses
             o   Tuberoinfundibular (Cell bodies in hypothalamus project to anterior pituitary and release DA prolactin
             o   Chemotactic trigger zone (activation of DA receptors  emesis
       Class                 Drug                           Mechanism                      Clincal Use                       Side Effects
 DA PRECURSORS             Levodopa            Prodrugdopamine: via aromatic      -Symptomatic relief          -Dyskinesias
                                               amino acid decarboxlase (aka dopa                                -―On-off‖ effects
                                               decarboxylase) in periphery & CNS                                -Psychosis
                                               -Take on an empty stomach, don’t                                 -In the periphery/GI tract n/v
                                               take w/ B6 (DA metabolism)                                      cardiac arrhythmias, hypotension,
                                               -Response after 3-5yrs (tolerance                               flushing
                                               + sensitization)                                                 CI: history of melanoma, concomitant
                                                                                                                use of MOA inhibitor
                           Carbidopa           Inhibits DOPA decarboxylase        -Blocks peripheral           L-dopa + carbidopa:
                                               CNS availability of L-dopa         effects of L-dopa            -Brown urine & saliva
                                               -Does not cross into CNS            -Always give L-dopa +        CI: B6 (Breakdown of L-dopa),
                                                                                   carbidopa                    psychotic patients, glaucoma,
                                                                                                                antipsychotics
      COMT           Increased L-DOPA causes a compensatory increase in COMT degradation of dopamine to 3-O-methyldopa, which competes w/ L-
  INHIBITORS         DOPA for active transport into CNS (decreasing L-DOPA in brain). 3-O-methyldopa is a partial agonist. So, in the presence of a
                     full agonist, it acts like an antagonist
                           Tolcapone           COMT inhibitor, crosses into CNS    -Use when other              -Fulminating hepatic necrosis
                                                                                   therapies fail
                          Entacapone           COMT inhibitor, acts only in        -Largely replaced
                                               periphery                           tolcapone
  DA AGONIST            Bromocriptine          Ergot derivative                    No longer available in       -Dyskinesias
                                                                                   USA                          -Psychosis
                                                                                                                -Pulmonary & retroperitoneal fibrosis
                           Pergolide
                          Pramipexole          Depends on good renal function
                         Apomorphine           Injectible                          -Acute management of         -Powerful emetic drug
                                                                                   ―off phenomenon‖
                           Ropinirole          Not an ergot derivative             Tx. of parkinsons            Lower incidence of postural
                                                                                                                hypotension, dyskinesia, vomiting and
                                                                                                                hallucination, unlike most DA agonists
                           Rotigotine          Available in transdermal
                                               formulation (once a day)
      ANTI-               Benztropine          Tremor and rigidity but have                                    -Many side effects similar to
  MUSCARINIC           Trihexyphenidyl         little effect on bradykinesia                                    atropine
                       Diphenhydramine                                                                          CI: glaucoma, prostatic hyperplasia,
                                                                                                                pyloric stenosis
                                                                                                                                 84
    MAO-B             MAO-A breaks down NE and serotonin. MOA-B breaks down dopamine. Since MAO-B does not interfere with tyramine
  INHIBITORS          breakdown there is no ―cheese‖ effect.
                           Selegiline       Inhibitor of MAO-B (not MAO-A                              -Insomnia
                                            at recommended doses)                                      -Severe HTN (@ doses)
                                            -Selegiline is metabolized in body
                                            to amphetamine
                           Rasagiline       -Irreversible inhibitor of MAO-B
                                            -5X more potent than selegiline
                                            -Not metabolized to amphetamine
     OTHERS               Amantadine        -MORE effective than                -Antiviral             Livedo Reticularis (skin mottling,
                                            anticholinergics against rigidity & -Tx of parkinson’s     purplic meshwork of blood vessels
                                            bradykinesia                                               generally around ankles)

                                                                 PSYCHOSIS
Schizophrenia is a mixture of positive and negative symptoms. To fight the positive symptoms, you need a depressant, but that would worsen the
negative symptoms. Also, to fight the negative symptoms you need an antidepressant (i.e. stimulant), which would worsen the positive symptoms. The
main mechanism by which drugs will fight psychosis is by a blockade of dopamine D2 receptors and block of 5HT-2 receptors.
If you block dopamine, side effects may include:
     1. Acute EPS from acute block of DA in the nigrostriatal
              a. Presents like a pseudoparkinsonism, dystonia, akathisia
              b. Management: antimuscarinics
     2. Chronic EPS (aka tardive dyskinesia) from chronic block of DA receptors in the nigrostriatal, which may be irreversible
              a. The brain may either upregulate the number or sensitivity of DA receptors, and the little DA around will cause hyperkinetic
                   movements
              b. Management: discontinue drug (may cause a tremendous epidosde of psychosis) & switch to an atypical psychotic
     3. Dysphoria, making compliance an issue
     4. Endocrine dysfunction
              a. Temperature regulation
              b. prolactin
              c. Eating (weight gain)
     5. Antimuscarinic effects (tachycardia, seizure threshold)
     6. -blocking (hypotension)
      TYPICAL            Chlorpromazine                                                                           Ocular deposits in the lens
ANTIPSYCHOTICS                                                                                                    Sedation
                          Thioridazine        Such a strong antimuscarinic that                                   -Little EPS
  (Phenothiazines)                            it autotreats its EPS effects                                       -Quinidine toxicity
                                              -Strong  block                                                     -Retinal deposits
                                              -Low potency                                                        Sedation
                          Fluphenazine        High potency
                                              Can give as depot form
 (Butyrophenones)          Haloperidol        Can give as depot form                                              -Most likely cause of neuroleptic
                                                                                                                  malignant syndrome and TD
                                                                                                                  -EPS
     ATYPICAL          Atypicals lack the tardive dyskinesias side effects. The newer antipsychotics also block the 5HT2 receptors, which are found
ANTIPSYCHOTICS presynaptically  increased release and synthesis of serotonin. This will address the negative symptoms of schizophrenia.
                            Clozapine         -Block D2C receptors (found                                         5-10% of pts suffer agranulocytosis
                                              mesolimbic, mesocortical)                                           (need weekly blood testing)
                                              -Blocks 5HT-2
                                              -Moderate antimuscarinic
                                              -Strong -blocker
                           Olanzapine         -Block D2C receptor (not as well)
                                              -Blocks 5HT-2
                           Risperidone                                                                            Some tardive dyskinesia
                          Aripiprazole        Partial agonist at D2 receptors       -Not for severe psychosis
                                              Blocks 5HT-2                          b/c of ceiling effect




                                                                                                                                 85
                                                               DEPRESSION
      Class                 Drug                        Mechanism                               Clincal Use                       Side Effects
      TCA           TCA have a number of SE:
                        1. Anti-cholinergic
                        2. Anti-adrenergic
                        3. Anti-histaminic
                        4. Other
                       Amitriptyline       Tertiary amines block the reuptake of          -Major depression            COMA, CONVULSIONS,
                         Imipramine        5-HT > NE                                      -Phobia                      CARDIOTOXICITY (the 3 C’s)
                                                                                          -OCD                         -Prevent antihypertensive action of
                                                                                          -Neuropathic pain            2 agonist & guanethidine
                         Nortriptyline        Secondary amines block the re-uptake                                     CI: MAO-I + TCA (if switching
                         Desipramine          of NE > 5-HT                                                             b/w give washout period of 2-3
                                                                                                                       weeks

      SSRI                Fluoxetine          Selectively block serotonin reuptake        -Major depression            -Sexual dysfunction (anorgasmisa)
                         Fluvoxamine                                                      -Bulimia
                          Sertraline                                                      -Anxiety disorder            Withdrawl: (―finish‖)
                          Paroxetine                                                                                   F = flu-like symptoms
                          Citalopram                                                                                   I = insomnia
                         Escitalopram                                                                                  N = nausea
                                                                                                                       I = imbalance
                                                                                                                       S = sensory stuff (e.g. itchy teeth)
                                                                                                                       H = headache/hyperarousal
     SNRI                 Duloxetine          5HT & NE reuptake inhibitor at all
                                              relevant doses
     MAO-I               Phenelzine           Irreversible, nonselective inhibitor of                                  ―Cheese effect‖ (HTN crisis)
                       Tranylcypromine        MAOs                                                                     -Serotonin syndrome (if SSRI +
                                                                                                                       MOA-I
                         Molobemide           Reversible, selelctive for MAO-A
     OTHER                Bupropion           Weak reuptake blocker of DA and             -Smoking cessation           Minimal sexual SE (b/c does not
                                              NE                                          -WAS an antidepress          enhance 5HT)
                         Mirtazapine          2 antagonist NE                                                       -HTN, tachycardia
                                                                                                                       -Weight gain
                          Trazodone           5HT by interfering w/ metabolism           Antidepressant               Cardiac arrhthmias
                                              -Metabolized  serotonin agonist                                         -Priapism
                                              - Block
                          Venlafaxine         Non-selective reuptake blocker devoid
                                              of ANS sideffects (like a TCA, but no
                                              SE)




                                                            BIPOLAR & ADHD
Rapid cycling Bipolar – at least 4 epidosdes of mood disturbances within the last 12 months
       Class                     Drug                        Mechanism                          Clincal Use                        Side Effects
                                Lithium          -Prevent the recycling of PIP2 -DOC for Bipolar                        -Tremor & life threatening
                                                 Ca                                                                     seizures (dose depend)
                                                 -Inhibit cAMP signaling                                                 -Hypothyroidism w/ goiter
                                                 -Therapeutic index = 1-2             -For Toxicity (give amiloride)     -Nephrogenic Diabetes
                                                 -Lithium ―looks like‖ Na+            -Chronic doses of diuretics        Insipidus
                                                                                      will clearance of lithium

                            Valproate                                                   Rapid cycling
                          Carbamezepine                                                 Pure and mixed mania
                                                                                                                                      86
        Methylphenidate   Amphetamine derivative (a
                          releaser)
         Atomoxetine      Selective NE reuptake inhibitor




Class        Drug                     Mechanism             Clincal Use   Side Effects




Class        Drug                     Mechanism             Clincal Use   Side Effects




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