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Pharm-NeuroBlockChart

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									                                                                                       Dyskinesia (oral, facial)
Parkinson's                 ↑ Dopamine Function
                                                                                               Psychosis (limiting factor) → mesolimbic path, ↑ in
                                                                                       elderly
                                                                                       N/V, Depression, Anxiety
                                                                                          Arrythmia (α, β)                 Large first-pass
                                                                                                         ..               * CNS by ACTIVE transport
Levodopa              L-Dopa —AAAD→ Dopamine     Treat Symptoms                          orthostatic hypotension
                                                                                       …………………………………………….                    * ↑ seratonin receptors
     (L-Dopa)                   D1 + D2 receptor   Not alter disease course                                      (+)          * avoid non-specific
                                                                                       Coombs, brown secretion        MAOIs           * free radical =
                                                        .                              …………………………………………………………………………………………………...........................................…


                                                                                                    Neuroleptic       ↑ neuron dmg
                                                               early stages                        …………………….



                                                                 (require DA                                Malignant Syn

Carbidopa                                                  neurons)                        minimize peripheral side
                      (-) AAAD                                                                                                                                             Periphery only
                                                                                         effects
                             ( ↑ L-Dopa in CNS )                                                                                                                                      NOT cross BBB
Benserazide                                                                                  ↑ t1/2 levadopa x2
                 give w/
                levadpoa                                                                                                                                                     Peripheral Only
Entacapone                                              enhance L-dopa uptake
                      (-) COMT                                                                                                                                                     Short duration
                                                          and efficacy
                         L-dopa →3-O methyldoma                                                                                                                            Central + Peripheral
Tolcapone                                                  ↓ "on/off" phenomenon                         Hepatotoxicity
                                                                                                                                                                                          Long Duration

Selegiline                                              Neuroprotective ?              ↑ amphetamine = anxiety, sleep
                      (-) MAOB                                                                                                                                             no tyramine interactions
                                                                         Delay                           Meperidine, TCA + SSRI
                              (type B = Brain)                                                                                                                                        DA in CNS only
Rasagiline                                                   levodopa 9-12 mo                              interactions

                                                                                         insomnia, HTN,                                                                    FQ inhibit metabolism
Ropinirole            D3 > D2
                                                        1st line or adjunt                  obsessive behavior                                                               * also tx restless leg synd
                      Receptor agonists
                      .                                      Late stages                                                                                                   transdermal
Rotigotine                                                                                       has some D1 effects                                                              * also tx restless leg
                                     * ↓ free radical             (not require DA)
                           damage           * reduce                           .                                                                                                        synd
                                                                                       insomnia, HTN, Nausea
Pramipexole                     "on/off" effect                                                                                                                                  cimetidine = ↑ t1/2
                                                                                                renal elimination

Bromocriptine                                                                                               insomnia, HTN
                          D1 and D2
                                                             Older - not used                                                                                                      Ergot derivatives
                             Receptor agonists
Pergolide                                                                                         valvular heart disease

                                                                                                                                                                           injectable (infusion pump)
                      D1, D2, D3 Agonist                rescue drug for                            pretreat nausea w/
Apomorphine (SubQ)                                                                                                                                                            avoid w/ (-) Seratonin-3,
                               * R-enantiomer *             "on/off" phenomenon                   trimethobensamide                                                                 anti-HTN, metabisulfite
                                                                                                                                                                                          allerge
                                                                                 Levadopa = Gold Standard for Treatment
                                                                                 On/Off phenomenon :: L-dopa has buffereing capacity (storage in striatum)
Parkinson's              other mechanisms

                    Adenosine-A2A                    ↑ Motor via Indirect path      neuroprotective ?                 * expressed only in striatum *
Istradefylline                                              (-)globus pallidus→
                         Receptor Blocker                                               No dyskenesia effects            Caffeine similar MAO = ↓PD
                                                                GABA
Buspirone
                     5-HT1A Agonists                 Dyskinesia side effects        prolong levadopa
                           (seratonin)                    Pronong L-Dopa duration        duration of action
Sarizotan

                                                                                    Agranulocytosis (limiting)       ↑ M-block (dryness)
Clozapine
                    Atypical Antipsych       Treat hallucinogenic                               Low ↑ Prolactin             Ø EPS/TD
                          (5-HT2 + D2 >> D1)            side effects
Quietiapine

                                                                                                                      ↓mitochondrial complex 1
Coenzyme Q10        antioxidant
                                                                 OTC                    high doses required                    in substantia nigra of
  (Upiquinone)          (↑ mitochondrial function)
                                                                                                                                    PD



                    Antiviral (Influenza A)                                         dizziness, lethargy
Amantadine                                             Early stages, mild cases
                                                                                                     anti-                  Adjunct to levadopa
                        (dopamine ? NMDA-R?)
                                                                                           cholinergic



Trimethobenzamide



                                                              Muscarinic Antagonists were used before L-dopa developed
                                                                - resting tremor improved
                                                                - postural impairments not affected
                                                                      * side effects = Atropine Like (sedate, dry, blurry vision)
Alzheimer's Disease :: 1) Excitotoxicity          2) Oxidative Stress + membrane peroxidation         → early :: ↓ Ach
  …………………………………         .. 3) Inflammation            4) Infection                                               late :: ↓ Glut, 5-HT
                                                      ↑ cognitive scores           side effects = cholinergic
AChE Inhibitors :: ↑ Ach                                          Early tx =                  N/V, diarrhea, ↓        Atropine = treat toxicity
                                                               protective                       HR
                                                      Early Stage
Tacrine                                                                                  Hepatotoxic L             Reversible, Non-competitive
                                                                        (weak                                          (reversible organophosphate-ish)
                                                          K+Channel blocker)
Donepezil                                                     ALL Stages            1x day, gradually ↑ dose                       AChE > BChE

                                                                                                                   pseudoirreversible (↑duration)
                           AChE inhibitors
Rivastigmine                                                   Early Stage           GI effect = discontinue           * carbamyl clvg into active
                                                                                                                      site         AChE = BChE
                                                                                                                     Reversible, competitive
                                                      Early Stage
Galantamine                                                                          Weight loss at ↑ dose         AChE > BChE              CYP
                                                             (Nicotinic Agonist)
                                                                                                                        2D6, 3A4 Substrate
                                                      Prevent Progression          hallucinate, catatonia,
NMDA - Blockers :: ↓ Excitoxicity                                                                                    Use in Combo with Donepezil
                                                          (↑ neurotrophic BDNF)             ↑ BP, anesthesia
                                                      Advanced stage
                    NMDA-R Blocker                                                 ↓ neuroleptics, barb, 5-HT3     use dependant, low affinity
Memantine                                               PD + Vascular Dementia
                          * non-competitive *                                           ↑ morphine, L-dopa            (learn = ↑ glut, overcome block)
                                                                Antiviral

Anti-Oxidants :: ↓ Oxidative Stress

                                                      ↑ cognitive scores
Vitamin E                    Antioxidant                                                not > 400 IU/day
                                                                ↓ progression ?

Omega 3 Fas                  Antioxidant                    ↑ cognitive scores

                    MAO-B inhibitor                                                NO tyramin toxicity
Selegiline                ↓ free radical                                                    B= Brain
                    production
                    (-) Aβ protein isoprenylation                                  Rhabdomyolysis                  CYP450 Substrate
Statins                             * not insert in   (-) HMG-CoA Reductase
                                                                                                                           -avoid imidazole,
                                                                                         muscle pain
                              membrane *
                    Bind soluble Aβ                                                                                         macrolides
Alzhemed                     (-) β sheet + amyloid      ↓ Inflammtory Response
                                  fibrils

Curcumin                  (-) Aβ formation

                                                                                   spontaneous cerebral beed
Gingko Biloba                       ?                                                           - avoid anti-
                                                                                            coagulants
Pioglitazone        PPAR-γ agonists                   ↓ inflammation in PD
   Rosiglitazone       * nuclear hormone receptor               Diabetes
Drugs to Treat other symptoms of dementia

Fluoxetine           SSRI's                              HD + AD
                                                                                  Depression
Carbamazepine        Anti-epileptic                      HD + AD

Baclofen             GABA-B agonist                        ALS                                              Intrathecal administration

                     α-2 Agonist
Tizanidine                                                 ALS                     Spasticity
                              … * pre-synaptic
                     inhibition
BZs                  GABA-A agonist                  ALS + AD + HD

                     (-) NMDA - R                                                                        increase ALS survival
Riluzole                        … - block Voltage
                                                        ALS + HD               * monitor hepatic
                                                                                                                   by 60 days
                     gated
Chlorpromazine                                                            * ↑ mortality > 6-12 wks
                     Anti-psychs L                          AD
    Haloperidol                                                                 (sudden cardial death)




Huntingon's Disease :: Mitochondrial role?, Caudate of Basal Gaglia → ↓ Ach, GABA
      …… * Autosomal Dominant, CAG repeat, 30-40s, Hyperkinetic, Choreiform movement, Progessive Dementia + Motor decline
Tetrabesine
                              movement                ↓ dopamine
 Reserpine
Fluoxetine
                       depression + irritability
 Carbamazepine
Clozapin
                         psychoisis, paranoia       treat with low dose
Carbamazepine

Benzodiazepines                 Anxiety




Amyotropic Lateral Sclerosis (ALS) :: (SOD1 gene) Ventral Horn + Corticospinal Motor Tracts
                  …… * Rapidly progressive weakness, atrophy, fasciculations, DEATH from RESPIRATORY 2-3 years
For all DAergic drugs:
PNS - arrythmias (B1)
.        hypotension
    CNS -N/V(emetic
center)     .   dyskinesia,
agitation .
hallucinations         (DA-
R in other parts of brain)
                     Weak Base: unionized → cross Lipid Membrane                            co-administer w/            α1-agonist = vasoconstrict
Local Anesthetics                    ,,,,,,,,,,,,,,,,,, ionized → Activated (require               * remain local, prolong effects + ↓ toxicity
                     acidic env)
                                                                                                  ADMINISTRATION
Procaine                                                                                  Topical ::                                       Short Duration.
                                                                                          Skin, Mucous Membrane, Cornea                     Infiltration, Nerve block, Spine
                                                                                             - EMLA :: mix 2+ solids = liquid                            NOT Topical
Chloroprocaine                                           DOC: Liver Problems              Infiltration ::
                                                                                          Inject SubQ tissue (dental, suture)
                                                                                            - Epi added except end-organ)                     Infiltration     …..
Tetracaine                                               Esters.                          Nerve Block :: Regional                                            Topical …...




                                                                                                                                                                                 Medium Duration
                                                                                          Inject Peripheral nerve/plexus
                                                             Metabolized by Plasma
                                                             Tissue Esterases             Spinal Intrathecal ::
Benzocaine                                               +
                                                                                                                                                       Topical only …...
                                                                                     ……………………………………
                                                                                      Inject Subarachnoid + tilt body
                        Block inactivated axonal                                        - headache from CSF leaking LP
                                                                                     ……………………………………
Dibucaine                     Na+ channel                                               - ↓ Respiration if ascend too high
                                                         Allergy via PABA metabolite ……………………………………
                                                                                                                                           Topical …..
   (exception to "-i ")                                                                 - meningitis (rare)                                     * hemorrhoids + rectal * …..
                             .                                                       ……………………………………
                                                                                      Epidural :: Systemic
                       (prevent depolarization)                                      ……..…………………………..
                                                                                      Injet Lumbar or Caudal epidural                      (-) NE uptake …..
Cocaine
                                 .                                                       - beware Cardio + Neurotoxic
                                                                                     ……………………………………                                               * vasoconstriction * …..
                                         .                                           ……………………………………                                        Class Ib antiarrythmic




                                                                                                                          Short Duration
Lidocaine                                            .                               ……..                                                     Infiltration, Epidural, Nerve block,
                                                                                                     .. Neurotoxicity                                   Spinal, Topical
                                         .                                                             .. CardioToxic
                                                                                                                                           Infiltration, Topical
                                                                                                            .. Allergies
Prilocaine                                                                                                                                 * toxic metabolite toluidine *
                        pain/temp ---------- motor       Amides.                                                                                      (met-hemoglobinemia)
                        C > B > Aδ > Aβ > Aα                                                                                                 Infiltration, Epidural, nerve block,
Bupivacaine               recovery in reverse                 Metabolized by Liver                                                                    spine, NOT topical
                                                                   Amidases




                                                                                                                          Long Duration
                                                                                                                                           Infiltration , nerve block
Etidocaine                                                                                                                                                   NOT Topical

                                                                                                                                           Infiltration, Epidural, nerve block
Ropivacaine                                                                                                                                                       NOT Topical
                                                                                        ↓ CV resistance,
General Anesthetics :: Inhaled ( ion channel signal transduction)
                                                                                                ↑ perfusion to brain
                            ::    -- after IV agent = can be rapidly regulated
                                                                                                     Bronchodilation
                                                          Analgesia                       NO CV or Respiratory            no metabolism                           ↓
Nitrous Oxide                                                NOT Unconscious            depression                        B/G = Fast, leat potent
                        Non-Halogenated
Gas                                                                  NOT muscle          megaloblastic anemia                                           (little
                                                                    relax                       - oxidize cobalt in B12              protein bound)

                                                                                        Hepatotoxic                       Slow
                                                          Surgery                        Cardiac Arrythmia                metabolites ::
Halothane                    Halogenated                                                                                              - hypersensitivity = fatal
                                                              (no analgesic effect)     Malignant hyperthermia
                        .                                                                                                 in 50%               - Hepatitis
                                                                                                          .
                               ….. ↓ MAC =
                   very potent           .                                              less CV toxicity
Enflurane
                                                                                                  more Resp
                                                              Muscle relaxation                                              Medium rate of induction
                         * less post-op N/V                                                depression
Isoflurane                             * dose-                                              Seizuer (high dose)
                   dependant ↓ RR, CV
                                     * Uterine                                              Irritat respiratory
Desflurane
                   Relax = cesarean                                                              epithelium
                                                                                                                                 Fast rate of induction
Sevoflurane                                                                                          J

   Drug/Class                    Mechanism                      Clinical Uses                  Side Effects                        Miscellaneous

General Anesthetics :: IV → CNS depression :: Unconscious, Analgesic, Amnesia, Muscle relax

                    Barbiturate                                                                                           fast-acting
Thiopental                                                Induction, short procedures       Resp & CV toxicity
                                  (GABA-A)                                                                                   lipid soluble = redistribute

Midazolam            Benzodiazepine                                                                                        slower actions
                                                           pre-op sedation / anxiety       less CV + Resp effects
  Diazepam                        (GABA-A)                                                                                 Countered with Flumazenil
                                                                                      ↑ Itracranial Press,
                                                          dissociative amnesia                                            medium-acting
                       (-) NMDA-Receptor                                                    ↑ Cardiovascular
Ketamine                                                                         DOC:                                                  Similar to PCP-
                            (glutamate)                                                                 ↑ BT,
                                                                   children                                               hallucinations     " special K "
                                                                                                 delerium
                                                                                                                          fast-acting
Propofol                           ? GABA ?                  Diagnostic procedures            ↓ Cardiac + CNS
                                                                                                                            not redististribute, no hangover
                                                          DOC : cardiac sx
Fentanyl           Opioid                        (μ→Gi)                                      NO cardiotoxicity                       fast-acting
                                                             twilight (w/ droperidol)
                                                          ER : rapid induction          Least effects on BP
Etomidate                        ? Histamine ?                                                                                   No analgesic effects
                                                               Anesthesia + sedation               Less CV
Opioid Agonists :: Presynapse: close Ca2+                                                                                         3 receptors = Gi-coupled        ↓ NE, 5-HT, Substance P
             ………………………………… .. Postsynapse: open K+                                                                                    μ (pain), κ, δ             (ACh parasympathetics dominate)

Morphine
                           Pain from trauma,
                                                        EFFECT + SIDE EFFECTS are similar for all Opiods                               Leutenant's are NARCCs that work VIS.
                               cancer, MI
Codeine                                        Antitussive (cough)                             * convert to morphine *
                                                                                                                                        L ongitude m. Relax / Circular constrict
          Hydrocodone                                                                                                                      - Constipation (Laxative + Lubricant)
                                                             * with ASA/Acetominophen *                    ↓ potency
                                                                                                                                              Cramping (Anti-Spasm = M-blocker)
(oral)                                                                                                                                             ex. Loperamide (tx diarrhea)
                          Moderate-Severe                                                      Oxycontin = slow release
Oxycodone      (oral)                                     * with ASA/Acetominophen *                                                        - Urinary Retention
                                  Pain                                                                           ↓ potency                  - Inc. Biliary Pressure
                                                                                               ↓ smooth m (miosis, urine)                   - Miosis (sphincter muscle = M3)
                                               pregnancy (labor), biliary dz
Meperidine                Acute-Severe Pain                                                               * toxic metabolite             N ausea + Vomitting
                                                      post-anesthesia shivers
                                                                                                              *                              - (+) chemoreceptor trigger zone
                                                                                               long acting                                   - area prostrema = no BBB
                             Chronic Pain
Methadone       (oral)                                      Less euphoria                               avoid rifampin +                 A nalgesia ( μ – Receptor )
                              Addiction
                                                                                                         tramadol                             - dissociation = ↑ tolerance, ↓ perception
                                                                                                                                         R espiratory Depress ( μ – Receptor )
                                                                                                                                              - ↓ response to ↑ PCO2
                                               100x more potent                                                                               - DON’T give O2 ; DO give naxolone
Fentanyl
                                                    (IV, epidural, intrathecal, transdermal)                                             C ough Suppression ( NOT μ )
                                                                                               minimal effects on ICP
                            Cardiovascular                                                                                  No           C ircular m. Constrict
Sufentanil                     Stability
                                                        1000x more potent                      Histamine release                         V asodilation, Cardiovascular (minor)
                                                                                                                                               - increase blood flow
                                                                                                    .                                         - Hypotension (histamine)
Alfentanil                                                     less potent
                                                                                                                             *           I tching (HS-Type I)
                                                                                                        muscle rigidity *                     - (+) histamine release
                          short procedures     * rapid onset, rapid recovery
Remifentanil (IV)                                                                                                                        S edation
                              w/ severe pain      (plasma esterase degrades)

                                                                                                                                                       Contraindications :
                                                                                                                                                1) Head Injury
Partial Agonists :: precipitate withdrawl b/c antagonistic effects                                                                                 - ↑ Intracranial Pressure

                                               (-) NE + 5HT reuptake, weak μ                   ↓ side-effects                                   2) Pulmonary Dysfunction
                          Mild-Moderate
Tramadol                                                                                                                    may                    - except edema or congestion
                                 Pain                             * with Acetaminophen *
                                                                                                         cause siezure
                           Moderate-Severe                                                                                                      3) Renal Failure
Pentazocine                                       κ agonist in spine + μ antagonist                                                                - glurcuronidation → M-6G
                                 Pain                                                                                                                                   (more acitve)

                          Moderate-Severe                                                      2-50x more potent                                4) Hepatic Failure
Buprenorphine                                               μ partial agonist
                               Addiction                                                             longer duration
                                                                                                                                                5) Adrenal / Thyroid dz
                          Acute-Severe                                                         Cardiovascular effects                              - increase response
Butorphanol     (nasal)                           κ agonist in spine + μ antagonist
                             Headache/CA                                                            ↑ pumonary a. pressure
                                                                                                                                                6) Pregnancy
                                                                                                                                                   - exception : meperidine
 Short-Acting (1-2 hrs)                    Long- Acting (6-8 hrs)                 Transdermal (48 hrs)
   Fentanyl, "-tanil"     Diphenoxylate, Loperamide, Dextromethorphan < Methadone    Fentanyl patch
                                                                                                                                                  Acute Toxicity Triad.
                                                                                                                                              1. Pinpoint Pupils
                                                                                                                                              2. Repsiratory Depression
                                                                                                                                              3. Coma
                                                                                                                                                 Tx : Supportive + IV naxolone
Other Uses for Opioids
                                                                                                              Opiate withdrawl:
                                                                                                       1)   Yawning
Diphenoxylate                                                               Combine with atropine      2)   Tears, Sweat, Salivation
                           Diarrhea          Meperidine Derivative                                     3)   Goosbumps
                                                                         Poorly absorbed               4)   Anxiety
Leperamide                                                                                             5)   Muscle cramps + Spasm
                                                                             (P-glycoprotein pump)
                                                                                                       6)   CNS Pain
                    Diarrhea
Paregoric                                     Camphorated opium
                           Teething                                                                  Tx: Supportive + Methadone
                                                                                                     …………………... Clonidine
Dextromethorphan          Anti-Cough




Neuropathic Pain = damaged neurons (opioids not effective)

                         Diabetic
Gabapentin                                    ↑ GABA (inhibitory)
                     Neuropathy
                    …………………………………..

                         Trigeminal     ↑ NE, 5-HT
TCAs                        Neuralgia                (-) Na-Channels




Antagonists

Naloxone (IV)                           reverse respiratory depression
                         block opiate
                           receptors      ↓ Addiction for EtOH and
Naltrexon (PO)
                                                   opiates
not > 48 hrs or high dose
        Drug/Class                      Mechanism                      Clinical Uses                       Side Effects                                    Miscellaneous
Na Channel Blockers :: prolong inactivation of Na channel                                          Blood Dyscrasias = Always monitor CBC
   …      .* ↓ axonal conductance, prevent Paroxysmal Depolarization Shift (PDS)                       Renal + Hepatotoxic = BUN/Creatinine + ALT/AST
                                                               ADULTS                              Minimal CNS depression           (+) CYP3A4                                                                                      ↑ metabolism, ↓ [ ]
                              Na Channel Blocker                 * teratogenic = cleft lip *                                                                                                                                                        OCT, antiepileptics
Phenytoin **                       .. * only target channels                                                                                   low [] = 1st order
                                                                        Partial
                                      …... open at high freq                                       .                                elim          high [] = zero                                                                     digitoxin, steroids
                                                                            Tonic-Clonic
                                                       .                                                         (-) Folate         order = toxic L                                                                                                                  Vit
                                                                                   Status
                                                                                                   metabolism             ... -                                                                                                     K, anticoags
                                               . "voltage +    Epilepticus                                                          .............................................................................................
                                                                                                   Megaloblastic Anemia
Fosphenytoin (IV)                                                                                                                   High Plasma Protein Binding                                                                       ..................

                              use dependant"                                      ** supplement                                                                                                                                        ↓ [phenytoin]
                                                                                       Vitamin K                      Hirsutism,
                                                                                                                                            .. - hypoalbumin,
                                                                with                                                                uremia= ↑Vd
                                                                                                                                                                                                                                           Antiepileptics
                              * Na Channel Blocker                                                 Cross BBB [CSF] = [Plasma]       (+) CYP3A4, 2C,                                                                                 ↑ metabolism, ↓ [ ]
                                         * Upreg.              Partial                                 .. - acute OD → stupor,           .... UDP                                                                                       itself, OCT
Carbamazepine
                              Adenosine-R                          Tonic-Clonic                    coma                             glucuronyltransferase                                                                                                     .
                (related to
                                                                         Bipolar (TCA)                      Aplastic anemia,                                                                  ↑
                               * (-) NE Reuptake                                                                                                       1st order
TCAs)                                                                           CN V + IX          leukopenia.          ... - may                                      [active metab]
                                                                                                                                    (linear) elimination J
                                                                 Neuralgia          Anti-          have to stop drug                                                       erythro, cimetidine
                                    .                                diuretic (↓ ADH)                                               * active metabolite =
                                                                                                                                                                            propoxyphene,
Oxycarbazepine                                                                                     ↓ side effects                      ….. carbamazepine epoxide
                                                                                                                                                                        fluoxetine, isoniazid
                              . "voltage + use dependant"                                                                                             * multiple daily
                                                                                                                                                                                                                                                  anti-epileptics
                              * Na Channel Blocker             Partial, Generalized
Topiramate                                                *          Myoclonic                     * well tolerated                          metabolized by CYP3A4
                              GABA, AMPA, Kainate                    Lennox-Gastaut

                                                               Partial, Tonic-Clonic               Stevens-Johnsons                 Substrate Glucuronidation                                                                       ↓ t1/2 lamotrigine
Lamotrigene                   * Na Channel Blocker                  Atypical Absence                        DIC, ataxia, dizzy,                   * phenyltriazine                                                                    Phenytoin, Phenobarb
   adjunt or monotherapy            * (-) Glut release                                             blurry             Anti-         derivative *
                                                                                                                                                                                                                                               Carbamazepine
                                                                    Juvenile Myoclonic,
                                                                                                   Folate agent
                                                                         Lennox-Gastaut

T-Type Ca Blockers :: Generalized + Absence Siezures.
                                                                                                       Absence :: Ethosuximide > Valproate > Lamotrigene
    (↓ pre-syn influx)……* Thalamus not relay to cortex (sensory except smell)
                                                                                                   Parkinsonian-like synd           NOT induce CYP450
                                                                                                      Photophobia, Rash, Lupus
Ethosuximide                  Ca blocker in Thalamus              DOC: Absence Seizure
                                                                                                                   GI issues, CNS
                                                                                                                                        * start low, gradually
                                                                                                   depression
                                                                                                   Blood dyscrasias, BMS            ↑dose            .. to minimize

Combined Na+ + Ca2+ Channel Blockers
                                                               * teratogenic = spina bifida *
                                                                                                   * used as combo drug *           (-) CYP2C9, UGT                                                                                       ↓ Effectiveness
Valproate                     * Na + Ca Channels                                    Partial,       Hepatotoxic, Pancreatitis                                  ..                                                                    Phenytoin, Phenobarb
    (valproic acid)                 * ↑ GABA synthesis          Tonic-Clonic, Myoclonic,
                                                               Absence
                                                                                                   Hyperammonemia                                                                                                                     .

                                                                       Bipolar Disorder                                                                                                                                                             ↑ [ ] = Salicylates
Zonisamide                                                     Partial, Generalized
         adjunt therapy       * Na + Ca Channels                           Absence
                                                                                                   Metabolic Acidosis               * Sulfonamide = sulfa allergy
                                                                                                                                                                                                                                    ↓ [ ] = anti-epileptics
GABA Agonists :: increase inhibitory tone
                                                                Simple Partial
                               Barbiturates                               Tonic-Clonic            * Low Toxicity, Tolerance                                                                        (+) CYP
Phenobarbital **
                                                  * Prolong                          Status            .                                                                                                           can be used in Absence
                               GABAA                            Partial  Epilepticus                 Sedation, ataxia
                                                                                                                                                                                                   active metab = Phenobarb
Primidone                       * ↑ duration of Cl opening                               Tonic-   slowed cognition
                                                                                                                                                                                                     * less potent
                                                                               Clonic
                                                                Absence, Myoclonic & Atonic                       Long-Term Managment
Clonazepam                                                                                        .                                        (children)
                                                                         in children                                   .
                               Benzodiazepines
                                                                                                                 * lowest                                                                          Metabolized by liver CYP450
Clorazepate                              * potentiate GABAA-
  adjunct with other drugs
                                                                               Partial            toxicity, Tolerance                                                                                                              Lipophillic : cross BBB,
                               R                    *↑                                            ..............................................................................................
                                                                                                                                                                                                                                      placenta
Diazepam **                    frequency Cl opening                                               Arythmia, ↓CNS, mild ↓ RR
                                                                          Status Epilepticus      Hypotension, Anxiety

Lorazepam **                                                                                                                                                                                       Short t1/2
Gabapentin                                                 Partial, Generalized
                                                                                         * low side effects                                                                                          ….. * multiple daily dosing
                               ↑   GABA release                 Migraine
          adjunt or                                                                        * well tolerated, side effect                                                                                                         Lipophillic : cross BBB,
                                     … - unknown mechanism         Diabetic Neuropathy
monotherapy                                                         Bipolar, herpes pain          .. disappear in first wks                                                                        placenta
                                                                                                                                                                                                   .......................................................................................................

                                                                                                                                                                                                   * start low, gradually ↑dose
                                                                Partial, Generalized              Amnesia, Hypersensitivity
Vigabatrin                     (-) GABA transaminase
                                                                   Refractory                     Blurred vision, eye pain
                                          ……      *                                                                                                                                                NOT metabolized by CYP450
              adjunt therapy                                                 LAST RESORT                            Blue-
                               irreversible                                 DRUG                  yellow blindness
Tiagabine                                                       Refractory Partial                Facilitate GABA effects                                                                          Substrate CYP3A
              adjunt therapy   (+) GAT-1 re-uptake                                                      .. * may cause Absence
                                                                             Tonic-Clonic                                                                                                            anti-epileptics ↓ t1/2
                                                                                                  sz

NMDA-R :: excessive activation dispaces Mg2+ block
                               …… * Ca2+ influx → (+) NOS → NO synthesis →
excessive Glutamate
                               * NMDA-R antagonist               Refractory Epilepsy              Aplastic Anemia (low risk)
Felbamate                                                                                                                                                                                                     metabolized by CYP3A4
                                    * Na + Ca Channels                (Lennox Gastaut)                    Hepatotoxic (high)



Inhibit Burst Firing WITHOUT affecting normal neural activity
Levetiracetam                  (-) Post-synaptic                Partial
    adjunct therapy                                                                               Excrete in Urine unchanged.                                                                                  NO CYP metabolism
                               ….. Binding site                             Tonic-Clonic

Status Epilepticus = **
Adjunt Therapy =
                         low [] = 1st order elim
                               high [] = zero order =
                         toxic         ................
                                              .................................

                                               CYP3A4 Inducer
                                              - anti-
                         epileptics, OCT, levadopa
                         ..methadone, anti-coag,
                                      - ↓ Vitamin K,
                         digitonin, steroids
                         CYP3A4 Inducer
                                                                            - ↑ by itself

                               - ↓ by erythromycin,
                         propoxyphen, cimetidine, fluoxetine,
                         isoniazid, anti-epileptics

                                                        ....................................................

                           ...........................................   * Increase metab of




                         difference helps reduce the impact on the liver of
                         metabolizing the drug, and also prevents the
                         serious forms of anemia or agranulocytosis
                         occasionally associated with carbamazepine.




prolonged period of depolarization, called the paroxysmal depolarization shift (PDS)
                                                                                                           Respiratory Depression
                                                                                                                                                    ↑ Tolerance -->↑TI
                                                                    Anitconvulsant, Euphoria, Sleep                       (small margin in
Barbiturates                     GABAA-gated Cl channel
                                                                          (↑total sleep time)                                                                     * cross tolerance w/
                                                                                                           anesthesia)
                                                                                                                                                      CNS                 depressants
                                                                                                                High dose :: ↓ BP, HR

Thiopental (IV)              * Prolong GABAA                                                                                                          General CP450 Inducer.
                                                                    Induce Anesthesia                      (lipid soluble→ redistribution)
          (very short                             ↑                                                                                                 (avoid in porphyrias)
                                                                                Emergency Siezure                         laryngospasm
acting)                      duration of Cl opening
Pentobarbital                                .                      Insomnia                                           short-acting
                                                                        Pre-Op Sedation
                                                 note: can                                                                                                                               *
Amobarbital                                                                 Emergency Seizure                   medium-acting
                            affect w/o GABA                                                                                                          ↑metabolism of Vit K/D, steroids/OCT,
                            .                                Status Epilepticus, Seizure               long-acting                                  cholesterol, bile acids
Phenobarbital                                                                           Daytime                          slow onset
                                    * (-) excitatory AMPA-R
                                                     * ↑ Tissue (skeletal m) SedationPerfused tissue (adipose)
Thiobarbiturates Distribution :: #1 BRAIN → Highly Perfused                   → Poorly                                                                       * All Cross Placenta *
        * INACTIVE METABOLITES BUT SLOW Metabolism = long half life / multiple dosing can be cumulative / residual CNS depression can last 24 hrs           Avoid in COPD, Asthma
                                      * Paradoxical Excitiement (Elderly), Allergy Common                                                                         Hypotension
                                                                                                              Barb withdrawl:
                    * Supportive, Gastric Lavage                                                          1) Agitation
OVERDOSE TX                     * Avoid CNS stimulants (↑ mortality)                                      2) anxiety
                                              * Alkanization of urine = ↑ excretion of                    3) Seizure (life-threatening)
                    acidic barbs

                             Mel1a = SCN, (Gq)                                                                                                     SCN = ↑ GABA
Melatonins                            Mel1b = retina,
                                                                    Tryptophan → Seratonin → Melatonin (Pineal Gland) →                        Hipp, Cortex = ↓ GABA
                             (Gq)
                                                                                                            Drowsiness, Hallucination               Beware in Pregnant, Children
Melatonin                       *circadian rhythms *                      Insomnia, Jet Lag                  EtOH, Caffeine = ↓                      ↑ Depression, ↓ Sex
                                                                                                             Flumazenil, naloxone = (-)                         avoid if on SSRI's

                                                                                                                                                    NO Dependance/Abuse
                                                                                              ↑ prolactin, ↓ testosterone     Fluvoxamide, ketoconazole
Ramelteon                            ML1, ML2 agonist                Insomnia (sleep latency)  Anaphylactic Allergies          (inhibit CYP metabolism)
                                                                                                   Avoid Pregancy (teratogen)       Rifampin, Fatty meal
                                                                                                                                                             (reduced effectiveness)



                                  Status Epilepticus (kids), Delerium Tremens
Paraldehyde                            Psychiatric Excitement, Abstinence Phenomenon


                              Insomnia, pre-op sedation             Cardiac, Renal,….
Chloral Hydrate                          Children (Dental)                   Hepatic Failure….
                                                                    Street Drug….
Meprobamate                                                                 similar to BZ….
                                                                                                    high
                                      Anxiety, Sedation                       dose = Barb….
Hydroxyzine
                                                                    Anti-Chlinergic…..
       (long-acting)
                                                                        (anti-DUMBELLS)…..
                                                                                additive w/ ↓CNS…..
                                                          Anti-Chlinergic…..
                                                              (anti-DUMBELLS)…..
                         1st gen anti-histamine.                      additive w/ ↓CNS…..
Diphenhydramine                      Insomnia




                                                           Barbiturates + Alcohol           linear = lethal...            * Pain unipaired until unconscious
                                                                  .                                              - more * small dose = ↑ pain
UNSAFE      .            coma
                Cardio &                                                                                          CNS...
                  Resp . medullary depression                                               plateau = safer..
                                                               Benzodiazepines                                            * less CNS = NOT anesthetic
                                                                                            - allosteric….                              … - Not relaxed,
            Inducers   . anesthesia                                .
                                                                                                                          still aware             … - pre-
                                                                                                                          anesthetic = amnesia
                          hypnosis
                                                                                                           - less CNS….
SAFE       .
                        sedation, anxiolytics + anti-seizure
       Drug Treatment .
          Drug Abuse   . Paradoxic Dis-Inhibition

                                      [Dose]



                                                                                                                                     Delerium
                                                                                                                                     Tremens

                                                                                   * cross tolerance b/n all 3                       * life-threatening withdraw
                                                                                                                                         1. Hyperactive.
                                                                                   * Abuse : BZ < Barb & EtOH.                                  * HTN, tremo
                                                                                                                                                * arrythmia
                                                                                                                                          2. Psychosis
                                                                                                                                                * visual & tactile
 unconscious
ain
                            BZ1 = sleep                                     GABA binding site = ↑ Cl- influx




                                                                                                                                  Hyperpol
Benzodiazepines                                                    α
                                                                  Clinical Uses                 Side Effects
                             BZ2 = memory/motor                      - γ                                                                     * require 2 GABA to activate
                                                                  Cl        BZ binding site = ↑ GABA binding
                                                                                                            (potentiation)                   * Penicillin binds inside channel
Beware :: Children, Liver Failure (CYP metab)                                   Barb binding site = ↑ K+ efflux
                                                                    β                                                                         * Tetanus(-) GABA release
                 Pregnancy, Sleep Apnea, COPD (Resp
Acidosis)
Midazolam                                                 Low Dose: Anxiety                       Arrythmia, ↓CNS, Hypotension,              most metabolized by liver
       Oxazepam                                            - Siezure                                                                                .... CYP3A4, CYP2C19
    Temazepam           * potentiate GABAA-R                                                               mild Respiratory                                       .
     Alprazolam                     .                        - Heart Vasodilate (IV)                                                                                 .......... **
                                                                                                                              .
    Lorazepam                            ↑ frequency Cl                            ..... *                                                   SAFER **
Diazepam                opening ......... = plateau       ↓ BP, HR                                                                               NO anesthesia or death
                                                                                                        Motor > Cognition
           .                                 .            High Dose: Sleep                                                                                                 toxic if
    BZ withdrawl: .                        note: NOT                           - Pre-                                                        combine w/ EtOH                     .
1) rebound insomnia                                                                                                                                                     Lipohillic
                        GABA receptor                     Anesthetic (amnesia)
2) anxiety                                                                                        CNS affects ↑ as age
                        ...... .. but require GABA                        … * NMJ block                                                      :: oral, cross BBB               ... *
3) Tremors
        .                                                 at high dose                                                                       redistribute (muscle, fat)
4) anorexia, fainting                                                                                         .
          .                                                        OTHER                                                                       ... * cross BBB, placenta
                                                                                                       Paradoxical
        .                                                                                                                                                   ... * excreted in
ANXIETY ::
Oxazepam       <   Lorazepam (IV) < Clonazepam < Alpralozam                            <      Chlordiazepoxide (IV), Diazepam (IV)
                 * extrahepatic conjugation               * panic disorder                        * alcohol withdrawl             * alcohol withdrawl
                      (glurcuronidation)                  * Seizure                                                               * Seizure
                                                                                                                                  * Spasm, Spasticity
                                                                                                                                   FULL BZ AGONIST
Insomnia::                                                                                                                            (-)Ionitropy :: ↑heart BF, ↓CO
 Zaleplon, Zolipedem < Triazolam              <   Temazepam < Estazolam                       <    Flurazepam
 * not change sleep stage                                                                                                                    IV = acute :: pre-op anesthesia



Zolpidem (Ambien),           BZ1 receptor                  sleep disorders
Zaleplon                                                   (sleep onset, not ∆ stages)
                            agonist
                                                                         .
                                ** not benzodiazepine
Eszopiclone                             **
                                                                                     dizzy,
                                                                   drosy, headache



Flunitrazepam                 10x more potent than         Date-Rape
        (Rohypnol)                 diazepam
                                                              * deep sedation, amnesia


                            BZ-binding site                ↑ anesthesia recovery,                 can't reverse ↓ CNS                        Also zolpidem and zaleplon
Flumazenil                                                                                                 * avoid in Barb b/c
                                    antagonist                     BZ overdose                                                                         (IV), t1/2 = 1 hr
                                                                                                              siezure
                            GABA-binding site
Bicuculline
                                    antagonist

								
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