Agent bradycardia

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					  Type or Classification           Drug Name                       Used In                Mechanism of action         Adverse/Side Effects           Contraindications               Other Notes
Adrenergic Agonists
Catecholamines                                                                          Termination by re-uptake
                            Norepinephrine                (1) Manage hypotension        Receptor selectivity α1/2   (1) Slow, forceful                                        (1) Heart β1 direct
                              (Levophed)                  by iv infusion                and β1 – very weak β2       (pounding) heart beat                                     effects (↑
                                                                                        effects (no action in the   (2) elevated BP                                           inotropic/chronotropic)
                                                                                        lungs nor does it dilate    (3) CNS effects: anxiety,                                 (2) Vasculature: α1
                                                                                        arterioles)                 HA                                                        vasoconstric which
                                                                                                                                                                              activates baroreceptors
                                                                                                                                                                              NET EFFECT: +inotropic
                                                                                                                                                                              effect, but refles
                                                                                                                                                                              bradycardia with ↑
                                                                                                                                                                              systolic and diastolic BP
                            Epinephrine*                  (1) Bronchial asthma-         Agonist at all adrenergic   (1) Arrhythmias               (1) HTN                     Prototypic drug
                                                          bronchdilation (2) and       receptors (α1/2, β1/2/3)    (2) Cerebral hemorrhage       (2) Shock                   Sympathomimetic
                                                          inhibition of antigen-        Potency slightly greater    (3) Necrosis distal to site   (3) Hyperthyroid
                                                          induced histamine             for β than α receptors,     of injection                  (4) Angina pectoris         Heart β1 mediated: (1)
                                                          release.                      but both stimulated         (4) CNS effects: anxiety,     (5) Degenerative heart dz   +inotropic effect, (2)
                                                          (2) Anaphylactic shock-       simultaneously              HA                                                        +cronotropic effect, (3)
                                                          improves breathing, plus                                                                                            ↑automaticity, (4)
                                                          inc BP and reverses           ↑ automaticity and ↑                                                                  ↑conduction rate in AV
                                                          edema (α1)                    conduction rate in AV                                                                 node
                                                          (3) Infiltration with local   node; rate and force of
                                                          anesthetics                   contraction are both ↑
                                                          (4) Cardiac resuscitation,    (↑CO); will see
                                                          IV cath                       constriction and dilation
                                                          (5) Topical for               depending on location
                                                          hemostasis
                            Isoproterenol                 (1) Bronchial asthma          β1 and β2 stimulant         Relatively limited use b/c                                Heart: +inotropic and
                               (Isuprel)                  (2) Heart Block                                           of intense cardiac                                        chronitropic effect
                                                                                                                    effects!                                                  Vasculatrue: vasodilat
                                                                                                                    (1) Tachycardia                                           skeletal mm arterioles
                                                                                                                    (2) Flushing                                              (β2 receptors on
                                                                                                                    (3) HA                                                    arterioles)
                                                                                                                    (4) Rapid pounding heart
                                                                                                                    (5) Arrhythmias
                                                                                                                    (6) Angina
                            Dopamine                      (1) Shock, particularly       Agonist at D1 receptors
                              (Intropin)                  hypovolemic (B1 benefit       (in kidney – leads to
                                                          CO, α1 inc BP)                vasodilation in kidney)
                                                                                        Agonist at β1, leads to
                                                                                        ↑CO
                                                                                        Agonist at α1, leads to
                                                                                        vasoconstriction
                            Dobutamine
*Prototypic drugs. Bolded names are on the drug list!!!
Notes from slides:
Alpha Adrenergic Effects                                                                                              Beta Adrenergic Effects
               constriction of blood vessels alpha1 (to lesser extent alpha2)                                            positive inotropic and chronotropic effects on heart Beta1
               mydriasis alpha1                                                                                          relaxation of bronchioles beta2
               contraction of the spleen alpha1                                                                          relaxation of the uterus beta2
               contraction of the uterus alpha1                                                                          relaxation of certain blood vessels (skeletal muscle arterioles, coronaries,
               inhibit release of insulin alpha2                                                                          some mesenteric) beta2
               constrict sphincter of bladder alpha1                                                                     metabolic effects (glycogenolysis beta2) (lipolysis beta2)
               gylcogenolysis – liver alpha1 (relatively weak comparted to beta2)                                        stimulate release of insulin beta2
               ejaculation vas deferens alpha1                                                                           stimulate release of renin beta1
               relaxation of intestinal smooth muscle alpha2                                                             relaxation of detrusor (bladder) beta2
                                                                                                                          relaxation of intestinal smooth muscle beta2
           Epinephrine Effects
           (1) Heart - Rate and Force of Contraction are both increased (CO is ↑). Therefore, oxygen consumption is increased.
           (2) Blood vessels – (a) Skeletal muscle arterioles: both 1 and 2 receptors are present: Physiological quantities see vasodilatation (2)/Pharmacological doses typically see
           vasoconstriction (1). (b) Veins: alpha-1; pure constriction. (c) Coronaries: vasodilate (d) kidney, skin, mucosa: vasoconstriction. (e) cerebral: unchanged
                 –     Net effects of BP (and cardiac fxn) depend on (1) dose, (2) circulatory status, (3) compensatory reflexes (baroreceptors-Stretch receptors located mainly in the carotid sinus (and
                       aortic arches) that sense blood pressure changes to maintain homeostasis. Signals are transmitted to the vasomotor center in the brain stem to alter parasympathetic and
                       sympathetic outflow to the heart and blood vessels.)
                 –     BP increases suddenly – sympathetic tone decreased; vagal tone to the SA node increased
                 –     BP decreases suddenly – sympathetic tone increased; vagal tone to the SA node decreased
           (3) Metabolic effects – (a) calorigenic effect and tremors in skeletal muscle (2), (b) mechanisms related to increased glycogenolysis (2) and lipolysis (3) at various organ sites (liver,
           skeletal muscle and adipocytes)

     •     FIRST GRAPH: NE and E have both been given at low doses. E widens the pulse pressure because it stimulates 2 receptor on arterioles, causing vasodilation. Because E at this dose does
           not raise mean blood pressure, no vagal reflexes are activated. Contrast these effects of those of NE, which essentially has no stimulant 2 effect
     •     SECOND GRAPH: In the next slide, notice that isoproterenol, a pure 1/2 agonist, has a greater vasodilating effect than E. This is because E is both a 2 agonist and also an 1 agonist. For
           E, The 1 effects partly offset the 2 effects at this dose. Indeed, if the dose of E is raised, only 1 agonist effects will be seen because E has more efficacy at 1 than 2 receptors.

                                                                     FIRST GRAPH                                               SECOND GRAPH
Type or Classification      Drug Name                     Used In                       Mechanism of action         Adverse/Side Effects        Contraindications         Other Notes
Adrenergic Agonists
Non-Catecholamines                                                                      Metabolized more slowly                                                           Longer acting, oral active
                            Phenylephrine*                (1) Nasal decongestant        Agonist at α1 adrenergic    Expect reflex                                         Prototypic drug for non-
                              (Neosynephrine)             (2) Infiltration with local   receptors – induces         bradycardia                                           catecholamine agonist
                                                          anesthetics                   vasocon and inc BP
                                                          (3) Pressor agent to
                                                          maintain BP
                                                          (4) Glaucoma
                                                          (5) Ocular exam –
                                                          mydriasis w/o affecting
                                                          accommodation
                            Tyramine                                                    Indirect acting agonist     Potential for HTN crisis    MAO-I – A classic drug    Prototypic drug for
                                                                                        (sympathomimetic)           in pts on MAO-I             interaction. Disastrous   indirect acting agonist
                                                                                                                                                HTN!!!                    Tyramine is found in
                                                                                                                                                                          foods (red wine, aged
                                                                                                                                                                          cheese, peanuts…).
                                                                                                                                                                          Normally subjected to
                                                                                                                                                                          large 1stpass effect that it
                                                                                                                                                                          never enters circulation
                            Cocaine                                                     Re-Uptake inhibitors                                                              Protytpic drug for
                                                                                        Blocks re-uptake of                                                               reuptake inhibitors
                                                                                        dopamine (abuse
                                                                                        mechanism), serotonin &                                                           Prolongs and intensifies
                                                                                        NE (effects on heart, BP)                                                         the actions of NE and E
                            Albuterol                     (1) Bronchial asthma          B2 selective agonist        Oral Route:                                           Prototypic drug for direct
                               (Proventil, Ventolin)      aerosol (acute) or PO                                     (1) hypotension                                       acting B2 agents
                                                          (chronic)                                                 (2) muscle tremors                                    2 receptors on skeletal
                                                                                                                    (3) tachycardia                                       muscles mediate inc
                                                                                                                    (4) hypokalemia                                       energy production
                                                                                                                                                                          Excess high energy
                                                                                                                                                                          compounds are reduced
                                                                                                                                                                          by muscle contraction
                            Ritodrine (Yutpoar)           Used to delay labor           B2 adrenergic agonist
                            Psuedoephedrine               (1) Nasal and eustachian      Indirect (releases NE)                                                            Naturally occurring in
                                                          tube decongestant –                                                                                             Ephedra. Relatively
                                                          release NE (decong bc of                                                                                        insensitive to
                                                          reduced pooling of blood                                                                                        degradation by MAO and
                                                          in venous circulation)                                                                                          COMT. Effective PO.
                                                                                                                                                                          Much less dependence
                                                                                                                                                                          that ephedrine – doesn’t
                                                                                                                                                                          penetrate CNS
                            Amphetamines                  (1) Narcolepsy                                            Insomina, Anxiety,                                    Non-polar and penetrate
                                                          (2) ADHD in children                                      Arrhythmias, N/V                                      CNS. No longer approved
                                                          (3) Obesity- anorexiant                                   Toxicity: convulsions,                                due to abuse potential!!
                                                          effect.                                                   coma, death
                                                                                                                    Chronic: abnl mental
                                                                                                                    state, wt loss, psychotic
                                                                                                                    reactions
*Prototypic drugs. Bolded names are on the drug list!!!
Notes from slides:
          Direct acting non-catecholamines: Synthetic agents, lacking the catechol moiety. Analogues of NE or EPI. Non-catecholamines are metabolized more slowly (they are not acted upon as
          readily by MAO, and often they are not stored in vessicles). Therefore they are generally longer acting and some are effective p.o.

          β2 Selective Agonists: As a group, 5-10X more potent at β2 than β1 adrenergic receptors. Therefore more selective for smooth than cardiac muscle. Longer acting than catecholamines.
          Tolerance may develop. (USED IN ASTHMA to RELAX BRONCHIOLES)
               1. Albuterol (Proventil)
               2. Metaproterenol (Metaprel, Alupent)
               3. Terbutaline (Brethine)
                          –      (aerosol and sc; sc for emergency tx of astma; only 2 agent available sc )
                          –      iv.and p.o. to delay delivery.
               4. Isoetherine (Bronkosol)
               5. Salmeterol (Serevent). Once a day agent for chronic but not acute treatment of asthma. Has slow onset of action

          Psuedoephedrine
                   Common OTC Products with Alpha 1 Effects (direct and indirect)
                        •  Naphazoline (Privine)
                        •  Tetrahyrolazine (Tyzine, Visine)
                        •  Xylometrazoline (Otrivin)
                        •  Oxymetazoline(Afrin)

          Amphetamines: Large group of drugs with high abuse potential (Schedule II). All are indirect acting. Release NE from adrenergic nerves. Also release dopamine in CNS, which is the
          mechanism of euphoria related to abuse. These agents are taken up into nerve terminals via the uptake-one mechanism. They also compete with and reduce NE and dopamine reuptake.
              •    Generally display a higher ratio of CNS to peripheral cardiovascular effects. However, vasoconstriction and a positive inotropic effect are present.
   Type or Classification              Drug Name                   Used In               Mechanism of action           Adverse/Side Effects           Contraindications           Other Notes
Adrenergic Blockers
α Blockers                   α blockers are antagonists (they have no intrinsic activity), but they do produce change!
   -sin                      They block the effects of any compound acting at α receptors (whether that compound acts directly or indirectly)
                             Phentolamine                                                Non-selective α blockers                                                           Prototype
                                (Regitine)                                               (block both α1 and α2)
                                Phenoxybenzamine                                         -Affinity is α1= α2
                                                                                         -Also an agonist at
                                                                                         muscarinic and histamine
                                                                                         receptors
                             Phenoxybenzamine              (1) Phenochromocytoma         Non-selective α blockers    Effects:                                               Onset is slow (several
                                (Dibenzyline)              – pre-op management to        (block both α1 and α2)      (1) Vascular. Blocks the effects of endogenous NE –    min for formation of
                                                           treat vascular effects of     Binds covalently to α1      reduces BP.                                            covalent linkages)
                                                           high circulating              and α2 receptors            (2) Cardiac. Reflex tachycardia. Reducing BP causes    Offset is very slow
                                                           catecholamines                                            sympathetic activation. B/c α2 receptors on            (elimination t½=24 hrs,
                                                           (2) Peripheral vascular                                   adrenergic nerves are blocked, this further inc NE     new receptors must be
                                                           disease (Raunaud’s                                        release at the heart, where NE can act on β1           synthesized).
                                                           syndrome)                                                 receptors.                                             Inc doses cause NE effect
                                                                                                                     (3) CNS. Lipophilic agent that crosses BBB. N/V,       to contract smooth mm
                                                                                                                     weakness may be signs of non-specific CNS effects.     to decrease.
                                                                                                                     (4) Other. Miosis, inhibition of ejaculation, stuffy
                                                                                                                     nose.
                             Prazosin                      (1) Benign prostatic          α1 selective blockers       Reflex tachycardia may                                 Due to orthostatic
                                (Minipress)                hypertrophy                                               occur, but sig less than                               hypotension, this agent
                                                           (2) Hypertension                                          with non-selective                                     has limited use
                                                                                                                     blockers                                               compared to newer
                                                                                                                     Syncope – seen when                                    drugs.
                                                                                                                     first administered.
                                                                                                                     Caused by orthostatic
                                                                                                                     hypotension and caution
                                                                                                                     pts to avoid sudden
                                                                                                                     postural changes.
                                                                                                                     Orthostatic hypotension
                                                                                                                     – limits use of drug
                             Terazosin (Hytrin)            Same uses as Prazosin         α1 selective blockers       Significantly less
                                                                                                                     orthostatic hypotension
                                                                                                                     compared to Prazosin if
                             Doxazosin (Cardura)                                                                                                                            Long t½=24 hr, makes
                                                                                                                     doses are low and given
                                                                                                                                                                            once daily dosing feasible
                                                                                                                     at bedtime
                             Tamsulosin (Flomax)           BPH – highly efficacious      α1A selective blockers                                                             Vascular effects of α
                                                                                                                                                                            blockers likely mediated
                                                                                                                                                                            by α1B receptor
Bolded names are on the drug list!!!
α adrenergic blockers
     •    They block the effects of any compound acting at a receptors (whether that compound acts directly or indirectly)
                –     Endogenous agonists (epinephrine; norepinephrine). Note: sympathetic tone explains why antagonists produce effects.
                –     Exogenously applied drugs (e.g. norepinephrine, phenylephrine, tyramine)
     •    Two families have been identified, each has 3 subtypes
                –     α1 family: α1A, α1B and α1D
                –     α2 family: α2A, α2B and α2C
     •    Some drugs differentiate α1 and α2 by family, but very few differentiate subtypes of receptors. The appearance of tamsulosin is particularly interesting in this regard.
     •    α1 receptor distribution and effects of stimulation
                –     arterioles and veins – constrict
                –     eye (radial muscle of the iris) – contracts (leads to pupil dilation)
                –     intestine – constricts sphincters, decreases motility (hyperpolarization leads to relaxation)
                –     prostate (note: this in an α1A receptor; vascular α receptors are likely α1B) – contraction, promotes tissue growth
                –     urinary bladder sphincters – constricts
     •    α2 receptor distribution and effects of stimulation
                –     NE nerve terminals – decreases NE outflow (autoreceptor)
                –     CNS – decreases sympathetic outflow
   Type or Classification            Drug Name                       Used In               Mechanism of action           Adverse/Side Effects           Contraindications             Other Notes
Adrenergic Blockers
β Blockers                    All 3 families of β receptors use Gs second message system
   -lol
                              Propranolol                   (1) Angina pectoris.         Non-selective β blockers     Effects:                      (1) Asthma                  Prototype
                                (Inderal)                   Reduces cardiac work         (block β1, β2, and β3)       (1) Heart. ↓CO, ↓HR, -        (2) Obstructive             High doses may have a
                                Nadolol (Corgard)           and O2 consumption.          Non-selective                inotrope, ↓spontaneous        pulmonary dz                non-receptor-related
                                Timolol (Blocarden)         (2) HTN. ↓in peripheral      competitive antagonist       pacemaker activity            (3) Cardiogenic shock       membrane-stabilizing
                                Pindolol*                   resistance due to            at β1 and β2 receptors       (2) Blood vessels. ↓renin     (4) Acute tx of heart       effect.
                                Carteolol*                  blockade of renin                                         release  ↓angiotensin        failure
                                                            release.                                                  and ↓aldosterone, slow        (5) 2nd and 3rd degree      Metabolism: following
                                                            (3) Migraine HA.                                          developing ↓ in               block                       PO admin, up to 2/3 may
                                                            (prophylactic tx).                                        peripheral resistance                                     be inactivated by 1st pass
                                                            (4) Arrhythmias                                           (3) Bronchial smooth                                      metabolism (low
                                                            (5) Pheochromocytoma                                      mm. Blocks relaxation.        Drug interactions:          bioavailability). Titrate
                                                            (6) Thyrotoxicosis                                        Watch out for                 -additive with              dose upward for each pt.
                                                            (7) Adjunctive tx of                                      bronchospasm where            hypotensive agents
                                                            anxiety                                                   sympathetic tone              -prolongs hypoglycemia      Sudden withdrawal –
                                                            (8) Reduce mortality post                                 maintains the airway.         in pts taking               may see rebound HTN
                                                            MI                                                        (4) Metabolic. Blocks         hypoglycemic agents.        and possibly anginal
                                                            (9) management of heart                                   lipolysis and                 Mask signs of               attacks. β receptor
                                                            failure                                                   glycogenolysis.               hypoglycemia.               synthesis is inc by β
                                                                                                                      SE:                           -mask symptoms of           blocker use (UP-
                                                            Timolol – glaucoma (dec                                   -Common: dizziness,           hyperthyroidism.            regulation)
                                                            synthesis of aqueous                                      tiredness, N/D,
                                                            humor)                                                    depression, constipation,                                 Nadolol – long duration
                                                                                                                      vivid dreams, impotence                                   of action (once daily
                                                                                                                      -Severe reactions:                                        dosing)
                                                                                                                      pupura, rash, fever
                                                                                                                      -Chronic use: inc VLDL
                                                                                                                      and dec HDL
                                                                                                                      -In IDDM – delays
                                                                                                                      recovery from
                                                                                                                      hypoglycemia
                              Metoprolol                                                 β1 (cardio) selective                                      Use caution with pts with   Prototype
                                Bexaolol                                                 blockers                                                   reactive (asthma)
                                Esmolol (Brevibloc)                                                                                                 airways.                    Esmolol – very short
                                Bisoprolol                                                                                                                                      acting, used in
                                Acebutolol                                                                                                                                      management of MI
                              Atenolol                      HTN, Stable angina           β1 (cardio) selective
                                (Tenormin)                                               blockers
Combined α and β blockers
                                Labetalol                   HTN                           Combined α and β
                                  (Normodyne, Trandate)                                   blockers
                                Carvedilol                  Heart failure
                                   (Coreg)                  HTN
*Partial agonist that aren’t blockers. They down regulate so you will see the action similar to blockers. See ISA notes on back. Bolded names are on the drug list!!!
βadrenergic blockers
     •    β1 receptor distribution and effects of stimulation
                –    Heart – increases rate and contractility, enhances conduction through the AV node
     •    β2 receptor distribution and effects of stimulation
                –    bronchioles – relaxation
                –    uterus – relaxation
                –    arterioles – relaxation, diastolic BP drops
                –    skeletal muscles – promote K uptake, increase high-energy compounds
                –    liver – increases glycogenolysis
                –    fat cells – increases lipolysis
     •    No drugs are available that selectively stimulate or block β3 receptors
     •    Non-selective beta-blockers with ISA (partial agonists)
                –    ISA – intrinsic sympathomimetic activity
                –    This term is used to describe an agent that blocks the effects of a full agonist such as EPI, but that also causes some modest beta-adrenergic stimulation.
                –    ISA actually means that the agent is a partial agonist.
                            -     Occupancy of beta receptors shields them from the effects of full agonists, thus it looks like a beta blocker
                            -     Weak efficacy appears as a slight beta stimulation
                            -     As described below, partial agonist drugs exist that are either non-selective (b1/b2) or cardio selective (b1)
                            -     In theory, these agents should be preferred because of less bronchospasm, less bradycardia, less negative inotropic features, and a better lipid profile
                            -     However, no clinical therapeutic advantages have been documented

				
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posted:12/12/2011
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