1. Catecholamine Agonists and Antagonists

2. Need-to-know Drugs Norepinephrine Norepinephrine Alpha 1 & 2 and Beta 1 agonist Alpha 1 & 2 and Beta 1 agonist Epinephrine Epinephrine Alpha 1 & 2 and Beta 1 & 2 agonist Alpha 1 & 2 and Beta 1 & 2 agonist Beta 3???? Beta 3???? Phenylephrine, Methoxamine Phenylephrine, Methoxamine Selective alpha 1 agonists Selective alpha 1 agonists Clonidine, Guanfacine, Brimonidine Clonidine, Guanfacine, Brimonidine Selective alpha 2 agonists Selective alpha 2 agonists Dobutamine Dobutamine Selective beta 1 agonist Selective beta 1 agonist Isoproterenol Beta 1 & 2 agonist Terbutaline, Albuterol, Ritodrine Selective Beta 2 agonists Tyramine Indirectly acting NE releasing agent Dopamine See DOPAMINE slide Cocaine NE uptake inhibitor

3. Directly Acting Agonists Selective alpha 1 agonists Selective alpha 1 agonists Phenylephrine, methoxamine Phenylephrine, methoxamine Selective alpha 2 agonists Selective alpha 2 agonists Clonidine, Brimonidine, guanfacine and guanabenz Clonidine, Brimonidine, guanfacine and guanabenz Mixed agonists Mixed agonists Norepinephrine (no B-2) and Epinephrine Norepinephrine (no B-2) and Epinephrine Selective Beta 1 agonist Selective Beta 1 agonist Dobutamine Dobutamine Beta 1 & 2 agonist Beta 1 & 2 agonist Isoproterenol Isoproterenol Selective Beta 2 agonist Selective Beta 2 agonist Terbutaline, albuterol, ritodrine Terbutaline, albuterol, ritodrine

4. Mixed Agonist Epinephrine at low doses: Epinephrine at low doses: Beta-adrenergic action more evident Beta-adrenergic action more evident Epinephrine at high doses: Epinephrine at high doses: Alpha mediated constriction of all vessels Alpha mediated constriction of all vessels Norepinephrine Norepinephrine Agonist ro alphas and beta 1 (not beta 2) Agonist ro alphas and beta 1 (not beta 2) Increases total peripheral resistance and blood pressure Increases total peripheral resistance and blood pressure Heart rate may go up or down Heart rate may go up or down “direct effects on ventricular musce not easily masked by baroreceptor reflex” (whatever that means) “direct effects on ventricular musce not easily masked by baroreceptor reflex” (whatever that means) Don’t assume balance of SNS and PNS Don’t assume balance of SNS and PNS

5. Indirectly acting sympathomimetics Elicit effects similar to NE. Read more in syllabus/text Elicit effects similar to NE. Read more in syllabus/text Releasing Agents Releasing Agents Amphetamine and tyramine Amphetamine and tyramine Uptake Inhibitors Uptake Inhibitors Cocaine Cocaine MAO/COMT inhibitors MAO/COMT inhibitors Pargyline and entacapone Pargyline and entacapone

6. Questions What indirect sympathomimetic agent is found in red wine, cheese, soybeans, and avocados? What indirect sympathomimetic agent is found in red wine, cheese, soybeans, and avocados? Tyramine (which causes the release of NE from the nerve terminal) Tyramine (which causes the release of NE from the nerve terminal) What are the 5 cardiovascular effects of pure alpha stimulation? What are the 5 cardiovascular effects of pure alpha stimulation? Constriction of vessels Constriction of vessels Increased TPR Increased TPR Reduced flow Reduced flow Increased BP Increased BP Decreased HR (little direct effect on the heart) Decreased HR (little direct effect on the heart) What are the cardiovascular effects of pure beta stimulation What are the cardiovascular effects of pure beta stimulation Dilation of skeletal muscle vasculature (b2) Dilation of skeletal muscle vasculature (b2) Decreased TPR, Decreased TPR, increased flow, increased flow, decreased BP, decreased BP, Increased HR (b1) Increased HR (b1)

7. Clinical Questions What agents can be used to relieve bronchoconstriction associated with asthma, pulmonary emphysema and bronchitis? What agents can be used to relieve bronchoconstriction associated with asthma, pulmonary emphysema and bronchitis? Beta 2s like albuterol or terbutaline Beta 2s like albuterol or terbutaline What agents can be used to restore activity to the heart in complete heart block or after cardiac arrest? What agents can be used to restore activity to the heart in complete heart block or after cardiac arrest? Beta 1s like isoproterenol or epinephrine (last ditch effort) Beta 1s like isoproterenol or epinephrine (last ditch effort) The alpha activity of epinephrine is useful for what conditions? The alpha activity of epinephrine is useful for what conditions? Hemostasis, anaphylaxis, reducing the diffusion of infiltration anesthetics, and maintaining BP if CO and perfusion are intact Hemostasis, anaphylaxis, reducing the diffusion of infiltration anesthetics, and maintaining BP if CO and perfusion are intact What conditions could be effectively treated by a selective alpha 1 agonist like phenylephrine? What conditions could be effectively treated by a selective alpha 1 agonist like phenylephrine? Nasal congestion, and as a mydriatic agent Nasal congestion, and as a mydriatic agent

8. Clinical Questions What agents are useful for treating Narcolepsy and minimal brain dysfunction? What agents are useful for treating Narcolepsy and minimal brain dysfunction? Modafinil (new/good) and amphetamines (old/bad) Modafinil (new/good) and amphetamines (old/bad) What drugs are useful for glaucoma? What drugs are useful for glaucoma? Specific alpha 2 agonists like Brimonidine (new) Specific alpha 2 agonists like Brimonidine (new) What else are alpha 2 agonists good for? What else are alpha 2 agonists good for? Treating hypertension and, as of 2007, treatment of ADHD Treating hypertension and, as of 2007, treatment of ADHD

9. Dopamine What are three mechanisms by which Dopamine acts as an administered drug? What are three mechanisms by which Dopamine acts as an administered drug? Altering release of NE from adrenergic neurons Altering release of NE from adrenergic neurons Interacting with alpha and beta 1 receptors Interacting with alpha and beta 1 receptors Interacting with periperal dopamine receptors Interacting with periperal dopamine receptors What are its effects (low dose/high dose)? What are its effects (low dose/high dose)? Low doses elicit vasodilation in renal, mesenteric, coronary, and intracerebral vascular beds (alpha dopamine 1 effect) Low doses elicit vasodilation in renal, mesenteric, coronary, and intracerebral vascular beds (alpha dopamine 1 effect) Slightly higher doses increase heart rate and contractility, particularly contractility. Increases heart O2 consumption LESS than Epi. Slightly higher doses increase heart rate and contractility, particularly contractility. Increases heart O2 consumption LESS than Epi. At High doses alpha mediated vasoconstriction occurs At High doses alpha mediated vasoconstriction occurs Dopamine may be used as an IV to enhance renal perfusion or as a positive inotrope. Dopamine may be used as an IV to enhance renal perfusion or as a positive inotrope. What’s better about Dobutamine? What’s better about Dobutamine? Similar to Dopamine, but has an even better inotropic/chronotropic ratio, so its even better for heart problems. It is a specific Beta 1 agonist. Similar to Dopamine, but has an even better inotropic/chronotropic ratio, so its even better for heart problems. It is a specific Beta 1 agonist.

10. Adrenoceptor Antagonists 9/25/07

11. Need-to-Know Drugs Phenoxybenzamine Phenoxybenzamine Alpha 1 (and some alpha 2) blocker Alpha 1 (and some alpha 2) blocker Phentolamine Phentolamine Nonselective alpha blocker Nonselective alpha blocker Prazosin, Terazosin, Doxazosin Prazosin, Terazosin, Doxazosin Selective Alpha 1 blockers, very useful Selective Alpha 1 blockers, very useful Propranolol, Timolol, Nadolol Propranolol, Timolol, Nadolol Nonselective Beta Blocker Nonselective Beta Blocker Atenolol, Esmolol Atenolol, Esmolol Selective Beta 1 antagonists, very useful Selective Beta 1 antagonists, very useful Labetalol Labetalol Mixed antagonist (B1 = B2 ≥ A1 > A2) Mixed antagonist (B1 = B2 ≥ A1 > A2)

12. Usefulness Which two classes of adrenoceptor antagonists are most clinically useful? Which two classes of adrenoceptor antagonists are most clinically useful? Selective alpha 1 antagonists: Prazosin, Terazosin, doxazosin Selective alpha 1 antagonists: Prazosin, Terazosin, doxazosin Selective Beta 1 antagonists: Metoprolol, Esmolol, Atenolol, Acebutolol, Alprenolol, Betaxolol, Celiprolol Selective Beta 1 antagonists: Metoprolol, Esmolol, Atenolol, Acebutolol, Alprenolol, Betaxolol, Celiprolol

13. Alpha Blockers Compare and contrast the three groups of Alpha Receptor Blockers Compare and contrast the three groups of Alpha Receptor Blockers 1) Phenoxybenzamine- (haloalkylamines) 1) Phenoxybenzamine- (haloalkylamines) Irreversible blockade of alpha 1 and 2 receptors through covalent bonds. Irreversible blockade of alpha 1 and 2 receptors through covalent bonds. May block histamine receptors and neuronal reuptake of catecholamines. May block histamine receptors and neuronal reuptake of catecholamines. Most important clinical effect is marked vasodilation of both arteries and veins, reducing TPR and BP. Increases blood flow to most vascular beds. Most important clinical effect is marked vasodilation of both arteries and veins, reducing TPR and BP. Increases blood flow to most vascular beds. Increases heart rate and contractility through baroreflex, inhibition of neuronal reuptake, and blocking alpha 2 presynaptic receptors (increasing NE). Increases heart rate and contractility through baroreflex, inhibition of neuronal reuptake, and blocking alpha 2 presynaptic receptors (increasing NE). Long duration, 2-3 days. Long duration, 2-3 days. Useful in treatment of pheochromocytoma, peripheral vascular disease like Renaud’s, as an adjunct in shock, prostatic hypertrophy. Useful in treatment of pheochromocytoma, peripheral vascular disease like Renaud’s, as an adjunct in shock, prostatic hypertrophy. Many adverse effects including: postural hypotension, tachycardia, arrhythmias, myocardial ischemia, misosis, nasal stuffiness, drowsiness, nausea, and failure to ejaculate. Many adverse effects including: postural hypotension, tachycardia, arrhythmias, myocardial ischemia, misosis, nasal stuffiness, drowsiness, nausea, and failure to ejaculate.

14. Alpha Blockers Compare and contrast the three groups of Alpha Receptor Blockers Compare and contrast the three groups of Alpha Receptor Blockers 2) Phentolamine (imidazolines) 2) Phentolamine (imidazolines) Reversible inhibition at alpha 1 & 2. Blocks serotonin at high doses Reversible inhibition at alpha 1 & 2. Blocks serotonin at high doses Mostly similar action as Phenoxybenzamine, but also enhances GI motility and secretion through histamine release by mast cells. Contraindicated in patients with gastritis or peptic ulcer. Mostly similar action as Phenoxybenzamine, but also enhances GI motility and secretion through histamine release by mast cells. Contraindicated in patients with gastritis or peptic ulcer. Much shorter duration Much shorter duration Silimar clinical uses as Phenoxybenzamine Silimar clinical uses as Phenoxybenzamine

15. Alpha Blockers Compare and contrast the three groups of Alpha Receptor Blockers Compare and contrast the three groups of Alpha Receptor Blockers 3) Prazosin, Terazosin, and Doxazosin (quinazoline derivatives) 3) Prazosin, Terazosin, and Doxazosin (quinazoline derivatives) Selectively blocks alpha 1 reversibly. Selectively blocks alpha 1 reversibly. Decreases peripheral vascular resistance, increases flow (vasodilator) and decreases pre-load, but does not induce reflex tachycardia (no alpha 2 activity). Decreases peripheral vascular resistance, increases flow (vasodilator) and decreases pre-load, but does not induce reflex tachycardia (no alpha 2 activity). Used for essential hypertension, CHF, BPH Used for essential hypertension, CHF, BPH Main side effect is postural hypotension. Main side effect is postural hypotension. Duration: Prazosin 7-10 hours. Terazosin and Doxazosin are more water soluble and last 18-36 hours. Duration: Prazosin 7-10 hours. Terazosin and Doxazosin are more water soluble and last 18-36 hours.

16. Beta Receptor Blockers What was the first beta adrenoreceptor antagonist introduced for clinical use in the U.S.? What was the first beta adrenoreceptor antagonist introduced for clinical use in the U.S.? Propranolol (nonselective beta blocker) Propranolol (nonselective beta blocker) Which isomers, levo or dextro, are more active as beta antagonists? Which isomers, levo or dextro, are more active as beta antagonists? levo levo

17. Beta Blocker Characteristics Mechanism Mechanism Reversible competitive antagonism of Beta receptors Reversible competitive antagonism of Beta receptors Main Effects Main Effects Decrease heart rate, contractility, CO, and conduction velocity, particularly when sympathetic activity is high. Decrease heart rate, contractility, CO, and conduction velocity, particularly when sympathetic activity is high. Reduce BP with chronic use, partly due to decreased renal renin release. Reduce BP with chronic use, partly due to decreased renal renin release. Decrease glycogenolysis and lipolysis. Decrease glycogenolysis and lipolysis. Increase airway resistance (decreased Beta 2) Increase airway resistance (decreased Beta 2) Reduce intraocular pressure in open angle glaucoma Reduce intraocular pressure in open angle glaucoma May have some membrane stabilizing or local anesthetic effect (propranolol) or have a slight intrinsic sympathomimetic activity (partial agonist; pindolol) May have some membrane stabilizing or local anesthetic effect (propranolol) or have a slight intrinsic sympathomimetic activity (partial agonist; pindolol) Clinical Uses Clinical Uses arrhythmias, angina, HTN, MI, hyperthyroidism, open angle glaucoma, prophylactic migraine treatment, acute dissecticing aortic anneurysm and pheochromocytoma (after alpha antagonists) arrhythmias, angina, HTN, MI, hyperthyroidism, open angle glaucoma, prophylactic migraine treatment, acute dissecticing aortic anneurysm and pheochromocytoma (after alpha antagonists)

18. Beta Blocker characteristics Clinical Problems Clinical Problems Heart effects can cause problems in CHF patients and those with conduction disturbances. Heart effects can cause problems in CHF patients and those with conduction disturbances. Bronchoconstriction. Even selective B1 blockers should be used with caution in asthmatics Bronchoconstriction. Even selective B1 blockers should be used with caution in asthmatics Hypoglycemic effect is dangerous in DM type 1 patients. Hypoglycemic effect is dangerous in DM type 1 patients. Side effects include: tiredness, insomnia, depression, nightmares, diarrhea, heartburn, rash, and fever. Side effects include: tiredness, insomnia, depression, nightmares, diarrhea, heartburn, rash, and fever. Must be discontinued slowly to prevent “beta-blocker withdrawl syndrome” Must be discontinued slowly to prevent “beta-blocker withdrawl syndrome” Selective Beta 1 Blockers Selective Beta 1 Blockers Atenolol and Esmolol (as well as metoprolol, acebutolol, alprenolol, atenolol, betaxolol, and celiprolol (from the chart)) Atenolol and Esmolol (as well as metoprolol, acebutolol, alprenolol, atenolol, betaxolol, and celiprolol (from the chart)) Selective Beta 2 Blocker Selective Beta 2 Blocker Butoxamine (clinically useless??) Butoxamine (clinically useless??)

19. Mixed Antagonists Examples Examples Lebtalol or Carvedilol Lebtalol or Carvedilol Mechanism Mechanism Competitive blocking of beta receptors and alpha 1 receptor Competitive blocking of beta receptors and alpha 1 receptor Some sympathomimetic activity at alpha 2 and Beta 2 Some sympathomimetic activity at alpha 2 and Beta 2 Direct, non-receptor mediated vasodilation (I guess on top of its alpha 1 blocking vasodilation) Direct, non-receptor mediated vasodilation (I guess on top of its alpha 1 blocking vasodilation) May block neuronal reuptake of catecholamines May block neuronal reuptake of catecholamines Clinical Use Clinical Use Chronic HTN, HTN + Angina, and Ischemic Heart disease Chronic HTN, HTN + Angina, and Ischemic Heart disease Clinical Problems Clinical Problems May cause excessie hypotension or “paradoxical presser effects,” GI distress, tiredness, sexual dysfunction May cause excessie hypotension or “paradoxical presser effects,” GI distress, tiredness, sexual dysfunction Dangerous in asthmatics and CHF patients (like any beta blockers) Dangerous in asthmatics and CHF patients (like any beta blockers)