Adrenergic Receptor Antagonists in therapy of Hypertension

1. Adrenergic Receptor Antagonists in therapy of Hypertension Dr. Thomas Abraham PHAR 417: Fall 2004

2. a -Adrenergic Receptor Antagonists

3. a -Adrenergic Receptor Antagonists • ØMay be classified as: • Reversible (equilibrium) competitive antagonists e.g. phentolamine, tolazoline, prazosin • Irreversible (nonequilibrium) competitive antagonists e.g. phenoxybenzamine, dibenamine • Øa1- and a2-adrenoceptors are responsible for the maintenance of total peripheral resistance to maintain blood pressure. In many pts. with essential hypertension TPR may be abnormally elevated due to increased a-adrenergic receptor stimulation.

4. a -Adrenergic Receptor Antagonists • ØAgents that antagonize both a1- and a2-adrenoceptors tend to be less efficacious in lowering BP than a1-selective agents: • ØBlockade of a2- adrenoceptors will cause enhanced release of NE at the sympathetic neurons leading to excess adrenoceptor stimulation (esp. b-receptors in heart).

5. a -Adrenergic Receptor Antagonists • Phentolamine is an example of a nonselective a-antagonist: binds to both a1- and a2-adrenoceptors with equivalent affinities ØApplication of an a-antagonist will decrease resting mean blood pressure as well as pressor responses to a-agonists such as epinephrine.

6. a -Adrenergic Receptor Antagonists • ØAgents (in this class) most often used in hypertension therapy are a1-selective antagonists: • ØPrazosin most prone to hepatic metabolism, has the shortest half-life of elimination and primarily eliminated in the bile. Doxazosin and terazosin have more renal elimination of the parent compound and longer t1/2 of elimination. • ØAntagonism of a1-adrenoceptors results in dilation of arteries, arterioles and veins: • Arterial/arteriolar dilation results in decreased afterload ( decreased TPR) • Afterload: the pressure that the heart has to work against • Venous dilation causes decreased preload (more venous pooling). Decreased preload decreases myocardial stretch and thus the CO

7. a -Adrenergic Receptor Antagonists • Some increase in the renin-angiotensin production seen with chronic therapy with these agents: ØIn hypertension therapy a1-selective antagonists have equivalent BP lowering capacity as calcium channel blockers and thiazide diuretics. ØAdverse effects are primarily due to extension of the pharmacological effect: hypotension (first dose or orthostatic), dizziness, headache, nasal congestion, impaired ejaculation, miosis. Prazosin may be the least well tolerated of the selective antagonists.

8. a -Adrenergic Receptor Antagonists • Øa1-selective antagonists may be contraindicated in right heart failure or cardiac valvular stenosis. • They can be used in combination with thiazides and possibly ACEIs and ARBs. Combination with CCBs may cause drastic hypotension. • ØAlternative use for a1-selective antagonists: benign prostatic hyperplasia (BPH, terazosin is DOC); • Irreversible (nonequilibrium) competitivea-antagonists • ØPhenoxybenzamine and dibenamine alkylate a1- and a2-adrenoceptors to cause decreases in receptors available for activation by catecholamines. • ØPrimarily used in pheochromocytoma (adrenal medullary tumors) where excess catecholamine production results in dangerously high BP.

9. b -Adrenergic Receptor Antagonists

10. b -Adrenergic Receptor Antagonists b-adrenergic receptor antagonists Øb1-adrenoceptors appear central to the hypotensive effects of these agents since b2- selective antagonists are without efficacy. However b1-selective agents have no additional advantages over nonselective antagonists with regard to hypertension. ØMajor characteristics that distinguish members of this class are: ob1 vs. b2 selectivity: propranolol has equivalent affinities for the two receptors while metaprolol, esmolol and atenolol show greater b1 receptor affinity. oIntrinsic sympathomimetic activity or partial agonism: propranolol is a pure antagonist with no ability to activate b-receptors, while pindolol and acebutolol behave more as a partial agonist.

11. b -Adrenergic Receptor Antagonists (Characteristic (cont) oa-adrenoceptor blocking activity: most agents in this class are relatively b-selective however labetalol and carvedilol have significant a1-blocking activity. oLipid solubility: the more lipophilic agents (propranolol) have greater CNS effects and “membrane-stabilizing” effects. ØGenerally b-blockade causes greater decreases in HR and contractility during sympathetic nervous system activity (exercise, stress, hypertension) than during rest or in normotensive pts.

12. b -Adrenergic Receptor Antagonists ØMajor effect to decrease cardiac rate and contractility to decrease CO, and thereby MBP. ØInitially TPR may rise due to b2-blockade and/or reflex baroreceptor mechanism to maintain BP. Agents with ISA or a-blocking activity may produce less increase in TPR. Øb-antagonists also decrease renin release from the juxtaglomerular cells in response to sympathetic stimulation: less circulating angiotensin II. ØMixed antagonists such as labetalol and carvedilol may produce decreases in BP by a1-blockade in the vasculature as well as b-blockade in the heart. Labetalol also appears to have partial b2-agonistic activity (may be advantage in peripheral vascular disease).

13. b -Adrenergic Receptor Antagonists ØAgents with ISA (pindolol, acebutolol) generally produce smaller decreases in CO: this may be preferred in pts. with bradycardias or decreased cardiac reserve. ØAdverse effects of these agents are primarily pharmacological: may induce heart failure, bradycardia, angina after withdrawal from prolonged therapy, bronchoconstriction in asthmatics and COPD, fatigue, insomnia, depression, decreased hypoglycemic recovery, increased plasma triglycerides. ØDrug interactions: cholestyramine, colestipol decrease drug absorption from GI tract; phenytoin, rifampim, phenobarbital increase plasma clearance of b-blockers and lidocaine clearance decreased by the antagonists; enhanced cardiac conduction defects with CCBs; NSAIDS may decrease effectiveness of b-blockers to decrease the BP.

14. b -Adrenergic Receptor Antagonists • ØTherapeutic uses: • oHypertension • oPost-myocardial infarction • oCongestive Heart Failure • o Cardiac arrhythmias • oMigraine prophylaxis • oStage-fright • oGlaucoma