Pharmacology of Alpha-Receptor Antagonist Drugs

1. Pharmacology of Alpha-Receptor Antagonist Drugs • Cardiovascular Effects • α-receptor antagonist drugs lower peripheral vascular resistance and blood pressure. • These drugs can prevent the pressor effects of usual doses of α agonists.

2. α -receptor antagonism converts the pressor response of epinephrine to a depressor response. Epinephrine reversal is demonstrated by tracings showing the response to epinephrine before (middle) and after (bottom) phentolamine Top tracing is Phentolamine .

3. Alpha-receptor antagonists cause orthostatic hypotension and reflex tachycardia. Blockade of α 2-presynaptic receptors in the heart leads to augmented release of NE from peripheral sympathetic nerves, which will stimulate β1 receptors in the heart leading to tachycardia and increased contractility of the heart. Nonselective (α 1 = α 2,) blockers usually cause significant tachycardia if blood pressure is lowered below normal. Contraction of veins is an important component of the normal capacity to maintain blood pressure in the upright position since it decreases venous pooling in the periphery.

4. Other Effects Miosis. Nasal congestion. Decreased resistance to the flow of urine. Alpha blockers, therefore, are used therapeutically for the treatment of urinary retention due to prostatic hyperplasia .

5. Phenoxybenzamine Binds covalently(irreversibly) to α receptors, causing irreversible blockade of long duration (14–48 hours or longer). It is somewhat selective for α 1 receptors but also blocks α 2 receptors. The drug also inhibits reuptake of released NE and blocks histamine (H1),ACh, and serotonin receptors. Causes relatively little fall in blood pressurein the supine position, it reduces blood pressure when sympathetic tone is high, e.g. in the upright posture. Cardiac output may be increased because of reflex effects and because of some blockade of presynaptic α 2 receptors in cardiac sympathetic nerves.

6. Phenoxybenzamine ispoorly absorbed after oral administration. The major use of phenoxybenzamine is in the treatment of pheochromocytoma . Adverse effects Orthostatic hypotension and tachycardia. Nasal stuffiness and inhibition of ejaculation also occur.

7. Phentolamine Potent competitive antagonist at α 1 and α 2 receptors Like phenoxybenzamine can cause orthostatic hypotension, tachycardia, increased heart contractility, and consequently increased cardiac output.

8. Phentolamine Phentolamine also has minor inhibitory effects at serotonin receptors and agonist effects at muscarinic and H1 and H2 histamine receptors. Phentolamine's principal adverse effects are related to cardiac stimulation, which may cause severe tachycardia, arrhythmias, and myocardial ischemia. Phentolamine has been used in the treatment of pheochromocytoma.

9. Prazosin Highly selective for α 1 receptors and typically 1000-fold less potent at α 2 receptors. This may partially explain the relative absence of tachycardia seen with prazosin compared with phentolamine & phenoxybenzamine. Relaxes both arterial and venous vascular smooth muscle, as well as smooth muscle in the prostate.

10. Terazosin Reversible α 1-selective antagonist that is effective in hypertension.Also approved for use in men with urinary symptoms due to benign prostatic hyperplasia (BPH). Terazosin has high bioavailability but is extensively metabolized in the liver, The half-life of terazosin is 9–12 hours. Doxazosin Efficacious in the treatment of hypertension and BPH. Differs from prazosin and terazosin in having a longer half-life of about 22 hours.

11. Tamsulosin Competitive α 1 antagonist with a structure quite different from that of most other α 1-receptor blockers. High bioavailability and a half-life of 9–15 hours. Higher affinity for α 1A and α 1D receptors than for the α 1B subtype. Has relatively greater potency in inhibiting contraction in prostate smooth muscle versus vascular smooth muscle compared with other α 1-selective antagonists. α 1A subtype may be the most important α subtype mediating prostate smooth muscle contraction. It is used to treat BPH. Compared with other antagonists, tamsulosin has less effect on standing blood pressure in patients.

12. Drugs with Alpha- Adrenoceptor Antagonistic Activity Labetalol Has both α 1-selective and β-antagonistic effects Chlorpromazine and Haloperidol Are potent dopamine receptor antagonists but are also antagonists at α receptors. Useful antipsychotic drugs. Their antagonism of α receptors probably contributes to some of their adverse effects, particularly hypotension. Ergot derivatives Ergotamine Dihydroergotamine Cause reversible α -receptor blockade,

14. Yohimbine An indole alkaloid, α 2-selective antagonist. Sometimes used in the treatment of orthostatic hypotension because it promotes norepinephrine release through blockade of presynaptic α 2 receptors. It was once widely used to improve male erectile dysfunction but has been superseded by phosphodiesterase-5 inhibitors like sildenafil Yohimbine can reverse the antihypertensive effects of an α 2-adrenoceptor agonist such as clonidine.

15. Clinical Pharmacology of the Alpha-Receptor–Blocking Drugs Pheochromocytoma is a tumor of the adrenal medulla or sympathetic ganglion cells. Patients have many symptoms and signs of catecholamine excess, including intermittent or sustained hypertension, headaches, palpitations, and increased sweating. Phenoxybenzamine is given orally in the preoperative period to control hypertension. It is also very useful in the chronic treatment of inoperable or metastatic pheochromocytoma.

16. Beta-receptor antagonists are required after α -receptor blockade to reverse the cardiac effects of excessive catecholamines. Beta antagonists should not be used prior to establishing effective α -receptor blockade, since unopposed β -receptor blockade could theoretically cause blood pressure elevation from increased vasoconstriction. Metyrosine (α -methyltyrosine), a competitive inhibitor of tyrosine hydroxylase, is especially useful in symptomatic patients with inoperable or metastatic pheochromocytoma. Because it has access to the central nervous system, metyrosine can cause extrapyramidal effects due to reduced dopamine levels

17. Hypertensive Emergencies: The α -adrenoceptor antagonist drugs have limited application in the management of hypertensive emergencies. Labetalol has been used in Hypertensive Emergencies In theory, α -adrenoceptor antagonists are most useful when increased blood pressure reflects excess circulating concentrations of agonists, eg, in pheochromocytoma, overdosage of sympathomimetic drugs, or clonidine withdrawal.

18. Chronic Hypertension α 1-selective antagonists are efficacious drugs in the treatment of mild to moderate systemic hypertension. They are generally well tolerated, but they are not usually recommended as monotherapy for hypertension because other classes of antihypertensives are more effective in preventing heart failure. Their major adverse effect is orthostatic hypotension, which may be severe after the first few doses(First-Dose Phenomenon). They may cause dizziness.

19. Peripheral Vascular Disease: Alpha-receptor–blocking drugs do not seem to be effective in the treatment of peripheral vascular occlusive disease characterized by morphologic changes that limit flow in the vessels. Occasionally, individuals with Raynaud's phenomenon and other conditions involving excessive reversible vasospasm in the peripheral circulation do benefit from prazosin or phenoxybenzamine, although calcium channel blockers may be preferable for most patients.

20. Urinary Obstruction: Benign prostatic hyperplasia is common in elderly men. α 1A-receptor antagonists have improved efficacy and safety in treating this disease. The mechanism of action in improving urine flow involves partial reversal of smooth muscle contraction in the enlarged prostate and in the bladder base. Prazosin, doxazosin, and terazosin are all efficacious in patients with BPH, but they also lower the blood pressure. Tamsulosin is efficacious in BPH and has relatively minor effects on blood pressure at a low dose. This drug may be preferred in patients who have experienced orthostatic hypotension with other α 1-receptor antagonists.