Alpha 1 adrenergic receptors antagonists (blockers): mechanism of action animation

Additional information about alpha 1 blocking drugs.  Source: Bertram G. Katzung, Basic & Clinical Pharmacology (Mc Graw-Hill Medical, 2007)

” Phentolamine, an imidazoline derivative, is a potent competitive antagonist at both alpha 1 and alpha 2 receptors . Phentolamine causes a reduction in peripheral resistance through blockade of alpha 1 receptors and possibly alpha 2 receptors on vascular smooth muscle. The cardiac stimulation induced by phentolamine is due to sympathetic stimulation of the heart resulting from baroreflex mechanisms. Furthermore, since phentolamine potently blocks alpha 2  receptors, antagonism of presynaptic alpha 2 receptors may lead to enhanced release of norepinephrine from sympathetic nerves. In addition to being an alpha 1- and alpha 1-receptor antagonist, phentolamine also has minor inhibitory effects at serotonin receptors and agonist effects at muscarinic and H1 and H2 histamine receptors.

Phentolamine has limited absorption after oral administration. Its pharmacokinetic properties are not well known; it may reach peak concentrations within an hour after oral administration and has a half life of 5-7 hours. The principal adverse effects are related to cardiac stimulation, which may cause severe tachycardia, arrhythmias, and myocardial ischemia, especially after intravenous administration. With oral administration, adverse effects include tachycardia, nasal congestion, and headache.

Phentolamine has been used in the treatment of pheochromocytoma -especially intraoperatively- as well as for male erectile dysfunction by injection intracavernosally and when taken orally (see below).

Phenoxybenzamine binds covalently to alpha receptors, causing irreversible blockade of long duration (14-48 hours or longer). It is somewhat selective for a1 receptors but less so than prazosin . The drug also inhibits reuptake of released norepinephrine by presynaptic adrenergic nerve terminals. Phenoxybenzamine blocks histamine (H1), acetylcholine, and serotonin receptors as well as a receptors .

The pharmacologic actions of phenoxybenzamine are primarily related to antagonism of alpha-receptor-mediated events. Most significant is that phenoxybenzamine attenuates catecholamine-induced vasoconstriction. While phenoxybenzamine causes relatively little fall in blood pressure in normal supine individuals, it reduces blood pressure when sympathetic tone is high, eg, as a result of upright posture or because of reduced blood volume. Cardiac output may be increased because of reflex effects and because of some blockade of presynaptic a2 receptors in cardiac sympathetic nerves.

Phenoxybenzamine is absorbed after oral administration, although bioavailability is low and its kinetic properties are not well known. The drug is usually given orally, starting with low doses of 10-20 mg/d and progressively increasing the dose until the desired effect is achieved. A dosage of less than 100 mg/d is usually sufficient to achieve adequate a-receptor blockade. The major use of phenoxybenzamine is in the treatment of pheochromocytoma (see below).

Many of the adverse effects of phenoxybenzamine derive from its a-receptor-blocking action; the most important are postural hypotension and tachycardia. Nasal stuffiness and inhibition of ejaculation also occur. Since phenoxybenzamine enters the central nervous system, it may cause less specific effects, including fatigue, sedation, and nausea. Because phenoxybenzamine is an alkylating agent, it may have other adverse effects that have not yet been characterized. Phenoxybenzamine causes tumors in animals, but the clinical implications of this observation are unknown.

Tolazoline is an obsolete agent similar to phentolamine. Ergot derivatives, eg, ergotamine, dihydroergotamine, cause reversible a-receptor blockade, probably via a partial agonist action .

Prazosin is a piperazinyl quinazoline effective in the management of hypertension . It is highly selective for a1 receptors and typically 1000-fold less potent at a2 receptors. This may partially explain the relative absence of tachycardia seen with prazosin compared with that reported with phentolamine and phenoxybenzamine. Prazosin leads to relaxation of both arterial and venous vascular smooth muscle, as well as smooth muscle in the prostate, due to blockade of a1 receptors. Prazosin is extensively metabolized in humans; because of metabolic degradation by the liver, only about 50% of the drug is available after oral administration. The half-life is normally about 3 hours.

Terazosin is another reversible a1-selective antagonist that is effective in hypertension; it is 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, with only a small fraction of unchanged drug excreted in the urine. The half-life of terazosin is 9-12 hours.

Doxazosin is efficacious in the treatment of hypertension and BPH. It differs from prazosin and terazosin in having a longer half-life of about 22 hours. It has moderate bioavailability and is extensively metabolized, with very little parent drug excreted in urine or feces. Doxazosin has active metabolites, although their contribution to the drug’s effects is probably small.

Tamsulosin is a competitive a1 antagonist with a structure quite different from that of most other a1-receptor blockers. It has high bioavailability and a long half-life of 9-15 hours. It is metabolized extensively in the liver. Tamsulosin has higher affinity for a1A and a1D receptors than for the a1B subtype. Evidence suggests that tamsulosin has relatively greater potency in inhibiting contraction in prostate smooth muscle versus vascular smooth muscle compared with other a1-selective antagonists. The drug’s efficacy in BPH suggests that the a1A subtype may be the most important a subtype mediating prostate smooth muscle contraction. Furthermore, compared with other antagonists, tamsulosin has less effect on standing blood pressure in patients. Nevertheless, caution is appropriate in using any a antagonist in patients with diminished sympathetic nervous system function”.

Source of animation: Medmovie

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