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Chapter: Basic & Clinical Pharmacology : Adrenoceptor Antagonist Drugs

Specific Agents

Phenoxybenzamine binds covalently toαreceptors, causing irre-versible blockade of long duration (14–48 hours or longer).


Phenoxybenzamine binds covalently toαreceptors, causing irre-versible blockade of long duration (14–48 hours or longer). It is somewhat selective for α1 receptors but less so than prazosin (Table 10–1). The drug also inhibits reuptake of released norepinephrine by presynaptic adrenergic nerve terminals. Phenoxybenzamine blocks histamine (H1), acetylcholine, and serotonin receptors as well as α receptors .

The pharmacologic actions of phenoxybenzamine are primarily related to antagonism of α-receptor–mediated events. The most significant effect is attenuation of catecholamine-induced vasocon-striction. While phenoxybenzamine causes relatively little fall in blood pressure in normal supine individuals, it reduces blood pres-sure when sympathetic tone is high, eg, as a result of upright pos-ture or because of reduced blood volume. Cardiac output may be increased because of reflex effects and because of some blockade of presynaptic α2 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 dosages of 10 mg/d and progressively increasing the dose until the desired effect is achieved. A dosage of less than 100 mg/d is usually suffi-cient to achieve adequate α-receptor blockade. The major use of phenoxybenzamine is in the treatment of pheochromocytoma .

Most adverse effects of phenoxybenzamine derive from its α-receptor–blocking action; the most important are orthostatichypotension 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.

Phentolamine is a potent competitive antagonist at bothα1and α2 receptors (Table 10–1). Phentolamine reduces peripheral resistance through blockade of α1 receptors and possibly α2 recep-tors on vascular smooth muscle. Its cardiac stimulation is due to antagonism of presynaptic α2 receptors (leading to enhanced release of norepinephrine from sympathetic nerves) and sympa-thetic activation from baroreflex mechanisms. 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 treat-ment of pheochromocytoma. In addition it is sometimes used to reverse local anesthesia in soft tissue sites; local anesthetics are often given with vasoconstrictors that slow their removal. Local phentolamine permits reversal at the end of the procedure. Unfortunately oral and intravenous formulations of phentolamine are no longer consistently available in the United States.

Prazosin is a piperazinyl quinazoline effective in the manage-ment of hypertension . It is highly selective for α1 receptors and typically 1000-fold less potent at α2 receptors. This may partially explain the relative absence of tachycardia seen with prazosin compared with that of phentolamine and phenoxyben-zamine. Prazosin relaxes both arterial and venous vascular smooth muscle, as well as smooth muscle in the prostate, due to blockade of α1 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 nor-mally about 3 hours.

Terazosin is another reversibleα1-selective antagonist that iseffective 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 metabo-lized 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 andBPH. 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 competitiveα1antagonist with a structurequite different from that of most other α1-receptor blockers. It has high bioavailability and a half-life of 9–15 hours. It is metabolized extensively in the liver. Tamsulosin has higher affinity for α1A and α1Dreceptors than for the α1Bsubtype. Evidence suggests thattamsulosin has relatively greater potency in inhibiting contraction in prostate smooth muscle versus vascular smooth muscle compared with other α1-selective antagonists. The drug’s efficacy in BPH suggests that the α1A subtype may be the most important α sub-type mediating prostate smooth muscle contraction. Furthermore, compared with other antagonists, tamsulosin has less effect on standing blood pressure in patients. Nevertheless, caution is appro-priate in using any α antagonist in patients with diminished sym-pathetic nervous system function. Patients receiving oral tamsulosin and undergoing cataract surgery are at increased risk of the intra-operative floppy iris syndrome (IFIS), characterized by the billow-ing of a flaccid iris, propensity for iris prolapse, and progressive intraoperative pupillary constriction. These effects increase the risk of cataract surgery, and complications are more likely in the ensu-ing 14 days if patients are taking these agents.

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