Most adverse effects of phenoxybenzamine derive from its α-receptor–blocking action; the most important are orthostatic hypotension and tachycardia. Nasal stuffiness and inhibition of ejaculation also occur. Since phenoxybenzamine enters the CNS, 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 both α1 and α2 receptors (Table 10–1). Phentolamine reduces peripheral resistance through blockade of α1 receptors and possibly α2 receptors 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 sympathetic 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 compensatory cardiac stimulation, which may cause severe tachycardia, arrhythmias, and myocardial ischemia. Phentolamine has been used in the treatment 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 competitive piperazinyl quinazoline effective in the management of hypertension (see Chapter 11). 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 phenoxybenzamine. 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 normally about 3 hours.
Terazosin is another reversible α1-selective antagonist that is effective in hypertension (see Chapter 11); it is also approved for use in men with urinary retention 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.