Prazosin & Other Alpha1 Blockers

PRAZOSIN & OTHER ALPHA₁ BLOCKERS

Mechanism & Sites of Action

Prazosin, terazosin, and doxazosin produce most of their antihy-pertensive effects by selectively blocking α₁ receptors in arterioles and venules. These agents produce less reflex tachycardia when lowering blood pressure than do nonselective α antagonists such as phentolamine. Alpha₁-receptor selectivity allows norepineph-rine to exert unopposed negative feedback (mediated by presynap-tic α₂ receptors) on its own release ; in contrast, phentolamine blocks both presynaptic and postsynaptic α receptors, with the result that reflex activation of sympathetic neurons by phentolamine’s effects produces greater release of transmitter onto receptors and correspondingly greater cardioacceleration. Alpha blockers reduce arterial pressure by dilating both resistance and capacitance vessels. As expected, blood pressure is reduced more in the upright than in the supine position. Retention of salt and water occurs when these drugs are administered with-out a diuretic. The drugs are more effective when used in combi-nation with other agents, such as a β blocker and a diuretic, than when used alone. Owing to their beneficial effects in men with prostatic hyperplasia and bladder obstruction symptoms, these drugs are used primarily in men with concurrent hypertension and benign prostatic hyperplasia.

Pharmacokinetics & Dosage

Pharmacokinetic characteristics of prazosin are listed in Table 11–2. Terazosin is also extensively metabolized but undergoes very littlefirst-pass metabolism and has a half-life of 12 hours. Doxazosin has an intermediate bioavailability and a half-life of 22 hours.Terazosin can often be given once daily, with doses of 5–20 mg/d. Doxazosin is usually given once daily starting at 1 mg/d and progressing to 4 mg/d or more as needed. Although long-term treatment with these α blockers causes relatively little postural hypotension, a precipitous drop in standing blood pressure devel-ops in some patients shortly after the first dose is absorbed. For this reason, the first dose should be small and should be administered at bedtime. Although the mechanism of this first-dose phe-nomenon is not clear, it occurs more commonly in patients who are salt- and volume-depleted.Aside from the first-dose phenomenon, the reported toxicities of the α₁ blockers are relatively infrequent and mild. These include dizziness, palpitations, headache, and lassitude. Some patients develop a positive test for antinuclear factor in serum while on prazosin therapy, but this has not been associated with rheumatic symptoms. The α₁ blockers do not adversely and may even beneficially affect plasma lipid profiles, but this action has not been shown to confer any benefit on clinical outcomes.

OTHER ALPHA-ADRENOCEPTOR– BLOCKING AGENTS

The nonselective agents, phentolamine and phenoxybenzamine, are useful in diagnosis and treatment of pheochromocytoma and in other clinical situations associated with exaggerated release of catecholamines (eg, phentolamine may be combined with propra-nolol to treat the clonidine withdrawal syndrome, described previously).