Drugs that selectively block a1 adrenergic receptors without affecting a2 adrenergic receptors also are used in hypertension (Table 32-2). Prazosin (minipress), terazosin (Hytrin), and doxazosin (Cardura) are the agents approved in the U.S. for this indication.
PHARMACOLOGICAL EFFECTS Initially, a1 adrenergic receptor antagonists reduce arteriolar resistance and increase venous capacitance; this causes a sympathetically mediated reflex increase in heart rate and plasma renin activity. During chronic therapy, vasodilation persists, but cardiac output, heart rate, and plasma renin activity return to normal, and renal blood flow is unchanged. The a1 adrenergic blockers variably cause postural hypotension, depending on the plasma volume. Retention of salt and water occurs in many patients, which attenuates the postural hypotension. a1 Receptor antagonists reduce plasma concentrations of triglycerides and total low-density lipoprotein (LDL) cholesterol and increase HDL cholesterol. These potentially favorable effects on lipids persist when a thiazide diuretic is given concurrently. The long-term consequences of these changes in lipids are unknown.
ADVERSE EFFECTS The use of doxazosin as monotherapy for hypertension increases the risk of developing congestive heart failure. This may be an adverse effect of all of the ax adrener-gic receptor antagonists.
An important precaution in the use of the ax receptor antagonists for hypertension is the so-called first-dose phenomenon, which may occur in up to 50% of patients, especially in patients who are already receiving a diuretic or a receptor antagonist. This effect is characterized by symptomatic orthostatic hypotension within 90 minutes of the initial dose of the drug or after a dosage increase; after the first few doses, patients become tolerant to this marked hypotensive response.
THERAPEUTIC USES ax Receptor antagonists are not recommended as monotherapy for hypertensive patients. They rather are used primarily in conjunction with diuretics, P blockers, and other antihypertensive agents. p Receptor antagonists enhance the efficacy of the ax blockers. a1 Receptor antagonists are not the drugs of choice in patients with pheochromocytoma, because a vasoconstrictor response to epinephrine can still result from activation of unblocked vascular a2 adrenergic receptors. ax Receptor antagonists are attractive drugs for hypertensive patients with benign prostatic hyperplasia, since they also improve urinary symptoms.
Labetalol (normodyne, trandate) (see Chapter 10) is a mixture of four stereoisomers. One isomer is an a1 antagonist (like prazosin), another is a nonselective P antagonist with partial agonist activity (like pindolol), and the other two isomers are inactive. Because of its capacity to block a1 adrenergic receptors, intravenous labetalol can reduce pressure sufficiently rapidly to be useful for the treatment of hypertensive emergencies. Labetalol has efficacy and side effects that would be expected with any combination of P and a1 receptor antagonists; as with any fixed-dose combination, the relative extents of a receptor and P receptor antagonism vary from patient to patient.
Carvedilol (coreg) is a P receptor antagonist with a1 receptor antagonist activity. The drug is approved for the treatment of hypertension and symptomatic heart failure. The ratio of a1 to P receptor antagonist potency for carvedilol is ~1:10. Carvedilol is oxidized by hepatic CYP2D6 and then glucuronidated. Carvedilol reduces mortality in patients with systolic heart failure when used as an adjunct to therapy with diuretics and ACE inhibitors. It should not be given to those patients with decompensated heart failure who are dependent on sympathetic stimulation. As with labetalol, efficacy and side effects of carvedilol in hypertension are predictable based on its properties as a P and a1 adrenergic receptor antagonist.
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