New alpha₁-adrenergic receptor antagonists for the treatment of hypertension: Role of vascular alpha receptors in the control of peripheral resistance

The pharmacology, clinical efficacy and safety of new alpha-adrenergic receptor antagonists for the treatment of hypertension was reviewed (Table XIV). Although all these agents block alpha1 receptors, some of them have additional effects on histamine, serotonin, dopamine, and alpha2 receptors. These other actions account for the differences in the side effect profiles observed, i.e., increased incidence of central nervous system side effects found with indoramin, ketanserin, and urapidil, as well as for some additional beneficial effects of ketanserin (i.e, antiplatelet aggregation activity). The magnitude of BP reduction observed with antagonists of alpha1-adrenergic receptors is modest. In most studies, the degree of BP reduction is comparable to that of prazosin, but less than that achieved with thiazide diuretics, beta-receptor antagonists, or methyldopa. Studies on the comparative efficacy and safety of new alpha1 antagonists with converting enzyme inhibitors or calcium-channel blockers are not available. In general, alpha1 antagonists produce greater reductions in standing than in supine BP, an effect due to the venodilatory action of these drugs. New alpha1 antagonists appear to have equal efficacy in black and white hypertensive individuals. Their comparative efficacy and safety in young vs elderly hypertensive individuals requires further investigation. No information about the possible development of tolerance during treatment with new alpha1 blockers was encountered. The effects of alpha1 antagonists on HR are variable and depend on how long after the oral dose the measurements were obtained. In most studies, no significant HR changes are noticed for readings obtained 24 hours post dose; whereas tachycardia has been observed at the time of peak hypotension. Since alpha1 antagonist-induced tachycardia is most likely of reflex nature, i.e., mediated to an increase in sympathetic activity, the increased HR may be associated with increases in myocardial contractility and in myocardial oxygen consumption. Consequently, a 24-hour HR monitoring during treatment with alpha1 antagonists should be required for evaluation of new agents. The hemodynamic, humoral, and hormonal effects of the newer alpha1-receptor antagonists are comparable to those of prazosin. The most consistent finding is a reduction in total peripheral resistance associated with either no change or with only small increases in cardiac index. These agents have been shown either not to change or to increase renal blood flow. Small increases in circulating plasma and blood volumes, hemodilution, and increases in body weight have been reported after chronic treatment. None of these agents seem to reduce exercise tolerance. Combination of newer alpha1 antagonists with other antihypertensive agents appears to be well tolerated. Most studies have shown that the new alpha1 antagonists have additive effects with thiazide diuretics and beta blockers. No information is available regarding their combination with centrally-acting alpha2 agonists, calcium-channel blockers, and/or converting-enzyme inhibitors. Substantial evidence indicates that in addition to hypertension, elevated serum cholesterol is a primary risk factor for the development of coronary artery disease170 and that increases in HDL cholesterol may serve as a protective factor against this disease.171 Administration of thiazide diuretics has been associated with increases in total cholesterol with no change in HDL cholesterol.172-175 Beta blockers have also been shown to increase triglycerides and to decrease HDL cholesterol.176, 177 Terazosin, doxazosin, trimazosin, indoramin, and ketanserin have either beneficial or no significant effects on serum lipids. Their effects are similar to those of prazosin, but significantly different from those of beta blockers and diuretics. In most studies, the new alpha antagonists lowered serum cholesterol and triglycerides, and increased HDL cholesterol as well as the HDL/total cholesterol ratio, although the effects were of small magnitude. When added to a thiazide diuretic, the alpha1 antagonists reversed or diminished the negative effects of the thiazides on serum lipids. However, it should be indicated that the clinical significance of the "unfavorable" effects of some antihypertensive drugs on serum lipids, or the "improvement" in the lipid profile produced by most alpha1 antagonists, is unknown. Extensive discussion of this problem is available in other publications.178-181. The major difference between prazosin and drugs such as terazosin and doxazosin relates to their clinical pharmacokinetics. Terazosin and doxazosin have two to six times longer half-lives than prazosin. This offers a therapeutic advantage, reducing the need for frequent drug administration and improving patient compliance. Single daily-dose administration or occasional twice-daily administration of divided doses of terazosin, doxazosin, and ketanserin is required to achieve BP control over a 24-hour period. In my opinion, this is the main advantage that these agents offer to the practicing physician. The inhibitory effects of ketanserin on platelet aggregation may also have important clinical advantages. The other drugs discussed (trimazosin, indoramin, ketanserin, and urapidil) require administration in several divided daily doses and/or have a higher incidence of side effects. In conclusion, terazosin, doxazosin, and trimazosin are more similar to prazosin than are indoramin, urapidil, and ketanserin. Terazosin and doxazosin appear to be exclusively alpha1-receptor antagonists and the quality and quantity of their side effects resemble that of prazosin. Because of their long serum half-life, these two agents may be used as monotherapy in single daily doses in patients with mild to moderate hypertension. In patients who require a second drug or who have moderate to severe or severe hypertension, these drugs could be safely combined with diuretics and/or beta blockers. Further investigations on the advantages of combined serotonin and alpha1-adrenergic blockade by ketanserin are forthcoming.