Adrenoceptor Antagonists

a-Adrenoceptors are subdivided into two major classes, ai and a2, each of which has three subclasses. Antagonists of a^adrenoceptors, e.g., quinazolines (prazosin, doxazosin, and terazosin), are antihypertensive (Figure 2). They are selective for a1-adrenoceptors, but not for any of the three subclasses (a1A, a1B, and a1D) Unlike older a-adrenoceptor antagonists phenoxybenzamine and phentolamine, quinazolines do not increase heart rate. Prazosin was widely used in the treatment of hypertension for a quarter of a century. The onset of action of prazosin is rapid: the maximal antihypertensive effect is usually reached within 2 h of oral administration of the drug. An important advantage of prazosin and other quinazolines over thiazides or ^-adrenoceptor antagonists is their favorable effect on blood lipids: they tend to decrease triglycerides and low-density lipoprotein, while increasing high-density lipoprotein cholesterol levels. Terazosin inhibits ex vivo platelet aggregation induced by epinephrine, collagen, or adenosine diphosphate.28 A well-recognized side effect of quinazolines and particularly of prazosin is so-called 'first-dose phenomenon' -orthostatic hypotension with a transient loss of consciousness after the first dose of the drug.29 This phenomenon can be avoided by a very gradual increase in the dose (starting with 0.5 mg of prazosin in the evening before retiring, maintaining it for 2 weeks, and then increasing to 1 and 2 weeks later to 2mg).

a1-Adrenoceptor antagonists are used primarily as second-line drugs, in combination with thiazides. Doxazosin differs from prazosin primarily in its pharmacokinetics; its half-life is 20 h. The onset of antihypertensive effect of doxazosin is more gradual than that of prazosin and it appears to be less likely to produce 'first-dose phenomenon.' Of concern is a recent report of increased heart failure risk in patients receiving doxazosin in comparison to those treated with chlorthalidone.30 With the advance of ACEIs and Ang II antagonists, the use of quinazolines in the therapy of hypertension markedly declined.

Since a1-adrenoceptors are present in the bladder musculature, a-adrenoceptor antagonists have been tested and found effective in improving urine flow in patients with benign prostatic hypertrophy (BPH) (see 6.24 Incontinence (Benign Prostatic Hyperplasia/Prostate Dysfunction)). Excellent results have been obtained in BPH with doxazosin, 4 mgday_ for periods up to 10 years.31 Terazosin has also been reported to inhibit growth and to induce apoptosis of prostate cancer cells,32 so that a-adrenoceptor antagonists are likely to have an additional therapeutic indication, not only in BPH, but also in the therapy of prostate cancer.

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