Blockade of α receptors in other tissues elicits miosis (small pupils) and nasal stuffiness. Alpha1 receptors are expressed in the base of the bladder and the prostate, and their blockade decreases resistance to the flow of urine. Alpha blockers, therefore, are used therapeutically for the treatment of urinary retention due 0 50 100 100 50 0 2.4 20 160 1.2 10 80 Percent of maximum tension Percent of maximum tension Control 20 µmol/L 10 µmol/L Control 0.4 µmol/L 0.8 µmol/L Competitive antagonist Irreversible antagonist
FIGURE 10–2 Dose-response curves to norepinephrine in the presence of two different α-adrenoceptor–blocking drugs. The tension produced in isolated strips of cat spleen, a tissue rich in α receptors, was measured in response to graded doses of norepinephrine. Left: Tolazoline, a reversible blocker, shifted the curve to the right without decreasing the maximum response when present at concentrations of 10 and 20 μmol/L. Right: Dibenamine, an analog of phenoxybenzamine and irreversible in its action, reduced the maximum response attainable at both concentrations tested. (Adapted, with permission, from Bickerton RK: The response of isolated strips of cat spleen to sympathomimetic drugs and their antagonists. J Pharmacol Exp Ther 1963;142:99.)
FIGURE 10–3 Top: Effects of phentolamine, an α-receptor–blocking drug, on blood pressure in an anesthetized dog. Epinephrine reversal is demonstrated by tracings showing the response to epinephrine before (middle) and after (bottom) phentolamine. All drugs given intravenously. BP, blood pressure; HR, heart rate.
TABLE 10–1 Relative selectivity of antagonists for adrenoceptors.
to prostatic hyperplasia (see below). Individual agents may have other important effects in addition to α-receptor antagonism (see below).
Phenoxybenzamine binds covalently to α receptors, causing irreversible blockade of long duration (14–48 hours or longer). It is somewhat selective for α1 receptors but less so than prazosin (Table 10–1). The drug also inhibits reuptake of released nor-epinephrine by presynaptic adrenergic nerve terminals. Phenoxybenzamine blocks histamine (H1), acetylcholine, and serotonin receptors as well as α receptors (see Chapter 16).
The pharmacologic actions of phenoxybenzamine are primarily related to antagonism of α-receptor–mediated events. The most significant effect is attenuation of catecholamine-induced vasoconstriction. While phenoxybenzamine causes relatively little fall in blood pressure in normal supine individuals, it reduces blood pressure when sympathetic tone is high, eg, as a result of upright posture or because of reduced blood volume. Cardiac output may be increased because of reflex effects and because of some blockade of presynaptic α2 receptors in cardiac sympathetic nerves.
Phenoxybenzamine is absorbed after oral administration, although bioavailability is low; its other pharmacokinetic properties are not well known. The drug is usually given orally, starting with dosages of 10 mg/d and progressively increasing the dose until the desired effect is achieved. A dosage of less than 100 mg/d is usually sufficient to achieve adequate α-receptor blockade. The major use of phenoxybenzamine is in the treatment of pheochromocytoma (see below).