Page 173 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 10 Adrenoceptor Antagonist Drugs 159

TABLE 10–1 Relative selectivity of antagonists for ejaculation also occur. Since phenoxybenzamine enters the CNS,
adrenoceptors. it may cause less specific effects including fatigue, sedation, and
nausea. Because phenoxybenzamine is an alkylating agent, it may
Drugs Receptor Affinity have other adverse effects that have not yet been characterized.
Alpha antagonists Phentolamine is a potent competitive antagonist at both α 1
and α receptors (Table 10–1). Phentolamine reduces peripheral
Prazosin, terazosin, doxazosin α 1 >>>> α 2 2
resistance through blockade of α receptors and possibly α recep-
Phenoxybenzamine 1 2
tors on vascular smooth muscle. Its cardiac stimulation is due
α 1 > α 2
Phentolamine α 1 = α 2 to antagonism of presynaptic α receptors (leading to enhanced
2
Yohimbine, tolazoline α 2 >> α 1 release of norepinephrine from sympathetic nerves) and sympa-
Mixed antagonists thetic activation from baroreflex mechanisms. Phentolamine also
Labetalol, carvedilol β 1 = β 2 ≥ α 1 > α 2 has minor inhibitory effects at serotonin receptors and agonist
effects at muscarinic and H and H histamine receptors. Phen-
Beta antagonists 1 2
tolamine’s principal adverse effects are related to compensatory
Metoprolol, acebutolol, alprenolol, β 1 >>> β 2 cardiac stimulation, which may cause severe tachycardia, arrhyth-
atenolol, betaxolol, celiprolol,
esmolol, nebivolol mias, and myocardial ischemia. Phentolamine has been used in
the treatment of pheochromocytoma. In addition, it is sometimes
Propranolol, carteolol, nadolol, β 1 = β 2
penbutolol, pindolol, timolol used to reverse local anesthesia in soft tissue sites; local anesthet-
ics are often given with vasoconstrictors that slow their removal.
Butoxamine β 2 >>> β 1
Local phentolamine permits reversal at the end of the procedure.
Unfortunately oral and intravenous formulations of phentolamine
to prostatic hyperplasia (see below). Individual agents may have are no longer consistently available in the United States.
other important effects in addition to α-receptor antagonism (see Prazosin is a competitive piperazinyl quinazoline effective in
below). the management of hypertension (see Chapter 11). It is highly
selective for α receptors and typically 1000-fold less potent at
1
α receptors. This may partially explain the relative absence of
2
SPECIFIC AGENTS tachycardia seen with prazosin compared with that of phentol-
amine and phenoxybenzamine. Prazosin relaxes both arterial and
Phenoxybenzamine binds covalently to α receptors, causing venous vascular smooth muscle, as well as smooth muscle in the
irreversible blockade of long duration (14–48 hours or longer). prostate, due to blockade of α receptors. Prazosin is extensively
1
It is somewhat selective for α receptors but less so than prazosin metabolized in humans; because of metabolic degradation by the
1
(Table 10–1). The drug also inhibits reuptake of released nor- liver, only about 50% of the drug is available after oral administra-
epinephrine by presynaptic adrenergic nerve terminals. Phenoxy- tion. The half-life is normally about 3 hours.
benzamine blocks histamine (H ), acetylcholine, and serotonin Terazosin is another reversible α -selective antagonist that is
1
1
receptors as well as α receptors (see Chapter 16). effective in hypertension (see Chapter 11); it is also approved for
The pharmacologic actions of phenoxybenzamine are primarily use in men with urinary retention symptoms due to benign pros-
related to antagonism of α-receptor–mediated events. The most tatic hyperplasia (BPH). Terazosin has high bioavailability but is
significant effect is attenuation of catecholamine-induced vaso- extensively metabolized in the liver, with only a small fraction of
constriction. While phenoxybenzamine causes relatively little fall unchanged drug excreted in the urine. The half-life of terazosin is
in blood pressure in normal supine individuals, it reduces blood 9–12 hours.
pressure when sympathetic tone is high, eg, as a result of upright Doxazosin is efficacious in the treatment of hypertension and
posture or because of reduced blood volume. Cardiac output may BPH. It differs from prazosin and terazosin in having a longer
be increased because of reflex effects and because of some blockade half-life of about 22 hours. It has moderate bioavailability and is
of presynaptic α receptors in cardiac sympathetic nerves. extensively metabolized, with very little parent drug excreted in
2
Phenoxybenzamine is absorbed after oral administration, urine or feces. Doxazosin has active metabolites, although their
although bioavailability is low; its other pharmacokinetic proper- contribution to the drug’s effects is probably small.
ties are not well known. The drug is usually given orally, starting Tamsulosin is a competitive α antagonist with a structure
1
with dosages of 10 mg/d and progressively increasing the dose quite different from that of most other α -receptor blockers. It has
1
until the desired effect is achieved. A dosage of less than 100 mg/d high bioavailability and a half-life of 9–15 hours. It is metabolized
is usually sufficient to achieve adequate α-receptor blockade. The extensively in the liver. Tamsulosin has higher affinity for α and
1A
major use of phenoxybenzamine is in the treatment of pheochro- α receptors than for the α subtype. Evidence suggests that
1B
1D
mocytoma (see below). tamsulosin has relatively greater potency in inhibiting contrac-
Most adverse effects of phenoxybenzamine derive from its tion in prostate smooth muscle versus vascular smooth muscle
α-receptor–blocking action; the most important are orthostatic compared with other α -selective antagonists. The drug’s efficacy
1
hypotension and tachycardia. Nasal stuffiness and inhibition of in BPH suggests that the α subtype may be the most important
1A