Page 198 - Basic _ Clinical Pharmacology ( PDFDrive )

184 SECTION III Cardiovascular-Renal Drugs

PRAZOSIN & OTHER ALPHA BLOCKERS β blocker to treat the clonidine withdrawal syndrome, described
1
previously). Their pharmacology is described in Chapter 10.
Mechanism & Sites of Action

Prazosin, terazosin, and doxazosin produce most of their antihy- VASODILATORS
pertensive effects by selectively blocking α receptors in arterioles Mechanism & Sites of Action
1
and venules. These agents produce less reflex tachycardia when
lowering blood pressure than do nonselective α antagonists such This class of drugs includes the oral vasodilators, hydralazine
as phentolamine. Alpha -receptor selectivity allows norepineph- and minoxidil, which are used for long-term outpatient therapy
1
rine to exert unopposed negative feedback (mediated by presyn- of hypertension; the parenteral vasodilators, nitroprusside and
aptic α receptors) on its own release (see Chapter 6); in contrast, fenoldopam, which are used to treat hypertensive emergencies; the
2
phentolamine blocks both presynaptic and postsynaptic α recep- calcium channel blockers, which are used in both circumstances;
tors, with the result that reflex activation of sympathetic neurons and the nitrates, which are used mainly in ischemic heart disease
by phentolamine’s effects produces greater release of transmitter but sometimes also in hypertensive emergencies (Table 11–3).
onto β receptors and correspondingly greater cardioacceleration. Chapter 12 contains additional discussion of vasodilators. All the
Alpha blockers reduce arterial pressure by dilating both resistance vasodilators that are useful in hypertension relax smooth muscle of
and capacitance vessels. As expected, blood pressure is reduced more arterioles, thereby decreasing systemic vascular resistance. Sodium
in the upright than in the supine position. Retention of salt and nitroprusside and the nitrates also relax veins. Decreased arterial resis-
water occurs when these drugs are administered without a diuretic. tance and decreased mean arterial blood pressure elicit compensatory
The drugs are more effective when used in combination with other responses, mediated by baroreceptors and the sympathetic nervous
agents, such as a β blocker and a diuretic, than when used alone. system (Figure 11–4), as well as renin, angiotensin, and aldosterone.
Owing to their beneficial effects in men with prostatic hyperplasia Because sympathetic reflexes are intact, vasodilator therapy does not
and bladder obstruction symptoms, these drugs are used primarily in cause orthostatic hypotension or sexual dysfunction.
men with concurrent hypertension and benign prostatic hyperplasia. Vasodilators work best in combination with other antihy-
pertensive drugs that oppose the compensatory cardiovascular
Pharmacokinetics & Dosage responses. (See Box: Resistant Hypertension & Polypharmacy.)
Pharmacokinetic characteristics of prazosin are listed in Table 11–2.
Terazosin is also extensively metabolized but undergoes very little HYDRALAZINE
first-pass metabolism and has a half-life of 12 hours. Doxazosin has
an intermediate bioavailability and a half-life of 22 hours. Hydralazine, a hydrazine derivative, dilates arterioles but not
Terazosin can often be given once daily, with doses of veins. It has been available for many years, although it was initially
5–20 mg/d. Doxazosin is usually given once daily starting at thought not to be particularly effective because tachyphylaxis to its
1 mg/d and progressing to 4 mg/d or more as needed. Although antihypertensive effects developed rapidly. The benefits of combi-
long-term treatment with these α blockers causes relatively nation therapy are now recognized, and hydralazine may be used
little postural hypotension, a precipitous drop in standing blood more effectively, particularly in severe hypertension. The combi-
pressure develops in some patients shortly after the first dose nation of hydralazine with nitrates is effective in heart failure and
is absorbed. For this reason, the first dose should be small and should be considered in patients with both hypertension and heart
should be administered at bedtime. Although the mechanism of failure, especially in African-American patients.
this first-dose phenomenon is not clear, it occurs more commonly
in patients who are salt- and volume-depleted. Pharmacokinetics & Dosage
Aside from the first-dose phenomenon, the reported toxici-
ties of the α blockers are relatively infrequent and mild. These Hydralazine is well absorbed and rapidly metabolized by the
1
include dizziness, palpitations, headache, and lassitude. Some liver during the first pass, so that bioavailability is low (averaging
patients develop a positive test for antinuclear factor in serum 25%) and variable among individuals. It is metabolized in part by
while on prazosin therapy, but this has not been associated with acetylation at a rate that appears to be bimodally distributed in the
rheumatic symptoms. The α blockers do not adversely and may
1
even beneficially affect plasma lipid profiles, but this action has TABLE 11–3 Mechanisms of action of vasodilators.
not been shown to confer any benefit on clinical outcomes.
Mechanism Examples
Release of nitric oxide from drug Nitroprusside, hydralazine,
OTHER ALPHA-ADRENOCEPTOR- or endothelium nitrates, histamine, acetylcholine
1
BLOCKING AGENTS Reduction of calcium influx Verapamil, diltiazem, nifedipine 1
Hyperpolarization of cell Minoxidil, diazoxide
The nonselective agents, phentolamine and phenoxybenzamine, membranes through opening of
are useful in diagnosis and treatment of pheochromocytoma and potassium channels
in other clinical situations associated with exaggerated release Activation of dopamine receptors Fenoldopam
of catecholamines (eg, phentolamine may be combined with a 1 See Chapter 12.