Page 197 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 11 Antihypertensive Agents 183

predictable extensions of the β -blocking action occur in patients Labetalol, Carvedilol, & Nebivolol
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with bradycardia or cardiac conduction disease, and those of the These drugs have both β-blocking and vasodilating effects. Labet-
β -blocking action occur in patients with asthma, peripheral alol is formulated as a racemic mixture of four isomers (it has
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vascular insufficiency, and diabetes. two centers of asymmetry). Two of these isomers—the (S,S)- and
When β blockers are discontinued after prolonged regular
use, some patients experience a withdrawal syndrome, mani- (R,S)-isomers—are relatively inactive, a third (S,R)- is a potent
α blocker, and the last (R,R)- is a potent β blocker. Labetalol
fested by nervousness, tachycardia, increased intensity of angina, has a 3:1 ratio of β:α antagonism after oral dosing. Blood pres-
and increase of blood pressure. Myocardial infarction has been sure is lowered by reduction of systemic vascular resistance (via
reported in a few patients. Although the incidence of these com- α blockade) without significant alteration in heart rate or cardiac
plications is probably low, β blockers should not be discontinued output. Because of its combined α- and β-blocking activity,
abruptly. The withdrawal syndrome may involve upregulation or labetalol is useful in treating the hypertension of pheochromocy-
supersensitivity of β adrenoceptors.
toma and hypertensive emergencies. Oral daily doses of labetalol
Metoprolol & Atenolol range from 200 to 2400 mg/d. Labetalol is given as repeated
intravenous bolus injections of 20–80 mg to treat hypertensive
Metoprolol and atenolol, which are cardioselective, are the most emergencies.
widely used β blockers in the treatment of hypertension. Meto- Carvedilol, like labetalol, is administered as a racemic mixture.
prolol is approximately equipotent to propranolol in inhibiting The S(-) isomer is a nonselective β-adrenoceptor blocker, but
stimulation of β adrenoceptors such as those in the heart but 50- both S(-) and R(+) isomers have approximately equal α-blocking
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to 100-fold less potent than propranolol in blocking β receptors. potency. The isomers are stereoselectively metabolized in the
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Relative cardioselectivity is advantageous in treating hypertensive liver, which means that their elimination half-lives may differ.
patients who also suffer from asthma, diabetes, or peripheral The average half-life is 7–10 hours. The usual starting dosage
vascular disease. Although cardioselectivity is not complete, of carvedilol for ordinary hypertension is 6.25 mg twice daily.
metoprolol causes less bronchial constriction than propranolol at Carvedilol reduces mortality in patients with heart failure and is
doses that produce equal inhibition of β -adrenoceptor responses. therefore particularly useful in patients with both heart failure and
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Metoprolol is extensively metabolized by CYP2D6 with high hypertension.
first-pass metabolism. The drug has a relatively short half-life of Nebivolol is a β -selective blocker with vasodilating properties
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4–6 hours, but the extended-release preparation can be dosed once that are not mediated by α blockade. d-Nebivolol has highly selec-
daily (Table 11–2). Sustained-release metoprolol is effective in tive β -blocking effects, while the l-isomer causes vasodilation;
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reducing mortality from heart failure and is particularly useful in the drug is marketed as a racemic mixture. The vasodilating effect
patients with hypertension and heart failure. may be due to an increase in endothelial release of nitric oxide via
Atenolol is not extensively metabolized and is excreted primar- induction of endothelial nitric oxide synthase. The hemodynamic
ily in the urine with a half-life of 6 hours; it is usually dosed once effects of nebivolol therefore differ from those of pure β block-
daily. Atenolol is reported to be less effective than metoprolol in ers in that peripheral vascular resistance is acutely lowered (by
preventing the complications of hypertension. A possible reason nebivolol) as opposed to increased acutely (by the older agents).
for this difference is that once-daily dosing does not maintain ade- Nebivolol is extensively metabolized and has active metabolites.
quate blood levels of atenolol. The usual dosage is 50–100 mg/d. The half-life is 10–12 hours, but the drug can be given once daily.
Patients with reduced renal function should receive lower doses. Dosing is generally started at 5 mg/d, with dose escalation as high
as 40 mg/d, if necessary. The efficacy of nebivolol is similar to that
Nadolol, Carteolol, Betaxolol, & Bisoprolol of other antihypertensive agents, but several studies report fewer

Nadolol and carteolol, nonselective β-receptor antagonists, are not adverse effects.
appreciably metabolized and are excreted to a considerable extent
in the urine. Betaxolol and bisoprolol are β -selective blockers Esmolol
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that are primarily metabolized in the liver but have long half- Esmolol is a β -selective blocker that is rapidly metabolized
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lives. Because of these relatively long half-lives, these drugs can be via hydrolysis by red blood cell esterases. It has a short half-life
administered once daily. Nadolol is usually begun at a dosage of (9–10 minutes) and is administered by intravenous infusion.
40 mg/d, carteolol at 2.5 mg/d, betaxolol at 10 mg/d, and bisoprolol Esmolol is generally administered as a loading dose (0.5–1 mg/kg),
at 5 mg/d. Increases in dosage to obtain a satisfactory therapeutic followed by a constant infusion. The infusion is typically started at
effect should take place no more often than every 4 or 5 days. 50–150 mcg/kg/min, and the dose increased every 5 minutes, up
Patients with reduced renal function should receive correspond- to 300 mcg/kg/min, as needed to achieve the desired therapeutic
ingly reduced doses of nadolol and carteolol. effect. Esmolol is used for management of intraoperative and post-
Pindolol, Acebutolol, & Penbutolol operative hypertension, and sometimes for hypertensive emergen-
cies, particularly when hypertension is associated with tachycardia
Pindolol, acebutolol, and penbutolol are partial agonists, ie, β or when there is concern about toxicity such as aggravation of
blockers with some intrinsic sympathomimetic activity. They lower severe heart failure, in which case a drug with a short duration of
blood pressure but are rarely used in hypertension. action that can be discontinued quickly is advantageous.