Beta-Adrenoceptor-Blocking Agents

BETA-ADRENOCEPTOR–BLOCKING AGENTS

Of the large number of β blockers tested, most have been shown to be effective in lowering blood pressure. The pharmacologic properties of several of these agents differ in ways that may confer therapeutic benefits in certain clinical situations.

Propranolol

Propranolol was the first β blocker shown to be effective in hyper-tension and ischemic heart disease. Propranolol has now been largely replaced by cardioselective β blockers such as metoprolol and atenolol. All β-adrenoceptor–blocking agents are useful for lowering blood pressure in mild to moderate hypertension. In severe hypertension, β blockers are especially useful in preventing the reflex tachycardia that often results from treatment with direct vasodilators. Beta blockers have been shown to reduce mortality after a myocardial infarction and some also reduce mortality in patients with heart failure; they are particularly advantageous for treating hypertension in patients with these conditions .

A. Mechanism and Sites of Action

Propranolol’s efficacy in treating hypertension as well as most of its toxic effects result from nonselective β blockade. Propranolol decreases blood pressure primarily as a result of a decrease in car-diac output. Other β blockers may decrease cardiac output or decrease peripheral vascular resistance to various degrees, depend-ing on cardioselectivity and partial agonist activities.

Propranolol inhibits the stimulation of renin production by catecholamines (mediated by β₁ receptors). It is likely that propra-nolol’s effect is due in part to depression of the renin-angiotensin-aldosterone system. Although most effective in patients with high plasma renin activity, propranolol also reduces blood pressure in hypertensive patients with normal or even low renin activity. Beta blockers might also act on peripheral presynaptic β adrenoceptors to reduce sympathetic vasoconstrictor nerve activity.

In mild to moderate hypertension, propranolol produces a significant reduction in blood pressure without prominent pos-tural hypotension.

B. Pharmacokinetics and Dosage

See Table 11–2. Resting bradycardia and a reduction in the heart rate during exercise are indicators of propranolol’s β-blocking effect, and changes in these parameters may be used as guides for regulating dosage. Propranolol can be administered twice daily, and slow-release preparations are available.

C. Toxicity

The most important of these predict-able extensions of the β-blocking action occur in patients with bradycardia or cardiac conduction disease, asthma, peripheral vascular insufficiency, and diabetes.

When propranolol is discontinued after prolonged regular use, some patients experience a withdrawal syndrome, manifested by nervousness, tachycardia, increased intensity of angina, and increase of blood pressure. Myocardial infarction has been reported in a few patients. Although the incidence of these com-plications is probably low, propranolol should not be discontinued abruptly. The withdrawal syndrome may involve up-regulation or supersensitivity of β adrenoceptors.

Metoprolol & Atenolol

Metoprolol and atenolol, which are cardioselective, are the most widely used β blockers in the treatment of hypertension. Metoprolol is approximately equipotent to propranolol in inhibit-ing stimulation of β₁ adrenoceptors such as those in the heart but 50- to 100-fold less potent than propranolol in blocking β₂ receptors. Relative cardioselectivity may be advantageous in treating hyper-tensive patients who also suffer from asthma, diabetes, or periph-eral vascular disease. Although cardioselectivity is not complete, metoprolol causes less bronchial constriction than propranolol at doses that produce equal inhibition of β₁-adrenoceptor responses. Metoprolol is extensively metabolized by CYP2D6 with high first-pass metabolism. The drug has a relatively short half-life of 4–6 hours, but the extended-release preparation can be dosed once daily (Table 11–2). Sustained-release metoprolol is effective in reducing mortality from heart failure and is particularly useful in patients with hypertension and heart failure.

Atenolol is not extensively metabolized and is excreted primarily in the urine with a half-life of 6 hours; it is usually dosed once daily. Recent studies have found atenolol less effective than metoprolol in preventing the complications of hypertension. A possible reason for this difference is that once-daily dosing does not maintain adequate blood levels of atenolol. The usual dosage is 50–100 mg/d. Patients with reduced renal function should receive lower doses.

Nadolol, Carteolol, Betaxolol, & Bisoprolol

Nadolol and carteolol, nonselective β-receptor antagonists, are not appreciably metabolized and are excreted to a considerable extent in the urine. Betaxolol and bisoprolol are β₁-selective blockers that are primarily metabolized in the liver but have long half-lives. Because of these relatively long half-lives, these drugs can be administered once daily. Nadolol is usually begun at a dosage of 40 mg/d, carteolol at 2.5 mg/d, betaxolol at 10 mg/d, and biso-prolol at 5 mg/d. Increases in dosage to obtain a satisfactory therapeutic effect should take place no more often than every 4 or 5 days. Patients with reduced renal function should receive corre-spondingly reduced doses of nadolol and carteolol.

Pindolol, Acebutolol, & Penbutolol

Pindolol, acebutolol, and penbutolol are partial agonists, ie, β blockers with some intrinsic sympathomimetic activity. They lower blood pressure by decreasing vascular resistance and appear to depress cardiac output or heart rate less than other β blockers, perhaps because of significantly greater agonist than antagonist effects at β₂ receptors. This may be particularly beneficial for patients with bradyarrhythmias or peripheral vascular disease. Daily doses of pindolol start at 10 mg; of acebutolol, at 400 mg; and of penbutolol, at 20 mg.

Labetalol, Carvedilol, & Nebivolol

These drugs have both β-blocking and vasodilating effects. Labetalol is formulated as a racemic mixture of four isomers (it has two centers of asymmetry). Two of these isomers—the (S,S)-and (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 has a 3:1 ratio of β:α antagonism after oral dosing. Blood pressure is lowered by reduction of systemic vascular resis-tance (via α blockade) without significant alteration in heart rate or cardiac output. Because of its combined α- and β-blocking activity, labetalol is useful in treating the hypertension of pheo-chromocytoma and hypertensive emergencies. Oral daily doses of labetalol range from 200 to 2400 mg/d. Labetalol is given as repeated intravenous bolus injections of 20–80 mg to treat hyper-tensive emergencies.

Carvedilol, like labetalol, is administered as a racemic mixture. The S(–) isomer is a nonselective β-adrenoceptor blocker, but both S(–) and R(+) isomers have approximately equalα-blockingpotency. The isomers are stereoselectively metabolized in the liver, which means that their elimination half-lives may differ. The aver-age half-life is 7–10 hours. The usual starting dosage of carvedilol for ordinary hypertension is 6.25 mg twice daily. Carvedilol reduces mortality in patients with heart failure and is therefore particularly useful in patients with both heart failure and hypertension.

Nebivolol is a β₁-selective blocker with vasodilating properties that are not mediated by α blockade. D-Nebivolol has highly selec-tive β₁ blocking effects, while the L-isomer causes vasodilation; the drug is marketed as a racemic mixture. The vasodilating effect may be due to an increase in endothelial release of nitric oxide via induction of endothelial nitric oxide synthase. The hemodynamic effects of nebivolol therefore differ from those of pure β blockers in that peripheral vascular resistance is acutely lowered (by nebi-volol) as opposed to increased acutely (by the older agents). Nebivolol is extensively metabolized and has active metabolites. The half-life is 10–12 hours, but the drug can be given once daily. Dosing is generally started at 5 mg/d, with dose escalation as high as 40 mg, if necessary. The efficacy of nebivolol is similar to that of other antihypertensive agents, but several studies report fewer adverse effects.

Esmolol

Esmolol is a β₁-selective blocker that is rapidly metabolized via hydrolysis by red blood cell esterases. It has a short half-life (9–10 minutes) and is administered by constant intravenous infusion. Esmolol is generally administered as a loading dose (0.5–1 mg/kg), followed by a constant infusion. The infusion is typically started at 50–150 mcg/kg/min, and the dose increased every 5 minutes, up to 300 mcg/kg/min, as needed to achieve the desired therapeutic effect. Esmolol is used for management of intraoperative and postoperative hypertension, and sometimes for hypertensive emergencies, particularly when hypertension is asso-ciated with tachycardia.