Therapeutic Uses

For the treatment of hypertension and angina, the initial oral dose generally is 40—80 mg/day, titrated upward until the desired response is obtained, typically at <320 mg/day. In hypertension, the full antihypertensive effect may not develop for several weeks. If propranolol is taken twice daily for hypertension, blood pressure should be measured just prior to a dose to ensure that the duration of effect is sufficiently prolonged. Adequacy of b adrenergic blockade can be assessed by measuring suppression of exercise-induced tachycardia.

Propranolol also is used to treat various arrhythmias (Chapter 34), myocardial infarction (Chapter 31), congestive heart failure (Chapter 33), pheochromocytoma, and migraine (prophy-lactically). Propranolol also has been used for several off-label indications including parkinson-ian tremors (sustained-release only), akathisia induced by antipsychotic drugs, variceal bleeding in portal hypertension, and generalized anxiety disorder.

Nadolol

Nadolol (corgard, others) is a long-acting antagonist with equal affinity for b1 and b2 receptors. Its pharmacological and pharmacokinetic properties are summarized in Table 10-4. Nadolol is used in hypertension and angina pectoris. Unlabeled uses have included migraine prophylaxis, parkinsonian tremors, and variceal bleeding in portal hypertension. Nadolol is water soluble and incompletely absorbed from the gut. The drug is largely excreted intact in the urine; thus, nadolol may accumulate in patients with renal failure, in whom dosage should be reduced. With its long t1/2, nadolol may be administered once daily.

Timolol

Timolol (blocadren, others) is a potent, non-subtype-selective b receptor antagonist, with properties summarized in Table 10-4. It is used for hypertension, congestive heart failure, migraine prophylaxis, open-angle glaucoma, and intraocular hypertension. Timolol is well absorbed from the GI tract. The drug is subject to first-pass metabolism and is metabolized extensively by hepatic CYP2D6 in the liver. The ophthalmic formulation of timolol ( timoptic, others), used for the treatment of glaucoma, may be extensively absorbed systemically (see Chapter 63), causing adverse effects in susceptible patients (e.g., those with asthma or congestive heart failure).

Pindolol

Pindolol (visken, others) is a non-subtype-selective b receptor antagonist, as described in Table 10-4. Notably, pindolol is a weak partial b agonist; such drugs may be preferred as antihyper-tensive agents in individuals with diminished cardiac reserve or a propensity for bradycardia.

01-SELECTIVE ADRENERGIC ANTAGONISTS Metoprolol

Metoprolol (lopressor, others) is a ^-selective antagonist lacking intrinsic sympathomimetic activity and membrane-stabilizing activity (see Table 10-4). Despite almost complete GI absorption, metoprolol's bioavailability is relatively low because of first-pass metabolism. Plasma concentrations vary widely, which may relate to genetically determined differences in hepatic CYP2D6 activity. The t1/2 of metoprolol (3-4 hours) can double in CYP2D6 poor metabolizers, who have a 5x higher risk for developing adverse effects compared to normal metabolizers. An extended-

release formulation (toprol xl) is available for once-daily administration.

For hypertension, the usual initial dose is 100 mg/day, increasing at weekly intervals until optimal reduction of blood pressure is achieved. If the drug is taken only once daily, confirm that blood pressure is controlled for the entire 24-hour period. Metoprolol generally is used in two divided doses for the treatment of stable angina. For the initial treatment of patients with acute myocardial infarction, an intravenous formulation of metoprolol tartrate is available; initiate oral dosing as soon as the clinical situation permits. Metoprolol generally is contraindicated for the treatment of acute MI in patients with heart rates <45 beats/min, heart block greater than first-degree (PR interval >0.24 second), systolic blood pressure <100 mm Hg, or moderate-to-severe heart failure. Metoprolol is also effective in chronic heart failure (see Chapter 33).

Atenolol

Atenolol (tenormin, others) is a fi-selective antagonist (see Table 10-4). The drug is excreted largely unchanged in the urine; thus, atenolol accumulates in patients with renal failure, and dosage should be reduced when creatinine clearance is <35 ml/min. The initial dose of atenolol for the treatment of hypertension usually is 50 mg/day, given once daily. The daily dose may be increased to 100 mg; higher doses are unlikely to provide any greater antihypertensive effect. Atenolol has been shown to be efficacious, in combination with a diuretic, in elderly patients with isolated systolic hypertension.

Esmolol

Esmolol (brevibloc, others) is a fi-selective antagonist that is administered intravenously when j blockade of short duration is desired or in critically ill patients in whom adverse effects of brady-cardia, heart failure, or hypotension may necessitate rapid withdrawal of the drug. The duration of action of esmolol is brief because esterases in erythrocytes rapidly degrade the drug. Onset and cessation of esmolol's j blockade are rapid; peak effects occur within 6-10 minutes of administration of a loading dose, and there is substantial attenuation of j blockade within 20 minutes of stopping an infusion. Because esmolol is used in urgent settings where immediate onset of j blockade is warranted, a partial loading dose typically is administered, followed by a continuous infusion of the drug. If an adequate therapeutic effect is not observed within 5 minutes, the same loading dose is repeated, followed by a maintenance infusion at a higher rate. This process may be repeated until the desired endpoint (e.g., lowered heart rate or blood pressure) is reached.

Acebutolol

Acebutolol (sectral, others) is a selective j1 adrenergic receptor antagonist. The drug undergoes significant first-pass metabolism to an active metabolite, diacetolol, which accounts for most of the drug's activity. The elimination t122 of acebutolol is ~3 hours, that of diacetolol, 8-12 hours. The initial dose of acebutolol in hypertension usually is 400 mg/day, given as a single dose or as two divided doses, as required to control blood pressure. Optimal responses usually occur with doses of 400-800 mg/day. For treatment of ventricular arrhythmias, acebutolol should be given twice daily.

Bisoprolol

Bisoprolol (zebeta) is a highly selective j1 receptor antagonist that is approved for the treatment of hypertension. Bisoprolol can be considered a standard treatment option when selecting a j blocker for use in combination with ACE inhibitors and diuretics in patients with stable, moderate-to-severe chronic heart failure (in whom it lowers all-case mortality; see Chapter 33) and in treating hypertension. Bisoprolol generally is well-tolerated; side effects include dizziness, bradycardia, hypotension, and fatigue.

B Antagonists with Additional Cardiovascular Effects (Third Generation B Blockers)

Some j adrenergic antagonists have additional vasodilating actions that are produced through a variety of mechanisms summarized in Table 10-5 and Figure 10-4.

Labetalol

Labetalol (normodyne, trandate, others) is a competitive antagonist at both a 1 and j receptors. The pharmacological properties of labetolol are complex, because each of four isomers displays

Summary of Adrenergic Agonists and Antagonists

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