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Chapter: Modern Pharmacology with Clinical Applications: Adrenoceptor Antagonists

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Drugs With Combined and Βeta-and Αlpha Blocking Activity

Labetalol (Normodyne, Trandate) possesses both α- blocking and β-blocking activity and is approximately one-third as potent as propranolol as a β-blocker and one-tenth as potent as phentolamine as an β-blocker.

DRUGS WITH COMBINED AND β-AND α BLOCKING ACTIVITY

Labetalol

Labetalol (Normodyne, Trandate) possesses both α- blocking and β-blocking activity and is approximately one-third as potent as propranolol as a β-blocker and one-tenth as potent as phentolamine as an β-blocker. The ratio of - to -activity is about 3:1 when labetalol is administered orally and about 7: 1 when it is adminis-tered intravenously. Thus the drug can be most conve-niently thought of as a β-blocker with some α-blocking properties.

Mechanism of Action

Labetalol produces equilibrium-competitive antagonism at  β--receptors but does not exhibit selectivity for β1- or β2-receptors. Like certain other β-blockers (e.g., pin-dolol and timolol), labetalol possesses some degree of intrinsic activity. This intrinsic activity, or partial ago-nism, especially at β2-receptors in the vasculature, has been suggested to contribute to the vasodilator effect of the drug. The membrane-stabilizing effect, or local anesthetic action, of propranolol and several other - blockers, is also possessed by labetalol, and in fact the drug is a reasonably potent local anesthetic.

The α-blockade produced by labetalol is also of the equilibrium-competitive type. In a manner similar to prazosin, labetalol exhibits selectivity for α1-receptors. Presynaptic α -receptors, which are of the 2 subclass, are not antagonized by labetalol. The drug also has some in-trinsic activity at α -receptors, although this action is less than its intrinsic  β--receptor–stimulating effects.

Labetalol appears to produce relaxation of vascular smooth muscle not only by α-blockade but also by a partial agonist effect at β2-receptors. In addition, la-betalol may produce vascular relaxation by a direct non–receptor-mediated effect.

Labetalol can block the neuronal uptake of norepi-nephrine and other catecholamines. This action, plus its slight intrinsic activity at α -receptors, may account for the seemingly paradoxical, although infrequent, increase in blood pressure seen on its initial administration.

Absorption, Metabolism, and Excretion

Labetalol is almost completely absorbed from the gas-trointestinal tract. However, it is subject to considerable first-pass metabolism, which occurs in both the gas-trointestinal tract and the liver, so that only about 25% of an administered dose reaches the systemic circula-tion. While traces of unchanged labetalol are recovered in the urine, most of the drug is metabolized to inactive glucuronide conjugates. The plasma half-life of labetalol is 6 to 8 hours, and the elimination kinetics are essen-tially unchanged in patients with impaired renal failure.

Pharmacological Actions

Although capable of antagonizing a variety of re-sponses in a number of effectors that are mediated by both β- and α -receptors, the most important actions of labetalol are on the cardiovascular system. These effects vary from individual to individual and depend on the sympathetic and parasympathetic tone at the time of drug administration.

The most common hemodynamic effect of acutely administered labetalol in humans is a decrease in pe-ripheral vascular resistance and blood pressure without an appreciable alteration in heart rate or cardiac output.

This pattern differs from that seen following adminis-tration with either a conventional β - or α-blocker. Acute administration of a β-blocker produces a de-crease in heart rate and cardiac output with little effect on blood pressure, while acute administration of an α- blocker leads to a decrease in peripheral vascular re-sistance and a reflexively initiated increase in cardiac rate and output. Thus, the pattern of cardiovascular re-sponses observed after labetalol administration com-bines the features of  β- and α-blockade, that is, a de-crease in peripheral vascular resistance (due to α-blockade and direct vascular effects) without an in-crease in cardiac rate and output (due to β-blockade).

Prolonged oral therapy with labetalol results in car-diovascular responses similar to those obtained follow-ing conventional β-blocker administration, that is, de-creases in peripheral vascular resistance, blood pressure, and heart rate. Generally, however, the de-crease in heart rate is less pronounced than after ad-ministration of propranolol or other β-blockers.

Clinical Uses

Labetalol is useful for the chronic treatment of primary hypertension. It can be used alone but is more often em-ployed in combination with other antihypertensive agents. Labetalol also has been used intravenously for the treatment of hypertensive emergencies. Like con-ventional β-blockers, labetalol may be useful for pa-tients with coexisting hypertension and anginal pain due to ischemia. It is also being investigated as a possi-ble therapeutic modality for ischemic heart disease, even in the absence of hypertension. The benefit derives from its β-blocking activity, which decreases cardiac work, and from its ability to decrease afterload by virtue of its α-blocking activity.

Labetalol, because it possesses both α- and β-block-ing activity, is useful for the preoperative management of patients with a pheochromocytoma.

Adverse Effects

There have been reports of excessive hypotension and paradoxical pressor effects following intravenous ad-ministration of labetalol. These latter effects may be due to a labetalol-induced blockade of neuronal amine uptake, which increases the concentrations of norepi-nephrine in the vicinity of its receptors.

 

Approximately 5% of the patients who receive la-betalol complain of side effects typical of noradrenergic nervous system suppression. These include postural hy-potension, gastrointestinal distress, tiredness, sexual dysfunction, and tingling of the scalp. Most of these ef-fects are related to α -blockade, although the tingling of the scalp may be due to the drug’s intrinsic activity at α - receptors. Side effects associated with β-blockade, such as induction of bronchospasm and congestive heart fail-ure, may also occur, but generally at a lower frequency than α-receptor–associated effects.

Skin rashes have been reported, as has an increase in the titer of antinuclear antibodies. Despite the latter observation, the appearance of a systemic lupus syn-drome is rare. Labetalol also has been reported to in-terfere with chemical measurements of catecholamines and metabolites.

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