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Chapter: Basic & Clinical Pharmacology : Adrenoceptor Antagonist Drugs

Clinical Pharmacology of the Beta Receptor Blocking Drugs

The β-adrenoceptor–blocking drugs have proved to be effective and well tolerated in hypertension.



The β-adrenoceptor–blocking drugs have proved to be effective and well tolerated in hypertension. Although many hypertensive patients respond to a β blocker used alone, the drug is often used with either a diuretic or a vasodilator. In spite of the short half-life of many β antagonists, these drugs may be administered once or twice daily and still have an adequate therapeutic effect. Labetalol, a competitive α and β antagonist, is effective in hypertension, though its ultimate role is yet to be determined. Use of these agents is discussed in greater detail earily. There is some evidence that drugs in this class may be less effective in the elderly and in individuals of African ancestry. However, these differences are relatively small and may not apply to an individual patient. Indeed, since effects on blood pressure are easily measured, the therapeutic outcome for this indication can be readily detected in any patient.

Ischemic Heart Disease

Beta-adrenoceptor blockers reduce the frequency of anginal epi-sodes and improve exercise tolerance in many patients with angina . These actions relate to the blockade of cardiac β receptors, resulting in decreased cardiac work and reduction in oxy-gen demand. Slowing and regularization of the heart rate may contribute to clinical benefits (Figure 10–7). Multiple large-scale prospective studies indicate that the long-term use of timolol, pro-pranolol, or metoprolol in patients who have had a myocardialinfarction prolongs survival (Figure 10–8). At the present time, data are less compelling for the use of other than the three mentioned β-adrenoceptor antagonists for this indication. It is significant thatsurveys in many populations have indicated that β-receptor antago-nists are underused, leading to unnecessary morbidity and mortal-ity. In addition, β-adrenoceptor antagonists are strongly indicated in the acute phase of a myocardial infarction. In this setting, relative contraindications include bradycardia, hypotension, moderate or severe left ventricular failure, shock, heart block, and active airways disease. It has been suggested that certain polymorphisms in β2-adrenoceptor genes may influence survival among patients receiving antagonists after acute coronary syndromes.

Cardiac Arrhythmias

Beta antagonists are often effective in the treatment of both supraventricular and ventricular arrhythmias . It has been suggested that the improved survival following myocardial infarction in patients using β antagonists (Figure 10–8) is due to suppression of arrhythmias, but this has not been proved. By increasing the atrioventricular nodal refractory period, β antagonists slow ventricular response rates in atrial flutter and fibrillation. These drugs can also reduce ventricular ectopic beats, particularly if the ectopic activity has been precipitated by catecholamines. Sotalol has antiarrhythmic effects involving ion channel blockade in addition to its β-blocking action;.

Heart Failure

Clinical trials have demonstrated that at least three β antagonists— metoprolol, bisoprolol, and carvedilol—are effective in reducing mortality in selected patients with chronic heart failure. Although administration of these drugs may worsen acute congestive heart failure, cautious long-term use with gradual dose increments in patients who tolerate them may prolong life. Although mecha-nisms are uncertain, there appear to be beneficial effects on myocardial remodeling and in decreasing the risk of sudden death .

Other Cardiovascular Disorders

Beta-receptor antagonists have been found to increase stroke vol-ume in some patients with obstructive cardiomyopathy. This beneficial effect is thought to result from the slowing of ventricu-lar ejection and decreased outflow resistance. Beta antagonists are useful in dissecting aortic aneurysm to decrease the rate of devel-opment of systolic pressure. Beta antagonists are also useful in selected at-risk patients in the prevention of adverse cardiovascular outcomes resulting from noncardiac surgery.

Glaucoma (See Box: The Treatment of Glaucoma)

Systemic administration of β-blocking drugs for other indications was found serendipitously to reduce intraocular pressure in patients with glaucoma. Subsequently, it was found that topical administration also reduces intraocular pressure. The mechanism appears to involve reduced production of aqueous humor by the ciliary body, which is physiologically activated by cAMP. Timolol and related β antagonists are suitable for local use in the eye because they lack local anesthetic properties. Beta antagonists appear to have an efficacy comparable to that of epinephrine or pilocarpine in open-angle glaucoma and are far better tolerated by most patients. While the maximal daily dose applied locally (1 mg) is small compared with the systemic doses commonly used in the treatment of hypertension or angina (10–60 mg), sufficient timolol may be absorbed from the eye to cause serious adverse effects on the heart and airways in susceptible individuals. Topical timolol may interact with orally administered verapamil and increase the risk of heart block.

Betaxolol, carteolol, levobunolol, and metipranolol are also approved for the treatment of glaucoma. Betaxolol has the poten-tial advantage of being β1-selective; to what extent this potential advantage might diminish systemic adverse effects remains to be determined. The drug apparently has caused worsening of pulmo-nary symptoms in some patients.


Excessive catecholamine action is an important aspect of the pathophysiology of hyperthyroidism, especially in relation to the heart . The β antagonists are beneficial in this condition. The effects presumably relate to blockade of adreno-ceptors and perhaps in part to the inhibition of peripheral conver-sion of thyroxine to triiodothyronine. The latter action may vary from one β antagonist to another. Propranolol has been used extensively in patients with thyroid storm (severe hyperthyroid-ism); it is used cautiously in patients with this condition to control supraventricular tachycardias that often precipitate heart failure.

Neurologic Diseases

Propranolol reduces the frequency and intensity of migraineheadache. Otherβ-receptor antagonists with preventive efficacyinclude metoprolol and probably also atenolol, timolol, and nadolol. The mechanism is not known. Since sympathetic activ-ity may enhance skeletal muscle tremor, it is not surprising that antagonists have been found to reduce certain tremors . The somatic manifestations of anxiety may respond dramatically to low doses of propranolol, particularly when taken prophylactically. For example, benefit has been found in musicians with performance anxiety (“stage fright”). Propranolol may contribute to the symptomatic treatment of alcohol withdrawal in some patients.


Beta-receptor antagonists have been found to diminish portal vein pressure in patients with cirrhosis. There is evidence that both propranolol and nadolol decrease the incidence of the first episode of bleeding from esophageal varices and decrease the mortality rate associated with bleeding in patients with cirrhosis. Nadolol in combination with isosorbide mononitrate appears to be more efficacious than sclerotherapy in preventing rebleeding in patients who have previously bled from esophageal varices. Variceal band ligation in combination with a β antagonist may be more efficacious.

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