β-adrenergic receptor blocking agents

Published on 07/02/2015 by admin

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β-adrenergic receptor blocking agents

Ian MacVeigh, MD

β-Adrenergic receptor antagonists are a heterogeneous group of drugs widely used in managing hypertension and cardiac disease. Key to understanding their physiologic effects is knowledge of the molecular mechanism of action of the β-adrenergic receptor.

β-Receptors are divided into β1-receptors, found primarily in the heart, and β2-receptors, found in the smooth muscle of the vasculature and bronchi.

The β1-adrenergic receptor located on the cardiac sarcolemma is coupled to adenyl cyclase via a G protein. When activated, adenyl cyclase converts adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP), a secondary intracellular messenger, that stimulates protein kinase A to phosphorylate membrane calcium channels, leading to an increase in cytoplasmic Ca2+. The consequences of β1-adrenergic stimulation are positive inotropy, chronotropy, dromotropy, and lusitropic relaxant effect (the latter by increasing the reuptake of cytosolic calcium into the sarcoplasmic reticulum). Because the secondary messenger cAMP is metabolized by phosphodiesterase, phosphodiesterase inhibitors augment β1 activity, which is manifested by sympathomimetic effects. Because of inhibition of G protein (e.g., vagal [muscarinic] stimulation), the coupling with adenyl cyclase is interrupted, resulting in attenuation of the effects described previously—the similar effects observed with inhibition of the β-receptor itself (Figure 91-1).

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Figure 91-1 β-Adrenergic receptor blocking agents differ with regard to their β1-selectivity, lipid solubility, and intrinsic sympathomimetic activity. NO, Nitric oxide; VD, vasodilatory.

Indications for β-adrenergic receptor blockade

Because β-adrenergic receptor blocking agents have negative inotropy and chronotropy—decreasing myocardial oxygen demand and improving myocardial perfusion—they are used in the treatment of a number of conditions. β-Adrenergic receptor blocking agents reduce the exercise-induced increase in contractility and blood pressure; therefore, they are used to treat all classes of angina except variant or Prinzmetal angina. When β adrenergic receptor blocking agents are administered correctly, patients will ideally have heart rates between 50 and 60 beats/min at rest and no more than 100 beats/min with exercise.

For similar reasons, β-adrenergic receptor blocking agents are very effective in reducing the frequency and number of ischemic episodes in patients with myocardial ischemia or acute coronary syndromes. By decreasing inotropy and chronotropy, heart rate, contractility, afterload, and myocardial wall stress are all decreased, which optimizes myocardial O2 supply/demand. Current recommendations for patients with acute coronary syndromes are for β-adrenergic receptor blocking agents to be started early, along with statins, antiplatelet drugs, and angiotensin-converting enzyme inhibitors. This quadruple therapy has been associated with a 90% reduction in mortality rates at 6 months following the diagnosis of acute coronary syndrome. In patients who have had an acute myocardial infarction, β-adrenergic receptor blocking agents are specifically indicated to treat ongoing pain, tachycardia, hypertension, or ventricular rhythm instability. The initiation of β-adrenergic receptor blocking agents early after infarction and continued long-term has been associated with a reduction in mortality rate by as much as 25%.

β-Adrenergic receptor blocking agents lower blood pressure by decreasing cardiac output and peripheral vascular resistance and are specifically indicated to treat hypertension in patients with congestive heart failure, with coronary artery disease, and after myocardial infarction. Patients with congestive heart failure, even if they are not hypertensive, can benefit from β-blockade; the administration of carvedilol and of metoprolol have been reported to improve cardiac ejection fraction, reverse abnormal patterns of gene expression toward normal, and decrease mortality rate.

Because of their negative dromotropy, inhibitory effects in the sinus and atrioventricular nodes, and other antiarrhythmic properties (Table 91-1), β-adrenergic receptor blocking agents are recommended to acutely and chronically treat a number of tachyarrhythmias. They are indicated to treat supraventricular tachycardias, to control the rate in patients with atrial fibrillation, and to treat ventricular tachyarrhythmias (specifically metoprolol and sotalol [class III antiarrhythmic]). β-Adrenergic receptor blocking agents also counteract the arrhythmogenic effects of excess catecholamine stimulation, as seen, for example, in patients after myocardial infarction.

Table 91-1

Characteristics of Commonly Used β-Adrenergic Receptor Blocking Agents

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Drug Bioavailability (%) Protein Binding (%) Elimination Half-life (h) Major Elimination Pathway Other Properties
Atenolol 50 15 6-9 Renal β1-Selective
Carvedilol 30 95

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