beta-agonists

Beta-adrenoceptor agonists (b-agonists) bind to b-receptors on cardiac and smooth muscle tissues. They also have important actions in other tissues, especially bronchial smooth muscle (relaxation), the liver (stimulate glycogenolysis) and kidneys (stimulated renin release). Beta-adrenoceptors normally bind to norepinephrine released by sympathetic adrenergic nerves, and to circulating epinephrine. Therefore, b-agonists mimic the actions of sympathetic adrenergic stimulation acting through b-adrenoceptors. Overall, the effect of b-agonists is cardiac stimulation (increased heart rate, contractility, conduction velocity, relaxation) and systemic vasodilation. Arterial pressure may increase, but not necessarily because the fall in systemic vascular resistance offsets the increase in cardiac output. Therefore, the effect on arterial pressure depends on the relative influence on cardiac versus vascular b-adrenoceptors. b-agonists cause b-receptor down-regulation, which limits their therapeutic efficacy to short-term application. Beta-agonists, because they are catecholamines, have a low bioavailability and therefore must be given by intravenous infusion.

Heart. Beta-agonists bind to beta-adrenoceptors located in cardiac nodal tissue, the conducting system, and contracting myocytes. The heart has both b₁ and b₂ adrenoceptors, although the predominant receptor type in number and function is b₁. These receptors primarily bind norepinephrine that is released from sympathetic adrenergic nerves. Additionally, they bind norepinephrine and epinephrine that circulate in the blood.

Beta-adrenoceptors are coupled to a Gs-proteins, which activate adenylyl cyclase to form cAMP from ATP. Increased cAMP activates a cAMP-dependent protein kinase (PK-A) that phosphorylates L-type calcium channels, which causes increased calcium entry into the cells. Increased calcium entry during action potentials leads to enhanced release of calcium by the sarcoplasmic reticulum in the heart; these actions increase inotropy (contractility). Gs-protein activation also increases heart rate by opening ion channels responsible for pacemaker currents in the sinoatrial node. PK-A phosphorylates sites on the sarcoplasmic reticulum, which enhances the release of calcium through the ryanodine receptors (ryanodine-sensitive, calcium-release channels) associated with the sarcoplasmic reticulum. This provides more calcium for binding the troponin-C, which enhances inotropy. Finally, PK-A can phosphorylate myosin light chains, which may also contribute to the positive inotropic effect of beta-adrenoceptor stimulation. In summary, the cardiac effects of a b-agonist are increased heart rate, contractility, conduction velocity, and relaxation rate.

Blood vessels. Vascular smooth muscle has b₂-adrenoceptors that are normally activated by norepinephrine released by sympathetic adrenergic nerves or by circulating epinephrine. These receptors, like those in the heart, are coupled to a Gs-protein, which stimulates the formation of cAMP. Although increased cAMP enhances cardiac myocyte contraction (see above), in vascular smooth muscle an increase in cAMP leads to smooth muscle relaxation. The reason for this is that cAMP inhibits myosin light chain kinase that is responsible for phosphorylating smooth muscle myosin. Therefore, increases in intracellular cAMP caused by b₂-agonists inhibits myosin light chain kinase thereby producing less contractile force (i.e., promoting relaxation).

Other tissues. Activation of b₂-adrenoceptors in the lungs causes bronchodilation. b₂-adrenoceptor activation leads to hepatic glycogenolysis and pancreatic release of glucagon, which increases plasma glucose concentrations. b₁-adrenoceptor stimulation in the kidneys causes the release of renin, which stimulates the production of angiotensin II and the subsequent release of aldosterone by the adrenal cortex.

Specific Drugs and Therapeutic Uses

There are several different b-agonists that are used clinically for the treatment of heart failure or circulatory shock, all of which are either natural catecholamines or analogs. Nearly all of these b-agonists, however, have some degree of a-agonist activity. These drugs along with their agonist properties are given in the table below. Note that for some of the drugs the receptor selectivity is highly dose-dependent. (Go to www.rxlist.com for specific drug information).

Drug Receptor Selectivity Clinical Use Comments

Epinephrine b₁ = b₂ > a₁*= a₂* Anaphylactic shock; cardiogenic shock; cardiac arrest Low doses produce cardiac stimulation and vasodilation, which turns to vasoconstriction at high doses. *At high plasma concentrations, a = b selectivity.

Norepinephrine b₁ = a₁ >
b₂= a₂ Severe hypotension; septic shock Reflex bradycardia masks direct stimulatory effects on sinoatrial node.

Dopamine b₁ = b₂ > a₁*

–Acute heart failure, cardiogenic shock and acute renal failure

Biosynthetic precursor of norepinephrine; stimulates norepinephrine release. *At low doses, it stimulates the heart and decreases systemic vascular resistance; at high doses, vasodilation becomes vasoconstriction as lower affinity a-receptors bind to the dopamine; also binds to D1 receptors in kidney, producing vasodilation.

Dobutamine b₁ > b₂ > a₁
Acute heart failure; cardiogenic shock; refractory heart failure
Net effect is cardiac stimulation with modest vasodilation.

Isoproterenol b₁ = b₂ Bradycardia and atrioventricular block Net effect is cardiac stimulation and vasodilation with little change in pressure.

Side Effects and Contraindications

A major side effect of b-agonists is cardiac arrhythmia. Because these drugs increase myocardial oxygen demand, they can precipitate angina in patients with coronary artery disease. Headache and tremor are also common.

Revised 06/17/08

DISCLAIMER: These materials are for educational purposes only, and are not a source of medical decision-making advice.