Image for Cardiovascular Pharmacology Concepts, Richard E Klabunde PhD

Cardiovascular Pharmacology Concepts

Richard E. Klabunde, PhD

Clinical Disorders:

Therapeutic Classes:

Mechanism Classes:


Also Visit
CVphysiology.com


Cardiovascular Physiology Concepts textbook cover

Click here for information on Cardiovascular Physiology Concepts, 2nd edition, a textbook published by Lippincott Williams & Wilkins (2011)

 

Cardiovascular Physiology Concepts textbook cover

Click here for information on Normal and Abnormal Blood Pressure, a textbook published by Richard E. Klabunde (2013)





Beta-Adrenoceptor Agonists (β-agonists)

beta-agonists and Gs-protein coupled stimulation of the heart

General Pharmacology

Beta-adrenoceptor agonists (β-agonists) bind to β-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 (stimulate renin release). Beta-adrenoceptors normally bind to norepinephrine released by sympathetic adrenergic nerves, and to circulating epinephrine. Therefore, β-agonists mimic the actions of sympathetic adrenergic stimulation acting through β-adrenoceptors. Overall, the effect of β-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 β-adrenoceptors. Long-term exposure to β-agonists can cause β-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.

Beta-Agonists

Cardiac effects

  • Increase contractility
    (positive inotropy)
  • Increase relaxation rate
    (positive lusitropy)
  • Increase heart rate
    (positive chronotropy)
  • Increase conduction velocity
    (positive dromotropy)

Vascular effects

  • Smooth muscle relaxation
    (vasodilation)

Other actions

  • Bronchodilation
  • Hepatic glycogenolysis
  • Pancreatic release of glucagon
  • Renin release by kidneys

The heart has both β1 and β2 adrenoceptors, although the predominant receptor type in number and function is β1. 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 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 β-agonist are increased heart rate, contractility, conduction velocity, and relaxation rate.

Blood vessels

Vascular smooth muscle has β2-adrenoceptors that have a high binding affinity for circulating epinephrine and a relatively lower affinity to norepinephrine released by sympathetic adrenergic nerves.

Increased intracellular cAMP by beta-2-agonists inhibits myosin light chain kinase thereby producing relaxation

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 β2-agonists inhibits myosin light chain kinase thereby producing less contractile force (i.e., promoting relaxation).

Other tissues

Activation of β2-adrenoceptors in the lungs causes bronchodilation. β2-adrenoceptor activation leads to hepatic glycogenolysis and pancreatic release of glucagon, which increases plasma glucose concentrations. β1-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 β-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 β-agonists, however, have some degree of α-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 β1 = β2 > α1* = α2* Anaphylactic shock; cardiogenic shock; cardiac arrest Low doses produce cardiac stimulation and vasodilation, which turns to vasoconstriction at high doses. *At high plasma concentrations,  α = β selectivity.
Norepinephrine β1 = α1 >
β2 = α2
Severe hypotension; septic shock Reflex bradycardia masks direct stimulatory effects on sinoatrial node.
Dopamine β1 = β2 > α1* 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 α-receptors bind to the dopamine; also binds to D1 receptors in kidney, producing vasodilation.
Dobutamine β1 > β2 > α1 Acute heart failure; cardiogenic shock; refractory heart failure Net effect is cardiac stimulation with modest vasodilation.
Isoproterenol β1 = β2 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 β-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 10/26/12

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