cardiovascular drug

Contractions

Inotropic agents are drugs that influence the force of contraction of cardiac muscle and thereby affect cardiac output. Drugs have a positive inotropic effect if they increase the force of the heart’s contraction. The cardiac glycosides, substances that occur in the leaves of the foxglove (Digitalis purpurea) and other plants, are the most important group of inotropic agents. Although they have been used for many purposes throughout history, the effectiveness of cardiac glycosides in heart disease was established in 1785 by English physician William Withering, who successfully used an extract of foxglove leaves to treat heart failure. The two compounds most often used therapeutically are digoxin and digitoxin.

Cardiac glycosides, however, have disadvantageous side effects. These include a tendency to block conduction of the electrical impulse that causes contraction as it passes from the atria to the ventricles of the heart (heart block). Cardiac glycosides also have a tendency to produce an abnormal cardiac rhythm by causing electrical impulses to be generated at points in the heart other than the normal pacemaker region, the cells that rhythmically maintain the heartbeat. These irregular impulses result in ectopic heartbeats, which are out of sequence with the normal cardiac rhythm. Occasional ectopic beats are harmless, but if this process continues to a complete disorganization of the cardiac rhythm (ventricular fibrillation), the pumping action of the heart is stopped, and death occurs within minutes unless resuscitation is performed. Because the margin of safety between the therapeutic and the toxic doses of glycosides is relatively narrow, they must be used carefully.

Cardiac glycosides are believed to increase the force of cardiac muscle contraction by binding to and inhibiting the action of a membrane enzyme that extrudes sodium ions from the cell interior. These drugs also enhance the release of calcium from internal stores, resulting in a rise in intracellular calcium. This subsequently increases the force of contraction, since intracellular calcium ions are responsible for initiating the shortening of muscle cells.

The disturbances of rhythm that may be caused by cardiac glycosides result partly from the depolarization and partly from the increase in intracellular calcium. Because these rhythm disturbances are caused by the same underlying mechanism that causes the beneficial effect, there is no likelihood of finding a cardiac glycoside with a significantly better margin of safety. Apart from their cardiac actions, these glycosides tend to cause nausea and loss of appetite. Because digoxin and digitoxin have long plasma half-lives (two and seven days, respectively), they are liable to accumulate in the body. Treatment with either of these drugs must involve careful monitoring to avoid the adverse effects that may result from their slow buildup in the body.

The second type of inotropic agents that increase the force of cardiac muscle contraction includes dobutamine. Administered intravenously in moderate doses, dobutamine will increase contractility without affecting blood pressure or heart rate.