Common Antiarrhythmic Drugs Affect the Ion Channels Responsible for the Cardiac Action Potential
Whereas ventricular fibrillation is generally lethal without electrical defibrillation, other tachycardias can often be treated successfully with antiarrhythmic drugs. Because tachyarrhythmias result from extra cardiac action potentials, effective anti- arrhythmic drugs must work by counteracting either the formation or the propagation of the extra action potentials.
Local anesthetics (e.g., quinidine, lidocaine) constitute one category of antiarrhythmic drugs. I hey act by binding to some of the fast Nat channels in cardiac muscle cells and preventing them from opening. This counteracts membrane depolarization and action potential formation. In essence, blocking some of the Na1 channels raises the threshold for action potential formation. This tends to “quiet” ectopic pacemakers and also to stifle reentrant arrhythmias. Na4 channel blockers such as lidocaine or procaine (Novocain) are called “local anesthetics” because, when applied to sensory neurons, they prevent the propagation of neural action potentials that would signal pain to the brain. The cardiac, antiarrhythmic effect of local anesthetics is not the result of their blockage of pain pathways.
A second category of antiarrhythmic drugs is the calcium channel blockers. Examples include verapamil, diltiazem, and nifedipine. These drugs bind to slow Ca2+ channels and prevent them from opening, which decreases the entry of Ca2+ into cardiac muscle cells during an action potential. Because Ca2i entry is the primary depolarizing influence during the plateau (phase 2) of the cardiac action potential, one major effect of a Ca2+ channel blocker is to lower the plateau (make the membrane potential less positive). A secondary consequence is to lengthen the action potential. The action potential is longer because of a complicated effect of the height of the plateau on K4 channels, as discussed earlier in connection with sympathetic effects on cardiac action potentials.
Drugs that lengthen the cardiac action potential also lengthen the refractory period, which makes it less likely that early extra action potentials will be formed in ectopic pacemakers or that they will propagate even if they are formed.The calcium channel blockers have especially strong effects on the cells of the SA and AV nodes. As mentioned, Ca2+ entry through slow Ca2+ channels is the main event in the slow action potentials of these cells. Not surprisingly, therefore, the amplitude of slow action potentials is greatly reduced by Ca2+ channel blockers, and these action potentials are also lengthened. Low-amplitude, long action potentials propagate very slowly from cell to cell, which decreases the likelihood that early extra action potentials will form or propagate in SA or AV node cells.
Calcium channel blockers are especially effective in protecting the ventricles from rapid rates in cases of persistent atrial flutter or fibrillation. By increasing the refractoriness and decreasing the conduction velocity of AV node cells, Ca2+ channel blockers cause many of the extra atrial action potentials to “die out” (through decremental conduction) in the AV node.
By reducing the entry of extracellular Ca2, into cardiac muscle cells during an action potential, Ca2 ’ channel blockers not only suppress tachyarrhythmias, but also decrease the strength of cardiac contractions. Less entry of extracellular “trigger” Ca~* means a less powerful stimulus for the release of stored Ca' from the sarcoplasmic reticulum. Therefore the cytosolic Ca2+ concentration does not increase as much as normal during the action potential, so there is a less forceful contraction. Some clinical situations in which it is desirable to decrease cardiac contractility are discussed in Chapter 21.
The cardiac glycosides (e.g., digitalis) constitute a third category of antiarrhythmic drugs. Cardiac glycosides act by inhibiting the Na+,K, pump in cell membranes.
As mentioned in Chapters I and 4, the Na',K+ pump is an antiport carrier that uses energy from ATP to transport Na’ out of cells and K+ into cells. The pump also indirectly supplies energy to a Na41Ca2+ antiporter that helps to transport Ca2* back out of cardiac cells after it enters during an action potential. Inhibition of the Na41Kt pump with a cardiac glycoside has several important effects on cardiac function. The effects are listed here without much explanation because the mechanisms are quite complex. First, cardiac muscle cells do not repolarize fully at the end of an action potential; the resting membrane potential is not as negative as normal. As a consequence, some Nat channels remain inactivated, which makes the ceils somewhat refractory with regard to the formation of subsequent action potentials. This tends to quiet ectopic pacemakers. Second, effects on the central nervous system lead to an increase in parasympathetic tone. This slows the heart rate, quiets atrial ectopic pacemakers, slows conduction through the AV node, and increases the refractory period of AV node cells. The overall effect is to suppress ectopic atrial action potentials or cause extra atrial action potentials to “die out" in the AV node and not to be conducted to the ventricles. A third effect of cardiac glycosides is to allow more Ca24 than normal to accumulate inside cardiac cells, resulting in the strength of cardiac contractions increasing. In summary, the cardiac glycosides are antiarrhythmic and also increase cardiac contractility.Beta-adrenergic antagonists (e.g., propranolol) constitute a fourth class of antiarrhythmic drug. Beta blockers, as they are called, bind to some of the β-adrenergic receptors on cardiac cells and prevent their activation by norepinephrine from sympathetic nerves or by epinephrine and norepinephrine from the adrenal medulla.
Sympathetic activation tends to promote tachyarrhythmias by increasing heart rate, shortening refractory period, and speeding conduction of action potentials, especially through the AV node. Beta blockers reduce these effects and therefore reduce the likelihood that extra action potentials will form or propagate. An additional effect of β blockers is to reverse sympathetic activation- induced increases in cardiac contractility.In summary, of the four categories of drugs used to treat tachyarrhythmias, three also have pronounced effects on cardiac contractility. The calcium channel blockers and β blockers decrease cardiac contractility, whereas cardiac glycosides increase contractility. Local anesthetics have little effect on contractility. This variety of effects allows a clinician to select the type of antiarrhythmic drug that is best matched to each patients cardiac contractile state.
Electrical dysfunction of the heart has been discussed in considerable detail to illustrate how specific abnormalities in the specialized cardiac conduction system can result in specific and serious arrhythmias. Electrical dysfunction of the heart is encountered often in clinical practice, and its consequences are often serious or even lethal. Because electrical dysfunction is so important, Chapter 20 is devoted to an explanation of the electrocardiogram, which is the most commonly used tool for evaluating electrical dysfunction of the heart.