O Antiarrhythmic Drugs

Cardiac arrhythmias are caused by a disturbance in the conduction of the impulse through the myocardial tissue, by disorders of impulse formation, or by a combination of these factors. The antiarrhythmic agents used most commonly affect impulse conduction by altering conduction velocity and the duration of the refractory period of heart muscle tissue. They also depress spontaneous diastolic depolarization, causing a reduction of automaticity by ectopic foci.

Many pharmacological agents are available for the treatment of cardiac arrhythmias. Agents such as oxygen, potassium, and sodium bicarbonate relieve the underlying cause of some arrhythmias. Other agents, such as digitalis, propranolol, phenylephrine, edrophonium, and neostigmine, act on the cardiovascular system by affecting heart muscle or on the autonomic nerves to the heart. Finally, there are drugs that alter the electrophysiological mechanisms causing arrhythmias. The latter group of drugs is discussed in this chapter.

Within the past 5 decades, research on normal cardiac tissues and, in the clinical setting, on patients with disturbances of rhythm and conduction has brought to light information on the genesis of cardiac arrhythmias and the mode of action of antiarrhythmic agents. In addition, laboratory tests have been developed to measure blood levels of antiarrhythmic drugs such as phenytoin, disopyramide, lidocaine, procainamide, and quinidine, to help evaluate the pharmacokinetics of these agents. As a result, it is possible to maintain steady-state plasma levels of these drugs, which allows the clinician to use these and other agents more effectively and with greater safety. No other clinical intervention has been more effective at reducing mortality and morbidity in coronary care units.

Cardiac Electrophysiology

The heart depends on the synchronous integration of electrical impulse transmission and myocardial tissue response to carry out its function as a pump. When the impulse is released from the SA node, excitation of the heart tissue takes

place in an orderly manner by a spread of the impulse throughout the specialized automatic fibers in the atria, the AV node, and the Purkinje fiber network in the ventricles. This spreading of impulses produces a characteristic electrocardiographic pattern that can be equated to predictable myocardial cell membrane potentials and Na+ and K+ fluxes in and out of the cell.

A single fiber in the ventricle of an intact heart, during the diastolic phase (see phase 4, Fig. 19.4), has a membrane potential (resting potential) of 90 mV. This potential is created by differential concentrations of K+ and Na+ in the intracel-lular and extracellular fluid. An active transport system (pump) on the membrane is responsible for concentrating the K+ inside the cell and maintaining higher concentrations of Na+ in the extracellular fluid. Diastolic depolarization is caused by a decreased K+ ionic current into the extracellular tissue and a slow inward leakage of Na+ until the threshold potential (60-55 mV) is reached. At this time, the inward sodium current suddenly increases, and a self-propagated wave occurs to complete the membrane depolarization process. Pacemaker cells possess this property, which is termed automaticity. This maximal rate of depolarization (MRD) is represented by phase 0 or the spike action potential (Fig. 19.4).

The form, duration, resting potential level, and amplitude of the action potential are characteristic for different types of myocardial cells. The rate of rise of the response (phase 0) is related to the level of the membrane potential at the time of stimulation and has been termed membrane responsiveness. Less negative potentials produce smaller slopes of phase 0 and are characterized by slower conduction times. The phase 0 spike of the SA node corresponds to the inscription of the P wave on the electrocardiogram (Fig. 19.10). Repolarization is divided into three phases. The greatest amount of repolarization is represented by phase 3, in which there is a passive flux of K+ ions out of the cell. Phase 1 repolarization is caused by an influx of Cl" ions. During phase 2, a small inward movement of Ca2+ ions occurs through a slow channel mechanism that is believed to be important in the process of coupling excitation with contraction. The process of repolarization determines the duration

Figure 19.10 • Normal electrocardiogram. (From Ganong, W. F.: Review of Medical Physiology, 9th ed. San Francisco, Lange Medical Publications, 1985.)

of the action potential and is represented by the QT interval. The action potential duration is directly related to the refractory period of cardiac muscle.

Mechanisms of Arrhythmias

The current understanding of the electrophysiological mechanisms responsible for the origin and perpetuation of cardiac arrhythmias is caused by altered impulse formation (i.e., change in automaticity), altered conduction, or both, acting simultaneously from different locations of the heart. The generation of cardiac impulses in the normal heart is usually confined to specialized tissues that spontaneously depolarize and initiate the action potential. These cells are located in the right atrium and are referred to as the SA node or the pacemaker cells. Although the spontaneous electrical depolarization of the SA pacemaker cells is independent of the nervous system, these cells are innervated by both sympathetic and parasympathetic fibers, which may cause an increase or decrease of the heart rate, respectively. Other special cells in the normal heart that possess the property of automaticity may influence cardiac rhythm when the normal pacemaker is suppressed or when pathological changes occur in the myocardium to make these cells the dominant source of cardiac rhythm (i.e., ectopic pacemakers). Automaticity of subsidiary pacemakers may develop when myocardial cell damage occurs because of infarction or from digitalis toxicity, excessive vagal tone, excessive catecholamine release from sympathomimetic nerve fibers to the heart, or even high catecholamine levels in plasma. The development of automaticity in specialized cells, such as that found in special atrial cells, certain AV node cells, bundle of His, and Purkinje fibers, may lead to cardiac arrhythmias. Because production of ectopic impulses is often caused by a defect in the spontaneous phase 4 diastolic depolarization ("T wave"), drugs that can suppress this portion of the cardiac stimulation cycle are effective agents for these types of arrhythmia.

Arrhythmias are also caused by disorders in the conduction of impulses and changes in the refractory period of the myocardial tissue. Pharmacological intervention is based on these two properties. The Purkinje fibers branch into a network of interlacing fibers, particularly at their most distant positions. This creates several pathways in which a unidirectional block in a localized area may establish circular (circus) microcellular or macrocellular impulse movements that reenter the myocardial fibers and create an arrhythmia (Fig. 19.11). Unidirectional block results from localized

Figure 19.11 • Reentry mechanism of Purkinje fibers. A. Normal conduction of impulses through triangular arrangement of cardiac fibers. B. Unidirectional block on left arm of triangular section allows impulse to reenter the regional conducting system and recycle.

Figure 19.10 • Normal electrocardiogram. (From Ganong, W. F.: Review of Medical Physiology, 9th ed. San Francisco, Lange Medical Publications, 1985.)

Figure 19.11 • Reentry mechanism of Purkinje fibers. A. Normal conduction of impulses through triangular arrangement of cardiac fibers. B. Unidirectional block on left arm of triangular section allows impulse to reenter the regional conducting system and recycle.

TABLE 19.4 Classes of Antiarrhythmic Drugs

Class

Drugs

Mechanism of Action

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