A Primer on Antiarrhythmic Drug Action

The use of drugs to favorably alter heart rhythm began in 1914 with quinidine, whose antiarrhythmic actions were found by accident. Since that time, the number and complexity of drug categories has evolved to the extent that we have come closer to understanding the relationship between drug action and the mechanisms of arrhythmias. In this review, we will first discuss some basic principles of electrophysiology. We will also look at an overview of the properties of antiarrhythmic drugs, which allow them to be effective in arrhythmia control. What s Going on in the Cell? Cardiac Cell States Cardiac cells exhibit a charge which is capable of changing throughout the cardiac cycle (Figure 1). The mechanism, which allows this dynamic process, is the flow of positively charged ions (cations) in or out of the cell. During the resting state (Figure 1A) the cell is said to be polarized, a reference to the cell interior having a different (opposite) charge compared to its exterior. Specifically, the inside is negative with respect to the outside. The K+ ion is the dominant cation inside the cell. Its continuous outward movement through the cell membrane is what maintains the intracellular negativity. A cell becomes depolarized (Figure 1B) when a wavefront of excitation comes its way, is properly oxygenated and has electrolytes in balance. There is a rapid influx of the positively charged sodium ion into the cell, causing the cell interior to become positive relative to its exterior. On the heels of sodium, calcium will more slowly begin crossing the cell membrane (slow calcium channels). The repolarized cell (Figure 1C) is in a recovering state, during which time it will return to the polarized state. The recovery of intracellular negativity is accomplished by the outward movement of K+ ions: a positive charge leaving the cell leaves behind relative negativity. The concepts of depolarization and repolarization can be viewed solely from the standpoint of the directions of cation movement: inward movements are depolarizing and are called inward currents, while outward movements are repolarizing and are called outward currents. Cardiac Cell Properties We need to begin this discussion by defining some of the terms we hear every day as we speak of drugs and arrhythmias. The first term is automaticity. The root word here is automatic. Cells of the conduction system are capable of automatically initiating an impulse, unlike the working muscle cells of the atria or ventricle. Under ordinary resting conditions, the SA node is capable of this at 50-110 times per minute; the junctional area at 40-60 times per minute; and the His-Purkinje region at 10-40 times per minute. A second important term is excitability. The root word for excitability is excite. How excitable is a cell at a given time? Will it respond to the approaching wavefront of activation? Excitability refers to the ease with which the cell can be depolarized. This concept relates the level of membrane potential at rest (resting membrane potential) to another level of membrane potential we call threshold potential. If the cell can be depolarized enough to exceed threshold potential, the all or none response of depolarization will take over. It is important to emphasize that a cell will not be capable of depolarization if the resting membrane potential is not good enough meaning not large enough. The more negative it is, the more likely the cell can be depolarized once threshold is exceeded. We know that certain situations can alter the excitability of a cell. For example, low extracellular potassium can increase excitability by moving resting membrane potential closer to threshold potential (a depolarizing influence). Such cells may be at risk of firing off spontaneously and cause certain arrhythmias. A low pO2 will act in a similar manner, ushering in the potential for arrhythmias that would not normally be seen. High extracellular potassium will suppress excitability, thus making it difficult or impossible for cells to respond to stimuli and may lead to inexcitability. Another term to know is conductivity, the root word here being conduct. This word describes the travel (as in conductor, trains, etc.) of an impulse from one area to another. We can observe this phenomenon in two places on a rhythm strip: PR interval (travel from the SA node to the beginning of ventricular activation) and QRS width (travel through the ventricles). Conductivity is very reliant on the level of resting membrane potential (RMP): the more negative (or higher) the RMP of the cell as it is about to be depolarized, the more effective that cell becomes as a stimulus to excite his neighbor. Thus, conduction or passing on of the depolarizing influence is optimal. Poor conduction of an impulse results when RMP is low (less negative). The term refractoriness describes the state of inexcitability that exists during the period of repolarization. Absolute refractoriness means inexcitability, because membrane potential is simply too low to support depolarization and it will remain this way until the cell s membrane potential gets much closer to its normal resting level. Relative refractoriness means that it is possible to achieve depolarization even though the cell has not fully repolarized, but it also means that a larger than normal stimulus may be necessary to achieve depolarization. The concepts of depolarization and repolarization can be remembered with a couple of analogies. The first analogy is of a row of dominoes (Figure 2). The standing position of the dominoes represents cells in a polarized state. When a wavefront of excitation reaches the first domino, it starts to fall. If the domino is not pushed far enough, then the threshold potential is not reached and nothing happens it was inexcitable. If it is pushed far enough, the domino will fall (depolarize) and knock down the next and the next (conductivity). Before the dominoes can be knocked down again, recovery must take place; thus, the dominoes must be put in standing position again (repolarization). Until they are standing, they cannot be made to fall (refractoriness). The other analogy involves an everyday activity, such as the flushing of a toilet; but this one cannot connote a conducted event only the actions of a single cell. Once the toilet is flushed (depolarization), you must wait for the tank to fill before you can flush again (refractoriness). A premature flush may lead to a weak, relatively inexcitable flush or no flush because refilling (repolarization) was interrupted. Action Potential Phases In this section, we will take a deeper look at the process of depolarization and repolarization. Using a purkinje cell as our example, we ll see what happens during these phases. In Figure 3, you see an action potential diagram, often an intimidating sight. However, this diagram holds a world of information, and can enhance your understanding of these processes in a normal cell and in a cell being affected by an antiarrhythmic medication. The various phases of electrolyte movement are numbered as 0, 1, 2, 3 and 4. Phase 0 represents the stimulation of a cell by an electrical stimulus. The cell, which begins in a negative state (-90mV) quickly becomes positive as the cell membrane becomes more permeable to sodium ions. The fast sodium channels are opened and sodium influx occurs. This corresponds with the inscription of a QRS on your rhythm strip tracing. Notice the horizontal line in the diagram labeled threshold potential. This line represents the required strength an impulse must have to cause the cell to participate electrically. A weak impulse may not have the strength to change the cell electrically beyond that point, and the cell would not respond then. This threshold line can change, based on cellular factors previously discussed such as potassium level. A low potassium lowers the bar and allows rhythms to occur that you normally would not see. A high potassium raises the bar, and may prevent the cell from participating even with normal stimulation, leading to inexcitability. Phase 1 is a period of rapid early repolarization or recovery which is only brief. The sodium influx in the fast channels has ended and the recovery process is now in place by the efflux of potassium ions. Phase 2 is known as the plateau phase. In this phase, there is some stifling of what would otherwise be an aggressive efflux of potassium ions. In addition, calcium and sodium ions are moving into the cell through slow channels. Notice how the return of the cell to its resting state is now delayed. The primary purpose of calcium entry is to promote contractability. Phase 3 marks the return of the cell to negativity. This occurs because of the continued loss of potassium from the cell but at a faster rate, and also because the opposing inward currents carried by Na and Ca have fallen off. Phase 4 marks the return of the resting membrane potential level of -90mV. Continued efflux of potassium ions is the basis for the maintenance of resting membrane potential. While this is happening, sodium ions are pumped out and potassium is pumped into the cell via the actions of the sodium-potassium pump. This will help restore their normal transmembrane concentrations. ATP is responsible for the pump actions, as is magnesium. Thus, the magnesium level may influence the efficiency of the repolarization process. Remember: torsades is associated with a long QT (prolonged repolarization) the drug of choice for torsades is magnesium. Antiarrhythmic medications work in part by altering the various action potential phases. Specific categories of drugs will block channels or change the time for various phases to occur. Local Variations in Action Potential Configurations Our discussion of action potential centered on the different phases in a purkinje cell. Figure 4 shows the appearance of action potentials in the other cells of the conduction system. Notice that the shapes vary. Each action potential will have a designated phase 0, etc. However, the timing will be different. Notice also the ability of the SA node cell to depolarize and repolarize quickly and be ready for the next impulse initiation. This capability is what makes the SA node the pacemaker of the normal heart, as it fires and recovers faster than cells from other regions.

Antiarrhythmic Drugs: Issues of Drug Effectiveness

The discussion of antiarrhythmics must begin with establishment of some basic understandings. The drugs we use are not arrhythmia suppressants, i.e., soothers of irritable areas. They act by binding to sites on cell walls, and blocking certain activities of cellular function. The channels being blocked could be resting, open, or inactive at any given time, leading to different behaviors at different sites. Since the opening and closing of cell channels does not occur in total unison (especially in diseased tissue), potential for proarrhythmia exists. This means that the drug used for arrhythmia control could also be responsible for causing arrhythmias. Vaughn Williams Drug Classification The most well known categorization of antiarrhythmics is the Vaughn Williams system. This physiologically-based classification system was first proposed in the 1970s and has increased in complexity with the development of new agents. It was originally based on receptor and ion channel-binding properties of drugs. The system consists of four classes of agents. Class I includes drugs which block the fast inward sodium current. This effect alters the phase 0 upstroke velocity, in addition to changing repolarization and refractoriness (see the action potential diagram). However, Class I drugs can cause these effects in a variety of ways. So three subclassifications within Class I have evolved: 1) Class IA, which depresses phase 0, slows conduction, and prolongs repolarization (Figure 5); 2) Class IB, which has the effect of depressing phase 0 in abnormal fibers and shortening repolarization (Figure 6); and 3) Class IC, which markedly depresses phase 0, markedly slows conduction, and has just a slight effect on repolarization (Figure 7). Examples of Class IA drugs are quinidine, procainamide, and disopyramide. Class IB agents are lidocaine, tocainide and mexilitine. Class IC drugs include flecainide and propafenone. Class II initially included drugs categorized as sympatholytic, but has evolved to include the beta-blockers. These drugs depress automaticity and conduction in the slow response cells (the SA node and AV node). All beta-blockers may be categorized as Class II. Class III includes drugs that prolong repolarization (Figure 8). This prolongation occurs via multiple mechanisms. These drugs are also known as potassium channel blockers. Class III agents include amiodarone, sotalol, bretyllium, azimilide, dofetilide, and ibutilide. Class IVA drugs block the calcium channels. The effect seen from these drugs is primarily in the SA and AV node. Drugs in this category include verapamil and diltiazem. Class IVB agents are adenosine receptor agonists (AI receptor and If channel). These agents stimulate adenosine receptors, leading to the opening of the potassium channel and a hyperpolarization. This causes a depression of automaticity in the SA nodal cells and depressed conduction in the AV nodal cells. Adenosine is in Class IVB. The Vaughn Williams system, though helpful as a learning tool, has been deemed by some to be problematic for current clinical practice. The drugs we use are much more complicated than originally believed. In addition, the effects attributed to the drug classes in this system are those seen in normal cells, not in cells which are diseased and have abnormal receptors and channels. Moreover, the way in which we use drugs for arrhythmia control is understated in this scheme. We use antiarrhythmics to prevent initiation of arrhythmias, to make tachycardias more tolerated, to stop arrhythmias, and to slow tachycardias. Thus, the categories we have used in the past do not do justice to the reality of the clinical setting. Sicilian Gambit An alternative to the Vaughn Williams system was proposed in 1990 by a group of physicians and scientists who met in Sicily to examine what was then known about antiarrhythmic therapy. As a result of their work, they suggested that pathophysiology should guide drug selection, changing the focus to the mechanism of the arrhythmia rather than drug action. Close examination of the drugs then in use showed that no two drugs had exactly the same properties, though sharing common classification. The effects of the various drugs included 1) channel blocking: slow, medium and fast sodium channel effects, alteration of the potassium channels Ik and If, and calcium channel blocking; 2) interaction with receptors: alpha adrenergic, beta adrenergic, M2 (muscarinic cholinergic receptor), and AI (adenosine); and 3) effects on the Na-K pump (Na/K ATPase). Thus, a variety of physiologic effects can occur which may impact therapeutic outcomes. The potential causes of arrhythmias are varied. The mechanisms include 1) triggers which start-up tachycardias; 2) the presence of cardiac structures that serve as substrates which maintain a tachycardia; and 3) abnormal physiologic states which contribute to the triggering mechanism and arrhythmia maintenance. Therefore, the Sicilian Gambit message is to carefully explore the origin of the arrhythmic problem and thoughtfully select a drug regimen. In conclusion, antiarrhythmic drug therapy challenges us both academically and clinically. Understanding of both drug actions and the cellular responses to drugs enhances our ability to care for patients in an effective and safe manner.