Potential, action

FIGURE 23-1 T The cardiac action potential recorded from a Purkinje cell. The effective refractory period is the time during which the cell cannot be depolarized, and the relative refractory period is the time in which a supranormal stimulus is required to depolarize the cell. Action potential phases [0-4] and the ionic basis for each phase are discussed in the text. From Keefe DLD, Kates RE, Harrison DC. New antiarrhythmic drugs their place in therapy. Drugs. 1981 22 363 with permission.] 

Phase 0. Rapid depolarization occurs because of the sudden influx of sodium ions into the cell. At some threshold level, the cell membrane suddenly becomes permeable to sodium ions because of the opening of sodium channels or gates, similar to the spike seen in skeletal muscle depolarization. 

Phase 1. An early, brief period of repolarization occurs because specific potassium channels in the cell membrane open to allow potassium to leave the cell. 

Phase 3. At the end of the plateau, repolarization is complete. This is primarily because of the closing (inactivation) of the calcium channels, which terminates the entry of calcium into the cell. Repolarization is completed by the unopposed exit of potassium ions. 

Phase 4. Phase 4 consists of a slow, spontaneous depolarization in certain cardiac cells (such as the one shown in Fig. 23-1). This spontaneous depolarization probably occurs because of the continuous leak of sodium ions into the cell, combined with a gradual decrease in potassium exit from the cell. This combination of sodium entry and decreased potassium exit causes a progressive accumulation of positive charge within 

Sodium channels open more rapidly than K+ channels because they are more voltage sensitive and a small depolarization is sufficient to open them. Larger changes in membrane potential associated with further cell excitation are required to open the less voltage-sensitive K+ channels. Therefore, the increase in the permeability of K+ ions occurs later than that of Na+ ions. This is functionally significant because if both types of ion channels opened concurrently, the change in membrane potential that would occur due to Na+ ion influx would be cancelled out by K+ ion efflux and the action potential could not be generated. 

During the course of the action potential, Na+ ions entered the cell and K+ ions exited it. In order to prevent eventual dissipation of the concentration gradients for Na+ and K+ ions across the cell membrane over time, these substances must be returned to their original positions. The slow but continuous activity of the Na+-K+ pump is responsible for this function and returns Na+ ions to the extracellular fluid and K+ ions to the intracellular fluid. 

A striking example of the importance of ion channels is their role in the propagation of impulses by neurons, the fundamental units of the nervous system. Here we give a thermodynamic description of the process. 

The cell membrane of a neuron is more permeable to K ions than to either Na+ or CT ions. The key to the mechanism of action of a nerve cell is its use of Na and K+ channels to move ions across the membrane, modulating its potential. For example, the concentration of K inside an inactive nerve cell is about 20 times that on the outside, whereas the concentration of Na+ outside the cell is about 10 times that on the inside. The difference in concentrations of ions results in a transmembrane potential difference of about —62 mV. This potential difference is also called the resting potential of the cell membrane. 

To estimate the resting potential, we need to understand that the cell is never at equilibrium, so the approach taken in Example 5.1 is not appropriate. Ions continually cross the membrane, which is more permeable to some ions than others. To take into account membrane permeabihty, we use the Goldman equation to calculate the resting potential  

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Excitability. Excitabihty refers to electrical responsiveness of the heart to various stimuli by the generation of local excitatory currents, action potentials, or fibrillation. 

Conductivity. Conductivity is an electrical property of excitable tissue which ensures that if one area of a membrane is excited to full activity, that area excites adjacent areas. Conduction of an impulse varies direcdy with the rate of development of phase 0 and the ampHtude of the action potential. Phase 0 is faster, and ampHtude of the action potential is greater, the more negative the transmembrane potential at the time of initiation of the impulse. Conduction velocity is faster when phase 0 is fast. 

The Class I antiarrhythmic agents inactivate the fast sodium channel, thereby slowing the movement of Na" across the cell membrane (1,2). This is reflected as a decrease in the rate of development of phase 0 (upstroke) depolarization of the action potential (1,2). The Class I agents have potent local anesthetic effects. These compounds have been further subdivided into Classes lA, IB, and IC based on recovery time from blockade of sodium channels (11). Class IB agents have the shortest recovery times (t1 ) Class lA compounds have moderate recovery times (t 2 usually <9 s) and Class IC have the longest recovery times (t 2 usually >9 s). 

Glass lA Antiarrhythmic Agents. Class lA antiarrhythmic agents decrease automaticity, ie, depress pacemaker rates, especially ectopic foci rates produce moderate depression of phase 0 depolarization and thus slow conduction in atria, A-V node, His-Purkinje system, and ventricles prolong repolarization, ie, lengthen action potential duration increase refractoriness and depress excitabiHty. These electrophysiological effects are manifested in the ECG by increases in the PR, QRS, and QT intervals. 

Glass IB Antiarrhythmic Agents. Class IB antiarrhythmic agents produce less inhibition of the inward sodium current than Class lA agents. In normal myocardial tissue, phase 0 may be unaffected or minimally depressed. However, in ischemic or infarcted tissue, phase 0 is depressed. Myocardial tissue exposed to Class IB agents exhibits decreased automaticity, shortened action potential duration, ie, shortened repolarization, and shortened refractory period. Excitability of the myocardium is not affected and conduction velocity is increased or not modified. The refractory period is shortened less than its action potential duration, thus the ratio of refractory period to action potential duration is increased by these agents. The net effect is increased refractoriness. The PR and QT intervals of the ECG are shortened and the QRS interval is unchanged (1,2). 

Glass IG Antiarrhythmic Agents. Class IC antiarrhythmic agents have marked local anesthetic effects. They slow the rapid inward sodium current producing marked phase 0 depression and slow conduction. Action potential duration of ventricular muscle is increased, ie, prolonged repolarization, but decreased in the His-Purkinie system by these agents. The effects on the ECG are increased PR interval, marked prolongation of the... 

Fleca.inide, Elecainide acetate, a fluorobenzamide, is a derivative of procainamide, and has been reported to be efficacious in suppressing both supraventricular and ventricular arrhythmias (26—29). The dmg is generally reserved for patients with serious and life-threatening ventricular arrhythmias. Elecainide depresses phase 0 depolarization of the action potential, slows conduction throughout the heart, and significantly prolongs repolarization (30). The latter effect indicates flecainide may possess some Class III antiarrhythmic-type properties (31). 

Pirmenol. Pirmenol hydrochloride, a pyridine methanol derivative, is a racemic mixture. It has Class lA antiarrhythmic activity, ie, depression of fast inward sodium current, phase 0 slowing, and action potential prolongation. The prolongation of refractory period may be a Class III property. This compound has shown efficacy in converting atrial arrhythmias to normal sinus rhythm (34,35). 

The Class III antiarrhythmic agents markedly prolong action potential duration and effective refractory period of cardiac tissue. The QT interval of the ECG is markedly prolonged. 

The electrophysiological effects of amiodarone may be a composite of several properties. In addition to prolonging action potential duration and refractory period in ad tissues of the heart, the compound is an effective sodium channel blocker (49), calcium channel blocker (50), and a weak noncompetitive -adrenoceptor blocking agent (51). Amiodarone slows the sinus rate, markedly prolongs the QT interval, and slightly prolongs the QRS duration (1,2). 

Verapamil. Verapamil hydrochloride (see Table 1) is a synthetic papaverine [58-74-2] C2qH2 N04, derivative that was originally studied as a smooth muscle relaxant. It was later found to have properties of a new class of dmgs that inhibited transmembrane calcium movements. It is a (+),(—) racemic mixture. The (+)-isomer has local anesthetic properties and may exert effects on the fast sodium channel and slow phase 0 depolarization of the action potential. The (—)-isomer affects the slow calcium channel. Verapamil is an effective antiarrhythmic agent for supraventricular AV nodal reentrant arrhythmias (V1-2) and for controlling the ventricular response to atrial fibrillation (1,2,71—73). 

Lowenstein (27) found an approximate correlation between the nerve action potential produced by 1.6% pyrethrins applied externally and 0.3% pyrethrins applied directly to the nerve cord. 

An Action Potential is a stereotyped (within a given cell) change of the membrane potential from a resting... 

Antiarrhythmic drugs are substances that affect cardiac ionic channels or receptors, thereby altering the cardiac action potential or its generation or propagation. This results in changes of the spread of activation or the pattern of repolarization. Thereby, these drugs suppress cardiac arrhythmia. 

Normal rhythmic activity is the result of the activity of the sinus node generating action potentials that are conducted via the atria to the atrioventricular node, which delays further conduction to the His-Tawara-Purkinje system. From the Purkinje fibres, action potentials propagate to the ventricular myocardium. Arrhythmia means a disturbance of the normal rhythm either resulting in a faster rhythm (tachycardia, still rhythmic) or faster arrhythmia (tachyarrhythmia) or slowed rhythm (bradycardia, bradyarrhythmia). 

In the following, the cardiac action potential is explained (Fig. 1) An action potential is initiated by depolarization of the plasma membrane due to the pacemaker current (If) (carried by K+ and Na+, which can be modulated by acetylcholine and by adenosine) modulated by effects of sympathetic innervation and (3-adrenergic activation of Ca2+-influx as well as by acetylcholine- or adenosine-dependent K+-channels [in sinus nodal and atrioventricular nodal cells] or to dqjolarization of the neighbouring cell. Depolarization opens the fast Na+ channel resulting in a fast depolarization (phase 0 ofthe action potential). These channels then inactivate and can only be activated if the membrane is hyperpolarized... 

I a With prolongation of action potential Quinidine, Procainamide, Disopyramide, Ajmaline, Prajmaline... 

I b With shortening of action potential Lidocaine, Mexiletine, Tocainide, Phenytoin, Aprindine... 

I c With only little effect on action potential duration Lorcainide, Flecainide, Propafenone... 

III Block of repolarizing potassium channels, prolongation of action potential Amiodarone, Dronedarone, Sotalol, Dofetilide, Ibutilide... 

Antiarrhythmic Drugs. Figure 1 Transmembrane ionic currents of the cardiac action potential. In the middle of the figure, a typical cardiac action potential is shown as can be obtained from the ventricular myocardium (upper trace). Below, the contribution of the various transmembrane currents is indicated. Currents below the zeroline are inward currents above the zero line are outward fluxes. In the left column the name of the current is given and in the right column the possible clone redrawn and modified after [5]. 

Not all cells in the heart express the fast sodium channel. Thus, sinus nodal and atrioventricular nodal cells lack the fast Na+ channel and instead generate their action potentials via opening of Ca2+ channels. This is the basis for their sensitivity to Ca2+ antagonists. 

A cell generates late afterdepolarizations (typically induced by catecholamines or digitalis) following a complete repolarization that may elicit an action potential. 

A cell may produce early afterdepolarizations that are depolarization during incomplete repolarization. This is possible if the action potential is considerably prolonged. This is the typical mechanism for elicitation of Torsade de Pointes arrhythmia, a typical complication of class III antiarrhythmics and many other drugs. 

Besides the class I-typical proarrhythmic risk class IA antiarrhythmics possess a marked proarrhythmic risk for the induction of torsade depointes arrhythmia (life-threatening polymorphic ventricular tachycardia observed with most action potential prolonging drugs). 

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