Action potential, cardiac cells antiarrhythmics

Optimal therapy of cardiac arrhythmias requires documentation, accurate diagnosis, and modification of precipitating causes, and if indicated, proper selection and use of antiarrhythmic drugs. These drugs are classified according to their effects on the action potential of cardiac cells and their presumed mechanism of action. 

Mechanism of action - Disopyramide is a class lA antiarrhythmic agent that decreases the rate of diastolic depolarization (phase 4), decreases the upstroke velocity (phase 0), increases the action potential duration of normal cardiac cells, and prolongs the refractory period (phases 2 and 3). It also decreases the disparity in refractoriness between infarcted and adjacent normally perfused myocardium and does not affect alpha- or beta-adrenergic receptors. 

Fig. 6. Influences of different types of antiarrhythmic agents (Vaughan-William s classification) on the shape of cardiac action potentials. First row Class I-agents action potentials of ventricular myocardial cells. Second row (from left to right) Action potential of SA-node cells influence of a )0-hlocker (class II). Action potential of ventricular myocardial cells influence of a class Ill-antiarrhythmic. Action potential of AV nodal cells influence of a class IV-antiarrhythmic (verapamil, diltiazem).

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.]... 

Action potentials recorded from various cardiac cells may vary somewhat from the action potential described previously. Some cells, for instance, totally lack phase 1 and have a slower phase 0. Such cells are said to have a slow response as opposed to the fast response just described. Also, action potentials from the nodal cells (see the next section, Normal Cardiac Rhythm ) differ somewhat from the fast response cells. Nonetheless, the fundamental ionic fluxes occurring during cardiac action potentials are similar in all cardiac cells. This ionic activity is pharmacologically significant because various antiarrhythmic drugs will affect the movement of sodium and other ions in an attempt to establish and maintain normal cardiac rhythm. 

In some types of rhythm disorders, antiar-rhythmics of the local anesthetic, Na+-channel blocking type are used for both prophylaxis and therapy. These substances block the Na+ channel responsible for the fast depolarization of nerve and muscle tissues. Therefore, the elicitation of action potentials is impeded and impulse conduction is delayed. This effect may exert a favorable influence in some forms of arrhythmia, but can itself act arrhythmogenically. Unfortunately, antiarrhythmics of the local anesthetic, Na+-channel blocking type lack suf -cient specificity in two respects (1) other ion channels of cardiomyocytes, such as K1 and Ca+ channels, are also affected (abnormal QT prolongation) and (2) their action is not restricted to cardiac muscle tissue but also impacts on neural tissues and brain cells. Adverse effects on the heart include production of arrhythmias and lowering of heart rate, AV conduction, and systolic force. CNS side effects are manifested by vertigo, giddiness, disorientation, confusion, motor disturbances, etc. 

Fig. 24.1 The action potential of a cardiac cell that is capable of spontaneous depolarisation (SA or AV nodal, or His-PurkInje) indicating phases 0-4 the figure illustrates the gradual increase in transmembrane potential (mV) during phase 4 cells that are not capable of spontaneous depolarisation do not exhibit increase in voltage during this phase (see text).The modes of action of antiarrhythmic drugs of classes I, II, III and IV are indicated in relation to these phases...

Mexiletine hydrochloride, like cla.ss I antiarrhythmic agents, blocks the fast Na channel in cardiac cells. It is especially effective on the Purkinje fibers in the heart. The drug increases the threshold of excitability of myocardial cells by reducing the rale of rise and amplitude of the action potential and decreases aulomaliciiy. 

Inhibits L-type Ca" channels in cardiac and vascular smooth muscle cells more selective for the myocardium with minimal vasodilatory effects compared with dihydropyridines class IV antiarrhythmic agents Inhibits L-type Ca " " channels in cardiac and vascular smooth muscle cells by modulating ion channel gating mechanisms decreases systemic blood pressure and heart contractility Binds with high affinity to the alpha2-delta subunit of voltagegated Ca " " channels in CNS anticonvulsant drug Inhibits neuronal fast Nay channels, and thus blocks the action potential inhibits also cardiac Nay channels... 

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