Antiarrhythmics of the Nachannel blocking type

Mexiletine

Electrophysiological Actions of Antiarrhythmics of the Na+-Channel Blocking Type

Action potential and ionic currents.

The transmembrane electrical potential of cardiomyocytes can be recorded through an intracellular microelectrode. Upon electrical excitation, a characteristic change occurs in membrane poten-tial—the action potential (AP). Its underlying cause is a sequence of transient ionic currents. During rapid depolarization (Phase 0), there is a short-lived influx of Na+ through the membrane. A subsequent transient influx of Ca2+ (as well as of Na+) maintains the depolarization (Phase 2, plateau of AP). A delayed efflux of K+ returns the membrane potential (Phase 3, repolarization) to its resting value (Phase 4). The velocity of depolarization determines the speed at which the AP propagates through the myocardial syncytium.

Transmembrane ionic currents involve proteinaceous membrane pores: Na+, Ca2+, and K+ channels. In A, the phasic change in the functional state of Na+ channels during an action potential is illustrated.

Effects of antiarrhythmics. Antiar-rhythmics of the Na+-channel blocking type reduce the probability that Na+ channels will open upon membrane depolarization ("membrane stabilization"). The potential consequences are (A, bottom): 1) a reduction in the velocity of depolarization and a decrease in the speed of impulse propagation; aberrant impulse propagation is impeded. 2) Depolarization is entirely absent; pathological impulse generation, e.g., in the marginal zone of an infarction, is suppressed. 3) The time required until a new depolarization can be elicited, i.e., the refractory period, is increased; prolongation of the AP (see below) contributes to the increase in refractory period. Consequently, premature excitation with risk of fibrillation is prevented.

Mechanism of action. Na+-channel blocking antiarrhythmics resemble most local anesthetics in being cationic amphiphilic molecules (p. 208, exception: phenytoin, p. 190). Possible molecular mechanisms of their inhibitory effects are outlined on p. 204 in more detail. Their low structural specificity is reflected by a low selectivity towards different cation channels. Besides the Na+ channel, Ca2+ and K+ channels are also likely to be blocked. Accordingly, cat-ionic amphiphilic antiarrhythmics affect both the depolarization and repola-rization phases. Depending on the substance, AP duration can be increased (Class IA), decreased (Class IB), or remain the same (Class IC).

Antiarrhythmics representative of these categories include: Class IA— quinidine, procainamide, ajmaline, dis-opyramide, propafenone; Class IB—lido-caine, mexiletine, tocainide, as well as phenytoin; Class IC—flecainide.

Note: With respect to classification, P-blockers have been assigned to Class II, and the Ca2+-channel blockers vera-pamil and diltiazem to Class IV.

Commonly listed under a separate rubric (Class III) are amiodarone and the P-blocking agent sotalol, which both inhibit K+-channels and which both cause marked prolongation of the AP with a lesser effect on Phase 0 rate of rise.

Therapeutic uses. Because of their narrow therapeutic margin, these antiar-rhythmics are only employed when rhythm disturbances are of such severity as to impair the pumping action of the heart, or when there is a threat of other complications. The choice of drug is empirical. If the desired effect is not achieved, another drug is tried. Combinations of antiarrhythmics are not customary. Amiodarone is reserved for special cases.

Antiarrhythmic Mechanism Action

Heart muscle cell

Heart muscle cell

lllp^ Phase 0

Slow Ca2+-entry Ionic currents during action potential

Fast

Na+-channels

Closed

Opening impossible (inactivated)

Closed

Opening possible (resting, can be activated)

Open (active)

States of Na+-channels during an action potential

Closed

Opening impossible (inactivated)

Closed

Opening possible (resting, can be activated)

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