Mechanisms Of Antiarrhythmic Drug Action

A single arrhythmia may result from multiple mechanisms. Drugs may be antiarrhythmic by suppressing the initiating mechanism or by altering a reentrant circuit. In some cases, drugs may suppress the initiator but nonetheless promote reentry (see below).

Drugs may slow automatic rhythms by altering any of the four determinants of spontaneous pacemaker discharge: increase maximum diastolic potential, decrease phase 4 slope, increase threshold potential, or prolong action potential duration. Adenosine and acetylcholine may increase maximum diastolic potential, and p adrenergic receptor antagonists (p blockers) may decrease phase 4 slope. Block of Na+ or Ca2+ channels usually results in altered threshold, and block of cardiac K+ channels prolongs the action potential.

Antiarrhythmic drugs may block arrhythmias owing to DADs or EADs by two major mechanisms: (1) inhibition of the development of afterdepolarizations and (2) interference with the inward current (usually through Na+ or Ca2+ channels), which is responsible for the upstroke. Thus, arrhythmias owing to digitalis-induced DADs may be inhibited by verapamil (which blocks the development of DAD) or by quinidine (which blocks Na+ channels, thereby elevating the threshold required to produce the abnormal upstroke). Similarly, two approaches are used in arrhythmias related to EAD-induced triggered beats (Tables 34-2 and 34-3). EADs can be inhibited by shortening action potential duration; in practice, heart rate is accelerated by isoproterenol infusion or by pacing. Triggered beats arising from EADs can be inhibited by Mg2+ without normalizing repolarization in vitro or QT interval. In patients with congenitally long QT syndrome, torsades de pointes often occurs with adrenergic stress; therapies include p adrenergic blockade (which does not shorten the QT interval) and pacing.

In anatomically determined reentry, drugs may terminate the arrhythmia by blocking propagation of the action potential. In the example of the WPW-related arrhythmia described above, drugs that prolong AV nodal refractoriness and slow AV nodal conduction (e.g., Ca2+ channel blockers, p adrenergic receptor antagonists, or digoxin) are likely to be effective but should be used with caution. On the other hand, slowing conduction in functionally determined reentrant circuits may change the pathway without extinguishing the circuit. Slow conduction generally promotes the development of reentrant arrhythmias, whereas the most likely approach for terminating functionally determined reentry is prolongation of refractoriness. In fast-response tissues, refractoriness is prolonged by delaying the recovery of Na+ channels from inactivation. Drugs that block Na+ channels generally shift the voltage dependence of recovery and so prolong refractoriness. Drugs that increase action potential duration without direct action on Na+ channels (e.g., by blocking delayed rectifier currents) also will prolong refractoriness. In slow-response tissues, Ca2+ channel block prolongs refractoriness.

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