A new drug has been developed to treat cardiac arrhythmias. The drug has high affinity for activated and inactivated sodium channels but relatively little affinity for resting sodium channels. An experiment is devised to maintain sodium channels in the inactivated state for a prolonged period, during which they are exposed to the new drug. After allowing the sodium channels to return to the resting state, the speed of the drug's dissociation from the sodium channels is recorded and shown below. The dissociation curve for quinidine is given for comparison. The pharmacologic action of the new drug is most similar to which of the following drugs?

Question

A new drug has been developed to treat cardiac arrhythmias.  The drug has high affinity for activated and inactivated sodium channels but relatively little affinity for resting sodium channels.  An experiment is devised to maintain sodium channels in the inactivated state for a prolonged period, during which they are exposed to the new drug.  After allowing the sodium channels to return to the resting state, the speed of the drug's dissociation from the sodium channels is recorded and shown below.  The dissociation curve for quinidine is given for comparison.  The pharmacologic action of the new drug is most similar to which of the following drugs?

Quizplus · Accepted Answer

11ec160b_3b77_7b08_9249_0527bcb6f2d9_MD0001_00 The drug described is representative of a class I antiarrhythmic medication, which blocks voltage-gated Na⁺ channels. Most of the clinically useful agents bind within the pore of the channel during the open and/or inactivated states; dissociation of the drug occurs during the resting state. This state-dependent manner of binding causes a phenomenon in which tissues undergoing frequent depolarization become more susceptible to blockage (use dependence). The faster the heart rate, the more time the Na⁺ channels spend in the open and inactivated states and the more that become blocked. The binding strength of class I antiarrhythmics varies between the different subclasses, with Class IB agents (eg, lidocaine) having the weakest binding compared to other class I antiarrhythmics. Dissociation from the channels occurs so rapidly that there is minimal cumulative effect over multiple cardiac cycles, resulting in little use dependence. These drugs are more selective for ischemic myocardium because the elevated (less negative) resting membrane potential delays Na⁺ channel transition from the inactivated to the resting state, resulting in increased drug binding. As such, class IB antiarrhythmics are useful for treating ischemia-induced ventricular arrhythmias. In contrast, class IC agents (eg, propafenone, flecainide) have the strongest binding (Choice B). They are the slowest to dissociate from the channel, which allows their blocking effects to accumulate over multiple cardiac cycles. This leads to substantially greater blockade at higher heart rates (high use dependence), making them particularly effective at terminating tachyarrhythmias. However, the prominent use-dependent effects of class IC drugs can cause an excessive delay in conduction speed that can promote arrhythmias, especially in patients with ischemic or structural heart disease. (Choice A) Disopyramide, quinidine, and procainamide are class IA antiarrhythmic drugs that have an intermediate dissociation speed. The dissociation curve for the new drug shows that drug-channel dissociation is faster than with quinidine, indicating that it is most similar to a class IB antiarrhythmic agent such as lidocaine. (Choice D) Propranolol is a nonselective beta-adrenergic blocker (class II antiarrhythmic). It causes decreased chronotropy and inotropy via beta-1 blockade. (Choice E) Class III antiarrhythmic drugs (amiodarone, sotalol, dofetilide) act predominantly by blocking potassium channels and prolonging phase 3 repolarization. Sotalol also has beta-blocking activity. (Choice F) Verapamil and diltiazem are calcium channel blockers that function as class IV antiarrhythmics due to their effects on cardiac slow-response tissue. Although nifedipine is a calcium channel blocker as well, it is selective for vascular smooth muscle and does not have a notable effect on the heart. Educational objective: For class I antiarrhythmics, sodium-channel-binding strength is IC > IA > IB. Use dependence describes the phenomenon in which higher heart rates lead to increased sodium channel blockade due to cumulative blocking effects over multiple cardiac cycles. Class IC antiarrhythmics demonstrate the most use dependence due to their slow dissociation from the receptor, and class IB drugs have the least use dependence as they rapidly dissociate.

A New Drug Has Been Developed to Treat Cardiac Arrhythmias