Antiarrhythmic Drugs

Correct Answer

C — Quinidine, procainamide, and disopyramide

Rationale

Quinidine, procainamide, and disopyramide are the three Class Ia sodium channel blockers. They share intermediate channel unbinding kinetics and prolong action potential duration by also blocking potassium channels. Lidocaine, mexiletine, and tocainide are Class Ib agents with fast unbinding. Flecainide and propafenone are Class Ic agents with slow unbinding. Amiodarone, sotalol, and dofetilide are Class Three potassium channel blockers.

Correct Answer

A — Class Ib sodium channel blocker

Rationale

Lidocaine is a Class Ib sodium channel blocker. The Ib subclass is characterized by fast channel unbinding kinetics and selective activity in ischemic or depolarized myocardial tissue. Lidocaine is available only in intravenous form and is used for acute ventricular arrhythmias. Mexiletine is the oral Class Ib equivalent. Class Ia agents (quinidine, procainamide, disopyramide) have intermediate unbinding. Class Ic agents (flecainide, propafenone) have slow unbinding. Class Three agents block potassium channels.

Correct Answer

D — Flecainide and propafenone

Rationale

Flecainide and propafenone are both Class Ic sodium channel blockers, characterized by slow unbinding kinetics and the most potent sodium channel blockade of any Class One subclass. They do not prolong the QT interval. Quinidine and procainamide are Class Ia agents. Lidocaine and mexiletine are Class Ib agents. Amiodarone and dronedarone are Class Three potassium channel blockers with multi-class properties.

Correct Answer

B — Mexiletine

Rationale

Mexiletine is the oral Class Ib sodium channel blocker. It shares the same subclass and mechanism as lidocaine — fast unbinding kinetics and selectivity for ischemic tissue — but can be administered orally, making it suitable for chronic management. Lidocaine is also a Class Ib agent but is available only in intravenous form due to extensive first-pass hepatic metabolism. Procainamide is a Class Ia agent. Flecainide is a Class Ic agent.

Correct Answer

C — Quinidine

Rationale

Quinidine is a Class Ia sodium channel blocker. The Class Ia subgroup includes quinidine, procainamide, and disopyramide. Lidocaine and mexiletine are Class Ib agents. Flecainide is a Class Ic agent. The subclass distinctions (Ia, Ib, Ic) are based on the kinetics of sodium channel binding and effects on action potential duration.

Correct Answer

A — Lidocaine and mexiletine

Rationale

Lidocaine and mexiletine are both Class Ib sodium channel blockers. Class Ib agents are characterized by fast sodium channel unbinding kinetics and a tendency to shorten action potential duration. Quinidine and procainamide are Class Ia agents. Flecainide and propafenone are Class Ic agents. Amiodarone and sotalol are Class Three potassium channel blockers.

Correct Answer

D — Ischemic tissue is partially depolarized, causing sodium channels to spend more time in inactivated states where Class Ib agents bind and unbind rapidly between beats

Rationale

Ischemic myocardium has an elevated resting membrane potential (less negative than normal) due to potassium efflux and metabolic acidosis. This partial depolarization causes sodium channels to dwell preferentially in the inactivated state rather than the resting state. Class Ib agents bind to inactivated sodium channels with high affinity and unbind rapidly during the brief time between action potentials. In normally polarized tissue, channels spend most of their time in the resting state where Class Ib affinity is low, so binding does not accumulate. In depolarized ischemic tissue, the inactivated state predominates and drug binding accumulates — producing selective suppression of arrhythmic foci without broadly suppressing normal myocardial conduction.

Correct Answer

B — In addition to blocking sodium channels, they also block potassium channels, slowing phase 3 repolarization and extending action potential duration

Rationale

Class Ia agents are not pure sodium channel blockers. They also block delayed rectifier potassium channels responsible for phase 3 repolarization. Slowing potassium efflux prolongs phase 3, extends action potential duration, and lengthens the QT interval. This dual channel activity distinguishes Class Ia from Class Ib (which shortens action potential duration) and Class Ic (which prolongs conduction time but does not meaningfully prolong the QT interval). The QT-prolonging effect of Class Ia agents confers a risk of torsades de pointes (a dangerous polymorphic ventricular arrhythmia triggered by QT prolongation), particularly at slower heart rates — a phenomenon called reverse use-dependence.

Correct Answer

A — Flecainide and encainide reduced ventricular ectopy but markedly increased mortality, establishing that Class Ic agents are contraindicated after myocardial infarction

Rationale

The Cardiac Arrhythmia Suppression Trial, published in 1989, randomized patients with asymptomatic ventricular ectopy after myocardial infarction to flecainide, encainide, or moricizine versus placebo. Although all active drugs suppressed ectopy effectively, flecainide and encainide more than doubled the risk of death compared to placebo — likely through proarrhythmic effects in the structurally abnormal post-infarction myocardium. The trial established the fundamental principle that suppressing a surrogate marker (ectopy) does not guarantee improved survival, and it remains the primary reason Class Ic agents are contraindicated in structural heart disease.

Correct Answer

C — Lidocaine undergoes extensive first-pass hepatic metabolism, leaving negligible systemic bioavailability after oral dosing

Rationale

Lidocaine is well absorbed from the gastrointestinal tract, but virtually all absorbed drug is extracted by the liver during its first pass through the portal circulation before reaching the systemic bloodstream. This extensive first-pass metabolism reduces oral bioavailability to less than 35 percent, making oral dosing impractical for achieving therapeutic plasma concentrations. Intravenous administration bypasses the liver on first pass, delivering drug directly to the systemic circulation. Mexiletine, the oral Class Ib equivalent, has a structurally similar mechanism but undergoes substantially less first-pass metabolism and achieves adequate oral bioavailability.

Correct Answer

D — Flecainide can organize atrial fibrillation into atrial flutter with 1:1 atrioventricular conduction, and nodal blockade prevents the resulting rapid ventricular rate

Rationale

Flecainide slows conduction throughout the atria. In doing so, it can convert the disorganized electrical activity of atrial fibrillation into the more organized pattern of atrial flutter, which typically cycles at around 200 to 250 beats per minute. If the atrioventricular node conducts every atrial impulse (1:1 conduction), the ventricular rate can reach 200 beats per minute or more — a hemodynamically dangerous situation. Pre-treatment with a beta-blocker or a non-dihydropyridine calcium channel blocker slows atrioventricular nodal conduction, ensuring that not every organized atrial impulse reaches the ventricles. This is the standard safety requirement before initiating the pill-in-pocket strategy with flecainide or propafenone.

Correct Answer

B — Slow unbinding means drug accumulates with each beat in tissue already conducting slowly due to fibrosis or ischemia, creating regions of conduction block that sustain re-entry

Rationale

Class Ic agents unbind so slowly from sodium channels that significant drug remains bound when the next action potential arrives, even at normal heart rates. In normal myocardium, this slows conduction but does not create block. In structurally diseased hearts — where fibrosis, scar tissue from prior infarction, or ischemia already slow conduction heterogeneously — Class Ic-mediated additional conduction slowing converts areas of slow conduction into areas of complete block. This creates the conditions for unidirectional block and re-entry, the substrate for potentially lethal ventricular arrhythmias. This is the mechanistic basis for the Cardiac Arrhythmia Suppression Trial findings and the structural heart disease contraindication.

Correct Answer

A — Procainamide — drug-induced lupus-like syndrome

Rationale

Procainamide is the Class One antiarrhythmic most strongly associated with drug-induced lupus-like syndrome. The syndrome is characterized by arthralgia, pleuritis, pericarditis, and a positive antinuclear antibody test. It occurs in up to 30 percent of patients on long-term therapy and resolves when the drug is discontinued. Quinidine causes a distinct syndrome called cinchonism (tinnitus, headache, blurred vision) and can cause thrombocytopenia. Disopyramide has prominent anticholinergic effects due to muscarinic receptor blockade, causing urinary retention, dry mouth, and constipation. Lidocaine at toxic concentrations causes central nervous system effects including perioral numbness, confusion, and seizures.

Correct Answer

C — Disopyramide — muscarinic receptor blockade producing anticholinergic effects

Rationale

Disopyramide has significant muscarinic receptor blocking activity in addition to its sodium channel blockade. This anticholinergic property produces the classic effects of parasympathetic inhibition: urinary retention (especially in men with prostate enlargement), dry mouth, constipation, blurred vision, and worsening of narrow-angle glaucoma. These effects limit disopyramide's tolerability and make it contraindicated in patients with urinary outflow obstruction or glaucoma. Quinidine blocks alpha-adrenergic receptors, which can cause hypotension, but does not have prominent muscarinic blockade. Procainamide's active metabolite N-acetylprocainamide contributes to QT prolongation rather than autonomic effects.

Correct Answer

D — Flecainide's slow sodium channel unbinding creates additional conduction slowing in fibrotic post-infarction tissue, generating re-entry substrates and increasing the risk of lethal ventricular arrhythmias

Rationale

The Cardiac Arrhythmia Suppression Trial demonstrated that flecainide, despite suppressing ventricular ectopy, markedly increased arrhythmic death in post-infarction patients. The mechanism is proarrhythmia: flecainide's slow unbinding from sodium channels imposes severe conduction slowing throughout the myocardium. In the post-infarction heart, scar tissue and border-zone fibrosis already create heterogeneous conduction. Superimposed Class Ic-mediated conduction slowing converts these areas of slow conduction into regions of complete block, establishing the unidirectional block and re-entry circuits needed for sustained ventricular tachycardia or ventricular fibrillation. Flecainide does not primarily prolong the QT interval (that is a Class Ia property) and does not have significant anticholinergic activity.

Correct Answer

B — Quinidine blocks potassium channels in addition to sodium channels, slowing phase 3 repolarization and extending action potential duration

Rationale

Quinidine is a Class Ia agent with dual channel activity: it blocks sodium channels (the defining Class One property) and also blocks delayed rectifier potassium channels. The potassium channel blockade slows outward potassium current during phase 3, prolonging repolarization and extending action potential duration throughout the ventricle. This manifests on the electrocardiogram as a longer QT interval. QT prolongation from Class Ia agents carries a risk of torsades de pointes (a dangerous polymorphic ventricular arrhythmia triggered by early afterdepolarizations arising during the prolonged repolarization phase). This risk is greater at slower heart rates — a property called reverse use-dependence. Slow sodium channel unbinding is characteristic of Class Ic agents, not Class Ia; calcium channel blockade is a Class Four property.

Correct Answer

A — Ischemic tissue is partially depolarized, causing sodium channels to dwell in the inactivated state where lidocaine binds preferentially, producing selective suppression of the ischemic arrhythmic focus

Rationale

Myocardial ischemia causes potassium efflux and acidosis that partially depolarize the resting membrane potential. This partial depolarization shifts the equilibrium of sodium channel states, causing channels to spend more time in the inactivated state rather than the resting state. Lidocaine (and other Class Ib agents) bind with high affinity to inactivated channels and unbind rapidly — fast enough to recover between beats in normally polarized tissue where channels mostly rest. In the partially depolarized ischemic focus, however, channels remain predominantly inactivated, drug binding accumulates, and conduction in the ischemic zone is selectively suppressed. Normal myocardium, with fully polarized channels spending most of their time in the resting state (where lidocaine affinity is low), is largely unaffected. This is the mechanistic basis of lidocaine's ischemic-tissue selectivity.

Correct Answer

C — The beta-blocker slows atrioventricular nodal conduction, preventing a rapid ventricular rate if flecainide organizes the atrial fibrillation into atrial flutter before achieving cardioversion

Rationale

Flecainide slows intra-atrial conduction, which can organize the chaotic activity of atrial fibrillation into the more regular circuit of atrial flutter cycling at around 200 to 250 beats per minute. If the atrioventricular node — the only electrical bridge between atria and ventricles — conducts every atrial impulse (1:1 conduction), the ventricular rate can reach 200 beats per minute or more, which is hemodynamically dangerous. The co-administered beta-blocker (or alternatively a non-dihydropyridine calcium channel blocker) slows atrioventricular nodal conduction and prolongs its refractory period, ensuring the node filters most of the rapid atrial impulses and limits the ventricular response. This protective nodal blockade is mandatory before initiating the pill-in-pocket approach with any Class Ic agent.