Antiarrhythmic Drugs

Sodium channels cycle through three states during each action potential: resting (closed and available), open (during phase 0 depolarization), and inactivated (immediately after opening, before recovery). Class I drugs bind preferentially to channels in the open or inactivated state. This means that at higher heart rates — when more channels are cycling through these states per unit time — more drug binding occurs per unit time and channel blockade intensifies. This property is called use-dependence or frequency-dependence.

The practical consequence is that Class I agents become more potent during tachycardias, which can be therapeutically useful, but also more dangerous in diseased myocardium where channels may already be partially inactivated due to membrane depolarization from ischemia or scarring. In that setting, use-dependent blockade can convert heterogeneous conduction slowing into a stable, fatal re-entrant circuit.

The clinically important distinction among Class I agents is the speed with which channels recover from drug-bound blockade during the diastolic interval between beats. This recovery kinetics is the basis of the Ia, Ib, and Ic subclassification.

Class Ia agents — quinidine, procainamide, and disopyramide — have intermediate recovery kinetics. They slow conduction moderately, prolong action potential duration and the QT interval (because they also block repolarizing potassium channels), and produce both QRS widening and QT prolongation on the electrocardiogram.

Class Ib agents — lidocaine and mexiletine — recover rapidly, faster than the diastolic interval at normal heart rates. This means their blockade is largely relieved between beats in normal tissue. Their net effect is conduction slowing that is most pronounced in ischemic or rapidly firing tissue where channels spend more time in inactivated states. They shorten action potential duration and cause minimal electrocardiogram changes at rest.

Class Ic agents — flecainide and propafenone — recover very slowly, slower than the diastolic interval even at slow heart rates. Channel blockade is not relieved between beats, producing tonic conduction depression at all heart rates that intensifies further during tachycardia. They produce marked QRS widening with minimal change in action potential duration. This combination of properties makes them highly effective in structurally normal hearts but profoundly dangerous when myocardial scarring is present.

Lidocaine is available only for intravenous use as an antiarrhythmic — oral bioavailability is too low for reliable dosing because of extensive first-pass hepatic metabolism. It blocks sodium channels with strong selectivity for inactivated channels, shortens action potential duration in Purkinje fibers, and has virtually no effect on atrial tissue or the atrioventricular node. QRS duration and QT interval remain unchanged at therapeutic concentrations.

Its antiarrhythmic action is most pronounced in ischemic myocardium, where the resting membrane potential is less negative than in normal tissue, keeping a larger fraction of sodium channels in the inactivated state and increasing drug binding. This is why lidocaine is effective in the acute management of ventricular tachycardia and ventricular fibrillation in the setting of ischemia or myocardial infarction. In contemporary Advanced Cardiac Life Support, lidocaine is a second-line agent after amiodarone for pulseless ventricular tachycardia or ventricular fibrillation.

Lidocaine toxicity is primarily neurologic and concentration-dependent. At mildly elevated concentrations, patients develop perioral numbness, lightheadedness, and tinnitus. At higher concentrations, dysarthria, confusion, and nystagmus appear. Severe toxicity produces seizures, which are treated with benzodiazepines. Cardiac depression — bradycardia, hypotension, atrioventricular block — is rare at therapeutic concentrations but can occur with massive overdose. Patients with heart failure or hepatic impairment require dose reduction because hepatic clearance of lidocaine is blood flow-dependent and reduced in low-output states.

Mexiletine is the oral analogue of lidocaine with an identical electrophysiologic mechanism. Its oral bioavailability is adequate (approximately 90 percent) and its longer half-life allows twice- or three-times daily dosing. It is used for chronic suppression of ventricular arrhythmias in patients where an oral agent is needed.

An important adjunctive use of mexiletine is in Long QT Syndrome Type 3, a congenital channelopathy caused by a gain-of-function mutation in the cardiac sodium channel that produces a persistent late inward sodium current during the action potential plateau, prolonging the QT interval. Mexiletine blocks this late sodium current and can shorten the QT interval in affected patients, reducing torsades de pointes risk.

The dominant adverse effect of mexiletine is gastrointestinal — nausea, vomiting, and abdominal discomfort occur in up to 40 percent of patients and are the most common reason for discontinuation. Taking mexiletine with food reduces but does not eliminate these effects. Neurologic toxicity (tremor, dizziness, ataxia) occurs at higher concentrations, mirroring lidocaine's central nervous system profile.

The Cardiac Arrhythmia Suppression Trial enrolled patients with prior myocardial infarction and asymptomatic or mildly symptomatic ventricular premature beats. The hypothesis — widely accepted at the time — was that suppressing ventricular ectopy after myocardial infarction would reduce sudden cardiac death. Patients who achieved ventricular premature beat suppression with encainide, flecainide, or placebo were enrolled and followed.

The trial was stopped early when encainide and flecainide were found to increase arrhythmic death and cardiac arrest compared to placebo, despite effectively suppressing ventricular premature beats. The drugs did exactly what they were supposed to do pharmacologically — and patients died at a higher rate than those who received sugar pills.

The mechanism: use-dependent sodium channel blockade in peri-infarct scar tissue converts minor, non-sustained re-entrant circuits into sustained, fatal ventricular tachycardia or ventricular fibrillation. Ventricular premature beat suppression is a surrogate endpoint, not a clinical benefit. This lesson — that surrogate endpoints can mislead — applies far beyond antiarrhythmic pharmacology.

The Cardiac Arrhythmia Suppression Trial findings drive a critical decision branch whenever rhythm control is considered for atrial fibrillation. The patient's cardiac substrate — not just the arrhythmia — determines which agents are safe.

Two proarrhythmic patterns are high-yield for second-year pharmacology and deserve explicit recognition alongside the Cardiac Arrhythmia Suppression Trial finding.

Torsades de pointes from Class Ia agents arises from QT interval prolongation due to potassium channel blockade, which enables early afterdepolarizations during a prolonged phase 3. Risk is highest at slow heart rates, with concurrent hypokalemia or hypomagnesemia, and when other QT-prolonging drugs are co-administered. Treatment is intravenous magnesium, electrolyte correction, and withdrawal of the offending agent. If episodes are pause-dependent, heart rate must be increased with isoproterenol or temporary cardiac pacing.

Paradoxical ventricular rate acceleration from Class Ic agents occurs when flecainide or propafenone slows the atrial flutter circuit rate from approximately 300 beats per minute to approximately 200 beats per minute. At the slower atrial rate, the atrioventricular node may conduct every impulse rather than blocking alternate ones, producing 1:1 atrioventricular conduction and a ventricular rate of 200 or more beats per minute. Co-prescription of a beta-blocker or non-dihydropyridine calcium channel blocker is mandatory whenever Class Ic agents are used for atrial arrhythmias.