Antiarrhythmic Drugs

Both verapamil and diltiazem block L-type calcium channels in nodal tissue, slowing atrioventricular nodal conduction and prolonging atrioventricular nodal refractoriness. The electrocardiogram effect is PR interval prolongation. Both also slow the sinoatrial node rate by reducing calcium-dependent automaticity. At therapeutic concentrations, their effect on ventricular myocardium (fast-response tissue) is minimal.

Verapamil produces potent atrioventricular nodal blockade and is effective for acute termination of atrioventricular node-dependent re-entrant tachycardias, including atrioventricular nodal reentrant tachycardia and atrioventricular reentrant tachycardia. Success rates approach 90 percent when given intravenously. It is second-line to adenosine for acute termination but preferred when adenosine is contraindicated (severe asthma).

Verapamil also terminates a specific ventricular tachycardia subtype called fascicular ventricular tachycardia (also known as verapamil-sensitive ventricular tachycardia or Belhassen ventricular tachycardia), which arises from the left posterior fascicle and is driven by a calcium-dependent mechanism. This is one of the very few situations where a calcium channel blocker is appropriate for ventricular tachycardia.

Verapamil has significant negative inotropic effects and moderate peripheral vasodilation. Its use in patients with reduced left ventricular function carries risk of hemodynamic deterioration.

Diltiazem shares verapamil's atrioventricular nodal blocking mechanism and indications but has substantially less negative inotropic effect and comparable peripheral vasodilation. This more favorable hemodynamic profile makes diltiazem the preferred non-dihydropyridine calcium channel blocker for rate control in atrial fibrillation, particularly when hemodynamic tolerance is uncertain or when the patient has borderline left ventricular function. Intravenous diltiazem can be run as a continuous infusion for sustained rate control in atrial fibrillation or flutter, an option not practical with intravenous verapamil.

Digoxin inhibits the sodium-potassium pump (sodium-potassium adenosine triphosphatase) on cardiac myocyte membranes. Pump inhibition raises intracellular sodium, which indirectly raises intracellular calcium by reducing the calcium-extruding activity of the sodium-calcium exchanger. The resulting calcium accumulation increases contractile force — the basis of digoxin's positive inotropic effect.

Its atrioventricular nodal slowing effect is primarily vagotonic: digoxin sensitizes cardiac baroreceptors and stimulates vagal outflow, increasing parasympathetic tone to the atrioventricular node. This slows atrioventricular nodal conduction and is effective at rest. During exercise or other sympathetic activation, catecholamines overwhelm the vagotonic effect and heart rate control is lost — explaining why digoxin is less effective than beta-blockers or calcium channel blockers for rate control during physical activity.

For ventricular rate control in atrial fibrillation, digoxin is used as an adjunct to beta-blockers or calcium channel blockers, particularly in sedentary or bedridden patients where exercise rate control is not a priority. Current guidelines recommend it as add-on therapy rather than monotherapy.

In heart failure with reduced ejection fraction, digoxin reduces hospitalizations but does not improve survival. Its inotropic benefit is modest, and toxicity risk limits its use. It is generally reserved for patients who remain symptomatic despite optimal neurohormonal therapy.

Digoxin is renally eliminated with a half-life of 36 to 48 hours in normal renal function, which extends to days or weeks in renal impairment. Dose reduction is required as kidney function declines. The therapeutic range for rate control is narrow: levels above 2 nanograms per milliliter are associated with toxicity, and levels should be drawn at least six hours after a dose.

Toxicity can occur even at levels within the traditional therapeutic range, particularly when predisposing factors are present. Hypokalemia is the most important precipitant — low intracellular potassium enhances digoxin binding to the sodium-potassium pump and amplifies toxicity. Other predisposing conditions include hypomagnesemia, hypercalcemia, hypothyroidism, renal impairment, and advanced age.

Non-cardiac manifestations appear early: nausea, vomiting, and anorexia are the most common initial symptoms. Visual disturbances — yellow-green xanthopsia and halos — are classic but not universal. Confusion and delirium occur in elderly patients.

Cardiac manifestations include virtually any arrhythmia. Bradyarrhythmias and atrioventricular block are most common. Paroxysmal atrial tachycardia with atrioventricular block is a classically described pattern. Bidirectional ventricular tachycardia — alternating axis on each beat — is a sign of severe toxicity.

Management begins with stopping digoxin, correcting hypokalemia (target potassium 4.0 to 5.0 mEq/L), and correcting hypomagnesemia. Calcium must be avoided as it worsens toxicity by raising intracellular calcium further. For life-threatening arrhythmias, digoxin-specific antibody fragments (Digibind or DigiFab) bind and inactivate digoxin rapidly; they are also indicated when serum potassium exceeds 5.5 mEq/L (a sign of severe toxicity) or after massive overdose.

Multiple drugs raise digoxin levels through inhibition of the transport protein that clears digoxin from the body. Amiodarone roughly doubles digoxin levels — halve the digoxin dose when amiodarone is added. Verapamil raises digoxin levels by approximately 70 percent — reduce and monitor. Quinidine approximately doubles digoxin levels — halve the dose. These interactions require active management, not just awareness.