Digoxin in heart failure: mechanism and side effects

Mechanism of action

• Digoxin binds the extracellular face of the alpha-subunit of the sarcolemmal Na+/K+-ATPase and reversibly inhibits it (Barash, Clinical Anesthesia, 9e, Digitalis Glycosides). Katzung says this inhibition is probably largely responsible for the positive inotropy and for much of the toxicity (Katzung's Basic and Clinical Pharmacology, 16th Ed, Pharmacodynamics).
• The chain of events is:
  1. The pump is inhibited, so intracellular Na+ rises.
  2. The Na+/Ca2+ exchanger (NCX) extrudes less Ca2+.
  3. Intracellular Ca2+ rises, and more Ca2+ is stored in and released from the sarcoplasmic reticulum.
  4. Contractility increases without a rise in heart rate. This gives a leftward and upward shift of the Frank-Starling curve, with a higher stroke volume and a lower filling pressure.
• Braunwald notes that the inotropic effect was long assumed to explain the benefit. The more likely mechanism in HF is different (see below) (Braunwald's Heart Disease, Cardiac Glycosides).

• Digoxin sensitizes Na+/K+-ATPase activity in vagal afferent nerves. This raises vagal tone and counterbalances the sympathetic overactivation of advanced HF (Braunwald's Heart Disease, Cardiac Glycosides).
• Higher vagal tone slows AV nodal conduction. This is why digoxin also controls ventricular rate in atrial fibrillation (AF).
• Digoxin also inhibits Na+/K+-ATPase in the kidney, which may blunt tubular sodium reabsorption (Braunwald's Heart Disease, Cardiac Glycosides).
• Other neurohormonal effects are reduced renin release and reduced sympathetic outflow (from my own knowledge, not retrieved from the library).

• At therapeutic levels, vagal action prolongs the AV nodal refractory period and slows conduction.
• At toxic levels, Ca2+ overload causes delayed afterdepolarizations and triggered automaticity. Braunwald links toxicity to cellular Ca2+ overload (Braunwald's Heart Disease, Beta1-Adrenergic and PKA Signaling section).
• The ECG shows scooped ST depression, T-wave flattening or inversion, and a shortened QT. These changes indicate digoxin effect, not toxicity.

• Typical dosing is 0.125 to 0.25 mg daily. Most patients should get 0.125 mg, with a serum level below 1.0 ng/mL. This applies especially to the elderly, those with renal impairment, and those with low lean body mass (Braunwald's Heart Disease, Cardiac Glycosides).
• It is used as add-on therapy in symptomatic HFrEF, usually when symptoms persist despite standard therapy. It is also used when AF with rapid ventricular rates coexists.

Side effects and toxicity

• Electrolytes:
  • Hypokalemia, often from diuretics, worsens toxicity. K+ normally competes with digoxin at the pump (Katzung, Digoxin; Tintinalli's).
  • Hypomagnesemia and hypercalcemia also raise the risk.
  • Acute overdose can cause hyperkalemia.
• Renal impairment: Digoxin is renally cleared, and the Washington Manual lists this as a risk factor.
• Interacting drugs:
  • Verapamil, diltiazem, erythromycin, and cyclosporine raise levels (Washington Manual).
  • Amiodarone, quinidine, and clarithromycin also raise levels (from my knowledge).
• Other: Elderly age, low body mass, hypothyroidism, and hypoxia or ischemia.

• Mild GI or visual symptoms generally need only a dose reduction (Katzung, Toxicity).
• Check the serum level, potassium, and ECG.
• Correct electrolytes. Give atropine for bradycardia.
• For life-threatening arrhythmias, use digoxin-specific Fab fragments. Lidocaine or phenytoin are options for ventricular arrhythmias (from my knowledge).
• Avoid IV calcium and avoid cardioversion where possible, because of the risk of refractory arrhythmias.
• Hyperkalemia in acute poisoning is treated with insulin and glucose. Classic teaching says to avoid IV calcium.

Recent evidence update

• Digitalis glycosides lowered the composite of cardiovascular death or first worsening-HF event (HR 0.85, 95% CI 0.80-0.90).
• The benefit came mainly from fewer worsening-HF events (HR 0.75).
• There was no effect on cardiovascular death (HR 0.99) or all-cause death (HR 0.97).