Pharm 101: Digoxin

Class

Antiarrhythmic

Pharmacodynamics

• Inhibits Na/K ATPase
• At therapeutic doses digoxin is a positive inotrope, shortens AP duration, and at low doses has predominately parasympathomimetic effects
• Multiple direct and indirect cardiovascular effects with both therapeutic and toxic consequences (see below)
• In addition, it has undesirable effects on CNS and gut

Cardiac effects

• Mechanical effects cause positive inotropy via a two-step process:
  1. Na/K ATPase inhibition increases intracellular Na
  2. This increase consequently reduces Ca expulsion by the Na/Ca exchanger
• The net result is increased intracellular Ca, which:
  • Increases contractility
  • Increases stroke volume/CO per beat

• Electrical effects are a mixture of direct and autonomic actions
• Direct effects cause a shortened AP duration, likely due to increased K conductance caused by increased intracellular Ca
• Autonomic effects are a mixture of parasympathetic and sympathetic systems
  • • At low therapeutic doses, cardioselective parasympathomimetic effects predominate
    • This involves baroreceptor sensitisation, central vagal stimulation, facilitation of muscarinic transmission at nerve ending-myocyte synapse. Cholinergic innervation is greater in the atria, therefore these actions affect atria and AV node more than ventricular/purkinje fibres
    • Slow HR allows greater stroke volume

Other organ system effects

• Effects on other organs: smooth muscle and CNS
  • GIT: anorexia, nausea/vomiting/diarrhoea
  • CNS: vagal and chemoreceptor trigger zone stimulation
• Interactions with K, Ca, Mg
  • K and digoxin inhibit each other’s binding to Na/K ATPase, therefore:
    • Hyperkalaemia reduces enzyme-inhibiting actions of digoxin
    • Hypokalaemia facilitates these actions
  • Ca facilitates toxic actions of digoxin by accelerating overloading of intracellular Ca stores that appear to be responsible for digitalis-induced abnormal automaticity:
    • Hypercalcaemia therefore increases risk of digitalis-induced arrhythmia
  • Effects of Mg are opposite to those of calcium

Pharmacokinetics

• Bioavailability 65-80%
• Large volume of distribution, widely distributed to all tissues including CNS
• 25% plasma protein bound
• Half-life 36-40 hours in normal renal function
• 2/3 excreted unchanged in urine
• Renal clearance is proportional to creatinine clearance

Clinical uses

• Heart failure

Adverse effects

Digoxin can cause virtually any arrhythmia, due to a combination of enhanced automaticity and decreased AV nodal conduction.

Most common cardiac manifestations of toxicity:

• AV junctional rhythm
• PVCs
• Bigeminy
• VT
• 2nd degree AV block
• Bradycardia, R on T

Other adverse effects include:

• Hyperkalaemia
• GIT:
  • Anorexia
  • Nausea/vomiting/diarrhoea
• CNS:
  • Disorientation
  • Hallucinations
  • Yellow/green vision
  • CTZ

Precautions/contraindications

• Drugs that increase effect of digoxin:
  • Amiodarone
  • Macrolide antibiotics (due to increased bioavailability)
  • Quinidine
  • K depleting drugs (increases likelihood of digitalis toxicity)
  • Ca channel blockers
• Drugs that decrease effect of digoxin:
  • Acid-reducing agents
• Patients in heart failure are more prone to digoxin toxicity:
  • Poor renal function from low cardiac output
  • Potential dehydration and other drug interactions (e.g. ACE-I, diuretics, Ca channel blockers)
  • Hypokalaemia from other heart failure medications especially diuretics
  • Poor cardiac reserve/output

Further Reading

• Long N. Digoxin poisoning
• Burns E. ECG library: Digoxin toxicity
• Long N. Digoxin Immune Fab

References

• Katzung BG. Basic & Clinical Pharmacology. 14th ed. United States of America: McGraw-Hill Education; 2018. 217-219, 1044-1045 p.