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

Pharmacology 101

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MBBS (UWA) CCPU (RCE, Biliary, DVT, E-FAST, AAA) Adult/Paediatric Emergency Medicine Advanced Trainee in Melbourne, Australia. Special interests in diagnostic and procedural ultrasound, medical education, and ECG interpretation. Editor-in-chief of the LITFL ECG Library. Twitter: @rob_buttner

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