Question 2

Compare and contrast amiodarone and digoxin.

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College Answer

Most candidates had a good structure for answering this question; a table was commonly used. Marks were awarded for indications and an explanation of the mechanism of action of both drugs, which was generally well explained. The pharmacodynamic effects were often listed in a general manner and more detail would have achieved a higher mark, including a list of the ECG effects. Some detail on the pharmacokinetics and adverse effects of the drugs was expected and this section was generally well answered. Better answers noted digoxin levels and potential drug interactions.


This question is virtually identical to Question 22 from the second paper of 2010.

Name Digoxin Amiodarone
Class Antiarrhythmic Class III antiarrhythmic
Chemistry Cardiac glycoside Iodinated benzofuran
Routes of administration Oral and IV; theoretically also IM Oral and IV
Absorption Oral bioavailability 80% (some is secreted back into the gut lumen by P-glycoprotein, an enterocyte efflux pump) Slow erratic GI absoprtion (slow onset when given orally, ~ 4.5 hrs to peak effect). Bioavailability = 20-80%
Solubility pKa = 7.15; basically insoluble in water. Highly lipid-soluble and poorly soluble in water; pKa = 6.56
Distribution VOD=5.1–7.4 L/kg; 25% protein-bound Extensively distributed to the tissues - VOD is about 66 L/kg. 96% protein bound
Target receptor Digoxin inhibits Na+/K+ ATPase. Mainly potassium (Ikr) channels, but also voltage gated calcium channels, beta and alpha adrenergic receptors, and L-type calcium channels
Metabolism Hepatic metabolism accounts for only abut 16% of clearance Hepatic metabolism by CYP3A4; main metabolite is desethylamiodarone, which is pharmacologically active
Elimination Elimination is renal, as unchanged drug, and slow because of the large VOD. Half-life is about 36-44 hrs Distributes widely, particularly into adipose tissue and lung. Elimination is extremely prolonged in chronic therapy, in excess of 100 days. Half-life is 29 days.
Time course of action Onset of effect is relatively rapid with IV infusion, or delayed by 2-3 hrs following oral loading. Onset of action is delayed because of the redistriution, and maximum effect (especially the Class I and Class IV effects) may take weeks to develop
Mechanism of action By inhibiting Na+/K+ ATPase, digoxin increases intracellular sodium, which increases sodium-calcium exchange by the Na+/Ca2+ exchanger (INCX) during Phase 1 of the cardiac action potential. The resulting increase in intracellular calcium promotes inotropy. It also acts as a vagotonic agent, which slows conduction through the AV node, and decreases the duration of the action potential mainly by reducing the duration of Phase 2. The slope of Phase 4 is increased, promoting automaticity, but then automaticity is overall suppressed by the vagotonic effects. Blocks repolarising potassium currents in Phase 3 of the cardiac action potential prolonging the repolarisation. Also decreases the velocity of Phase 0 by its Class I effect, and acts as a noncompetitive beta-blocker, and inhibits L-type calcium channels.
Clinical effects Bradycadia, AV block, shortened QT interval, tachyarrhythmias (including VF and Vt which can be bidirectional), nausea, anorexia, depressed level of consciousness, and arterial vasoconstriction. Toxicity is exacerbated by hypokalemia Hypotension with rapid IV administration, which is due to its IV excipient (polysorbate 80).
Prolonged AV node refractory period, slowed conduction along His and Purkinje system, bradycardia, QT prolongation, many other side effects (skin discolouration, hypothyroidism, cataracts, hepatitis) 
Single best reference for further information FDA data sheet Hamilton et al (2020)


Worthley, L. I., and A. W. Holt. "Digoxin in the critically ill patient." Critical Care and Resuscitation 1.3 (1999): 252.

van Erven, Lieselot, and Martin J. Schalij. "Amiodarone: an effective antiarrhythmic drug with unusual side effects." Heart 96.19 (2010): 1593-1600.