Compare and contrast the pharmacology of digoxin and amiodarone.
This question required a structured approach to a comparative description of the pharmacology of
two commonly used and encountered drugs in intensive care practice. Candidates who did not
gain a sufficient mark, did so because of a poor knowledge of this topic, as well as a critical failure
to structure their answer.
References: Stoelting, Pharmacology and Physiology in Anaesthetic Practice pg 280 and 339,
Peck Hill and Williams, Pharmacology for Anaesthesia and Intensive Care, pgs 224, 232
|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.