Question 13

Outline the pharmacology of amiodarone.

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College Answer

This was a repeat question and was generally answered well. Some candidates lost marks for 
being too approximate on the pharmacokinetics.

Discussion 

It is ironic that the examiners might complain about a lack of detail by writing a two-line comment. To avoid being too approximate, the answer here should contain a satisfying number of precise measurements.

Class Class III antiarrhythmic
Chemistry Iodinated benzofuran
Routes of administration Oral and IV
Absorption Slow erratic GI absorption (slow onset when given orally, ~ 4.5 hrs to peak effect). Bioavailability = 20-80%
Solubility Highly lipid-soluble and poorly soluble in water; pKa = 6.56
Distribution Extensively distributed to the tissues - VOD is about 66 L/kg. 96% protein bound
Target receptor Mainly potassiu (Ikr) channels, but also voltage gated calcium channels, beta and alpha adrenergic receptors, and L-type calcium channels
Metabolism Hepatic metabolism by CYP3A4; main metabolite is desethylamiodarone, which is pharmacologically active
Elimination 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 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 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 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 Hamilton et al (2020)

References

Kowey, Peter R., et al. "Intravenous amiodarone." Journal of the American College of Cardiology 29.6 (1997): 1190-1198.

Andreasen, F. H. P. H., et al. "Pharmacokinetics of amiodarone after intravenous and oral administration." European journal of clinical pharmacology 19.4 (1981): 293-299.

Gough, William B., et al. "Hypotensive action of commercial intravenous amiodarone and polysorbate 80 in dogs." Journal of cardiovascular pharmacology 4.3 (1982): 375-380.

Hamilton, David, et al. "Amiodarone: a comprehensive guide for clinicians." American Journal of Cardiovascular Drugs (2020): 1-10.

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