Question 5

Outline the pharmacology of amiodarone.

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College Answer

Successful candidates applied, a systematic approach/format to answer questions that refer to
outlining pharmacology of select drugs. A number of useful mnemonics are suggested in the
recommended texts for use when answering such a question. All candidates correctly stated
what amiodarone is used for but most were not structured methodically and thus suffered
from significant omission. Amiodarone is an important class III anti-arrhythmic (with some
characteristics of all 4 Vaughan-Williams classes). For a good pass candidates were expected
to actions of amiodarone (eg blocks inactivated Na channels, decreases Ca current, noncompetitive
adrenergic blocking effect, blocks myocardial K channels which contributes to
slowing of conduction and prolongation of refractory period in AV node, prolongs refractory
period in all cardiac tissues, prolongs cardiac action potential duration) and it’s
pharmacokinetics (eg bioavailability, large volume of distribution, high protein binding,
complex metabolism and long elimination half life – 29 days)
Syllabus: C2c
Reference Text: Goodman and Gillman’s The Pharmacological basis of Therapeutics 11th ed
2006 and Pharmacology and Physiology in Anaesthetic Practice / Stoelting 4th ed 2006

Discussion

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.