Pharm-10B3 Describe the mechanism of action, pharmacokinetics and major
side effects of intravenously administered amiodarone.
Background
Amiodarone is a benzofuran class III anti-arrhythmic agent
Its chemical structure shares similarities with thyroxine
Uses
Management of atrial (SVT, AF, WPW) and ventricular tachyarrhythmias (VT, VF)
Typical intravenous doses
Resuscitation of VT/VF – 300 mg slow bolus
Completion of loading dose – 900 mg over subsequent 24 hours
Mechanism of Action
Amiodarone is categorised as class III under the Vaughan-Williams classification
scheme for antiarrhythmic agents but it also exhibits class Ia, II and IV actions
Class Ia – interfere with depolarisation via Na+ channel blockade à threshold
potential and prolongs refractory period
Class II – non-competitive b-blockade à ¯inotropy, ¯chronotropy, ¯dromotropy
Class III – prolong repolarisation via fast K+ channel blockade à AP duration
Class IV – calcium channel blockade à dromotropy
Non competitive a1-blockade à vasodilatation à ¯SVR à ¯MAP
Pharmacokinetics
Absorption
IV and PO formulations
Bioavailability ≈ 30%
Distribution
High protein binding (95%) and able to displace other protein bound drugs
One of the largest VD (up to 70L/kg) – due to high tissue affinity for fat, muscle,
heart, thyroid
Metabolism
Hepatic metabolism by CYP3A4 to desethylamiodarone (DEA has some
antiarrhythmic activity)
CYP450 inhibitor
Elimination
Biliary excretion
Minimal renal excretion of amiodarone or DEA
Elimination half time ≈ 50 days (significant inter-individual variability)
Adverse Effects
CVS – ¯SVR à ¯MAP, bradycardia, heart block, QTc à risk of torsades
RESP – pulmonary fibrosis (chronic), ARDS (acute)
CNS – peripheral neuropathy, optic neuropathy, benign corneal microdeposits
ENDO – thyroid dysfunction (both hyper and hypo), blocks peripheral conversion
from T4 to T3
GIT – nausea + vomiting (common), hepatotoxicity
SKIN – photosensitivity, blue-grey pigmentation, may precipitate toxic epidermal
necrolysis syndrome (TENS)
PREGNANCY – category C and should be avoided in pregnancy and lactation
(neonatal hyper/hypothyroidism, goitre)
Drug Interactions
Other antiarrhythmics
Digoxin – digoxin level
Warfarin – impair metabolism à INR
Statins – impair metabolism à risk of rhabdomyolysis (\use pravastatin)
Cyclosporin – cyclosporin level
Grapefruit juice – ¯amiodarone metabolism
Macrolide and fluoroquinolones – QTc
Examiner’s comments – 70% of candidates passed this question.
A structured approach was expected and marks were distributed to the three main
areas – MOA, pharmacokinetics and adverse effects.
Candidates were expected highlight the various mechanisms of action such that
amiodarone can fit within most elements of the Vaughan Williams classification.
A clear structure addressing the main areas relating to pharmacokinetics was helpful.
It was expected candidates would appreciate:
§ the very long half life,
§ high protein binding,
§ significant tissue binding, and
§ large volume of distribution.
Specific comments regarding the main toxicities were expected.
§ In particular, the pulmonary toxicity (both acute and chronic variations) is
important.
§ In addition a variety of other issues should be mentioned, including thyroid
changes and the well described skin and ocular changes.
§ Cardiac toxicity with bradycardia, QT prolongation and this risk of Torsades that
this may pose was mentioned by many candidates and gained specific credit.
Additional credit was given for more detailed explanations, comments on enzyme
metabolism and examples of drug interactions.
Comments on dosing and infusions gained additional marks.
Well organized answers such as those with an ordered list of subheadings were
rewarded.
