G7iii / 14B13: Outline the pharmacology of Amiodarone

14B13: Exam Report

Outline the pharmacology of amiodarone.

77% of candidates passed this question.

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

G7iii / 14B13: Outline the pharmacology of Amiodarone

Chemical

Iodinated benzofurane derivative

37% iodine by weight

Resembles thyroxine structure

Class II anti-arrhythmic

Use

  1. Ventricular tachyarrhythmias
  2. SVTs

Presentation

Clear, colourless vial 50mg/mL

PO tablets 100/200mg

Dose

300mg/30min IV load

Then 1500mg/24hrs infusion

PO → load 900mg/day for 2/52

      → maintenance 200mg/day

Route

PO/IV → Rapid IV infusion risks circulatory collapse

Onset

IV → suppression of arrhythmia < 1hr

PO → suppression of arrythmia 72hrs

DoA

4 hrs

MoA (mechanism)

All 4 V-W class actions

1) Blocks K+ channels

    • Prolongs effective refractory period
    • ∴ prolongs AP duration & QT interval

2) Na+ channel blockade

    • ↓slope of Ph 0
    • ↓aplitude AP
    • ↓conduction velocity ( – CHRONO) so there is slower transmission of AP
    • Especially slows conduction through His Purkinje & Ventricles

3) Anti-adrenergic

    • Non-competitive block of α & β adrenoreceptors
    • ↓HR
    • ↓AV Nodal conduction

4) Ca2+ channel block

    • Mild direct -ve inotrope

ECG effects

  • Prolong PR interval
  • Widened QRS
  • QT prolongation

PD

CVS

  • Prolongs refractory period in all cardiac tissue

→ ↓HR

→ May cause AV block

→ Prolonged QT risks TdP

  • Mild negative inotropy
  • Potent vasodilation → CA but also ↓BP
  • Irritates veins

PK

A

Incomplete

Highly variable

OBA 20 – 90%

Titrated on an individual basis

D

Huge tissue affinity

Myocardial concentration x 10 that of plasma

∴ not a good relation b/w plasma [  ] & PD effects

Large VD 70L/kg

Extensive PPB > 99%

Not removed well in HD

M

Liver metabolism to desmethylamiodarone which is active & has a longer t ½ cf. amiodarone

E

Small renal excretion mainly in bile & faeces

Elimination is v. long ~30 days

Adverse Effects

CVS

  • Irritant to veins
  • Bradycardia → resistant to atropine
  • Prolongs QT → risks TdP
  • Potent VD → risks cardiovascular collapse → esp. with rapid IV bolus
  • Complete AV block

Resp

  • Pulmonary fibrosis secondary to alveolitis
  • Pulmonary toxicity is dose-related → esp. >400mg/day for >4wks

CNS

  • Sleep disturbance
  • Headache
  • Peripheral neuropathy
  • Tremors/proximal skeletal m. weakness

Ocular

  • Corneal microdeposits → virtually all patients
  • Halo development in peripheral fields
  • Optic neuritis may progress to blindness

Dermatologic

  • Blue slate skin
  • Photodermatitis esp. to sun-exposed areas

GI

  • Fatty infiltration of liver
  • ↑transaminases
  • Hypersensitivity hepatitis

Endocrine

  • 5% pats → hyper/hypo-thyroidism
  • More likely with pre-existing thyroid disease
  • Hyperthyroidism → from release of iodine during metabolism
  • Hypothyroidism → when Ami inhibits peripheral deiodination of T4 → T3

Pregnancy

  • Amiodarone & its metabolite demethylamiodarone (DEA) are found in placenta & breast milk
  • Can cause infant hypothyroidism

DRUG INTERACTIONS

  • Displaces drugs from plasma proteins 2° large PPB
  • ↑plasma [ ] of other antiarrhythmics; DIGOXIN, PROCAINAMIDE, PROPANOLOL, VERAPAMIL
  • Plasma digoxin x 50%
  • Amiodarone is a substrate for CYP3A4
  • ∴ drugs inhibit CYP3A4 = ↑ plasma amiodarone
  • e. H2 blocker cimetidine
  • Drugs which induce CYP3A4 ↓amiodarone e. rifampicin
  • Amiodarone inhibits P450 enzyme & ↑levels of drugs: statins, digoxin, warfarin
  • WARFARIN needs to ↓ 1/3 of dose with amiodarone
  • Erythromycin → also prolongs QT interval = ↑risk TdP

 NOTE: K+ channel blocking takes days to become evident

∴ only if you need urgent rate control for AF, do you give amiodarone IV

Initial action = ↓ventricular rate in RAF without reverting to SR

↓

Then the K+ blocking takes place & reverts to SR seen