24A19: Exam Report

Describe the pharmacology of amiodarone using the following headings:

  1. Indications for use (5% of marks)

  2. Dose (10% of marks)

  3. Mechanism of Action (20% of marks

  4. Pharmacodynamics including adverse effects (25% of marks)

  5. Pharmacokinetics (25% of marks)

  6. Drug Interactions (15% of marks)

65% of candidates passed this question.

The headings were provided to candidates to ensure that information was limited to these domains.

This question required specific detail about amiodarones action at K+, Na+ , B and Ca channels, including second messenger systems and effects on SA / AV and myocyte action potential.

Simply stating that there is hepatic metabolism and renal excretion is not enough information for pharmacokinetics and some detail was expected regarding the mechanism of metabolism, presence (or absence) of active metabolites and organs involved in clearance with rough figures for half life, Vd, loading dose and clearance values.

It is recommended to include the mechanisms by which side effects occur rather than just listing them.

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 / 24A19 / 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