Core pharmacology

Class Group

Antiarrhythmic –
Vaughan Williams Class III
K channel blocker

Legacy Cicm Level

Level 1

Introduction

benzofuran derivative - 37% iodine by weight

class III antiarrhythmic displays actions of all four classes.

Indications Uses

critical care for treating many arrythmias
- SV arrhythmias: preferred antiarrhythmic in patients with structural heart disease
- Ventricular arrhythmias: Cardiac arrest due to VT / unstable VT, stable sustained or nonsustained VT, Prevention of IVD shocks, Primary and secondary prevention of SCD due to VT, symptomatic ventricular premature beats

Chemical Pharmaceutics

structurally resembles thyroxine.

Presentation

tablets – 100/ 200mg. clear colourless solution 50mg/ml for inf. Therapeutic range (1-2.5mg/L) but monitoring rarely necessary

Mechanism of action

inhibits adrenergic stimulation (alpha- and beta-blocking properties), affects sodium, potassium, and calcium channels, prolongs the action potential and refractory period in myocardial tissue; decreases AV conduction and sinus node function

Onset Peak Duration

onset / duration 2 days to 3 wks / 1 wk to 5 mon

Physiological effects

- Sinus rhythm slowed by 15% secondary to slowed diastolic depolarization of nodal cells
- AV nodal automaticity is decreased and AV nodal conduction speed is slowed 25%
- After IV administration decreased SVR and LV contractility
- Coronary artery vasodilation with increased coronary blood flow
- QT prolongation

Adverse Effects Toxicity

CVS - not arrhythmogenic despite QT prolongation (likely because of its multiple actions), bradycardia and hypotension
Resp- pneumonitis, fibrosis or pleuritis.
Endo - it may cause hypothyroidism (6%) or hyperth (1%).
Hepa - cirrhosis, hepatitis, jaundice. LFT monitoring.
Corneal microdeposits common- resolve on cessation.

Absorption

poorly absorbed, BA 40-70%

Protein binding

96%

Volume of distribution

66L/kg

Metabolism

complex metabolism, hepatic via de-ethylation catalysed by CYP 2C8 and 3A4. active metabolite N-desethylamiodarone

Excretion

via skin, faeces, urine, lachrymal glands

Half-life

~40-55 days

Special Points

Mainly due to its effects on CYP450 enzymes (CYP3A4, CYP2C9, CYP2D6) and P-glycoprotein (P-gp)

Increased Drug Levels:
- Inc Bleeding risk (Warfarin, DOACs)
- Inc Toxicity risk (Digoxin, Phenytoin, Cyclosporine, Tacrolimus)
- Myopathy risk (Statins)

Additive Effects:
- Beta-blockers, Verapamil/Diltiazem: Bradycardia and hypotension.
- QT-prolonging drugs: Risk of torsades de pointes.

Reduced Effectiveness:
- Alters thyroid metabolism (causing hypo-/hyperthyroidism).
- May affect oral antidiabetics' efficacy.

Route And Dose

doses PO 200mg TDS 1/52, BD 1/52, then OD
IV 5mg/kg (max 150+150mg) over 1hr → 15mg/kg (max 900mg) over 24 hrs IV