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
- Ventricular tachyarrhythmias
- 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