Question 19

Pass rate
65%
Other SAQs in this paper:
Other SAQs in this topic:

Describe the pharmacology of amiodarone using the following headings:

(i) Indications for use (5% of marks)

(ii) Dose (10% of marks)

(iii) Mechanism of Action (20% of marks)

(iv) Pharmacodynamics including adverse effects (25% of marks)

(v) Pharmacokinetics (25% of marks)

(vi) Drug Interactions (15% of marks).

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College Answer

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.

Discussion

Indications for use:

  • Chemical cardioversion of AF
  • Rate control for rapid AF
  • Prevention of VT
  • To improve the chances of defibrillation in refractory VF

Dose

  • In cardiac arrest: 300mg bolus
  • Intravenous: 15mg/kg/24hrs
  • Orally: 600 to 1600 mg per day in divided doses until a total of 10 g has been given; then 200 mg per day

Mechanism of Action

  •  Blocks repolarising potassium currents in Phase 3 of the cardiac action potential prolonging the repolarisation.
  • Decreases the velocity of Phase 0 by acting as Class I antiarrhythmic (sodium channel blocker effect)
  • Noncompetitive beta-blocker
  • L-type calcium channels inhibitor

Pharmacodynamics including adverse effects

  • Prolongs AV node refractory period, slows conduction along His and Purkinje system,
  • Adverse effects:
    • Bradycardia
    • QT prolongation
    • many other side effects (skin discolouration, hypothyroidism, cataracts, hepatitis) 

Pharmacokinetics

  • Absorption: slow erratic GI absoprtion (slow onset when given orally, ~ 4.5 hrs to peak effect).
  • Bioavailability = 20-80%
  • Solubility: Highly lipid-soluble and poorly soluble in water; pKa = 6.56
  • Distribution: extensively distributed to the tissues - VOD is about 66 L/kg.
  • 96% protein bound
  • Metabolism: hepatic, by CYP3A4; main metabolite is desethylamiodarone, which is pharmacologically active.
    Elimination extremely prolonged in chronic therapy, in excess of 100 days. Half-life is 29 days.

Drug Interactions

  • P-glycoprotein inhibitor
    • Elevates digoxin levels by interfering with excretion
  • CYP 3A4 inhibitor: impaired clearance of:
    • Warfarin
    • Atorvastatin and simvastatin
    • Flecainide
    • Quinidine
    • Phenytoin
    • Cyclosporin

References

Vassallo, Patricia, and Richard G. Trohman. "Prescribing amiodarone: an evidence-based review of clinical indications." Jama 298.11 (2007): 1312-1322.

Kowey, Peter R., et al. "Intravenous amiodarone." Journal of the American College of Cardiology 29.6 (1997): 1190-1198.

Andreasen, F. H. P. H., et al. "Pharmacokinetics of amiodarone after intravenous and oral administration." European journal of clinical pharmacology 19.4 (1981): 293-299.

Polster, Pl, and J. Broekhuysen. "The adrenergic antagonism of amiodarone." Biochemical pharmacology 25.2 (1976): 131-134.

Lubic, Stephen P., et al. "Antiarrhythmic agent amiodarone possesses calcium channel blocker properties." Journal of cardiovascular pharmacology 24.5 (1994): 707-714.

Kodama, Itsuo, Kaichiro Kamiya, and Junji Toyama. "Cellular electropharmacology of amiodarone." Cardiovascular research 35.1 (1997): 13-29.

Hamilton, David, et al. "Amiodarone: a comprehensive guide for clinicians." American Journal of Cardiovascular Drugs (2020): 1-10.

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