Mechanism of Action of Amiodarone (Class III Antiarrhythmic)

Introduction

Amiodarone is a powerful Class III antiarrhythmic agent used to treat various life-threatening cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and atrial fibrillation. It has a complex pharmacology, affecting multiple phases of the cardiac action potential and multiple ion channels.

Due to its broad antiarrhythmic profile, multi-organ toxicity, and exam relevance, amiodarone is a high-yield drug for students preparing for USMLE, NCLEX, NAPLEX, GPAT, and NEET-PG.

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Mechanism of Action of Amiodarone: Step-by-Step

1. Class III primary action – K⁺ channel blockade
   Amiodarone prolongs phase 3 repolarization of the cardiac action potential by blocking potassium channels, increasing the action potential duration and refractory period.
2. Class I action – Na⁺ channel blockade
   Inhibits fast inward sodium channels (Class I effect), reducing the rate of depolarization (phase 0).
3. Class II action – β-adrenergic receptor blockade
   Exerts non-competitive beta-blocking effects, reducing sympathetic activity on the heart (Class II effect).
4. Class IV action – Ca²⁺ channel blockade
   Weakly inhibits L-type calcium channels, slowing conduction through the AV node (Class IV effect).
5. Result: Broad antiarrhythmic profile
   The net result is slowed conduction, prolonged refractoriness, and suppressed abnormal automaticity, making it effective in both supraventricular and ventricular arrhythmias.

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Pharmacokinetic Parameters of Amiodarone

Parameter	Value
Bioavailability	35–65%
Half-life	25–60 days (!), very long
Protein binding	~95%
Metabolism	Hepatic (CYP3A4)
Excretion	Primarily biliary (feces)
Time to onset	Delayed (up to weeks for oral form)

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Clinical Uses of Amiodarone

• Ventricular tachycardia (VT)
• Ventricular fibrillation (VF)
• Atrial fibrillation (AF) (especially with structural heart disease)
• Supraventricular tachycardia (SVT)
• Wolff–Parkinson–White (WPW) syndrome

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Adverse Effects of Amiodarone (Cumulative & Multi-system)

• Pulmonary fibrosis
• Hepatotoxicity
• Thyroid dysfunction (hypo- or hyperthyroidism due to iodine content)
• Corneal microdeposits
• Photosensitivity and blue-grey skin discoloration
• Bradycardia and heart block
• QT prolongation (risk of torsades is low but present)
• Neuropathy and tremor

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Comparative Analysis: Amiodarone vs Sotalol (Both Class III)

Feature	Amiodarone	Sotalol
Class III mechanism	K⁺ channel blockade	K⁺ channel blockade
Additional effects	Class I, II, IV actions	β-blocker only
Half-life	Extremely long (weeks)	Shorter (12–20 hrs)
Use in HF/MI	Preferred	Caution due to β-blockade
Risk of torsades	Lower (despite QT prolongation)	Higher
Organ toxicities	Pulmonary, liver, thyroid	Less common

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Practice MCQs

Q1. What is the primary mechanism of amiodarone?
a. Na⁺ channel blockade
b. K⁺ channel blockade ✅
c. Ca²⁺ channel blockade
d. β-receptor agonism

Q2. Amiodarone has the following class effects EXCEPT:
a. Class I
b. Class II
c. Class III
d. Class V ✅

Q3. Which organ system is commonly affected by chronic amiodarone use?
a. Kidneys
b. Lungs ✅
c. Pancreas
d. Spleen

Q4. Amiodarone causes hypo- or hyperthyroidism due to:
a. Potassium loss
b. Iodine content ✅
c. Liver enzyme induction
d. Sodium retention

Q5. The elimination of amiodarone is primarily through:
a. Renal
b. Pulmonary
c. Fecal (biliary excretion) ✅
d. Salivary

Q6. Which is NOT a side effect of amiodarone?
a. Pulmonary fibrosis
b. Hepatotoxicity
c. Myelosuppression ✅
d. Photosensitivity

Q7. The long half-life of amiodarone can lead to:
a. Acute toxicity
b. Cumulative toxicity ✅
c. Rapid onset of effect
d. Diuretic action

Q8. Amiodarone is effective in all EXCEPT:
a. Atrial fibrillation
b. Ventricular fibrillation
c. Bradyarrhythmias ✅
d. Supraventricular tachycardias

Q9. Which test is important before and during amiodarone therapy?
a. Serum calcium
b. TSH and liver function ✅
c. Urinalysis
d. INR

Q10. Why is amiodarone preferred in heart failure patients?
a. Positive inotrope
b. No proarrhythmic risk
c. Safe beta-blockade
d. Minimal negative inotropy ✅

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FAQs

Q1: Is amiodarone safe in pregnancy?
No. It is generally avoided due to risks of fetal hypothyroidism and bradycardia.

Q2: Can amiodarone be used long-term?
Yes, but only with regular monitoring due to long-term toxicity.

Q3: What labs are needed during treatment?
TSH, liver enzymes, pulmonary function, eye exams, and ECG monitoring.

Q4: Does it interact with other drugs?
Yes. It inhibits CYP3A4 and P-gp, increasing levels of warfarin, digoxin, statins, etc.

Q5: How fast does it work?
IV onset is rapid, but oral onset is delayed, requiring loading doses.

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References

• KD Tripathi – Essentials of Medical Pharmacology
• Goodman & Gilman – The Pharmacological Basis of Therapeutics
• Sparsh Gupta – Review of Pharmacology
• NCBI: https://www.ncbi.nlm.nih.gov/books/NBK459338/