Amiodarone

Amiodarone: The Potent, Perilless Pan-Arrhythmic

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Introduction

Amiodarone is one of the most effective and broad-spectrum antiarrhythmic drugs available. Classified as a Class III agent (potassium channel blocker) in the Vaughan-Williams classification, it is a truly "dirty" drug, exhibiting pharmacologic properties of all four classes. While its efficacy in treating both ventricular and supraventricular arrhythmias is unparalleled, its use is tempered by a formidable and multi-system toxicity profile. For the anesthesiologist, understanding its complex pharmacology and the management of its side effects is essential.

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1. Chemical Structure

Amiodarone is an iodinated benzofuran derivative. It is a large, lipophilic molecule. Two key structural features dictate its clinical behavior:

1. High Iodine Content: A single 200 mg tablet contains about 75 mg of organic iodine, which is released during metabolism and is responsible for its thyroid-related side effects.
2. Lipophilicity: This allows it to distribute extensively into fat, muscle, and organs, leading to a massive volume of distribution and an extraordinarily long half-life.

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2. Mechanism of Action (MOA)

Amiodarone's efficacy comes from its multi-channel blockade, which stabilizes the myocardial cell membrane.

• Class III Effect (Primary): Blocks potassium channels (primarily IKr and IKs), which prolongs the action potential duration and the effective refractory period (ERP) in atrial, ventricular, and nodal tissue. This suppresses re-entrant circuits, the mechanism behind most tachyarrhythmias.
• Class II Effect: Acts as a non-competitive beta-adrenergic antagonist, contributing to its rate-controlling effects and anti-ischemic properties.
• Class I Effect: Blocks fast sodium channels (in a use-dependent manner), slowing conduction velocity.
• Class IV Effect: Blocks L-type calcium channels, contributing to negative inotropy and vasodilation (especially with IV administration).
• Thyroid Effect: Inhibits the peripheral conversion of thyroxine (T4) to the more active triiodothyronine (T3).

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3. Pharmacokinetics

• Onset: Variable. IV onset is rapid (minutes). Oral onset is slow, taking days to weeks for a full effect due to extensive tissue loading.
• Distribution: Highly lipophilic. It accumulates in adipose tissue, liver, lung, and skin, leading to a massive volume of distribution.
• Metabolism: Extensively metabolized in the liver by the CYP3A4 enzyme system. It is also a potent inhibitor of CYP3A4, leading to numerous drug interactions.
• Half-life: Extremely long and variable: 50-60 days on average, but can be up to 100 days.
  • Clinical Implication: The drug's therapeutic and toxic effects persist for months after discontinuation. Dosing adjustments are made very slowly, and toxicity cannot be rapidly reversed by stopping the drug.

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4. Pharmacodynamics

The net effect is a dose-dependent depression of automaticity and conduction. It slows the sinus rate, prolongs AV nodal conduction, and increases the refractory period of all cardiac tissue. The IV formulation, due to its solvent (polysorbate 80), can cause more pronounced vasodilation and hypotension than the oral form.

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5. Clinical Uses in Anesthesia

1. Acute Management of Life-Threatening Arrhythmias (IV):

   • Refractory Ventricular Fibrillation (VFib) or Pulseless Ventricular Tachycardia (VT): It is a primary antiarrhythmic in the ACLS algorithm when defibrillation and epinephrine fail.
   • Hemodynamically Stable Monomorphic VT: When other agents are ineffective or contraindicated.
   • Atrial Fibrillation (A-fib) with Rapid Ventricular Response (RVR): Used when rate control with beta-blockers or calcium channel blockers is impossible, ineffective, or contraindicated (e.g., in severe heart failure).

2. Chronic Oral Therapy (Perioperative Considerations):

   • Many patients presenting for surgery will be on chronic amiodarone for A-fib or prevention of VT. The anesthesiologist must be aware of its cumulative effects and potential for interactions with anesthetic drugs.

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6. Dosage

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7. Adverse Effects

Adverse effects are common, dose- and duration-dependent, and affect nearly every organ system.

• Cardiac: Bradycardia, sinus arrest, AV block. QT prolongation leading to Torsades de Pointes (though paradoxically less common than with other Class III drugs). IV formulation can cause hypotension.
• Pulmonary: The most feared toxicity. Can cause interstitial pneumonitis, which can progress to irreversible pulmonary fibrosis. Presents with dyspnea and non-productive cough.
• Thyroid:
  • Hypothyroidism (Type 1): Most common. Caused by the iodine load inhibiting thyroid hormone synthesis.
  • Hyperthyroidism (Type 2): Caused by direct destructive thyroiditis from the drug itself.
• Hepatic: Asymptomatic elevation of transaminases is common. Can progress to acute hepatitis or cirrhosis.
• Dermatologic: Photosensitivity is very common. A slate-grey or blue-grey discoloration of the skin can occur with long-term use.
• Ocular: Corneal microdeposits (verticillata) are universal but harmless. Rarely, it can cause optic neuropathy, which is a medical emergency.
• Neurologic: Tremor, peripheral neuropathy, ataxia, and nightmares.

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8. Contraindications

• Absolute Contraindications:
  • Second- or Third-Degree AV Block (without a functioning permanent pacemaker).
  • Severe Sinus Node Dysfunction (sick sinus syndrome).
  • Known hypersensitivity to amiodarone or iodine.
• Relative Contraindications / Use with Extreme Caution:
  • Pre-existing significant pulmonary disease.
  • Pre-existing significant liver disease.
  • Uncontrolled thyroid disease.
  • Concomitant use with other QT-prolonging drugs (e.g., ondansetron, certain antibiotics).

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9. Special Section: The Amiodarone Toxicity Checklist for Trainees

For any patient on chronic amiodarone presenting for surgery, or for whom you are initiating therapy, a systematic approach to monitoring is crucial.