Amiodarone

Indications and Common Uses¹

• Amiodarone is indicated in the setting of pulseless ventricular tachycardia (VT) or ventricular fibrillation (VFib).
• It is administered intravenously (IV) or intraosseous after cardiopulmonary resuscitation has been established and defibrillation has been attempted.
• It is also used in the treatment and prophylaxis of recurrent VFib and unstable VT.
• Amiodarone is commonly used to treat atrial fibrillation (AFib) and supraventricular tachycardias refractory to other therapies; however, it is not FDA-approved for these indications.

Mechanism of Action¹

• Amiodarone is an iodinated benzofuran derivative medication that is classified as a class III antiarrhythmic. It primarily inhibits potassium rectifier currents that normally repolarize the cardiac myocytes during phase 3 of the action potential. This inhibition allows for longer action potentials and, consequently, longer refractory periods, thereby affording an increased window for the native function to return.
• Amiodarone has secondary actions that include class I (sodium channel blockade), class II (beta receptor blockade), and class IV (calcium channel blockade) antiarrhythmics.
  • Sodium channel blockade slows the action potential upstroke, which is effective in slowing conduction across the myocytes.
  • Beta receptor blockade reduces sympathetic stimulation, slowing the native heart rate and atrioventricular (AV) conduction.
  • Calcium channel blockade acts on the L-type calcium channels, reducing calcium influx during the action potential and slowing AV node conduction.

Contraindications¹

• Patients with a known hypersensitivity are at risk for bronchospasm, angioedema, and hypotension.
  • These reactions are more common with documented iodine allergies.
• Cardiogenic shock can worsen with amiodarone due to bradycardia.
• Marked sinus bradycardia can worsen.
• Second- or third-degree heart block can worsen.
  • It is acceptable to use if a pacemaker is in place.
• Preexcitation syndromes, when AFib is present, can progress to VFib.

• Central access for infusions greater than 2 mg/ml should be used.²
• Rapid infusions significantly greater than recommended can result in hepatocellular death and acute renal failure.²

Systemic Effects

Central Nervous System⁵

• Amiodarone does cross the blood-brain barrier. Adverse effects include tremors, ataxia, peripheral neuropathy, paresthesia, sleep disturbances, dizziness, fatigue, and headaches. Psychiatric symptoms like altered mental status have been reported, but are rare.

Ocular System⁶

• Corneal microdeposits are very common (up to 98%) with long-term use. Lenticular changes, optic opacities (occurring in 50-60% of cases after 1-2 months of use), loss of eyelashes/eyebrows, papilledema, scotoma, macular degeneration, and optic neuropathy have also been reported.
• Around 10% of patients may experience visual symptoms like photophobia, optic neuropathy, and visual halos. Ophthalmologic assessment is recommended before long-term use.

Endocrine System⁵

• Functional thyroid disorders are common with amiodarone due to high iodine content. Thyroid abnormalities have been reported in 14-18% of patients receiving long-term therapy. Amiodarone affects thyroid hormone function in several ways out of the scope of this summary.
• A complex series of effects can result in hypothyroidism (more commonly in iodine areas like the US with high iodine intake) or hyperthyroidism (more common in areas like Europe with lower iodine intake).
• Amiodarone can induce thyrotoxicosis, which occurs due to hyperthyroidism in abnormal glands (type 1) or due to the destruction of thyroid follicular cells releasing hormone into the bloodstream (type 2). They can be distinguished by Doppler because type 1 will be hypervascular and type 2 will not.
• Amiodarone-induced hypothyroidism is 1.5 times more common in women, which can be treated with amiodarone discontinuation or exogenous thyroid hormone.
• Amiodarone can rarely induce a syndrome of inappropriate antidiuretic hormone secretion. The most common time is after the loading dose.

Pulmonary System^6,7

• Pulmonary toxicity with chronic amiodarone use can resemble interstitial lung disease. It can also manifest as organizing pneumonia, pleural effusion, acute respiratory distress syndrome, or diffuse alveolar hemorrhage.
• Symptoms may include cough, dyspnea, fever, or weight loss. Risk factors include male sex, old age, higher cumulative dose, preexisting lung disease, or chronic kidney disease. Symptoms can occur at any point, but are most common when receiving 400 mg PO daily for more than 2 months or lower doses for more than 2 years. It can develop up to a year after discontinuation.

Cardiovascular System^6,7

• Bradycardia and hypotension are common adverse effects with acute use. Atrioventricular block and QT prolongation are also possible. Rarely, amiodarone can cause torsades de pointes; therefore, QT monitoring is recommended.
• Because amiodarone augments the QRS timing, AV and intraventricular conduction abnormalities are possible. Torsades de pointes is possible even with a previously normal Qtc, but this is rare with chronic oral use.

Gastrointestinal System⁷

• Gastrointestinal distress is common with oral amiodarone. It is recommended to take it with food.

Hepatic and Renal Systems⁶

• Hepatotoxicity, characterized by an increase in liver enzymes, occurs in approximately 25% of patients. Symptomatic hepatitis, cirrhosis, or hepatic failure occurs in less than 3% of patients. Amiodarone is known to inhibit hepatic and renal metabolism.

Musculoskeletal System

• Amiodarone is known to accumulate in muscle and fat cells. Myopathy with proximal muscle weakness and elevated creatine kinase is rare. Other neuromuscular symptoms related to include ataxia, tremor, paresthesia, or gait disturbances that often improve with drug discontinuation.

Hematologic Systems⁶

• Pancytopenia, hemolytic anemia, and aplastic anemia are rare side effects.

Dermatologic System⁶

• Photosensitivity (24-57%) and blue-gray skin discoloration with sun exposure (1-7%) are the most common. There is also a rare potential for pruritic, erythematous lesions that appear after several months of use in sun-exposed areas.

Common Drug Interactions⁷

• Amiodarone has many drug interactions due to inhibition of CYP450 and P-glycoprotein metabolism. Recommendations on how to manage these common drug interactions are listed below.
• Class I/III antiarrhythmics: Combining with amiodarone should be avoided due to heightened risk of QT prolongation and torsades de pointes.
• Flecainide: The dose should be reduced by 50% when used in combination with amiodarone.
• Beta-blockers & nondihydropyridine CCBs: Clinicians should use cautiously due to risk of bradycardia and AV block.
• Digoxin: The dose should be reduced by 50% and monitored closely due to increased serum levels.
• Statins (Simvastatin, Lovastatin): Clinicians should use cautiously due to increased risk of rhabdomyolysis; pravastatin is preferred.
• Warfarin: Due to enhanced anticoagulation, dose should be reduced by 25–33% and monitored international normalized ratio closely.
• Direct oral anticoagulants: Clinicians should avoid using together due to a potential increased bleeding risk resulting from P-gp/CYP3A4 inhibition. Please refer to the 2021 European Heart Rhythm Association practical guide on the use of nonvitamin K antagonist oral anticoagulants in patients with atrial fibrillation if combined use is necessary.⁸
• SGLT2 inhibitors: Clinicians should use cautiously due to potential enhanced antiarrhythmic effects. It is recommended to monitor electrolytes (especially potassium).
• QT-prolonging drugs (e.g., macrolides, fluoroquinolones, azoles): These drugs should be avoided due to risk of torsades de pointes.
• Cholestyramine: Avoid use because of accelerated amiodarone elimination. It is actually useful for toxicity management.
• Cyclosporine: It may require dose reduction and requires close monitoring.
• Antiretrovirals: Due to complex interactions, regimens with NRTIs and raltegravir/dolutegravir are preferred.
• Rifampicin: It induces amiodarone metabolism.
• Fentanyl: Clinicians should use with caution due to risk of bradycardia and hypotension.
• GLP-1 receptor agonists: These may reduce AFib recurrence; electrolyte balance and effects in patients with significant weight loss should be monitored.
• Grapefruit juice: Ingestion should be avoided while taking amiodarone due to decreased efficacy.
• There are several medications that precipitate with amiodarone, so it is recommended to infuse without other medications present in the tubing.²

Special Populations^1,9

• Hepatic impairment: It is recommended to reduce the dose
• Renal impairment: No required dose adjustment
• Pregnancy: There are limited data on the efficacy of use in pregnancy. No teratogenic risks have been identified. The neonate is at risk for congenital goiter, thyroid abnormalities, bradycardia, and QT prolongation.
• Breastfeeding mothers: Acute amiodarone use is not contraindicated, but it is recommended to monitor the infant for harm, such as thyroid dysfunction.
• Pediatric patients:⁹ During pulseless VT and VFib, the PALS algorithm recommends using amiodarone at a dose of 5mg/kg, which may be repeated twice more. The maximum single dose is 300 mg. For treating VT or SVT, 5 mg/kg is still appropriate, but it is administered over 20-60 minutes. Chronic use and dosing are out of scope of this summary. Amiodarone use in pediatric populations is considered “off-label.”
• Geriatric patients: Amiodarone should be used with caution. QT-prolonging medications like amiodarone have been implicated in increased hospital stay and 100-day all-cause mortality in elderly patients treated for AFib.