Amiodarone Hydrochloride

Approved Indications:

• Ventricular Arrhythmias:
• Treatment of life-threatening recurrent ventricular fibrillation (VF).
• Treatment of hemodynamically unstable ventricular tachycardia (VT) unresponsive to other antiarrhythmic agents.

Off-label / Clinically Accepted Uses:

• Atrial Fibrillation (AF):
• Rhythm control in paroxysmal, persistent, or permanent AF, especially in patients with structural heart disease or left ventricular dysfunction.
• Atrial Flutter:
• Control of atrial flutter in patients who are unsuitable for other antiarrhythmic therapies.
• Supraventricular Tachycardia (SVT):
• Treatment and prophylaxis of recurrent supraventricular tachyarrhythmias, including those associated with Wolff-Parkinson-White (WPW) syndrome.
• Post-cardiac surgery arrhythmia prevention, especially AF following cardiothoracic surgery.
• Heart failure with arrhythmias, where other antiarrhythmics are contraindicated.

Adults:

• Oral (Maintenance):
• Initial: 800–1600 mg/day in divided doses for 1–3 weeks.
• Titration: Reduce to 600–800 mg/day for 1 month.
• Maintenance: 100–400 mg/day.
• Intravenous (IV):
• Loading dose: 150 mg over 10 minutes.
• Followed by 1 mg/min for 6 hours, then 0.5 mg/min for 18 hours or longer.
• Max cumulative dose: 2.2 g in the first 24 hours.

Pediatrics:

• Not FDA-approved for children, but used off-label.
• IV: 5–15 mcg/kg/min infusion; exact dose individualized.
• Oral: 5–10 mg/kg/day in divided doses, tapering over time.

Elderly:

• Initiate at lower doses due to reduced hepatic clearance and increased risk of toxicity.
• Regular monitoring required (EKG, liver, thyroid, pulmonary function).

Renal Impairment:

• No specific dose adjustment required as amiodarone is not renally excreted, but monitor for accumulation and toxicity.

Hepatic Impairment:

• Use with caution; metabolized by the liver.
• Monitor liver enzymes regularly; dose adjustment may be necessary.

Administration Notes:

• Oral tablets taken with food to reduce GI upset.
• IV infusion via central line preferred due to risk of phlebitis.
• Continuous ECG monitoring during IV administration.

Amiodarone primarily acts by blocking potassium channels (Class III antiarrhythmic effect), prolonging the phase 3 repolarization of the cardiac action potential. It also exhibits Class I (sodium channel blockade), Class II (noncompetitive β-blockade), and Class IV (calcium channel blockade) properties. These combined actions lead to prolonged refractory period, slowed conduction through the AV node, and reduced automaticity in the sinoatrial (SA) node and Purkinje fibers. This multifaceted mechanism suppresses both ventricular and supraventricular arrhythmias effectively.

• Absorption:
• Oral bioavailability: 35%–65%; affected by food (enhances absorption).
• Distribution:
• Large volume of distribution (~60 L/kg); accumulates in adipose tissue.
• Highly lipophilic.
• 95% protein-bound.
• Metabolism:
• Hepatic, primarily via CYP3A4 and CYP2C8 to active metabolite desethylamiodarone (DEA).
• Excretion:
• Primarily biliary; minimal renal excretion.
• Not dialyzable.
• Half-life:
• Terminal half-life is 20–100 days.
• Steady-state reached in 2–3 months with chronic use.
• Onset:
• IV: ~1 hour; Oral: Delayed onset due to tissue accumulation.

• Pregnancy:
• FDA Category D (positive evidence of human fetal risk).
• Associated with fetal hypothyroidism, bradycardia, and growth retardation.
• Use only if potential benefit justifies the risk to the fetus.
• Lactation:
• Excreted in breast milk.
• Breastfeeding not recommended due to risk of bradycardia and thyroid suppression in infants.
• Caution:
• Avoid in pregnancy and lactation unless absolutely necessary and under close supervision.

• Primary Class:
• Antiarrhythmic Agent
• Subclass:
• Class III Antiarrhythmic (with actions from Class I, II, and IV)

• Known hypersensitivity to amiodarone or iodine.
• Severe sinus node dysfunction or second-/third-degree AV block (without pacemaker).
• Bradycardia causing syncope (without pacemaker).
• Cardiogenic shock.
• Pregnancy and breastfeeding (unless benefits outweigh risks).

• Pulmonary Toxicity (Black Box Warning):
• Risk of fatal interstitial pneumonitis or pulmonary fibrosis. Monitor with baseline and periodic chest X-rays and pulmonary function tests.
• Hepatotoxicity:
• Monitor liver enzymes regularly; discontinue if significant elevation occurs.
• Thyroid Dysfunction:
• Both hypothyroidism and hyperthyroidism may occur. Check TSH, T3, T4 at baseline and every 6 months.
• Cardiac Effects:
• Bradycardia, QT prolongation, torsades de pointes (rare). Monitor ECG regularly.
• Ophthalmic Effects:
• Optic neuropathy/neuritis, corneal microdeposits. Annual ophthalmologic exams recommended.
• Dermatologic Effects:
• Photosensitivity and blue-grey skin discoloration with chronic use.
• Neurotoxicity:
• Peripheral neuropathy, tremors, ataxia, sleep disturbances, cognitive impairment.

• Common:
• Gastrointestinal: Nausea, vomiting, constipation.
• Neurologic: Tremor, fatigue, insomnia.
• Thyroid: Hypo- or hyperthyroidism.
• Skin: Photosensitivity, skin discoloration.
• Serious/Rare:
• Pulmonary fibrosis or pneumonitis.
• Hepatotoxicity.
• QT prolongation, bradycardia, AV block.
• Optic neuritis or visual disturbances.
• Severe dermatologic reactions (e.g., Stevens-Johnson syndrome – rare).
• Onset & Severity:
• Most adverse effects are dose- and duration-dependent.
• Some (e.g., pulmonary, hepatic, thyroid) may be delayed and require long-term monitoring.

• Enzyme Involvement:
• Major substrate of CYP3A4, CYP2C8.
• Inhibits CYP2C9, CYP2D6, CYP3A4, P-glycoprotein.
• Major Interactions:
• Increased toxicity of: Warfarin (↑ INR), digoxin, phenytoin, cyclosporine.
• Risk of QT prolongation with: Macrolides, fluoroquinolones, antipsychotics, SSRIs.
• Statins: Increased risk of myopathy (especially simvastatin, lovastatin).
• Beta-blockers & calcium channel blockers: Additive bradycardia or AV block.
• Grapefruit juice: May increase plasma levels; avoid.
• Avoid concurrent use of other QT-prolonging agents.

• Recent Guidelines (AHA/ACC/HRS):
• Amiodarone remains recommended for refractory AF, VF/VT, especially in structural heart disease.
• Preference for non-amiodarone agents (e.g., dronedarone, dofetilide) where feasible due to toxicity profile.
• Safety Alerts:
• Reinforcement of long-term monitoring protocols (pulmonary, hepatic, thyroid, ocular).
• Caution issued by regulatory bodies regarding early detection of toxicity signs.

• Tablets:
• Store at 20°C to 25°C (68°F to 77°F).
• Protect from light and moisture.
• Keep in original container if possible.
• IV Solution:
• Store between 15°C to 30°C (59°F to 86°F).
• Use glass or polyolefin containers (adsorption occurs in PVC).
• Protect from light.
• Do not refrigerate; may precipitate.
• Stable for 24 hours at room temperature after dilution.