19th May 2025

Amiodarone

Indications

The main indications for amiodarone are: 

• atrial arrhythmias (restoration and maintenance of sinus rhythm in patients with atrial fibrillation, ventricular rate control in atrial fibrillation with rapid ventricular response, atrial flutter, atrial tachycardias)
• ventricular arrhythmias (ventricular premature beats, non-sustained ventricular tachycardia, sustained ventricular tachycardia and ventricular fibrillation)
• secondary prevention of ventricular arrhythmias in patients with implantable cardioverter-defibrillators (ICD) 
• for resuscitation during cardiac arrest in patients with a shockable rhythm, after 3 shocks have been delivered. 

Drug class and mechanism of action

Amiodarone is a class III antiarrhythmic agent. It blocks potassium channels within cardiac tissues, thus blocking outward flowing potassium currents. This influences the cardiac excitation process by prolonging the repolarisation time, action potential duration and refractory period. It also exerts effects on calcium channels, adrenergic receptors, and blocks sodium channels in the depolarised state, particularly the late sodium current.

Adverse effects

Adverse effects of amiodarone will be subdivided into pulmonary toxicity, thyroid toxicity, cardiac toxicity, hepatoxicity, adverse ocular effects, and adverse dermatological effects.

Pulmonary toxicity

Pulmonary toxicity is one of the commonest adverse effects of amiodarone. Pulmonary toxicity may take several weeks to several years to develop. The most common form of pulmonary toxicity secondary to long-term exposure to amiodarone is chronic interstitial pneumonitis, the typical presentation of which is dyspnoea, dry cough, pleuritic pain, fever and weight loss. Other forms of pulmonary toxicity that have been demonstrated secondary to amiodarone therapy include:

• eosinophilic pneumonia
• organising pneumonia
• alveolar haemorrhage
• pulmonary nodules
• acute respiratory distress syndrome. 

The pathogenesis of pulmonary toxicity is thought to occur either through direct cytotoxicity, or via an indirect immune-mediated reaction (for further details see ‘Drug-induced interstitial lung disease’ section of this chapter). Risk factors include higher cumulative doses, higher daily doses, increased age and pre-existing lung disease. Treatment includes drug discontinuation and systemic corticosteroid therapy.

Thyroid toxicity

Thyroid toxicity may be the commonest adverse reaction to amiodarone. Again, higher individual doses and higher cumulative doses are risk factors. Pre-existing thyroid pathology and iodine intake influence the nature of thyroid dysfunction that occurs; both hypothyroidism and hyperthyroidism are seen as a result of amiodarone use. Their presentation is similar to non-iatrogenic hypo- and hyperthyroidism respectively, but the beta-blocking effect of amiodarone may make symptoms of hyperthyroidism harder to detect. The effects of amiodarone on thyroid function are due to both its iodine content and its intrinsic drug properties.

Intrinsic drug effects of amiodarone on thyroid function are as follows:

• inhibition of 5’-monodeiodination of thyroxine (T4) outer ring and resulting reduction in triiodothyronine (T3) production
• reduced T3-nuclear receptor binding due to direct blocking by amiodarone molecules and its metabolites, leading to diminished expression of certain genes involved in thyroid hormone production
• direct toxic effect on thyroid follicular cells causing a destructive thyroiditis.

The iodine-related effects of amiodarone are:

• development of goitre and hypothyroidism in patients with underlying Hashimoto’s disease, due increased iodine load and disruption of the normal mechanisms that inhibit iodine transport and thyroid hormone synthesis when iodine levels are raised
• increased thyroid hormone synthesis and thyrotoxicosis in patients with a nodular goitre containing regions of thyroid tissue that function autonomously.

Individuals with underlying Hashimoto’s thyroiditis or positive antithyroid antibodies are more likely to develop hypothyroidism secondary to amiodarone therapy. Those with underlying multinodular goitre or latent Graves’ disease are at risk of developing hyperthyroidism, as the excess iodine from amiodarone leads to increased thyroid hormone production. 

In parts of the world where individuals tend to be iodine-replete, amiodarone induced hypothyroidism is more common than hyperthyroidism; however, in regions that are iodine-deficient, the opposite is true. Patients with hypothyroidism can be treated with thyroid hormone replacement and may be able to continue on amiodarone therapy, while those with hyperthyroidism may require cessation of amiodarone and treatment with an alternative antiarrhythmic medication; endocrinologist input is also required in the management of amiodarone-induced hyperthyroidism.

Cardiac toxicity

Table 9: Cardiac Toxicity

Hepatotoxicity

Around one quarter of patients demonstrate a transient rise in serum aminotransferase levels after amiodarone is initiated. A much smaller proportion of patients (around 3%) develop symptomatic hepatitis, which may progress in some circumstances to cirrhosis, and liver failure. A rise in bilirubin and clinical jaundice can also be seen with amiodarone use. The hepatic effects of amiodarone are believed due to both direct hepatotoxicity of the drug, and idiosyncratic effects of its metabolites. 

Adverse ocular effects

The two main ocular effects of amiodarone to be aware of are corneal micro-deposition and optic neuropathy. 

Corneal microdeposits are present in most patients on long-term amiodarone treatment and rarely affect vision, or produce only mild effects. They occur due to secretion within tears produced by the lacrimal gland, and accumulate on the corneal surface at the junction of the lower third and upper two thirds of the cornea, in a pattern resembling cat’s whiskers. Visual acuity is not affected, but a minority of patients may complain of halos around lights, visual blurring or photophobia. 

Optic neuropathy can occur secondary to amiodarone therapy and cause unilateral or bilateral visual loss. It has the potential to progress to permanent blindness, and therefore cessation of amiodarone therapy and treatment with an alternative antiarrhythmic drug is advised where possible in the event of this adverse drug effect. More evidence is required to determine whether this effect is related to the duration of amiodarone therapy.