Amiodarone Lung Toxicity - An Overview

What Is Amiodarone?

Amiodarone is an antiarrhythmic agent used for the treatment of atrial fibrillation (irregular heartbeat) and ventricular arrhythmia (irregular heartbeats originating in the ventricles). The drug prevents ventricular arrhythmia recurrence and reduces the chance of death in high-risk individuals. In cases where long-term treatment with amiodarone is required, the potential adverse effects and drug interactions should be considered.

What Are the Clinical Indications of Amiodarone?

• For secondary prevention of ventricular arrhythmia that are life-threatening.

• Treatment of ventricular arrhythmias like ventricular fibrillation and recurrent ventricular tachycardia.

• Treatment of atrial fibrillation.

• As a primary prevention measure to prevent sudden death in high-risk individuals, however, studies suggest that ICDs (implantable cardioverter-defibrillators) are a better option than amiodarone for reducing mortality risk in the high-risk groups.

What Is the Pharmacology of Amiodarone?

Amiodarone is structurally similar to thyroxine. So, it may cause hyper or hypothyroidism in some individuals. The drug is an iodine-containing compound and thus affects the thyroid gland. The bioavailability of the drug varies from 22 to 95 percent. The drug absorption is increased when taken along with food.

As it is a lipid-soluble drug, it is mainly stored in the muscles and fat, but storage also occurs in the lungs, liver, and spleen. The primary metabolite is DEA (desethylamiodarone), and metabolism mainly occurs in the liver with the help of cytochrome enzymes. Excretion mostly occurs through the biliary system; only a small amount of the drug and its metabolite is found in urine. Neither the drug nor its metabolite can be removed by dialysis.

What Is Amiodarone Lung Toxicity?

Amiodarone is an iodine-containing medication that accumulates in different organs, including the lungs. It can result in various adverse effects, of which pulmonary or lung toxicity is the most severe. The incidence of these complications can be lowered using the lowest effective dosage. The incidence rate of Amiodarone-induced pulmonary toxicity (APT) is 5 percent for a dose of 400 milligrams or more daily. APT is more frequently reported in males and the elderly. Those with pre-existing lung diseases are more susceptible to developing APT. Lung toxicity can occur indirectly due to immune-mediated hypersensitivity or by releasing free radicals (direct injury to lung cells).

The risk factors include:

• Males.

• Increased age.

• Pre-existing lung disease.

• High-dose supplemental oxygen.

• Ethnicity(e.g., Japanese).

• Pulmonary angiography.

• Cardiothoracic surgery.

APT can result in various lung conditions, these include:

1. Acute Respiratory Disease Syndrome (ARDS):

ARDS is an uncommon but life-threatening form of amiodarone toxicity. Amiodarone-induced ARDS is seen in individuals undergoing pulmonary angiography or thoracic surgery. The affected presents with acute onset of symptoms like dyspnea, impaired oxygenation, and ground glass appearance on radiographic findings. Management options include

• Amiodarone cessation.

• Supportive care.

• Mechanical ventilation.

• Steroid therapy.

The mortality rate is high in such cases.

2. Interstitial Pneumonitis:

Interstitial pneumonitis due to amiodarone presents a gradual onset of non-productive cough and dyspnea. The symptoms usually start after six to twelve of therapy. It is the most common form of APT. In this condition, the air sac within the lungs accumulates fluid and inflammatory cells, thus reducing the diffusion capacity of the lungs. Chest X-rays show patchy interstitial infiltrates, and pulmonary function test shows reduced diffusing capacity. Treatment options include drug cessation and steroid therapy.

3. Eosinophilic Pneumonia:

Eosinophilic pneumonia is uncommon with amiodarone. The radiograph shows ground glass opacities. BAL (bronchoalveolar lavage) fluid shows more significant than 25 percent eosinophils.

4. Organizing Pneumonia:

Organizing pneumonia is present in about one-fourth of the cases of APT. An acute or subacute onset resembles an infectious pneumonia, but the condition does not respond to antimicrobial therapy. Treatment includes amiodarone cessation and steroid therapy.

5. Pulmonary Masses And Nodules:

A solitary pulmonary mass (single lung opacity not greater than 3 cm) or multiple pulmonary masses may be seen radiographically; these may resemble a lung malignancy. A biopsy is required to exclude malignancy.

6. Pleural Effusion:

These are uncommon manifestations of Amiodarone toxicity and are primarily present in association with interstitial pneumonitis.

7. Diffuse Alveolar Hemorrhage:

Diffuse alveolar hemorrhage associated with amiodarone toxicity presents with an acute onset of symptoms like cough, dyspnea, and hemoptysis (coughing blood).

What Are the Clinical Findings Associated With Amiodarone Lung Toxicity?

1. Clinical Examination:

The most common clinical presentation is interstitial/alveolar pneumonitis with a subacute onset. The patient presents with symptoms like

• Fever.

• Non-productive cough.

• Malaise.

• Weight loss.

• Pleuritic chest pain (occasional).

• Shortness of breath.

Patients who show a new onset of cough or breathing issues, are under Amiodarone therapy or have recently discontinued treatment are suspected of toxicity.

In mild cases, a physical examination would not be remarkable; in severe cases, signs of respiratory distress and hypoxemia are seen.

2. Lab Findings:

Lab finding shows leukocytosis (increased white blood cell count). A non-specific elevation of serum KL-6 (a high molecular weight glycoprotein marker of disease activity in interstitial lung disease) or lactic dehydrogenase is seen. Elevation in erythrocyte sedimentation count and C-reactive protein is also seen. Elevation in eosinophil count is not seen typically. Amiodarone levels are usually in the normal range and do not diagnose toxicity.

3. Radiographic Features:

Radiograph plays a vital role in diagnosis. Chest X-rays show patchy infiltrates on both lungs (primarily bilateral). These infiltrates offer a “ground-glass appearance in some cases. The right upper lobe of the right lung is the frequently affected region.

4. Pulmonary Function Test:

Pulmonary function tests suggest a restrictive pattern and low lung volume. A lowered diffusing capacity of the lungs for carbon monoxide is seen. Hypoxemia is measured in varying degrees using arterial blood gas analysis or pulse oximetry.

What Are the Treatment Options?

The treatment options include

• Cessation of Amiodarone.

• Administration of systemic corticosteroids. Mostly, prednisolone is started at a dose of 40 to 60 milligrams per day (orally), and then the dose is tapered slowly. Because of the long elimination half-life of amiodarone, steroid therapy may be needed for a longer period.

• Recurrence of toxicity was reported in cases of early steroid withdrawal.

The prognosis of APT is mostly favorable on early diagnosis. However, severely progressed cases may result in death. Mortality is high in cases of ARDS.

What Are the Preventive Measures That Can Be Taken?

• Those under Amiodarone therapy should be informed of the potential side effects. They should be asked to report in cases of any new onset of respiratory symptoms.

• Regular assessment is needed for patients undergoing Amiodarone therapy to analyze drug efficacy, adverse effects, potential drug interactions, and dosage appropriateness.

The patient follow-up includes baseline assessment like

• Complete physical examination and history, especially regarding arrhythmia symptoms and concomitant medications.

• Chest X-rays.

• Thyroid function tests.

• Pulmonary function tests.

• Checking liver transaminase levels.

• Ophthalmologic examination in case of pre-existing visual problems.

• Close monitoring of prothrombin time in case of Warfarin therapy.

• Analyze Digoxin level in case of Digoxin therapy.

Conclusion

Amiodarone-induced pulmonary toxicity (APT) is amiodarone's most potentially serious adverse effect. The risk factors that can increase the toxicity are suggested to be advanced age, pre-existing lung disease, daily dose above 400 milligrams, and cumulative doses. The most common clinical presentation is interstitial/alveolar pneumonitis. Treatment options include drug cessation and steroids. The condition has a favorable prognosis if diagnosed early.