Amiodarone pulmonary toxicity

Amiodarone is widely used to treat cardiac arrhythmias and is very effective in preventing these disorders. However, its use is limited by a wide range of adverse effects, mainly affecting the lungs, and ranging from mild shortness of breath to pulmonary fibrosis. Amiodarone has been shown to accumulate strongly in lung tissue, exceeding its plasma concentration by a hundredfold. However, the site of accumulation and the mechanisms of transport are not fully understood. In this study, we used live cell imaging of primary rat alveolar type II cells to show that amiodarone specifically accumulates in large amounts in lamellar bodies, the surfactant storage organelles. Fluorescence imaging and correlation, and colocalization studies combined with confocal Raman microscopy identified these organelles as a major target for sequestration. Accumulation was rapid, on the order of a few hours, while storage was much more persistent. Partial uptake was observed in chemically fixed, dead cells, or cells treated with bafilomycin A1. Not only was uptake pH dependent, but intraluminal pH, measured with lysosomotropic pH sensitive dyes, was also affected. From these observations and from the physicochemical properties of amiodarone, we propose that passive diffusion, ion-trapping and lipophilic interactions are the main mechanisms for intracellular bioaccumulation. Furthermore, we demonstrate that measurement of amiodarone autofluorescence is highly useful for tracking cellular uptake and sequestration.

Amiodarone is the most potent antiarrhythmic drug available and is commonly prescribed to treat and prevent not only life-threatening ventricular arrhythmias but also atrial fibrillation (AF). The latest European Society of Cardiology AF guidelines state that amiodarone is recommended for long-term rhythm control in all AF patients but that other antiarrhythmic drugs should be considered first whenever possible, due to its extracardiac toxicity. In patients without significant or with only minimal structural heart disease, amiodarone is not listed as a possibility in their therapeutic scheme. Still, amiodarone is widely and liberally used, and is the most prescribed antiarrhythmic drug for patients with AF despite its high toxicity profile. Non-cardiovascular death was more frequent with amiodarone treatment than with a rate control strategy in AFFIRM, while meta-analyses suggest an association between amiodarone use in patients without structural heart disease and increased non-cardiovascular mortality. Severe or even fatal outcomes due to amiodarone may occur years after treatment initiation and are often not acknowledged by the prescribing physician, who may no longer be following the patient. The lack of widely accepted diagnostic criteria and symptom definitions may lead to underestimation of the incidence of severe side effects and of its toxicity. Unlike the underestimated risk of toxicity with amiodarone, severe complications associated with catheter ablation are usually directly ascribed to the treatment even by non-medical personnel, possibly resulting in overestimation of risks. This brief review will address the issue of amiodarone overuse and the frequent underestimation of its toxicity, while suggesting scenarios in which its use is entirely reasonable, and compare it with catheter ablation.

A amiodarona é o fármaco antiarrítmico mais potente de que dispomos e é frequentemente prescrita para tratar e prevenir não apenas arritmias ventriculares malignas, mas também fibrilhação auricular (FA). Nas mais recentes diretrizes da Sociedade Europeia de Cardiologia, a «Amiodarona é recomendada para o controlo do ritmo a longo prazo em todos os doentes com FA». No entanto, os autores afirmam que «outros fármacos antiarrítmicos devem ser considerados primeiro sempre que possível» atendendo à toxicidade extracardíaca da amiodarona. Em doentes sem cardiopatia estrutural significativa, a amiodarona não está sequer listada como uma possibilidade no seu diagrama terapêutico. Ainda assim, a amiodarona é amplamente prescrita e liberalmente utilizada, representando o fármaco antiarrítmico mais prescrito para doentes com FA, apesar do seu elevado perfil de toxicidade. A morte não cardiovascular foi mais frequente com a amiodarona do que com uma estratégia de controlo de frequência no estudo AFFIRM, enquanto dados meta-analíticos sugerem uma associação entre o uso de amiodarona em doentes sem doença cardíaca estrutural e o aumento da mortalidade não cardiovascular. Eventos adversos graves e mesmo fatais devidos à amiodarona podem ocorrer anos após o início do tratamento e, muitas vezes, não são reconhecidos pelo médico que prescreveu o fármaco que pode já não estar a seguir o doente. A falta de critérios de diagnóstico amplamente aceites pode levar a uma subestimativa da incidência de efeitos secundários graves e a uma perceção subestimada da sua toxicidade. Contrariamente ao risco subestimado de toxicidade da amiodarona, as complicações graves associadas à ablação por cateter são facilmente atribuíveis ao tratamento, mesmo por pessoal não médico, resultando numa perceção possivelmente sobrestimada dos seus riscos. Esta breve revisão abordará o problema do uso excessivo de amiodarona e a perceção por norma subestimada da sua toxicidade e sugerirá cenários em que a sua utilização é inteiramente razoável.

Daptomycin is a widely used antibiotic. Rhabdomyolysis related to daptomycin is one of the adverse effects of treatment, justifying the need for regular monitoring of muscle enzymes throughout treatment. Daptomycin may also lead to eosinophilic pneumonia. However, risk factors for this adverse reaction have not been identified and do not permit targeting of at-risk populations who could benefit from appropriate monitoring.

Literature was reviewed for cases of daptomycin-induced eosinophilic pneumonia (DIEP), which that were compared to cases of patients without this adverse effect.

Fifty patients with DIEP and 54 controls were identified. Age, sex, and treatment dose are not associated with the occurrence of DIEP. A high dose of daptomycin is not associated with an early onset of DIEP. About one third of patients with eosinophilic lung disease have diabetes or renal impairment.

Further studies may help to identify additional factors.

Numerous drugs can cause pulmonary reactions in children. Chemotherapeutic agents are most frequently implicated, although toxic effects of other medications have been recognized. Reactions to chemotherapeutic agents may be dose-related; most reactions to noncytotoxic agents develop idiosyncratically. Clinical/pathologic syndromes described include diffuse interstitial pneumonitis and fibrosis, hypersensitivity pneumonitis, noncardiogenic pulmonary edema, pleural effusion, bronchiolitis obliterans, and alveolar hemorrhage. Presenting symptoms vary but often include fever, cough, and dyspnea, and radiologic studies demonstrate diffuse alveolar and/or interstitial abnormalities. Abnormalities in lung function may precede symptoms and radiographic changes. Patterns of abnormalities on chest CT, bronchoalveolar fluid analysis and cultures, and lung histopathology may be useful in categorizing and defining extent of disease but may be nonspecific. Other disorders, including infection, hemorrhage, lung disease related to underlying disease, and radiation damage, must be considered. Criteria for the diagnosis of drug-induced lung disease have been outlined. Although some drug-induced lung injury is reversible, persistent and even fatal dysfunction may occur. Survivors of childhood cancer require follow-up as lung disease may develop remotely from drug exposure and be progressive. More precise information about risk factors, including genetic predisposition and mechanisms of injury, along with more sensitive diagnostic and monitoring approaches are needed for development of improved therapeutic strategies, including early intervention.