Chest
Volume 93, Issue 6, June 1988, Pages 1242-1248
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Today's Practice of Cardiopulmonary Medicine
Amiodarone Pulmonary Toxicity: Recognition and Pathogenesis (Part 2)

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PHARMACOKINETICS OF AMIODARONE

Prior to a discussion of possible mechanisms, some basic pharmacologic principles should be kept in mind in the assessment of patients with APT. Although amiodarone concentrations in the blood correlate with an increased risk of developing an adverse reaction to the drug,10 amiodarone blood and lung tissue levels have not been successfully utilized to predict or confirm APT. In general, the overall risk of APT can be correlated with total cumulative dose4, 11, 12 but not predictably with daily

EVIDENCE FOR DIRECT PULMONARY TOXICITY BY AMIODARONE

Many drugs are thought to injure the lung parenchyma as a result of direct cytotoxicity to susceptible target lung cells.21 Cancer chemotherapy drugs represent a class of therapeutic agents which, for the most part, are suspected to manifest their pulmonary toxicity by this mechanism. It is likely the biochemical mechanism of injury to normal lung parenchymal cells is similar to the proposed mechanism of cytotoxicity to cancer cells. Why the lung is the site of toxicity is less clear. There may

MECHANISM OF PHOSPHOLIPIDOSIS

The mechanism of phospholipid accumulation in the lungs of subjects with APT is thought to be secondary to inhibition of phospholipid degradation within the cells.23, 24, 25, 26 Both in vivo animal24, 25, 26 and in vitro cell culture studies23 suggest that phospholipids accumulate following amiodarone treatment because amiodarone is an extremely potent inhibitor of phospholipase A. The inhibition of phospholipase A activity appears to be equally potent for phospholipase A1 and A223, 24 and is

EVIDENCE FOR INDIRECT MECHANISMS

Although amiodarone has the potential to be directly toxic to the lung, several lines of evidence argue against this representing the sole mechanism of toxicity. First, there is a poor correlation of amiodarone daily dosages or blood levels with the development of pulmonary toxicity.2, 4, 12, 13 Preliminary studies suggest that various immunologic markers of disease activity are present in patients with APT.43, 44, 45 Finally, data from some patients with APT indicate a marked

SUMMARY

The pulmonary toxicity associated with amiodarone therapy is clinically complex and likely reflects underlying mechanisms of lung injury that result from direct toxic effects of the drug (or its metabolites) as well as indirect inflammatory and immunologic processes induced by the drug therapy (Fig 2). A role for the direct toxicity of the drug is likely because (a) toxicity in part is related to dosage and duration of therapy, (b) many patients with amiodarone pulmonary toxicity have no

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    Supported in part by NIH grant HL36124. Part 1 appeared in the May issue of Chest.

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