Pulmonary toxicity, drug-induced

PULMONARY TOXICITY Drug-Induced Pyrimethamine- Hypersensitivity pneumonitis... 

Kehrer, J. P Witschi, H. Effects of drug metabolism inhibitors on butylated hydroxyto-luene-induced pulmonary toxicity in mice. Toxicol. Appl. Pharmacol 1980,53,333-342. 

Oral- Amiodarone may cause a clinical syndrome of cough and progressive dyspnea accompanied by functional, radiographic, gallium scan, and pathological data consistent with pulmonary toxicity. The frequency varies from 2% to 17% fatalities occur in about 10% of cases. However, in patients with life-threatening arrhythmias, discontinuation of amiodarone therapy due to suspected drug-induced pulmonary toxicity should be undertaken with caution. 

Approximately 30% of patients using sulfasalazine discontinue the drug because of toxicity. Common adverse effects include nausea, vomiting, headache, and rash. Hemolytic anemia and methemoglobinemia also occur, but rarely. Neutropenia occurs in 1-5% of patients, while thrombocytopenia is very rare. Pulmonary toxicity and positive double-stranded DNA are occasionally seen, but drug-induced lupus is rare. Reversible infertility occurs in men, but sulfasalazine does not affect fertility in women. The drug does not appear to be teratogenic. 

The G-CSF can cause severe pulmonary toxicity in patients who are not receiving concomitant chemotherapy. For example, several reports have suggested that G-CSF administration for drug-induced agranulocytosis can play a role in the development or worsening of the adult respiratory distress syndrome (ARDS) (33). 

In a patient with nitrofurantoin-induced pulmonary toxicity, in whom high resolution CT scans initially showed a widespread reticular pattern and associated distortion of the lung parenchyma, thought to represent established and irreversible fibrosis, follow-up CT scans after withdrawal of the drug showed resolution of the pulmonary changes. 

Drugs may produce serious pulmonary toxicity as part of a more generalized disorder. The pleural thickening, effusions, and flbrosis that occur as an extension of the retroperitoneal flbrotic reactions of methysergide and practolol or as part of a drug-induced lupus syndrome are the most common examples (Table 29-8). 

Jessurun GAJ, Boersma WG, Crijns HJGM. Amiodarone-induced pulmonary toxicity Predisposing factors, clinical symptoms and treatment. Drug Safety 1998 18 339-344. 

One of the unique features of BLM is its lack of significant hepatic, renal, and bone marrow toxicities, undesired effects of many anticancer drugs. Two drawbacks are the tumor resistance and the BLM-induced pulmonary toxicity. Both effects are related to the level of BLM hydrolase, a protease that binds to DNA and inactivates BLM by hydrolyzing the /3-alanine carboxamide moiety (14, 15). Cells with high levels of BLM hydrolase are resistant to bleomycin, whereas lungs are sensitive to BLM-induced tissue injuries because of low levels of this enzyme. The structure of this protease, which binds DNA and is conserved from bacteria to humans, has been solved (16). 

Both carmustine and lomustine can induce thrombocytopenia and leukopenia, leading to hemorrhage and massive infection. Acute (as well as potentially fatal delayed) pulmonary toxicity also is a risk. Pulmonary toxicity is dose-related, and individuals who received the drug in childhood or early adolescence are at higher risk for the delayed reaction. The grand mal seizures that are possible from the wafer formulation of carmustine appear to result from the wafer rather than from the nitrosourea. 

Mitomycin is administered IV in the treatment of disseminated adenocarcinoma of the stomach or pancreas, and it has been used intravesically in superficial bladder cancer. Biotransformation pathways are saturable, and approximately 10% of an administered dose is eliminated unchanged via the kidneys. Myelosuppression is the major use-limiting side effect of this drug, which is slow to manifest but quite prolonged in duration. Severe skin necrosis can occur on extravasation, and potentially fatal pulmonary toxicities have been noted as well. Mitomycin can induce hemolytic uremia accompanied by irreversible renal dysfunction and thrombocytopenia, and the drug should not be administered to patients with serum creatinine levels greater than 1.7 mg/dL. Severe bronchospasm also has been noted in patients treated with vinca alkaloids who also are receiving (or who have previously received) mitomycin. 

Farer LS (1976) Isoniazid and liver injury. Ann Intern Med 84 753 Feinmann L (1975) Lung parenchymal changes due to ingested substances. Drug-induced lung disease pulmonary eosinophilia and sulphonamides. Proc R Soc Med 68 440 Fellner MJ (1970) Nebenwirkungen durch Isonicotinsaurehydrazid. Hautarzt 21 320 Flach A (1981) Photosensitivity to sulfisoxazole ointment. Arch Ophthalmol 99 609 Fleck R (1981) Nitrofurantoin toxicity. Pa Med 84 36... 

The time frame in which pulmonary drug-induced toxicity occurs is also highly variable, ranging from acute hypersensitivity reactions (e.g., methotrexate, nitrofurantoin toxicides) to delayed presentations (e.g., nitrosoureas, or radiation recall seen with bleomycin, as discussed below). This along with the fact that combination treatments have become commonplace, in particular in the context of chemotherapy protocols, may further hamper the clinician s ability to identify the culprit medication. In addition, several drugs may be implicated in an additive or synergistic fashion and further confuse the clinical picture. 

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