Induced Pulmonary Disorders

Mayo Clinic College of Medicine, Rochester, Minnesota, U.S.A. 

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. 

The mechanisms by which drugs may lead to adverse pulmonary reactions are still incompletely understood. Several types of pulmonary toxicity have however been described in details and are thought to explain most of these 

In every case, alternative explanations for the respiratory symptoms observed must be carefully excluded. A constellation of suggestive clinical and radiographical findings, and if necessary, supported by a compatible histopathological diagnosis should alert the clinician and prompt discontinuation of the drug. In selected cases, the initiation of judicious corticosteroid therapy may also be indicated. 

Importantly, the toxicity of bleomycin is cumulative. Total doses in excess of 450 units are associated with a significantly increased incidence of adverse lung reactions and death. The incidence of bleomycin-induced lung toxicity has been reported between 0% and 46% with a mortality rate of 3% (5,7). As mentioned above, high cumulative dose, extreme of age, uremia, the use of supplemental oxygen, and radiation therapy are well-documented risk factors for bleomycin toxicity. Other chemotherapeutic agents (cyclophosphamide and vincristine) may also have a synergistic effect with bleomycin. Finally, bleomycin may occasionally reactivate a prior radiation-induced pneumonitis, a phenomenon known as radiation-recall.  

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Langerhans cell histiocytosis (Dr. Vassallo et al.), lymphangioleiomyomatosis (Dr. McCormack), pulmonary alveolar proteinosis (Dr. Wang et al.), amyloidosis (Dr. Berk), and drug-induced pulmonary disorders (Drs. Maldonado and Limper). 

Antioxidant therapy might be promising medication for the treatment of some lung disorders. For example, lecithinized phosphatidylcholine-CuZnSOD suppressed the development of bleomycin-induced pulmonary fibrosis in mice [284] these findings could be of relevance for the treatment of bleomycin-stimulated pulmonary fibrosis in humans. Davis et al. [285] recently demonstrated that the treatment of premature infants with recombinant human CuZnSOD may reduce early pulmonary injury. 

Pulmonary disorders Dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, and sarcoidosis, some resulting in respiratory failure and/or patient deaths, may be induced or aggravated by peginterferon alfa-2b or alpha-interferon therapy. 

The usual oral dose for adults is 10-20 mg, administered 3 or 4 times daily. The intramuscular dose for adults is 5-10 mg, administered 2 or 3 times daily [1]. Isoxsuprine may cause transient flashing, hypotension, tachycardia, rashes, and gastrointestinal disorders [39]. It has also been reported to induce pulmonary edema [46]. 

Grassi L, Biancosino B, Pavanati M, Agostini M, Manfredini R. Depression or hypoactive delirium A report of ciprofloxacin-induced mental disorder in a patient with chronic obstructive pulmonary disease. Psychother Psychosom 2001 70(l) 58-9. 

Respiratory Disorders. Topically applied P-blockers can induce asthma or dyspnea in patients with preexisting chronic obstructive pulmonary disease. Clinicians should inquire about a history of pulmonary disorders before initiating glaucoma treatment with P-blockers. A history of restrictive airway disease also contraindicates the use of opioids for treatment of ocular pain. 

The selective /32-adrenergic agonists terbutaUne and ritodrine have been reported to induce pulmonary edema when used as tocolytics. This disorder commonly occurs 48 to 72 hours after tocolytic therapy. This has never occurred with their use in asthma patients, even in inadvertent overdosage. This reaction may result from excess fluid administration used to prevent the hypotension from /32-mediated vasodilation or the particular hemodynamics of pregnancy. In a review of 330 patients who received tocolytic therapy and were monitored closely for their fluid status, no episode of pulmonary edema was reported. ... 

Recent in vitro studies have shown that a subpopulation of airway vagal afferent nerves express TRPM8 receptors and that activation of these receptors by cold and menthol excite these airway autonomic nerves. Thus, activation of TRPM8 receptors may provoke an autonomic nerve re ex to increase airway resistance. It was postulated that this autonomic response could provoke menthol- or cold-induced exacerbation of asthma and other pulmonary disorders (Xing et al, 2008). Direct cold stimulation or inhalation of menthol can cause immediate airway constriction and asthma in some people perhaps, the TRPM8 receptor expression is up regulated in these subjects. The situation is far from clear. 

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