Drugs and Agents Fallen Out of Favor

Prescription hexamethonium, mecamylamine, aminorex, l-tryptophan, fenfuramine, dexfenfuramine, phentermine, and benfuorex caused interstitial lung disease, ARDS, eosinophilic tissue damage, or pulmonary hypertension. These drugs are not available anymore. They are still indexed in Pneumotox, because any recalled drug may be obtained from a shelf somewhere, be synthetized in the home, be used experimentally, regain popularity in light of new indications (e.g., thalidomide), or because drug congeners may produce the same or similar adverse reactions (e.g., benfuorex v. fenfuramine). Mitomycin-C is far less used now that it was in the past and mitomycin pulmonary toxicity has become a rare occurrence, though rare cases emerge following instillation of the drug in the urinary bladder to treat bladder carcinoma [66]. The same concerns apply to mitomycin-induced hemolytic and uremic syndrome.

The antirheumatics, gold and penicillamine, have fallen into disuse since the advent of methotrexate, lefunomide, and the newer TNF-alfa and JAK antagonists. Gold-induced pneumonitis and penicillamine-associated obliterative bronchiolitis are for now diseases of the past. Penicillamine was not cited in a recent paper on airway disease in rheumatoid arthritis (RA) [67].

Amphetamine-like anorectics (aminorex in the 1960s, fenfuramine-dexfenfuramine in the 1990s, benfuorex in the 2000s) were recalled due to an epidemiologically signi cant surge of acquired pulmonary hypertension (PHT) and valvular heart disease. In the 1970s, aminorex was shown to cause pulmonary hypertension and plexiform pulmonary arterial changes in young women who used the drug as a weight reducing agent. Death occurred after an average 3.5 years on the drug from right ventricular failure. An epidemic of PHTn and valvular heart disease was also reported with the use of the then newer anorexigens fenfuramine and dextro-isomer dexfenfuramine in the 1980s and 1990s [68]; this resolved with recall of the drugs. Household manufacture of aminorex was responsible for sporadic PHT. Aminorex is a metabolite of levamisole, a veterinary antihelminthic agent widely present as an adulterant added by purveyors in cocaine. Only one case of pulmonary hypertension has been reported following exposure to cocaine-levamisole. Benfuorex, which was marketed as an antidiabetic drug is in fact closely related to fenfuramine. An epidemic of valvular heart disease and PHT developed (mostly in France) following long-term exposure to the drug [69], prior to its recall in 2009.

Several members of the thiazolidinedione (glitazones) family were discontinued in some countries owing to their propensity to cause capillary leak, pleural effusions, and irreversible heart failure.

l-tryptophan once was a popular nutraceutical. The compound produced an epidemic of “eosinophilia-myalgia syn-

drome,” with an increase in blood eosinophils. About half of affected patients presented with small irregular or dense radiographic opacities in the lung and with pleural effusion. An ARDS picture was noted in a few. Minute amounts of contaminants formed during the synthesis of tryptophan at the Showa Denko plant in Japan were blamed as the cause for the syndrome. Incident cases diminished sharply after l-tryptophan was recalled. Only sporadic cases are now being reported.

Dronedarone was designed to supplant amiodarone. Unfortunately, severe liver injury and sporadic ILD cases have prevented this drug from being released [3, 4].

Flavocoxid, a dietary supplement/medical food marketed under the tradename Limbrel® was recalled by the company in 2017–2018 under FDA action following reports of severe ILD.

A thorough history for DIRD must include use of herbal therapies, as many plants have been reported to cause pulmonary in ltrates, ARDS, bronchiolitis obliterans or arrhythmia.

Potentially Life-Threatening Drug-Induced/

Iatrogenic Emergencies (Table 42.6)

Pulmonologists, internal medicine specialists, oncologists, radiologists, anesthesiologists, surgeons, emergency physicians, intensive care and ENT specialists, nurses, dental surgeons may be confronted with unexpected acute life-threatening drug-induced respiratory and/or systemic emergencies. Acute reactions may affect the lung, upper airway, small airways, pulmonary circulation, pleura, pericardium or they can be systemic with associated pulmonary involvement. Clinical presentations include diffuse pulmonary in ltrates, acute airway obstruction, pleural or pericardial effusion, acute pulmonary hypertension. Causality can be straightforward when a reaction occurs during or immediately following administration of the drug. Onset can be within seconds. Some reactions develop electively during the intraor perioperative period, leading to dif cult diagnostic and management challenges. Consideration of drug-induced etiologies is paramount as drug withdrawal can be life-saving.

Acute Drug-Induced/Iatrogenic Emergencies with Di use Pulmonary Infltrates and ARDS (Table 42.7)

The Adult Respiratory Distress Syndrome (ARDS) is de ned by the triad of pulmonary in ltrates in the absence of cardiac failure, and a ratio of partial pressure of oxygen in arterial blood to FiO2 of less than 200. Different underlying pulmonary processes can lead to an ARDS picture including pulmonary edema, diffuse alveolar damage, severe in ltrative

lung disease including cellular NSIP, organizing pneumonia, eosinophilic pneumonia, or alveolar hemorrhage. In practice, lung tissue is rarely available for review. However, certain clinical and gas exchange features are suggestive of particular histopathological pattern-based classi cations

used by pathologists, which has practical implications as regards recognition and management, assessment of drug causality, and treatment. For instance, the majority of ARDS cases de ned clinically show features of diffuse alveolar damage (DAD) on pathological examination [60, 70, 71]. In

Table 42.7  Drug-induced/Iatrogenic ARDS

Reactions Induced-Drug Emergent and Rare, Unusual, on Emphasis With Disease: Respiratory Induced/Iatrogenic-Drug  42

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Table 42.7  (continued)

5.Acute vasculopathy

Abbreviations, see text

a AM: macrophages containing foreign body inclusions

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