US Pharm. 2016;41(7):35-39.
ABSTRACT: Drug-induced disease of any system in the body is associated with a high degree of morbidity or mortality; however, when it affects the pulmonary system, the risks grow substantially. Over 100 medications can adversely affect the lungs. Adverse drug reactions include asthmatic exacerbations, cough, interstitial pneumonitis, and pleural effusions. Medications implicated in life-threatening pulmonary reactions include cardiovascular drugs, cytotoxic agents, and antimicrobials, as well as smoking and alcohol use. It is imperative that clinicians obtain an accurate, detailed, and current medication history, including alternative medicines to enable accurate differentiation between drug-induced pulmonary disorders and other pulmonary diseases.
Adverse drug reactions (ADRs) have been estimated to be the third leading cause of death in the United States, following heart disease and cancer.1,2 Drug-induced pulmonary disorders (DIPDs) are an important subset of ADRs.
Although the liver is the primary drug-metabolizing organ of the body, the lungs are also capable of drug metabolism.3,4 DIPD should be suspected when new signs and symptoms develop with recently introduced therapy.5-7 DIPD can affect the pulmonary parenchyma, pleura, airways, pulmonary vasculature, the mediastinum, and the neuromuscular system that enables respiration.6
DIPD can present as a range of manifestations, including pleural effusion, drug-induced lupus, or pneumothorax.5-7 Effects on the pulmonary vasculature can take the form of pulmonary hemorrhage, hemoptysis, pulmonary vasculitis, hematoma, or alveolar hemorrhage.5-7 Clinically, patients experiencing DIPD can develop pleuritic chest pain, at rest or activity-induced dyspnea, cough, wheezing, and fever.5-7
Proposed mechanisms of DIPD include biotransformation and oxidative reactions of CYP450 enzymes in the lungs.3 Cytotoxic damage from chemotherapeutic agents, as well as inflammatory and immune-mediated processes, have also been described.3,4 Toxic drug metabolites are also implicated.3
Risk factors for DIPD can be categorized into two main groups: drug-related and patient-related.8-20 Drug-related factors include the chemical, pharmacologic, and pharmacokinetic properties; the dose or administration rate; and treatment duration.8-15 The cumulative dose, oxygen therapy, and radiotherapy all predispose individuals receiving chemotherapy to DIPD.8,9,13-15
Patient-related factors are of importance in determining risk for developing DIPD.16-24 Patients at extremes of age are at particular risk for DIPD.6-7 Patients with rheumatoid arthritis (RA) have higher incidences of DIPD, including interstitial lung disease (ILD), since the disease process itself is associated with ILD.16-21 The risk for DIPD, especially ILD, increases with preexisting lung disease, immune-mediated diseases (RA, systemic lupus erythematosus [SLE]), in immunocompromised patients, and in those with impaired renal and hepatic function.3,4,16-21
Racial differences in risks for drug-induced ILD and ILD-associated mortalities exist. Japanese and Korean patients have experienced much higher incidence and mortality rates when using tumor necrosis factor (TNF) and methotrexate.20-22 In Korean RA patients treated with an anti-TNF agent, 25% died after less than 10 months of therapy, mostly related to ILD.21 There is a single case report in the biomedical literature of an African-American patient who developed life-threatening pulmonary toxicity following treatment with the proteasome inhibitor bortezomib for multiple myeloma.24 Of note, this is the first report of life-threatening pulmonary toxicity after bortezomib in a non-Japanese patient without prior history of an autologous peripheral stem cell transplant.
Prospective patients should be screened for preexisting lung disease and renal, hepatic, and cardiac function. A thorough risk-benefit analysis should be undertaken, and therapy with high-risk DIPD drugs should be initiated at lowest effective therapeutic doses with pulmonary, renal, and hepatic function monitoring.6
Over 100 medications can adversely affect the lungs.25 Agents implicated in life-threatening pulmonary reactions include cardiovascular drugs, cytotoxic agents, and antimicrobials (TABLE 1).
Pneumonitis and Fibrosis: Dose-dependent symptoms of pneumonitis and fibrosis, including dyspnea, cough, and pulmonary crackles, were reported with many medications, most notably, amiodarone.25,26
Nitrofurantoin may cause DIPDs, which include pulmonary fibrosis, pneumonitis, bronchiolitis obliterans, diffuse alveolar damage, pneumonia, diffuse alveolar hemorrhage, lupus-like syndrome, and allergic reactions.27
Hypersensitivity Lung Disease: Drug hypersensitivity presents as an immediate reaction with urticaria, angioedema, rhinitis, conjunctivitis, dyspnea, and bronchospasm.28 Discontinuation of the agent, along with corticosteroid and antihistamine treatment, often results in symptom resolution.26
Nonsteroidal anti-inflammatory drug (NSAID)-induced hypersensitivity lung disease is dose-dependent and may present as severe asthma exacerbation with breathlessness, requiring emergency treatment.29
Noncardiogenic Pulmonary Edema: Patients who present with drug-induced pulmonary edema experience persistent cough, tachypnea, dyspnea, tachycardia, and hypoxemia.30 Edema may lead to hyperplasia, fibrosis, and eventually hemorrhage.30,31 Oxygen, diuretics, and corticosteroids are often prescribed in pulmonary edema treatment.31
Bronchospasm: Drug-induced bronchospasm can be sudden and severe, causing asphyxia and irreversible brain damage.25 NSAIDs are reported to cause broncho-spasm.32 Asthma and chronic obstructive pulmonary disease (COPD) can be exacerbated in the presence of NSAIDs, anti-infective agents, and beta-blockers.26,32
Alveolar hemorrhage presents itself as shortness of breath (SOB), cough, and hemoptysis.31 Chemotherapy agents, anticoagulants, nitrofurantoin, sirolimus, and gefitinib may result in alveolar hemorrhage.33
Bronchiolitis obliterans organizing pneumonia (BOOP) manifests itself with cough, fever, dyspnea, and areas of consolidation.25 Medications known to cause BOOP include acebutolol, amiodarone, amphotericin B, bleo-mycin, carbamazepine, cephalosporins, cyclophosphamide, doxorubicin, gold salts, interferon alfa and beta, methotrexate, nitrofurantoin, penicillamine, phenytoin, sulfasalazine, ticlopidine, and tetracyclines.25,34,35
Eosinophilic reactions with pulmonary infiltrates can occur with the use of nitrofurantoin, methotrexate, sulfonamides, tetracycline, chlorpropamide, phenytoin, NSAIDs, and imipramine.30 Symptoms include fever, nonproductive cough, dyspnea, and cyanosis.30,36
Drugs can induce hypoventilation by depressing the respiratory drive or potentiating neuromuscular blockade.26 Medications include alcohol, narcotics, sedatives, and hypnotics.30 Aminoglycosides, clindamycin, polymyxin, and neuromuscular blockers may cause respiratory muscle dysfunction.26,30
Pulmonary-renal syndrome, seen after long-term penicillamine therapy, presents as acute-onset rapidly progressing dyspnea, hematuria, hemoptysis, and pleuritic chest pain.26,37 Hydralazine has been described in the literature to cause vasculitis, which presents as pulmonary-renal syndrome.38,39
A variety of medications can cause SLE symptoms. The list includes hydralazine, isoniazid, phenytoin, procainamide, and sulfonamides.25,26 Anti-TNF-alpha agents cause a variety of serious ADRs, including drug-induced lupus.40
Differential With Pulmonary Pathology of Other Causes
DIPD is a diagnosis of exclusion and should be suspected if the patient has been exposed to the drug and develops new signs and symptoms, which remit if the medication is discontinued. Chest x-rays and CT scans are helpful in establishing the diagnosis.6,41
CAM-Induced Pulmonary Disease
Complementary and alternative medicine (CAM) has gained wide acceptance, but these agents are not FDA-approved for safety, and like all medications, have the potential for harm. Common adverse pulmonary effects are allergic reactions, which can affect breathing.42,43 CAM appetite suppressants may contain sympathomimetic ingredients associated with increased risk of pulmonary hypertension (TABLE 2).44-47 In addition, there is the possibility of interactions between CAM and conventional therapy.46
Illicit Drug Use
Illicit drug use may result in pulmonary diseases, mainly bacterial infections.48 The mechanisms that result in increased prevalence of infection with illicit drug use, especially IV use, are not completely understood but include use of contaminated drugs and needles, skin colonization by unusual or virulent microorganisms from previous hospitalizations, and changes in normal bacterial flora due to repeated courses of antibiotics. COPD exacerbation is common in illicit drug smokers.49 Common illicit drugs implicated include heroin (via IV, intradermal, inhalation, and oral routes), cocaine (via inhalation and IV routes), marijuana (via inhalation route), and oxycodone, methylphenidate, methamphetamine, methadone, benzodiazepines, and opiates (via oral and IV routes).50
Diluents (e.g., talc) used in the manufacture of illicit drugs may result in a granulomatous foreign-body response or may occlude blood vessels, leading to pulmonary hyper-tension.51-54
Approximately 17% of the U.S. adult population smoke, with lung cancer as the number-one cancer killer.55 The U.S. Preventive Services Task Force currently recommends an annual cancer screening for smokers.56
Smoking causes the majority of cases of COPD, increases severity of chronic lung disease, and increases the risk for respiratory infections (e.g., tuberculosis).57 Secondhand smoke causes more frequent and severe asthma attacks and respiratory infections.58 Beyond lung cancer, smoking is associated with many pulmonary diseases, as toxins in tobacco smoke damage tissues and cells.
Alcohol is excreted into the airways as evidenced by its presence in the breath test (i.e., Breathalyzer). The most significant pulmonary effects are an increased risk for bacterial infection.59 Additives such as sulfites and the metabolite acetaldehyde are known triggers for asthma.60-62
Role of the Pharmacist
To minimize morbidity and mortality, it is incumbent upon pharmacists to consider medications that may induce pulmonary disease. Improved awareness of medications that can cause pulmonary disease can expedite diagnosis and treatment of patients and facilitate harm reduction to prevent future complications. Additionally, knowledge of drugs and other substances that may induce pulmonary disease can represent a prime opportunity for patient counseling. Before starting any medication, pharmacists should counsel patients about potential adverse effects. A detailed medication history (including prescription drugs, OTC products, herbals, tobacco, alcohol) to identify underlying risk and causative factors for DIPD is essential.
Smoking cessation through patient counseling and OTC product selection is helpful.63 Smoking cessation is the first-line treatment for many smoking-related pulmonary diseases. Through patient counseling and OTC product selection (i.e., nicotine replacement gums, patches, lozenges), pharmacists play a crucial role in assisting patients in smoking cessation. Every patient at each pharmacy visit should be asked if he or she smokes and is interested in quitting.
Pulmonary diseases can result from a number of agents and can have myriad presentations. DIPDs are common, although underreported. An analysis of the risks and benefits of administration of medication with documented pulmonary ADRs should be undertaken. DIPD should be considered in the differential diagnosis of many respiratory conditions.64
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