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

Etiology

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

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.

Prevention

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

Common DIPDs

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

Atypical DIPDs

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

Tobacco

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

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.

Conclusion

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

REFERENCES

1. Starfield B. Is US health really the best in the world? JAMA. 2000;284(4):483-485.
2. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients. A meta-analysis of prospective studies. JAMA. 1998;279(15):1200-1205.
3. Delaunois LM. Mechanisms in pulmonary toxicity. Clin Chest Med. 2004;25(1):1-14.
4. Ryrfeldt A. Drug-induced inflammatory responses to the lungs. Toxicol Lett. 2000;112-113:171-176.
5. Rosenow EC 3rd. Drug-induced pulmonary disease. Dis Mon. 1994;40(5):253-310.
6. Byrd RP Jr. Drug-induced pulmonary toxicity. Medscape. http://emedicine.medscape.com/article/1343451-overview. Accessed March 14, 2016.
7. Fagan NL, Foral PA, Malesker MA, Morrow LE. Therapeutic update on drug-induced pulmonary disorders. US Pharm. 2011;36(7):HS3-HS8.
8. Okuno SH, Frytak S. Mitomycin lung toxicity. Acute and chronic phases. Am J Clin Oncol. 1997;20(3):282-284.
9. Imokawa S, Colby TV, Leslie KO, Helmers RA. Methotrexate pneumonitis: review of the literature and histopathological findings in nine patients. Eur Respir J. 2000;15(2):373-381.
10. Cameron RJ, Kolbe J, Wilsher ML, Lambie N. Bronchiolitis obliterans organising pneumonia associated with the use of nitrofurantoin. Thorax. 2000;55(3):249-251.
11. Vleeming W, van Amsterdam JG, Stricker BH, de Wildt DJ. ACE inhibitor-induced angioedema. Incidence, prevention and management. Drug Saf. 1998;18(3):171-188.
12. Wechsler ME, Wong DA, Miller MK, Lawrence-Miyasaki L. Churg-Strauss syndrome in patients treated with omalizumab. Chest. 2009;136(2):507-518.
13. Lim KH, Chang YH. Interstitial lung disease and gefitinib. N Engl J Med. 2010;363(16):1579-1580.
14. Hillerdal G, Lee J, Blomkvist A, et al. Pleural disease during treatment with bromocriptine in patients previously exposed to asbestos. Eur Respir J. 1997;10(12):2711-2715.
15. Camus P, Fanton A, Bonniaud P, et al. Interstitial lung disease induced by drugs and radiation. Respiration. 2004;71(4):301-326.
16. Cavagna L, Monti S, Grosso V, et al. The multifaceted aspects of interstitial lung disease in rheumatoid arthritis. Biomed Res Int. 2013;2013:759760.
17. Wollner A, Mohle-Boetani J, Lambert RE, et al. Pneumocystis carinii pneumonia complicating low dose methotrexate treatment for rheumatoid arthritis. Thorax. 1991;46(3):205-207.
18. Suissa S, Hudson M, Ernst P. Leflunomide use and the risk of interstitial lung disease in rheumatoid arthritis. Arthritis Rheum. 2006;54(5):1435-1439.
19. Roubille C, Haraoui B. Interstitial lung diseases induced or exacerbated by DMARDs and biologic agents in rheumatoid arthritis: a systematic literature review. Semin Arthritis Rheum. 2014;43(5):613-626.
20. Furukawa H, Oka S, Shimada K, et al; Rheumatoid Arthritis-Interstitial Lung Disease Study Consortium. HLA-A*31:01 and methotrexate-induced lung disease in Japanese rheumatoid arthritis patients: a multidrug hypersensitivity marker? Ann Rheum Dis. 2013;72(1):153-155.
21. Koo BS, Hong S, Kim YJ, et al. Mortality in patients with rheumatoid arthritis-associated interstitial lung disease treated with an anti-tumor necrosis factor agent. Korean J Intern Med. 2015;30(1):104-109.
22. Kudoh S, Kato H, Nishiwaki Y, et al; Japan Thoracic Radiology Group. Interstitial lung disease in Japanese patients with lung cancer: a cohort and nested case-control study. Am J Respir Crit Care Med. 2008;177(12):1348-1357.
23. Gingo MR, George MP, Kessinger CJ, et al. Pulmonary function abnormalities in HIV-infected patients during the current antiretroviral therapy era. Am J Respir Crit Care Med. 2010;182(6):790-796.
24. Ohri A, Arena FP. Severe pulmonary complications in an African-American patient after bortezomib therapy. Am J Ther. 2006;13(6):553-555.
25. Foucher P, Camus PH. The drug-induced respiratory disease website. Pneumotox Online [database online]. Updated January 2016. www.pneumotox.com. Accessed March 10, 2016.
26. Fagan N, Foral P, Malesker M, et al. Therapeutic update on drug-induced pulmonary disorders. US Pharm. 2011;36(7):HS3-HS8.
27. Madani Y, Mann B. Nitrofurantoin-induced lung disease and prophylaxis of urinary tract infections. Prim Care Respir J. 2012;21(3):337-341.
28. Joerger M. Prevention and handling of acute allergic and infusion reactions in oncology. Ann Oncol. 2012;23(suppl 10):x313-x319.
29. Sánchez-Borges M. NSAID hypersensitivity (respiratory, cutaneous, and generalized anaphylactic symptoms). Med Clin North Am. 2010;94(4):853-864.
30. Raissy HH, Harkins M. Chapter 15. Drug-induced pulmonary diseases. In: DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 9th ed. New York, NY: McGraw-Hill; 2014.
31. Lee-Chiong T Jr, Matthay RA. Drug-induced pulmonary edema and acute respiratory distress syndrome. Clin Chest Med. 2004;25(1):95-104.
32. Leuppi JD, Schnyder P, Hartmann K, et al. Drug-induced bronchospasm: analysis of 187 spontaneously reported cases. Respiration. 2001;68(4):345-351.
33. Rabe C, Appenrodt B, Hoff C, et al. Severe respiratory failure due to diffuse alveolar hemorrhage: clinical characteristics and outcome of intensive care. J Crit Care. 2010;25(2):230-235.
34. Schwaiblmair M, Behr W, Haeckel T, et al. Drug induced interstitial lung disease. Open Respir Med J. 2012;6:63-74.
35. Epler GR. Drug-induced bronchiolitis obliterans organizing pneumonia. Clin Chest Med. 2004;25(1):89-94.
36. Desai KR, Burdette SD, Polenakovik HM. Ceftaroline-induced eosinophilic pneumonia. Pharmacotherapy. 2013;33(7):e166-e169.
37. Foral PA, Malesker MA, Dewan NA, et al. Drug-induced pulmonary disorders. US Pharm. 1999;24(7):HS3-HS19.
38. Marina VP, Malhotra D, Kaw D. Hydralazine-induced ANCA vasculitis with pulmonary renal syndrome: a rare clinical presentation. Int Urol Nephrol. 2012;44(6):1907-1909.
39. Agarwal G, Sultan G, Werner SL, Hura C. Hydralazine induces myeloperoxidase and proteinase 3 anti-neutrophil cytoplasmic antibody vasculitis and leads to pulmonary renal syndrome. Case Rep Nephrol. 2014;2014:868590.
40. Kelly D, O’Connell O, Henry M. Adalimumab-induced lupus serositis. BMJ Case Rep. 2015 Mar 4;2015.
41. Tamura M, Saraya T, Fujiwara M, et al. High-resolution computed tomography findings for patients with drug induced pulmonary toxicity, with special reference to hypersensitivity pneumonitis-like patterns in gemcitabine-induced cases. Oncologist. 2013;18(4):454-459.
42. Bossuyth L, Dooms-Goossens A. Contact sensitivity to nettles and chamomile in alternative remedies. Contact Derm. 1994;31(2):131-132.
43. Reider N, Sepp N, Fritsch P, et al. Anaphylaxis to chamomile: clinical features and cross sensitivity. Clin Exp Allergy. 2000;10:1436-1443.
44. Niggemann B, Gruber C. Side effects of contemporary and alternative medicine. Allergy. 2003;58(8):707-716.
45. Lee SK, Cho HK, Cho SH, et al. Occupational asthma and rhinitis caused by multiple herbal agents in a pharmacist. Ann Allergy Asthma Immunol. 2001;86:469-474.
46. Herbal medications. Herbal King. www.herbalmed.org. Accessed March 10, 2016.
47. Li M, Zhu L, Liu B, et al. Tea tree oil nanoemulsions for inhalation therapies of bacterial and fungal pneumonia. Colloid Surf Biointerfaces. 2016;141:408-416.
48. Megarbane B, Chevillard L. The large spectrum of pulmonary complications following illicit drug use: features and mechanisms. Chem Biol Interact. 2013;206:444-451.
49. Yadavilli R, Collins A, Ding WY, et al. Hospital readmissions with exacerbation of obstructive pulmonary disease in illicit drug smokers. Lung. 2014;192(5):669-673.
50. Sherman CB, Hudson LD, Pierson DJ. Severe precocious emphysema in intravenous methylphenidate (Ritalin) abusers. Chest. 1987;92(6):1085-1087.
51. Venkatanarasimha N, Rock B, Riordan RD, et al. Imaging of illicit drug use. Clin Radiol. 2010;65:1021-1030.
52. Wolff AJ, O’Donnell AE. Pulmonary effects of illicit drug use. Clin Chest Med. 2004;25:203-216.
53. Wurcel AG, Merchant EA, Clark RP, Stone DR. Emerging and unrecognized complications of illicit drug use. Clin Infect Dis. 2015;61(12):1840-1849.
54. Tomashefski JF, Felo JA. The pulmonary pathology of illicit drug and substance abuse. Curr Diagn Pathol. 2004;10:413-426.
55. Centers for Disease Control and Prevention. Current cigarette smoking among adults—United States, 2014. Morb Mortal Wkly Rep. www.cdc.gov/tobacco/data_statistics/fact_sheets/adult_data/cig_smoking/index.htm. Accessed March 10, 2016.
56. U.S. Preventive Services Task Force. Screening for Lung Cancer: Recommendation Statement. AHRQ publication. July 2015. www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/lung-cancer-screening. Accessed March 10, 2016.
57. U.S. Department of Health and Human Services. The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General. Atlanta, GA: CDC; 2014.
58. Cheng S, Mohammed LH. Diffuse smoking-related lung disease: emphysema and interstitial lung disease. Semin Roentgenol. 2014;50(1):16-22.
59. Boe DM, Vandivier RW, Burnham EL, Moss M. Alcohol abuse and pulmonary disease. J Leukoc Biol. 2009;86:1097-1104.
60. Vally H, Klerk N, Thompson PJ. Alcoholic drinks: important triggers for asthma. J Allergy Clin Immunol. 2000;105:462-467.
61. Sisson JH. Alcohol and airways function in health and disease. Alcohol. 2007;41(5):293-307.
62. Shimoda T, Kohno S, Takao A, et al. Investigation of the mechanism of alcohol-induced bronchial asthma. J Allergy Clin Immunol. 1996;97:74-84.
63. Kroon LA, Hudmon KS, Corelli RL. Smoking cessation. In: Berardi RR, Ferreri SP, Hume AL, et al, eds. Handbook of Nonprescription Drugs. 18th ed. Washington, DC: American Pharmacists Association; 2012.
64. Dulohery MM, Maldonado F, Limper AH. Chapter 71. Drug-induced pulmonary disease. In: Broaddus VC, Mason RJ, Ernst JD, eds. Murray and Nadel’s Textbook of Respiratory Medicine. 6th ed. Philadelphia, PA: Elsevier Saunders; 2016:1275-1294.

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