Dr. Mohammed Hussain Kamel MBBCH. MSC. MD. Ass.professor of chest disease Benha University. Drug induced airways diseases.
BackgroundMore than 600 drugs are known to cause pulmonary toxicity. This number will undoubtedly continue to increases as new therapeutic agents and illicit drugs are developed. Because the medications that cause respiratory diseases are used by a variety of healthcare providers, including generalists, specialists, and subspecialists, virtually no area of medicine is free from encounters of patients experiencing adverse drug reactions.To minimize the potential morbidity and mortality from drug – induced respiratory diseases, health care providers should be familiar with the possible adverse effects of the medications they prescribe, Recognition of drug – induced lung disease is difficult because the clinical, radiological, and histological findings are nonspecific. Instead, health care providers can make a correct diagnosis only if they are aware of the drugs that have been identified to cause pulmonary reactions and their specific manifestation. (Tamura M, et al, 2013).
Pathophysiology Medications can elicit a wide variety of thoracic tissue effects and responses. The adverse reactions can involve the pulmonary parenchyma, the pleura, the airways, the pulmonary vascular system, the mediastinum, and neuromuscular system. The clinical and histopathological entities reported as drug – induced pulmonary toxicities are listed below. (Tamura M, et al, 2013). Adverse reactions involving the airways are as follows: - Bronchospasm, bronchoconstriction, asthma. - Bronchiolitis obliterans. - Cough - Dysphonia or hoarseness. - Calcification of cartilaginous rings - Eosinophilic granulomatosis with polyangiitis (Churg- Strauss syndrome) - Cryptogenic organizing pneumonia. ( Tamura M, et al, 2013).
Mechanisms of pulmonary injury:Pulmonary toxicity secondary to drugs may be due to a variety of mechanisms, which are as follows oxidant injuryPulmonary vascular damage. Deposition of phospholipids within cells. Immune system- mediated injury. Central nervous system (CNS) depression. Direct toxic effect.(De Vuyst P, et al.1997).
Risk factors-Adveanced age. - Cumulative dose. - Simultaneous oxygen therapy. - Combination therapy. - Radiation therapy. - Occupational factors. - Underlying lung disease. - Genetic factors. (Hillerdal G, et al,1997).
Bronchospasm Anti – inflammatory drugs AspirinAspirin – induced asthma (AIA) occurs in less than 1% of healthy individuals and up to 20% of asthmatic individuals. The pathogensis of AlA is mediated by the production of potent inflammatory and bronchoconstrictor leukortiene (LT) mediatiors such as LTC4, LTD4 , and LTE4 via activation of the 5- lipoxygenase pathway. In addition to whezzing, reactions are usually accompanied by nasal and ocular sympthoms. Including congestion. Rhinorrhea, and tearing. Facial flushing, angioedema, and gastrointestinal symptoms can also occur. The Samter triad is asthama, nasal polyps, and aspirin sensitivity. The treatment of AIA is streroid therapy and discontinuation of aspirin and NSAIDs.Of elderly patients on long –term aspirin therapy, 10-15% develop NCPE. It usually occurs when the serum salysalate level is greater than 40 mg/dl. Treatment is usually supportive, but some patients require Hemo dialysis. Long – term salicylate ingestion can manifest as pseudoseptic syndrome (fever, tachycardia, elvated white blod cell count, hypotension, ARDS, and altered mental status). Elevated salicylate levels are Helpful in diagnosing this condition (Meune, et al., 2000).
Penicillamine Penicillamine is an anti- inflammatory agent mostly used in the treatment of rheumatoid arthristis. It can cause bronchiolitis obliterans, penicillamine - inuced systemic lupus erythmatosus, pulmonary – renal syndrome, and pneumonitis. Management includes withdrawal of the drug. Supportive therapy, and consideration of a trial of corticosteroids. In general, the prognosis is poor (Fisma et al.,2002).
Bronchospasm has also been reported with the use of the following agents: - inhaled pentamidine. - Amphotericin B . - Amiodarone - Angiotensin- converting enzyme (ACE) inhibitors. - Dipyridamole. - Nitrofurantion - Beta- blockers - Penicillamine. Because HIV infection is now better controlled and patients are treated for many years. Further study of antiretroviral therapy (ARVT) and lung function will determine whether bronchospasm reverses after cessation of ARVT. In one study of pulmonary function abnormalities in patients with HIV receiving ARVT. University analysis demonstrated the ARVT is a risk factor for airway obstruction unresponsive to bronchodilator treatment. With an odds ratio of 4.71. (Gingu et al., 2010).
ACE inhibitors : Up to 20% of patients develop a dry cough after talking ACE inhibitor. The exact mechanism of ACE inhibitor Cough is unknown. But it is thought to be linked to the accumulation of substances normally metabolized by ACEI Theses substances include bradykinin or tackykinins (with the consequent stimulation of vagal afferent nerve fibers) and substance P. Resolution of ACE inhibitor – induced cough usually occurs within 1-4 days but may take weeks to months. Patients can be switched to an Anegiotensine receptor blocker. Which rarely induces cough. Salindac has been reported to be benefit in the management of ACE inhibitor – induced cough. Studies have also suggested that intermediate doses of aspirin (500mg/d) , but not low doses (100mg/d), can suppress ACE inhibitor cough. Although ACE inhibitors are generally safe in most patients with obstructive airways disease, Case reports suggest that in a subpopulation of patients, these agents can increase bronchial reactivity, asthma symptoms, or exacerbations. Another symptom of ACEI therapy is angioneuotic edema (0.68% of patients). It manifests as swelling of the tongue. Lips, and mucous membranes within hours or weeks after initiating treatment and can rapidly evolve in to respiratory distress. This complication can be treated with a subcutaneous injection of epinephrine every 15-20 minutes, diphenhydramine, and steroid therapy.(Skotis et. al., 2004) .
Beta – Blockers Beta – blockers can precipitate bronchospasm in patients with asthma or chronic obstructive pulmonary disease (COPD). The benefits of using beta – blockers Like any other drug Must be weighed on a case – by – case basis against the risk of adverse effects. In patients with stable COPD or asthma, beta – blockers can be started at low doses, with careful monitoring for adverse effects, Because of its cardioselecitvity, atenolol is the drug of choice for an individual with obstructive airways disease who needs a beta – adrenergic antagonist. Esmolol is the drug of choice in critically ill patients with asthma or COPD who require a beta- blocker (unstable angina), owing to its beta 1 selectivity and extremely short half – life (9 min). Importantly, ophtalmic beta – blockers, such as timolol, which are used in the tratement of glaucoma have produces a number of deaths secondary to exacerbation of COPD and asthma. Betaxolol ophthalnmic may be a safer altermative to timolol (Dunn et al., 1986).
Cocaine Cocaine is one of the most frequently used illicit drugs in the United State. Inhalation of Cocaine may result in pneumomediastinum and pneumothorax. Smoking of cocaine is associated with the following effects. Acute exacerbations of asthma. Bronchiolitis obliterans. Cardiogenic pulmonary edema. NCPE. (Donnel et al.,1991).
Diagnosis : Correct identification of the drug, its dose, and its duration of administration. Exclusion of other primary or secondary lung diseases. Temporal eligibility – Appropriate latent period (exposure to toxicity). Recurrence with rechallenge (a practice not commonly performed). Singularity of drug (ie, other drugs the patient is taking). Remission of symptoms with removal of the drug. Characteristic pattern of reaction to a specific drug (perhaps previous documentation). Quantification of drug levels that confirm abnormal levels (especially for overdoses). Degree of certainty of drug reaction (ie, causative, probable, or possible) (Tamera et al., 2013). .
Management The treatment of drug – induced lung disease consists of immediately discontinuing the offending drug and appropriately managing the pulmonary symptoms. Acute episodes of drug – induced pulmonary disease ofen remit 24-48 hours after the drug has been discontinued. Chronic syndromes may take a month or months to resolve. General supportive measures include the following: Smoking cessation. Control of other chronic underlying lung disease. Prompt treatment of concomitant respiratory infections. Anecdotal reports indicate that glucocorticoid therapy has been associated with rapid improvement in gas exchange and reversal of radiographic abnormalities in some drug – induced pulmonary toxicities (Iry et al., 1976)
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