7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Pulmonary disease induced by cardiovascular drugs : Edward D Chan, MD, Talmadge E King, Jr, MD : Kevin R Flaherty, MD, MS : Paul Dieffenbach, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Aug 16, 2021. INTRODUCTION A number of cardiovascular drugs have the potential to cause respiratory impairment, although diffuse parenchymal lung disease is quite rare ( table 1A-B). Several different respiratory adverse effects have been identified: upper airway angioedema or hematoma, bronchoconstriction, cough, interstitial pneumonitis, organizing pneumonia, eosinophilic pneumonia, drug-induced lupus, acute respiratory distress syndrome, diffuse alveolar hemorrhage, pleuritis, pleural effusion, methemoglobinemia, and solitary lung mass. This topic review will provide an overview of the lung diseases induced by various cardiovascular drugs. The clinical manifestations, diagnosis, and management of pulmonary toxicity due to amiodarone and an approach to the diagnosis of interstitial lung disease are discussed separately. (See "Amiodarone pulmonary toxicity" and "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Approach to the adult with interstitial lung disease: Diagnostic testing".) AMIODARONE Pulmonary toxicity is a well-known adverse effect of the antiarrhythmic agent amiodarone. Several forms of pulmonary disease have been described, including interstitial pneumonitis, organizing pneumonia, acute respiratory distress syndrome (ARDS), diffuse alveolar hemorrhage (DAH), eosinophilic pneumonia, pulmonary nodules, solitary masses, and also (rarely) pleural https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 1/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate effusion. The clinical presentation, pathogenesis, diagnosis, and treatment of amiodarone pulmonary toxicity are discussed separately. (See "Amiodarone pulmonary toxicity".) ANGIOTENSIN CONVERTING ENZYME INHIBITORS Angiotensin converting enzyme (ACE) inhibitors are associated with cough, angioedema, and, rarely, pneumonitis. Cough All of the ACE inhibitors can induce a dry, persistent, and often nocturnal cough (in 5 to 20 percent of patients). The cough may develop within hours of the first dose or weeks to months later. It is more common in women, non-smokers, and persons of Chinese origin. The cough typically resolves one to four weeks after discontinuation of the ACE inhibitor but in a subgroup of coughers, resolution may take several months [1]. One important caveat is that cough may be a symptom of heart failure, and a thorough history and physical examination are needed to ascertain whether the cough is truly related to the ACE inhibitor therapy. (See "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers" and "Causes and epidemiology of subacute and chronic cough in adults".) Angioedema Angioedema, particularly of the oropharynx and larynx, complicates ACE inhibitor therapy in approximately 0.1 to 0.7 percent of recipients. Since ACE inhibitor- associated angioedema typically causes swelling of the mouth, lips, tongue, larynx, pharynx, and subglottic tissues, upper airway compromise may be the presenting sign. Pruritus and urticaria are typically absent. Unlike classical hereditary angioedema, C1 inhibitor level and function and thus the C4 levels are normal in ACE inhibitor-associated angioedema. (See "An overview of angioedema: Pathogenesis and causes", section on 'ACE inhibitors' and "ACE inhibitor-induced angioedema", section on 'Pathophysiology'.) Interstitial pneumonitis Captopril and perindopril have rarely been associated with the development of diffuse interstitial pneumonitis. An eosinophilic pneumonia was found in most cases, but an acute hypersensitivity pneumonitis with lymphocytic infiltration has been described [2-6]. The radiographic appearance is nonspecific, with bilateral patchy ground glass or consolidative opacities being the most frequent finding. The diagnosis is usually made on the basis of peripheral blood or bronchoalveolar lavage eosinophilia, exclusion of infection, and/or response to empiric drug discontinuation. Occasionally, a lung biopsy is needed. Therapy consists of drug withdrawal; occasionally systemic glucocorticoids have been used for patients with more severe respiratory impairment [5,6]. (See "Approach to the adult with interstitial lung disease: Diagnostic testing".) https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 2/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate ANGIOTENSIN RECEPTOR BLOCKERS The incidence of cough appears not to be increased with use of the angiotensin receptor blockers (ARB). Angiotensin receptor blockers (ARB) are associated with a low rate of angioedema (0.1 to 0.2 percent in large trials). However, the cross-reactivity with angiotensin converting enzyme (ACE) inhibitors is difficult to ascertain because of the phenomenon that patients with ACE inhibitor induced angioedema may continue to have episodes for weeks to months following discontinuation of the ACE inhibitor, which may overlap with initiation of the ARB. In a systematic review and meta-analysis of 11 randomized trials evaluating ARB in patients intolerant to ACE inhibitors, ARB had cough and angioedema incidences similar to placebo [7]. ANTICOAGULANT MEDICATIONS Use of anticoagulant and anti-platelet medications (vitamin K antagonists, glycoprotein IIB/IIIA antagonists) and thrombolytic agents in patients with coronary artery disease have been associated with diffuse alveolar hemorrhage (DAH) [8-23]. DAH has a similar presentation to pulmonary edema, so a high index of suspicion is needed, particularly when a patient with presumed pulmonary edema does not respond promptly to diuresis. The diagnosis and management of DAH are discussed separately. (See "The diffuse alveolar hemorrhage syndromes".) Rarely, spontaneous pharyngeal and laryngeal hematomas associated with warfarin anticoagulation have caused airway obstruction [24-26]. A few cases have been reported of interstitial pneumonitis due to ticlopidine and clopidogrel [27-30]. ASPIRIN In patients with aspirin-exacerbated respiratory disease (AERD) such as that seen with Samter's triad (asthma, nasal polyposis, and acute bronchoconstriction secondary to aspirin ingestion), ingestion of aspirin can result in acute bronchoconstriction. Some patients are able to tolerate 81 mg, but develop symptoms at 162 or 325 mg. Thus, AERD should be suspected in patients who develop dyspnea within three hours of initiation of aspirin therapy or an increase in the dose. Most patients will experience a combination of nasal congestion, rhinorrhea, wheezing, and dyspnea. Additional symptoms may include facial flushing/erythema, laryngospasm, abdominal cramps, epigastric pain, and hypotension. Bronchoconstriction is typically reversible https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 3/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate with an inhaled bronchodilator, which should be given promptly. Aspirin desensitization is an option for patients with AERD who require aspirin therapy; in addition, such protocolized desensitization has been shown to improve nasal-sinus and asthma symptoms in those with suboptimal control of their asthma [31]. When undertaking desensitization, premedication with a leukotriene-modifying agent such as montelukast is recommended. The protocol for aspirin desensitization is discussed separately. (See "Aspirin-exacerbated respiratory disease" and "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization", section on 'Challenge protocols and procedures'.) BETA BLOCKERS Beta blockers can exacerbate diseases of the airways (eg, chronic obstructive lung disease [COPD] and asthma) and the pulmonary vasculature (eg, portopulmonary hypertension). However, only rarely have they been associated with pleural or pulmonary parenchymal diseases, such as drug-induced lupus and interstitial pneumonitis. Asthma and COPD Beta-blocking medications are commonly used to treat hypertension, heart failure, and symptomatic coronary artery disease. However, beta-blocking medications that act on beta2 receptors can also cause bronchoconstriction. Since beta-adrenergic receptors of large and small airway smooth muscle are primarily the beta2 subtype, nonselective beta1/beta2 blockers (eg, propranolol) are more likely to cause bronchoconstriction in susceptible individuals [32]. In contrast, selective beta1-blockers (eg, atenolol, metoprolol) have a 20-fold greater affinity for beta1 adrenergic receptors than beta2 adrenergic receptors and, therefore, are less likely to induce bronchoconstriction. Studies of selective beta1-blockers are reassuring regarding their safety in patients with COPD, including those with a reversible component. In a meta-analysis that examined the effect of cardioselective beta-blockers given as a single dose or for longer duration, the beta1-blockers did not reduce the forced expiratory volume in one second (FEV ) or increase respiratory 1 symptoms compared with placebo, and beta1-blocker treatment did not reduce the improvement in FEV following inhaled beta2-agonists [33]. A subgroup analysis revealed no 1 change in results for those participants with severe chronic airways obstruction or for those with a reversible obstructive component. The benefits of using beta blockers, like any other drug, must be weighed on a case-by-case basis against the risk of side effects. Nonselective beta-blockers should be avoided in patients with asthma and used with caution in patients with an exacerbation of COPD. The use of selective beta1-blockers in patients who have COPD and a cardiovascular indication is discussed https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 4/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate separately. (See "Management of the patient with COPD and cardiovascular disease", section on 'Treatment of CVD in patients with COPD' and "Arrhythmias in COPD", section on 'Multifocal atrial tachycardia' and "Primary pharmacologic therapy for heart failure with reduced ejection fraction".) Portopulmonary hypertension Beta-blockers are used prophylactically to prevent variceal hemorrhage in patients with cirrhosis complicated by portal hypertension. However, in patients with cirrhosis and portopulmonary hypertension, beta blockers can cause worsening exercise capacity and increased pulmonary vascular resistance. (See "Primary prevention of bleeding from esophageal varices in patients with cirrhosis", section on 'Preventive strategies' and "Portopulmonary hypertension" and "Prevention of recurrent bleeding from esophageal varices in patients with cirrhosis".) Drug-induced lupus The development of anti-nuclear antibodies is not uncommon with beta- blocker use, but the incidence of a symptomatic lupus syndrome attributed to a beta-blocker is distinctly less common ( table 2) [34]. Beta-blocker induced lupus syndrome with pleuritis and pneumonitis has rarely been reported [35]. (See "Drug-induced lupus".) Interstitial lung disease Organizing pneumonia and eosinophilic pneumonia have rarely been reported with beta-blocking agents, such as sotalol and acebutolol [36-38]. As an example, migratory radiographic opacities were described in a patient on sotalol [36]. On lung biopsy, features of both organizing pneumonia and eosinophilic pneumonia were seen. Partial improvement was noted with addition of systemic glucocorticoids; complete recovery was seen only after sotalol was stopped. (See "Cryptogenic organizing pneumonia" and "Idiopathic acute eosinophilic pneumonia".) HYDRALAZINE Hydralazine, a vasodilating agent, is associated with drug-induced lupus (pleural and pericardial effusions), antineutrophil cytoplasmic antibody positive-pulmonary vasculitis, and diffuse alveolar hemorrhage [39]. (See "Drug-induced lupus", section on 'Causative drugs' and "Drug- induced lupus", section on 'Clinical spectrum of drug-induced lupus'.) MINOXIDIL Minoxidil is uncommonly used, mainly to treat recalcitrant hypertension. Fluid retention is a potential adverse effect of the drug. Minoxidil has been associated with the development of pericardial and pleural effusions, which may be exudative [40,41]. https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 5/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate NITRATES Overdoses of nitrate medications, such as intravenous infusions of nitroglycerin or nitroprusside, can cause methemoglobinemia. The clinical presentation may include dyspnea, respiratory depression, cyanosis, lethargy, altered consciousness, hypotension, and seizures. Measurement of oxygen saturation by a pulse oximeter may be inaccurate for assessing oxygen saturation as severe methemoglobinemia causes the SpO to trend towards 85 percent and thus 2 may either overestimate or underestimate the true arterial oxygen saturation (SaO ) as 2 measured by arterial blood gas analysis [42]. Methemoglobinemia is suspected when the arterial tension of oxygen (PaO ) is normal despite clinical cyanosis. The diagnosis is based upon 2 laboratory measurement of methemoglobin. (See "Methemoglobinemia", section on 'Evaluation and diagnosis (acquired/toxic)'.) PACLITAXEL-ELUTING STENTS Paclitaxel is an antineoplastic agent that can cause an interstitial pneumonitis when used to treat cancer. Paclitaxel has also been used to prevent restenosis after placement of coronary artery drug-eluting stents (DES), and case reports have described interstitial pneumonitis associated with these stents [43,44]. The onset of dyspnea, fever, and progressive respiratory insufficiency occurred within days of stent placement. Chest radiographs showed bilateral diffuse opacities. Due to the rarity of these events, the optimal management is not known. The three reported patients succumbed to progressive respiratory failure despite systemic glucocorticoid therapy [43,44]. Paclitaxel DES are rarely used due to the better performance of newer generation DES. (See "Taxane-induced pulmonary toxicity" and "Intracoronary stents: Stent types", section on 'Early-generation drug-eluting stents' and "Periprocedural complications of percutaneous coronary intervention", section on 'Hypersensitivity reactions'.) PROCAINAMIDE The antiarrhythmic agent procainamide is associated with drug-induced lupus, antiphospholipid antibody syndrome, interstitial pneumonitis, and respiratory muscle weakness. A number of extrapulmonary adverse effects are also associated with use of procainamide, including nonspecific systemic symptoms, blood dyscrasias, and cardiac toxicity. (See "Major side effects of class I antiarrhythmic drugs".) Use of procainamide is obviously decreasing with availability of more effective antiarrhythmics such as amiodarone. https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 6/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate Drug-induced lupus Procainamide can cause a syndrome of drug-induced lupus with protean clinical manifestations, including fever, arthralgia, rashes, myositis, vasculitis, serositis, and Raynaud phenomenon ( table 2) [45,46]. Respiratory system involvement includes pleuritis (pleural effusions and pleurisy) and, less commonly, diffuse parenchymal lung disease. (See "Drug-induced lupus".) Among patients with procainamide-induced lupus, pleuritis occurs in approximately half. While a high pleural fluid antinuclear antibody (ANA) may be seen in drug-induced lupus pleuritis, it lacks specificity and does not differentiate systemic lupus erythematosus (SLE) from drug-induced lupus. There are, however, a number of features that help to distinguish drug-induced lupus from SLE, including the general absence of renal and central nervous system disease with drug-induced lupus and the presence of anti-double stranded DNA antibodies and hypocomplementemia with SLE ( table 2). The clinical manifestations and diagnosis of drug-induced lupus are discussed separately. (See "Drug-induced lupus", section on 'Diagnostic approach' and "Pleural fluid analysis in adults with a pleural effusion".) One sensitive serologic indicator of drug-induced lupus is the presence of antibodies directed against the histone complex H2A-H2B [47]; the absence of this autoantibody essentially rules out drug-induced lupus. However, approximately 60 to 80 percent of patients with active spontaneous SLE also have this antibody. Thus, the presence of anti- histone antibodies does not discriminate between idiopathic SLE and drug-induced lupus. (See "Drug-induced lupus".) Antiphospholipid antibodies Antiphospholipid antibodies are also associated with procainamide, although the antiphospholipid antibody syndrome due to procainamide is rare [48,49]. Respiratory muscle weakness Procainamide may rarely have adverse effects on respiratory muscles by several mechanisms [50]. First, it can competitively block the acetylcholine receptor, thereby impairing neuromuscular transmission and causing postoperative apnea and/or a myasthenia gravis-like syndrome. Second, myositis has also been reported in association with drug-induced lupus and can impair respiratory muscle function. Lastly, procainamide may induce a myasthenic crisis in patients with underlying autoimmune myasthenia gravis [51]. QUINIDINE https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 7/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate The antiarrhythmic agent quinidine has been associated with drug-induced lupus, respiratory muscle weakness, acute pneumonitis, and diffuse alveolar hemorrhage (DAH) in case reports [50,52,53]. The incidence of drug-induced lupus is much lower than with procainamide, which may be explained by quinidine's lack of an amine group [54]. Similar to procainamide, the pulmonary manifestations associated with quinidine-induced lupus are primarily related to pleuritis [54]. (See 'Drug-induced lupus' above.) Quinidine can rarely cause a myasthenia gravis-like syndrome and has been shown to exacerbate autoimmune myasthenia gravis [50]. Two cases of DAH have been reported in patients with quinidine sulfate-induced thrombocytopenia [52,55]. STATINS Various statins have been associated with interstitial lung disease (fibrotic, eosinophilic, nonspecific) in case reports [56-58]. Onset of lung disease was 1 week to 10 years after initiation of statin therapy. Radiographic findings included ground glass, consolidative, and reticular opacities. While a case control study of patients with idiopathic pulmonary fibrosis (IPF) did not find an increased risk of IPF associated with statin use [59], this observation does not exclude the possibility of a drug-induced pneumonitis due to a statin medication. Conversely, a post hoc analysis of 624 patients randomized to placebo in three trials of pirfenidone in the treatment of IPF suggest that statins may have a beneficial effect on clinical outcomes in IPF [60]. Similarly, a potential beneficial effect on clinical outcomes has been found for patients taking a statin in trials of nintedanib for IPF [61]. A meta-analysis of randomized trials determining the clinical impacts of statin therapy on patients with pulmonary hypertension secondary to lung diseases (group 3) has suggested that statins might be safe and beneficial for patients with pulmonary arterial hypertension due to chronic lung diseases [62,63]. No prospective clinical trials have been performed to validate these findings. TOCAINIDE The anti-arrhythmic agent tocainide (no longer sold in the United States, limited availability elsewhere) has uncommonly been associated with an interstitial pneumonitis that develops after a few months of therapy [64-66]. Computed tomography (CT) typically shows septal thickening https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 8/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate and consolidative opacities [65]. The lung disease may be characterized initially by a neutrophilic alveolitis with organizing pneumonia; irreversible fibrosis may develop with continuing inflammation. In most cases, symptoms remit with discontinuation of therapy. However, progressive respiratory failure has been described in patients with advanced fibrosis despite discontinuation of tocainide [64]. Systemic glucocorticoids may hasten recovery in more severe disease. SUMMARY AND RECOMMENDATIONS A number of cardiovascular drugs have the potential to cause dyspnea, cough, and radiographic abnormalities, although the incidence of diffuse parenchymal lung disease associated with cardiovascular drugs is quite rare. Several different respiratory adverse effects have been identified: upper airway angioedema or hematoma, bronchoconstriction, cough, interstitial pneumonitis, organizing pneumonia, eosinophilic pneumonia, drug- induced lupus, acute respiratory distress syndrome, diffuse alveolar hemorrhage, pleuritis, pleural effusion, and solitary lung mass ( table 1A-B). (See 'Introduction' above.) Angiotensin converting enzyme (ACE) inhibitors are associated with cough, angioedema, and, rarely, pneumonitis. The cough is typically nonproductive, persistent, and often nocturnal (in 5 to 20 percent of patients) and frequently requires cessation of therapy. (See 'Angiotensin converting enzyme inhibitors' above and "Major side effects of angiotensin- converting enzyme inhibitors and angiotensin II receptor blockers".) Treatment of coronary artery disease with anticoagulant and anti-platelet medications (vitamin K antagonists, glycoprotein IIB/IIIA antagonists) and thrombolytic agents has been associated with diffuse alveolar hemorrhage (DAH). Rare cases of upper airway obstruction due to retropharyngeal or glottic hematoma have been reported. Clopidogrel and ticlopidine have infrequently been associated with interstitial pneumonitis. (See 'Anticoagulant medications' above.) Aspirin causes acute bronchoconstriction in patients with aspirin-exacerbated respiratory disease (triad of asthma, nasal polyps, acute bronchoconstriction due to aspirin). The dose of aspirin that provokes a reaction varies among patients; some patients are able to tolerate 81 mg, but develop symptoms at 162 or 325 mg. Aspirin desensitization, a protocol that may also help improve asthma symptoms, is an option for patients with AERD who require aspirin therapy. (See 'Aspirin' above and "Aspirin-exacerbated respiratory disease" and "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization".) https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 9/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate Nonselective beta1/beta2 blockers (eg, propranolol) can cause bronchoconstriction in susceptible individuals, but this effect is substantially less likely to occur with selective beta1 blockers (eg, atenolol, metoprolol). (See 'Beta blockers' above and "Management of the patient with COPD and cardiovascular disease".) Eosinophilic pneumonitis has rarely been found in patients taking ACE inhibitors, beta- blocker medications, and statins. Organizing pneumonia has been reported in association with amiodarone, beta-blocker medications, and tocainide. (See 'Amiodarone' above and 'Angiotensin converting enzyme inhibitors' above and 'Beta blockers' above and 'Statins' above and 'Tocainide' above.) Drug-induced lupus has been reported with beta-blocker medications, hydralazine, procainamide, and quinidine. The diagnosis of drug-induced lupus is based on the combination of clinical manifestations (eg, pleuropericarditis), serologic evaluation, and response to discontinuation of the implicated medication. Features that help to differentiate drug-induced lupus from systemic lupus erythematosus (SLE) are listed in the table ( table 2). The presence of anti-histone antibodies in the absence of other autoantibodies (eg, anti-double stranded DNA, anti-ribonucleoprotein, anti-Smith) strongly favors drug-induced lupus. (See 'Drug-induced lupus' above and 'Hydralazine' above and 'Procainamide' above and 'Quinidine' above and "Drug-induced lupus".) Procainamide and quinidine can cause respiratory muscle weakness by unmasking or exacerbating underlying myasthenia gravis. Rarely, a drug-induced myopathy has been reported; this effect is likely a manifestation of drug-induced lupus ( table 2). (See 'Procainamide' above and 'Quinidine' above.) Minoxidil is rarely associated with development of pleural and pericardial effusions. Overdoses of nitrates can cause methemoglobinemia. Statins, paclitaxel-eluting stents, and tocainide have been associated with pneumonitis in case reports. (See 'Minoxidil' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Dicpinigaitis PV. Angiotensin-converting enzyme inhibitor-induced cough: ACCP evidence- based clinical practice guidelines. Chest 2006; 129:169S. 2. Benard A, Melloni B, Gosselin B, et al. Perindopril-associated pneumonitis. Eur Respir J 1996; 9:1314. https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 10/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate 3. Kidney JC, O'Halloran DJ, FitzGerald MX. Captopril and lymphocytic alveolitis. BMJ 1989; 299:981. 4. Schatz PL, Mesologites D, Hyun J, et al. Captopril-induced hypersensitivity lung disease. An immune-complex-mediated phenomenon. Chest 1989; 95:685. 5. Slesnick TC, Mott AR, Fraser CD Jr, Chang AC. Captopril-induced pulmonary infiltrates with eosinophilia in an infant with congenital heart disease. Pediatr Cardiol 2005; 26:690. 6. Watanabe K, Nishimura K, Shiode M, et al. Captopril, an angiotensin-converting enzyme inhibitor, induced pulmonary infiltration with eosinophilia. Intern Med 1996; 35:142. 7. Caldeira D, David C, Sampaio C. Tolerability of angiotensin-receptor blockers in patients with intolerance to angiotensin-converting enzyme inhibitors: a systematic review and meta- analysis. Am J Cardiovasc Drugs 2012; 12:263. 8. Awadh N, Ronco JJ, Bernstein V, et al. Spontaneous pulmonary hemorrhage after thrombolytic therapy for acute myocardial infarction. Chest 1994; 106:1622. 9. Masip J, Vecilla F, P ez J. Diffuse pulmonary hemorrhage after fibrinolytic therapy for acute myocardial infarction. Int J Cardiol 1998; 63:95. 10. Ayyub M, Barlas S, Iqbal M, Khurshid SM. Diffuse alveolar hemorrhages and hemorrhagic pleural effusion after thrombolytic therapy with streptokinase for acute myocardial infarction. Saudi Med J 2003; 24:217. 11. Kilaru PK, Schweiger MJ, Kozman HA, Weil TR. Diffuse alveolar hemorrhage after clopidogrel use. J Invasive Cardiol 2001; 13:535. 12. Conley M, Patino G, Romick B, et al. Abciximab-induced alveolar hemorrhage after percutaneous coronary intervention. Can J Cardiol 2008; 24:149. 13. Mikkilineni H, Bruhl SR, Colyer WR, Pandya U. A retrospective analysis and case series of glycoprotein IIb/IIIa inhibitor associated diffuse alveolar hemorrhage: two case reports. Cases J 2009; 2:8553. 14. Waness A, Aldabbagh T, Harakati M. Diffuse alveolar haemorrhage secondary to warfarin therapy for atrial fibrillation: a case report and literature review. BMJ Case Rep 2009; 2009. 15. Uysal E, evik E, Solak S, et al. A life-threatening complication of warfarin therapy in ED: diffuse alveolar hemorrhage. Am J Emerg Med 2014; 32:690.e3. 16. Erdogan D, Kocaman O, Oflaz H, Goren T. Alveolar hemorrhage associated with warfarin therapy: a case report and literature review. Int J Cardiovasc Imaging 2004; 20:155. 17. Hanf W, Duntze J, Hida H, et al. [The implication of a direct antithrombine in the appearance of (serious) postoperative acute respiratory distress]. Ann Fr Anesth Reanim 2009; 28:885. https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 11/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate 18. Kim Y, Lim J, Lim J, et al. Pulmonary Alveolar Hemorrhage after Clopidogrel Use for ST Elevation Myocardial Infarction. Korean Circ J 2013; 43:497. 19. Ikeda M, Tanaka H, Sadamatsu K. Diffuse alveolar hemorrhage as a complication of dual antiplatelet therapy for acute coronary syndrome. Cardiovasc Revasc Med 2011; 12:407. 20. Guo J, Xu M, Xi Y. Tirofiban-induced diffuse alveolar hemorrhage: after primary angioplasty. Tex Heart Inst J 2012; 39:99. 21. Gill DS, Ng K, Ng KS. Massive pulmonary haemorrhage complicating the treatment of acute coronary syndrome. Heart 2004; 90:e15. 22. Kalra S, Bell MR, Rihal CS. Alveolar hemorrhage as a complication of treatment with abciximab. Chest 2001; 120:126. 23. Iskandar SB, Kasasbeh ES, Mechleb BK, et al. Alveolar hemorrhage: an underdiagnosed complication of treatment with glycoprotein IIb/IIIa inhibitors. J Interv Cardiol 2006; 19:356. 24. Ako lu E, Seyfeli E, Ako lu S, et al. Retropharyngeal hematoma as a complication of anticoagulation therapy. Ear Nose Throat J 2008; 87:156. 25. Sinert R, Scalea T. Retropharyngeal and bowel hematomas in an anticoagulated patient. Acad Emerg Med 1994; 1:67. 26. Chiti-Batelli S, Vaz F, Coman S. Traumatic retropharyngeal haematoma in an anticoagulated patient: Case report and proposal for a clinical protocol. Acta Otolaryngol 2005; 125:443. 27. Persoz CF, Cornella F, Kaeser P, Rochat T. Ticlopidine-induced interstitial pulmonary disease: a case report. Chest 2001; 119:1963. 28. Nakamura R, Imamura T, Onitsuka H, et al. Interstitial pneumonia induced by ticlopidine. Circ J 2002; 66:773. 29. Tamagaki G, Matsushita H, Suzumura T, et al. [A case of drug-induced pneumonia caused by clopidogrel]. Nihon Kokyuki Gakkai Zasshi 2010; 48:404. 30. Mizuno Y, Shimizu H, Yamashita M, et al. [A case of clopidogrel-induced eosinophilic pneumonia]. Nihon Kokyuki Gakkai Zasshi 2011; 49:838. 31. Berges-Gimeno MP, Simon RA, Stevenson DD. Long-term treatment with aspirin desensitization in asthmatic patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 2003; 111:180. 32. McGavin CR, Williams IP. The effects of oral propranolol and metoprolol on lung function and exercise performance in chronic airways obstruction. Br J Dis Chest 1978; 72:327. 33. Salpeter S, Ormiston T, Salpeter E. Cardioselective beta-blockers for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2005; :CD003566. https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 12/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate 34. Cody RJ Jr, Calabrese LH, Clough JD, et al. Development of antinuclear antibodies during acebutolol therapy. Clin Pharmacol Ther 1979; 25:800. 35. Record NB Jr. Acebutolol-induced pleuropulmonary lupus syndrome. Ann Intern Med 1981; 95:326. 36. Faller M, Quoix E, Popin E, et al. Migratory pulmonary infiltrates in a patient treated with sotalol. Eur Respir J 1997; 10:2159. 37. Camus P, Lombard JN, Perrichon M, et al. Bronchiolitis obliterans organising pneumonia in patients taking acebutolol or amiodarone. Thorax 1989; 44:711. 38. Markou N, Antzoulatos N, Haniotou A, et al. A case of drug-induced pneumonitis caused by carvedilol. Respiration 2004; 71:650. 39. Espinosa MC, Ding B, Choi K, et al. A simultaneous presentation of drug-induced lupus with drug-induced ANCA vasculitis secondary to hydralazine use in a patient with sarcoidosis. Proc (Bayl Univ Med Cent) 2019; 32:231. 40. Webb DB, Whale RJ. Pleuropericardial effusion associated with minoxidil administration. Postgrad Med J 1982; 58:319. 41. Siddiqui A, Ansari M, Shakil J, Chemitiganti R. Minoxidil-associated exudative pleural effusion. South Med J 2010; 103:458. 42. Chan ED, Chan MM, Chan MM. Pulse oximetry: understanding its basic principles facilitates appreciation of its limitations. Respir Med 2013; 107:789. 43. Kato K, Fukuda S, Fujimaki T, et al. Paclitaxel-induced interstitial pneumonia after drug- eluting stent implantation: report of a fatal case. Intern Med 2009; 48:911. 44. Fujimaki T, Kato K, Fukuda S, et al. Acute interstitial pneumonitis after implantation of paclitaxel-eluting stents: a report of two fatal cases. Int J Cardiol 2011; 148:e21. 45. Zitnik, RJ. Drug-induced lung disease: Antiarrhythmic agents. J Respir Dis 1996; 17:254. 46. Arnaud L, Mertz P, Gavand PE, et al. Drug-induced systemic lupus: revisiting the ever- changing spectrum of the disease using the WHO pharmacovigilance database. Ann Rheum Dis 2019; 78:504. 47. Totoritis MC, Tan EM, McNally EM, Rubin RL. Association of antibody to histone complex H2A-H2B with symptomatic procainamide-induced lupus. N Engl J Med 1988; 318:1431. 48. Merrill JT, Shen C, Gugnani M, et al. High prevalence of antiphospholipid antibodies in patients taking procainamide. J Rheumatol 1997; 24:1083. 49. Asherson RA, Zulman J, Hughes GR. Pulmonary thromboembolism associated with procainamide induced lupus syndrome and anticardiolipin antibodies. Ann Rheum Dis 1989; 48:232. https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 13/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate 50. Aldrich TK, Prezant DJ. Adverse effects of drugs on the respiratory muscles. Clin Chest Med 1990; 11:177. 51. Godley PJ, Morton TA, Karboski JA, Tami JA. Procainamide-induced myasthenic crisis. Ther Drug Monit 1990; 12:411. 52. Alperin JB, deGroot WJ, Cimo PL. Quinidine-induced thrombocytopenia with pulmonary hemorrhage. Arch Intern Med 1980; 140:266. 53. Poukkula A, P kk P. Quinidine-induced reversible pneumonitis. Chest 1994; 106:304. 54. McCormack GD, Barth WF. Quinidine induced lupus syndrome. Semin Arthritis Rheum 1985; 15:73. 55. LeBlanc KE. A second case of quinidine-induced thrombocytopenia with pulmonary hemorrhage. Arch Intern Med 1980; 140:1250. 56. Fern ndez AB, Karas RH, Alsheikh-Ali AA, Thompson PD. Statins and interstitial lung disease: a systematic review of the literature and of food and drug administration adverse event reports. Chest 2008; 134:824. 57. Liebhaber MI, Wright RS, Gelberg HJ, et al. Polymyalgia, hypersensitivity pneumonitis and other reactions in patients receiving HMG-CoA reductase inhibitors: a report of ten cases. Chest 1999; 115:886. 58. Lisco t-Loheac N, Andr N, Couturaud F, et al. [Hypersensitivity pneumonitis in a patient taking pravastatin]. Rev Mal Respir 2001; 18:426. 59. Ponnuswamy A, Manikandan R, Sabetpour A, et al. Association between ischaemic heart disease and interstitial lung disease: a case-control study. Respir Med 2009; 103:503. 60. Kreuter M, Bonella F, Maher TM, et al. Effect of statins on disease-related outcomes in patients with idiopathic pulmonary fibrosis. Thorax 2017; 72:148. 61. Kreuter M, Costabel U, Richeldi L, et al. Statin Therapy and Outcomes in Trials of Nintedanib in Idiopathic Pulmonary Fibrosis. Respiration 2018; 95:317. 62. Zhang MZ, Qian DH, Xu JC, et al. Statins may be beneficial for patients with pulmonary hypertension secondary to lung diseases. J Thorac Dis 2017; 9:2437. 63. Faraj R, Paine D, Black SM, Wang T. Anti-inflammatory Effects of Statins in Lung Vascular Pathology: From Basic Science to Clinical Trials. Adv Exp Med Biol 2021; 1303:33. 64. Feinberg L, Travis WD, Ferrans V, et al. Pulmonary fibrosis associated with tocainide: report of a case with literature review. Am Rev Respir Dis 1990; 141:505. 65. Stein MG, Demarco T, Gamsu G, et al. Computed tomography: pathologic correlation in lung disease due to tocainide. Am Rev Respir Dis 1988; 137:458. https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 14/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate 66. Van Natta B, Lazarus M, Li C. Irreversible interstitial pneumonitis associated with tocainide therapy. West J Med 1988; 149:91. Topic 4345 Version 23.0 https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 15/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate GRAPHICS Pulmonary complications of cardiovascular drugs Agent Syndrome Frequency Potential mechanism Procainamide SLE-like syndrome 50 to 90 percent of patients have positive Autoantibodies against histone H2A-H2B complex, potentially ANA test; 10 to 20 percent become symptomatic; pleuritis, pleural effusion, and parenchymal infiltrates are common induced by interaction of drug metabolites with DNA, or drug- induced alteration in T-cell DNA methylation Quinidine SLE-like syndrome Rare; pleuritis and pleural Autoantibodies against histone effusions are most common pulmonary signs; parenchymal infiltrates uncommon H2A-H2B complex, potentially induced by interaction of drug metabolites with DNA, or drug- induced alteration in T-cell DNA methylation Tocainide Pneumonitis/fibrosis Incidence is about 0.3 percent Unknown Flecainide Pneumonitis/fibrosis Rare Unknown Mexiletine Pneumonitis/fibrosis Rare Unknown; interferes with theophylline metabolism and can cause toxic elevations in theophylline levels in serum ACE inhibitors Cough Incidence is 5 to 15 percent; occurs with all Decreased degradation of irritant and bronchoconstrictive ACE inhibitors; whether these agents precipitate bronchospasm in patients with asthma is controversial mediators (bradykinin and substance P); direct increase in sensitivity to irritant-induced cough; genetic predisposition (based on differences in ACE gene). Angioneurotic Rare; can lead to Unknown edema respiratory failure Sotalol Bronchospasm Occurs in 2 percent of Direct blockage of 2-receptors patients Adenosine Bronchospasm Occurs with rapid Induction of mast cell mediator infusion in 5 to 10 percent of patients; may release https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 16/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate trigger acute bronchospasm in patients with asthma or COPD. Reversible with aminophylline Redrawn from Zitnik, RJ, J Respir Dis 1996; 17:254; and Zitnik, RJ, J Respir Dis 1996; 17:293. Graphic 54967 Version 1.0 https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 17/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate Pulmonary complications of cardiovascular drugs Potential mechanism Agent Syndrome Frequency Beta blockers Cough or bronchospasm Common; usually occurs in patients with asthma or COPD; 1-selective agents, labetalol, esmolol, and pindolol are better tolerated than nonselective agents Direct antagonism of 2 receptor-mediated bronchodilation