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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 Pulmonary fibrosis Rare Unknown Lupus-like syndrome Rare Unknown Hydralazine Lupus-like syndrome Renal disease more common than in other drug-induced lupus-like Unknown; slow acetylation may be a risk syndromes factor Dipyridamole Bronchospasm Occurs in about 0.15 percent of Induction of mast cell (IV form only) patients during infusion for stress testing mediator release Protamine Anaphylaxis, uritcaria, angioedema, bronchospasm Occurs in 0.2 percent of patients Unknown Pulmonary hypertension Mild pulmonary hypertension and systemic hypotension in up to 5 percent of patients; severe Antiprotamine antibodies; activated neutrophils; reaction rare thromboxane A2 generation Redrawn from Zitnik, RJ, J Respir Dis 1996; 17:254; and Zitnik, RJ, J Respir Dis 1996; 17:293. Graphic 69778 Version 1.0 https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 18/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate Features of spontaneous and drug-induced lupus Clinical feature Idiopathic SLE Drug-induced lupus Gender predisposition (F:M) 9:1 1:1 Acetylation type Slow = Fast Slow (described for hydralazine and procainamide) Symptom onset Gradual Abrupt Usual age 20 to 40 Drug-dependent, tends to be older population than idiopathic (>50)* Race All Less likely to occur in black patients Fever/malaise 40 to 85 percent 40 to 50 percent Arthralgias/arthritis 75 to 95 percent 80 to 95 percent Rash (all) 50 to 70 percent 10 to 30 percent Rash (discoid) 20 percent Rare Rash (malar/acute cutaneous) 42 percent 2 percent Raynaud's 35 to 50 percent <25 percent Pleuritis/pleural effusion 16 to 60 percent 10 to 50 percent (procainamide) Pulmonary infiltrates 0 to 10 percent 5 to 40 percent (procainamide) Pericarditis 6 to 45 percent 2 to 18 percent Hepatomegaly/splenomegaly 10 to 45 percent 5 to 25 percent Renal involvement 30 to 50 percent 0 to 5 percent CNS/neurologic involvement 25 to 70 percent 0 to 2 percent Hematologic Common Unusual Laboratory feature Idiopathic SLE Drug-induced lupus ANA 95 to 98 percent 95 to 100 percent Anti-dsDNA 50 to 80 percent <5 percent (rare) Anti-Smith 20 to 30 percent <5 percent (rare) Anti-RNP 40 to 50 percent 20 percent Anti-Ro/SS-A 30 to 40 percent Uncertain Anti-histone 60 to 80 percent 90 to 95 percent Low complement levels 40 to 65 percent Rare https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 19/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate Anemia 30 to 90 percent 0 to 46 percent Leukopenia 35 to 66 percent 2 to 33 percent Positive Coombs' test 18 to 65 percent 0 to 33 percent CNS: central nervous system; ANA: anti-nuclear antibody; LE: lupus erythematosus; RNP: ribonucleoprotein; dsDNA: double-stranded deoxyribonucleic acid. Minocycline-induced disease tends to occur in young females, consistent with greater use of the medication than other groups. Case reports of drug-induced discoid lupus with anti-TNF drug exposure. Insufficient data are available to provide an accurate estimate for (systemic) drug-induced lupus. The antibodies are present in 70 to 90 percent of patients with drug-induced subacute cutaneous lupus. Overall presence of anti-histone antibodies in drug-induced lupus; prevalence varies markedly between implicated drugs (may be less with minocycline or tumor necrosis factor inhibitors, and data are lacking for many agents). (Merola JF. Lupus-like syndromes related to drugs. In: Lupus Erythematosus: Clinical Evaluation and Treatment, Schur PH, Massarotti E. (Eds), Springer, New York, pp. 211-221). Most common with methyldopa exposure. Graphic 69467 Version 7.0 https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 20/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate Contributor Disclosures Edward D Chan, MD No relevant financial relationship(s) with ineligible companies to disclose. Talmadge E King, Jr, MD No relevant financial relationship(s) with ineligible companies to disclose. Kevin R Flaherty, MD, MS Grant/Research/Clinical Trial Support: Boehringer Ingelheim [IPF]. Consultant/Advisory Boards: Arrowhead [Interstitial lung disease]; AstraZeneca [Interstitial lung disease]; Bellerophon [Interstitial lung disease]; CSL Behring [Interstitial lung disease]; Daewong Pharmaceuticals [Interstitial lung disease]; DevPro [Interstitial lung disease]; Dispersol [Interstitial lung disease]; Fibrogen [Interstitial lung disease]; Horizon [Interstitial lung disease]; Immunmet [Interstitial lung disease]; Insilco [Interstitial lung disease]; Lupin [Interstitial lung disease]; NeRRe Therapeutics [Interstitial lung disease]; Pliant [Interstitial lung disease]; Polarean [Interstitial lung disease]; PureHealth [Interstitial lung disease]; PureTech [Interstitial lung disease]; Respivant [Interstitial lung disease]; Roche/Genentech [Interstitial lung disease]; Shionogi [Interstitial lung disease]; Sun Pharmaceuticals [Interstitial lung disease]; Trevi Pharmaceuticals [Interstitial lung disease]; United Therapeutics [Interstitial lung disease]; Vicore [Interstitial lung disease]. All of the relevant financial relationships listed have been mitigated. Paul Dieffenbach, MD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 21/21