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drug adverse effects of NSAIDs

Etiology: Risk factors for adverse effects [3] 1) age > 60 years 2) history of gastritis or peptic ulcer 3) history of alcohol abuse 4) history of kidney disease 5) history of chronic systemic illness a) diabetes mellitus b) rheumatoid arthritis c) others 6) history of cardiovascular disease 7) history of hypertension 8) Helicobacter pylori infection 9) use of NSAID at maximal dose 10) concurrent use of multiple NSAIDs 11) coadministration of glucocorticoid 12) coadministration of anticoagulant Adverse effects: 1) gastrointestinal (GI) intolerance a) NSAID gastropathy 1] dyspepsia (may or may not be present) 2] occult blood loss & iron deficiency anemia 3] release of nitric oxide seems to protect against NSAID gastropathy [6] 4] concurrent proton-pump inhibitor diminishes risk [13] b) peptic ulcer 1] 25% of NSAID users 2] may be asymptomatic [3] 3] risk factors a] age > 65 years b] high-dose NSAID c] concurrent use of low-dose aspirin, anticoagulants, or glucocorticoids d] history of peptic ulcer [3] 4] standard dose proton pump inhibitors are 1st line for prevention of NSAID-related peptic ulcers [3] 5] combining COX-2 inhibitor with proton pump inhibitor is the most effective strategy to reduce the risk of peptic ulcer complications [33] c) gastroesophageal reflux [3] d) NSAID enterocolopathy - diarrhea [47] - chronic blood loss & iron-deficiency anemia [47] - worsening of inflammatory bowel disease [47] - small increase in risk of inflammatory bowel disease - 6-7 additional cases per 100,000 person-years - exception is aspirin [24] e) nausea/vomiting f) constipation 2) renal (NSAID nephropathy) a) reduced renal blood flow secondary to intrarenal vasoconstriction - most frequently occurs in patients with volume depletion, heart failure, cirrhosis b) reduced glomerular filtration rate - NSAID use by older adults (mean age, 74 years) is not associated with a decline in glomerular filtration rate or an increase in albuminuria [43] c) pyuria d) allergic interstitial nephritis* e) papillary necrosis, acute tubular necrosis f) membranous nephropathy g) nephrotic syndrome - minimal change glomerulonephropathy [41] h) hyperkalemia & type IV renal tubular acidosis (RTA) i) hyperkalemia via inhibition of renin synthesis & aldosterone secretion resulting in hyporeninemic hypoaldosteronism [3] j) hyponatremia k) fluid retention - Na+ retention - may exacerbate congestive heart failure (CHF) [4,34] l) hypertension m) excess cases of acute & chronic kidney disease in young adults, ~50 excess cases per 100,000 people annually [39] 3) hepatic a) mild elevation in serum transaminases b) rarely associated with severe liver damage 4) hematologic a) bone marrow suppression 1] agranulocytosis 2] aplastic anemia 3] thrombocytopenia [45] b) hemorrhage - NSAIDs are associated with increased risks for bleeding & thromboembolism in patients with atrial fibrillation [30] - increased risk with or without anticoagulation [30] - NSAIDs not associated with postoperative bleeding [44] c) iron deficiency anemia - a decrease in blood hemoglobin of > 2 g/dL - 1.9-2.0% of patients treated with celecoxib - 3.3-5.7% of patients treated with diclofenac [23] d) platelet aggregating defect 5) neurologic a) confusion & delirium b) headache c) dizziness d) blurred vision e) mood swings f) aseptic meningitis 6) dermatologic a) urticaria b) erythema multiforme c) toxic epidermal necrolysis d) oral ulcers e) dermatitis 7) pulmonary a) pulmonary infiltrates b) non-cardiac pulmonary edema c) bronchospasm, exacerbation of asthma 8) cardiovascular a) peripheral edema b) increased risk of heart failure - increased mortality & cardiovascular morbidity in patients with heart failure [8] - NSAIDS may increase salt & water retention & in the setting of compensated heart failure, can lead to decompensated heart failure [34] - increased risk for heart failure hospitalization [35] - NSAID use increases risk of first hospitalization for heart failure in patients with diabetes mellitus type 2 [46] - older age, higher hemoglobin A1c & new NSAID used increases susceptibility [46] c) hypertension - antagonism of beta-blockers & Ca+2 channel blockers - on average, NSAIDs increase blood pressure ~5 mmHg in patients with hypertension [28] - RR= 1.38 with frequent use [4,12]; RR=1.26 with aspirin) d) increased risk of heart attack or stroke [32] e) increased risk of myocardial infarction [7] - RR: 1.2-1.5 for use within 3 months of MI - risk begins to appear within 1st week of use [21,37] f) increased mortality after myocardial infarction - may be due to inhibition of COX-2 mediated prostacylin formation - relative risk, see below g) high-dose NSAIDs including COX-2 inhibitors is associated with increased cardiovascular risk - exception is naproxen [26] h) use of high-dose* NSAID after acute myocardial infarction is associated with increased risk of mortality (during time patient is taking NSAID) - risk greater for COX2 inhibitors [9,26] i) nonselective agents with COX-1 > COX-2 inhibition not associated with increased cardiovascular risk in women [31] j) risk allegedly lowest for naproxen [20] - naproxen is associated with increased cardiovascular risk in women (RR=1.22) [31] - naproxen alone among NSAIDs not associated with increased risk of myocardial infarction [38] 9) anaphylaxis [29] 10) nasal polyps 12) gestational [4, 7] a) increased risk of miscarriage [22] - no increase in risk [27] - indomethacin may be exception [27] b) prolonged gestation, delayed labor, increased bleeding c) fetal renal toxicity leading to low levels of amniotic fluid [42] d) premature closure of ductus arteriosus after 30 weeks [3] 13) tinnitus [45] - increased risk of hearing loss in women (RR=1.1) [36] * 10 days of NSAID therapy prior to interstitial nephritis [15] Overdose: 1) manifestations: a) lethargy b) nausea/vomiting c) epigastric pain d) gastrointestinal hemorrhage 2) management: supportive care NSAID Dose Relative risk of death Rofecoxib high-dose* 5.0 Rofecoxib low-dose 2.2 Celecoxib high-dose# 4.2 Celecoxib low-dose 1.7 Diclofenac high-dose 3.8 Diclofenac low-dose 0.7 Ibuprofen high-dose 2.0 Ibuprofen low-dose 0.7 Naproxen high-dose 1.0 Naproxen low-dose 1.0 $ * Rofecoxib (high-dose) 25 mg/day # Celecoxib high-dose 200 mg/day $ No increased risk for naproxen [11] gastrointestinal effects (cont) [10] 1) Ulcerations of the a) stomach b) duodenum c) jejunum d) ileum e) colon 2) inflammation, strictures & perforation of the small bowel a) a 2 week course of slow-release diclofenac 75 mg PO BID results in small bowel lesion in 68% of subjects b) mucosal breaks (40%) c) petechiae (33%) d) blood in small bowel lumen (8%) 3) relative risks of upper GI bleed (vs no NSAID) a) NSAID in general: 4.5 b) celecoxib: 1.4 c) rofecoxib: 2.1 d) ibuprofen: 2.7 e) diclofenac: 4/0 f) meloxicam: 2.7 g) indomethacin: 5.3 h) naproxen: 5.6 i) ketoprofen: 5.6 j) piroxicam: 9.9 k) ketorolac 14.5 [19]

Properties

DRUGS: non-steroidal anti-inflammatory agent FORM: drug adverse effects non steroidal anti inflammatory agent

References

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