Non Steroidal Anti Inflammatory Agent

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Contents 1 More Specific Terms 2 Introduction 3 Indications 4 Contraindications 5 Dosage 6 Pharmacokinetics 7 Monitor 8 Adverse-effects 9 Drug-interactions 10 Mechanism-of-action 11 More General Terms 12 Additional Terms 13 References

More Specific Terms

• amfenac
• bromfenac (Duract, Xibrom)
• cyclooxygenase-2 (COX-2) specific inhibitor
• diclofenac (Voltaren, Cataflam, Flector patch, Cambia, Pennsaid, Zipsor)
• diflunisal (Dolobid)
• etodolac (Lodine)
• exisulind; sulindac sulfone (Aptosyn)
• fenoprofen (Nalfon)
• flurbiprofen (Ansaid, Ocufen, Ropion, Flurofen)
• ibuprofen (Motrin, Advil, Nuprin, Rufen, NeoProfen, Caldolor)
• indomethacin (Indocin)
• ketoprofen (Orudis Oruvail)
• ketorolac (Toradol, Acular)
• meclofenamate (Meclomen)
• mefenamic acid (Ponstel)
• meloxicam (Mobic)
• metamizole; dipyrone (Busprina, Conmel, Dalmasin, Neo-Melubrina, Prolidina, Mexican aspirin)
• nabumetone (Relafen)
• naproxen (Naprosyn, Aleve Anaprox)
• nepafenac (Nevanac)
• NO aspirin (NCX-4016, nitric oxide releasing)
• oxaprozin (Daypro)
• phenylbutazone (Butazolidin)
• piroxicam (Feldene)
• salicylamide (Flarpirina)
• salicylate
• salsalate (Salflex, Disalcid, sasapyrine)
• sulfinpyrazone (Anturane)
• sulindac (Clinoril)
• suprofen (Profenal)
• tolmetin (Tolectin)

Introduction

• An aspirin-like drug that reduces pain & inflammation arising from injured tissue through inhibition of prostaglandin synthesis.

Indications

• reduction of pain & inflammation
• reduction of fever
• investigational treatment of Alzheimer's disease
• may reduce risk of colon cancer [5]; (see Nurses Health Study)
• may reduce risk of prostate cancer [5]

Contraindications

• Cautions:
• NSAIDs may cause severe asthma
• a triad of asthma, nasal polyposis & aspirin sensitivity shows cross-reactivity with other NSAIDs
• avoid in patients with:

• congestive heart failure [8]
• peptic ulcer disease
• renal insufficiency

Dosage

• (administration)
• see specific NSAID
• Guidelines for use [17] {based on expert opinion}

• patients with low GI & low cardiovascular risks should receive a non-specific NSAID
• patients with low GI & high cardiovascular risks should receive naproxen
• patients with high GI & low cardiovascular risks should receive a COX-2 inhibitor plus a proton-pump inhibitor
• patients with high GI & high cardiovascular risks should receive a careful assessment to prioritize risks
• NSAIDs should be prescribed at the lowest effective dose & for the shortest possible duration.

Pharmacokinetics

• NSAIDs bind extensively to plasma proteins

Monitor

• monitor blood pressure as hypertension can occur with NSAIDs
  
• monitor with non steroidal anti-inflammatory agents (NSIADs)

Adverse-effects

• gastrointestinal ( GI) intolerance

• NSAID gastropathy

• dyspepsia (may or may not be present)
• occult blood loss & iron deficiency anemia
• release of nitric oxide seems to protect against NSAID gastropathy [6]
• proton pump inhibitor provides symptomatic relief [13]

• NSAID enterocolopathy [12]

• renal

• reduced renal blood flow secondary to intrarenal vasoconstriction
• reduced glomerular filtration rate
• increased creatinine clearance
• pyuria
• interstitial nephritis
• papillary necrosis
• membranous nephropathy
• nephrotic syndrome
• hyperkalemia & type IV renal tubular acidosis ( RTA)
• hyponatremia
• fluid retention

• Na+ retention
• may exacerbate congestive heart failure ( CHF) [8]

• hepatic

• mild elevation in serum transaminases
• rarely associated with severe liver damage

• hematologic

• bone marrow suppression

• agranulocytosis
• aplastic anemia

• iron deficiency anemia
• platelet aggregating defect

• neurologic

• confusion & delirium
• headache
• dizziness
• blurred vision
• mood swings
• aseptic meningitis

• dermatologic

• urticaria
• erythema multiforme
• toxic epidermal necrolysis
• oral ulcers
• dermatitis

• pulmonary

• pulmonary infiltrates
• non- cardiac pulmonary edema
• bronchospasm

• anaphylaxis
• nasal polyps
• hyperkalemia via inhibition of aldosterone secretion
• gestational [4, 7]

• increased risk of miscarriage
• prolonged gestation & labor, increased bleeding
• fetal renal toxicity
• premature closure of ductus arteriosus

• cardiovascular risk

• increased risk of myocardial infaction [14] RR: 1.2-1.5 for use within 3 months of MI
• increased mortality & cardiovascular morbidity in patients with heart failure [16]
• risk allegedly lowest for naproxen [18,19]

• hypertension

• antagonism of beta-blockers & Ca+2 channel blockers
• on average, NSAIDs increase blood pressure ~5 mmHg in patients with hypertension [19]
  

• Overdose:

• manifestations:

• lethargy
• nausea/vomiting
• epigastric pain
• gastrointestinal hemorrhage

• management: supportive care
  
• drug adverse effects of NSAIDs

Drug-interactions

• NSAIDs enhance hemostatic effect of warfarin
• NSAIDs may attenuate antihypertensive effects of:

• diuretics
• beta blockers
• ACE inhibitors

• NSAIDs may enhance catabolism (elimination) of:

• methotrexate (high dose)
• lithium
• oral hypoglycemic agents

• NSAIDs in combination with ACE inhibitors increase risk of hyperkalemia
• NSAIDs may increase toxicity of diuretics [16]
  
• drug interaction(s) of lithium carbonate with NSAIDs
• drug interaction(s) of NSAIDs with SSRIs
• drug interaction(s) of aspirin with NSAIDs
• drug interaction(s) of NSAIDs with beta blockers
• drug interaction(s) of NSAIDs with ARBs
• drug interaction(s) of NSAIDs with ACE inhibitors
• drug interaction(s) of NSAIDs, diuretics & angiotensin II receptor antagonists
• drug interaction(s) of NSAIDs, diuretics & ACE inhibitors
• drug interaction(s) of NSAIDs & loop diuretics
• drug interaction(s) of NSAIDs & aspirin

Mechanism-of-action

• inhibition of cyclooxygenase, thus reducing formation of prostaglandins

• anti-inflammatory actions of NSAIDs are primarily due to cyclooxygenase-2 ( COX-2) inhibition
• toxic reactions are primarily due to inhibition of COX-1
• blocking of arachidonate to prostaglandins by NSAIDs increases substrate for conversion of arachidonate to lipoxygenase metabolites including leukotrienes

• inhibition of renal afferent arteriolar dilatation, thus diminishing renal blood flow & GFR
• inhibition of renin production

More General Terms

• anti-inflammatory agent
• analgesic (antalgic)
• antipyretic agent
• enzyme inhibitor

Additional Terms

• cyclooxygenase (prostaglandin endoperoxide synthase, COX)
• investigational therapies for treatment of Alzheimer's disease
• NSAID enterocolopathy
• NSAID gastropathy

References

1. Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 792
2. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 14, 598, 853
3. Medical Knowledge Self Assessment Program (MKSAP) 11, American College of Physicians, Philadelphia 1998
4. Prescriber's Letter 8(3):14 2001
5. Prescriber's Letter 9(5):29 2002
6. Journal Watch 23(8):63, 2003 Fiorucci S et al Gastrointestinal safety of NO-aspirin (NCX-4016) in healthy human volunteers: a proof of concept endoscopic study. Gastroenterology 124:600, 2003 PMID: [1]
   - Peura DA Mandate to modify a medicinal mantra: maybe not yet? Gastroenterology 124:842, 2003 PMID: [2]
7. Prescriber's Letter 10(10):58 2003
8. Journal Watch 24(14):109, 2004 Mamdani M, Juurlink DN, Lee DS, Rochon PA, Kopp A, Naglie G, Austin PC, Laupacis A, Stukel TA. Cyclo-oxygenase-2 inhibitors versus non-selective non-steroidal anti-inflammatory drugs and congestive heart failure outcomes in elderly patients: a population-based cohort study. Lancet. 2004 May 29;363(9423):1751-6. PMID: [3]
9. Prescriber's Letter 12(2): 2005 Update on the Safety and Use of COX-2 Inhibitors and Traditional NSAIDs Detail-Document#: [4] (subscription needed) [5]
10. Prescriber's Letter 12(5): 2005 FDA Announces Important Changes and Additional Warnings for COX-2s and NSAIDs Detail-Document#: [6] (subscription needed) [7]
11. FDA MedWatch COX-2 Selective (includes Bextra, Celebrex, and Vioxx) and Non-Selective Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) [8]
12. Journal Watch 25(13):102, 2005 Maiden L, Thjodleifsson B, Theodors A, Gonzalez J, Bjarnason I. A quantitative analysis of NSAID-induced small bowel pathology by capsule enteroscopy. Gastroenterology. 2005 May;128(5):1172-8. PMID: [9]
13. Journal Watch 25(13):102, 2005 Hawkey C, Talley NJ, Yeomans ND, Jones R, Sung JJ, Langstrom G, Naesdal J, Scheiman JM; NASA1 SPACE1 Study Group. Improvements with esomeprazole in patients with upper gastrointestinal symptoms taking non-steroidal antiinflammatory drugs, including selective COX-2 inhibitors. Am J Gastroenterol. 2005 May;100(5):1028-36. PMID: [10]
14. Journal Watch 25(16):126, 2005
    - Hippisley-Cox J, Coupland C. Risk of myocardial infarction in patients taking cyclo- oxygenase-2 inhibitors or conventional non-steroidal anti- inflammatory drugs: population based nested case-control analysis. BMJ. 2005 Jun 11;330(7504):1366. <PubMed> PMID: [11] <Internet> [12]
15. Prescriber's Letter 12(9): 2005 Non-narcotic Analgesics and the Risk of Hypertension in Women Detail-Document#: [13] (subscription needed) [14]
16. Gislason GH et al Increased mortality and cardiovascular morbidity associated with the use of nonsteroidal anti-inflammatory drugs in chronic heart failure. Arch Intern Med 2009 Jan 26; 169:141. PMID: [15]
17. Rostom A et al. Canadian consensus guidelines on long-term nonsteroidal anti-inflammatory drug therapy and the need for gastroprotection: Benefits versus risks. Aliment Pharmacol Ther 2009 Mar 1; 29:481. PMID: [16]
18. Prescriber's Letter 17(8): 2010 Managing NSAID Risks Detail-Document#: [17] (subscription needed) [18]
19. Prescriber's Letter 18(12): 2011 NSAIDs and Hypertension Detail-Document#: [19] (subscription needed) [20]
20. NSAIDs and Peptic Ulcers [21]
21. National Guideline Clearinghouse Use of nonsteroidal antiinflammatory drugs: an update for clinicians. A scientific statement from the American Heart Association. ngc-guideline: [22]

non-steroidal anti-inflammatory agent (NSAID)