Nonsteroidal Anti-inflammatory Drugs: Safety, Toxicity, and Clinical Implications

1. Nonsteroidal Anti-inflammatory Drugs: Safety, Toxicity, and Clinical Implications Brett A. Roth, MD, FACEP, FACMT

2. The Need: Epidemiology • The most frequently prescribed agents in the world • Used by 30-50 million persons daily • 10-20% of persons >65 yo have a current prescription • 40% of elderly Medicaid patients received at least one NSAID prescription

3. Uses • Mild to Moderate Pain • Inflammation • Fever

4. Classification • Para-aminophenol derivatives • Acetaminophen, Phenacetin, Acetanilide • Salicylic acid derivatives • Acetylsalicylic acid, diflunisal, salsalate, etc. • Other Non-selective NSAIDs • Ibuprofen, Indomethacin, Sulindac,… • COX-2 inhibitors • Celecoxib, Rofecoxib, Meloxicam

5. Overview • Common denominator: • All NSAIDs inhibit cyclooxygenase (COX) • Differences: • Anti-inflammatory effects • COX selectivity • Toxicity • Cost • Drugs interactions

6. Mechanisms of Action • Steroids • Dec. production lipooxygenase / Cyclic Endoperoxides • NSAIDs • Dec. production prostaglandins/ prostacyclins/ thromboxane • LTRA • Act directly on leukotriene pathway

8. Toxicology: Acetaminophen

9. Acetaminophen Acute Toxicity • Toxic dose: • Minimal hepatotoxic dose 7.5 g in adults; >150 mg/kg body weight in children; severe toxicity possible if dose >20 g • Mechanism: • Toxicity depends on metabolism to an active metabolite (NAPQI) • Antidote: • N-acetylcysteine is universally effective if given within 8 hours • Epidemiology • 200 deaths/ yr in the US reported to AAPCC

11. Acetaminophen: Acute Toxicity

12. APAP: Acute Toxicity • Clinical Implications • Beware of the different products that may contain acetaminophen (analgesics, cold remedies, products for cramping) • Check serum APAP levels on all pts with acute overdose • Administer antidote within 10 hours prior to glutathione depletion if toxic

13. APAP: Susceptible Individuals • APAP Hepatotoxicity in Alcoholics: A Therapeutic Misadventure* • 25 cases accidental overdose. • 17/24 reported taking doses that exceeded the maximum recommended dose of 4.0 gm/d • Measurement of APAP levels not described for any patient Conclusion: Alcoholics may be more susceptible to overdose *Seef et al, 1986; Ann Inter Med, 104: 399-404

15. APAP: Susceptible Individuals • Alcoholics • 200 alcoholics admitted to Denver detoxification center • 1 gm APAP vs. placebo for four doses x2 days • Conclusion: alcoholic patients treated maximal therapeutic daily doses of acetaminophen did not develop evidence of hepatoxicity Kuffner E, et al Clin Tox 37; p 641 #143

16. APAP: Susceptible Individuals • Cirrhosis/ Hepatitis • Limited data • Two small studies*: • Recommended doses were not associated with hepatotoxicity • Down regulation of cytochrome p450; • Insufficient generation of reactive intermediate *Benson GD, Clin Pharmacol Ther 1983;33(1): 95-101 Jorup-Ronstrom, et al. Clin Pharmacokinet 1986;11(3):250-6

17. Chronic Liver Disease and Acetaminophen Benson et al. Pilot study in six subjects with advanced cirrhosis Benson et al, Clin Phar Ther, 1983,33(1) 95-101

18. Chronic Liver Disease and Acetaminophen Benson et al .20 pts assigned to either 4.0 gm of APAP daily or placebo for 13-d period. Benson et al, Clin Phar Ther, 1983,33(1) 95-101

20. APAP Toxicity:Susceptible Individuals

21. Acetaminophen Preparations • Acetaminophen drops (Tylenol, Anacin-3, Liquiprin, Panadol, or Tempra) • Strength: 80 mg per dropper • Acetaminophen syrup • Strength: 160 mg per 1.0 tsp (5.0 mL) • Chewable acetaminophen • Strength: 80 mg tablets and 160 mg tablets • Suppositories • Strength: 120 mg, 325 mg, and 650 mg

22. APAP: Chronic Toxicity • Analgesic nephropathy syndrome • Histopathology: • Papillary necrosis/ chronic interstitial nephritis • Mechanism: • Repetitive daily ingestion of compound analgesic mixtures Perneger et al. NEJM. 1994;331:1675-1579 Sandler et al. Ann Intern med 1991; 115:165-172

23. APAP: Renal Toxicity • Analgesic nephropathy syndrome • Acetaminophen may be involved but study results vary and most implicate phenacetin, and analgesic mixtures taken over years • National Kidney Foundation still recommends APAP as the non-narcotic analgesic of choice for episodic use in patients with underlying renal disease • Clinical Implication: • Supervise long-term analgesic use

24. Salicylate: Overdose • Toxic dose: • 150-200 mg/kg produce mild toxicity • 300-500 mg/kg produce severe intoxication • Mechanism: • Uncoupling oxidative phosphorylation and interruption of glucose and fatty acid metabolism • Antidote: • Sodium bicarbonate, multiple dose activated charcoal, hemodialysis

25. Salicylate: Overdose • Clinical Manifestations: • Acute ingestion: • Mixed respiratory alkalemia and metabolic acidosis, coma seizures, hypoglycemia, hyperthermia, pulmonary edema • Death: cardiovascular collapse, CNS failure • Chronic intoxication: • Young/ confused elderly, nonspecific presentation: confusion, dehydration, metabolic acidosis. High mortality (up to 25%), lower serum levels • Death: Cerebral and pulmonary edema

26. Salicylates: Acute Toxicity • Anaphylaxis • Clinical Scenario: • 25% of adult asthmatics with nasal polyps or chronic urticaria manifest an acute asthmatic attack minutes after NSAID exposure • 2.5% cross-reactivity noted in patients allergic to tartrazine dyes • Mechanism: • increased production of LTC4, LTD4, LTE4

27. Salicylate Exposure/ Overdose

28. NSAIDs: Acute Toxicity • Overdose • Clinical manifestations: N/V, metabolic acidosis, CNS and respiratory depression, acute renal failure, aseptic meningitis, hallucinations. • Toxic Dose: Generally large doses >6 gms • Villains: Phenylbutazone and mefenamic acid are considered the most toxic due to their ability to provoke all the above symptoms, as well as seizures • Mechanism of toxicity poorly understood

29. NSAID Overdose

30. NSAIDs: GI Toxicity • Prevalence of gastric and duodenal ulcers • 9-22% • Bleeding, perforation, or obstruction • 1/10 NSAID-induced peptic ulcer • GI bleeding • 35% of all peptic ulcer complications • Most common serious ADE in US • 10,000-20,000 deaths/year • Economic implications • 200,000-4000,000 hospitalizations each year in US • > $4 billion health care cost

31. NSAIDs- Epidemiology Singh G, et al. J Rheumatol 1999; 26:Suppl 26:18-24.

32. Mechanism of GI toxicity

33. 65 y Of Age Concomitant Corticosteroid Or Anticoagulant Use Previous History Of Ulcers Or GI Bleeds Risk Factors Alcohol Consumption Smoking Risk Factors For NSAID-Mediated GI Bleeding Piper et al. Ann Intern Med. 1991;114:735.Shorr et al. Arch Intern Med. 1993;153:1665. Silverstein et al. Ann Intern Med. 1995;123:241.

34. NSAIDs: Age as a risk factor Percent of NSAID users among patients hospitalized with bleeding peptic ulcers Somerville et al. Lancet 1986;1:462-464

35. Partial selectivity = GI toxicity / • Comparison of the toxicity of five NSAIDs at endoscopy • with the COX-2/COX-1 inhibition ratios Geis et al J Rheumatol 1991;18 suppl 28: 11-4 Vane et al Imporoved NSAIDs. Boston, Mass: Kluwer publisher

36. NSAIDs: GI Toxicity

37. Wolfe et al. NEJM;1999, 30(24)1888-1899

38. NSAIDs: Renal Toxicity • Epidemiology • 90% drug-induced toxicity caused by: aminoglycosides, contrast materials, or NSAIDs (15%) • 1-5% of patients taking NSAIDs develop a nephrotoxic syndrome • 20% of NSAID using pts are considered at risk because of underlying conditions.

39. NSAIDs: Acute Renal Toxicity

40. 65 y Of Age Concomitant Use Of Diuretics Or ACE Inhibitors Intrinsic Renal Disease Risk Factors Volume Depletion Hepatic Disease (cirrhosis) Congestive Heart Failure Risk Factors For NSAID-MediatedAdverse Renal Effects

41. NSAIDs: Acute Deterioration in Renal Function • Mechanism: inhibition of important vasodilatory PGs (PGI2, PGE2) • PGs become major factors in maintaining renal functions when circulating blood volume is reduced by hypotension or volume depletion, • Histopathology: Acute tubular necrosis • Cardinal Signs: • Elevated BUN/ Cr, K+, weight gain, oliguric or nonoliguric

42. NSAIDs: Acute Renal Toxicity

43. NSAIDs: Nephrotic Syndrome • Mechanism • Tubular inflammatory process through production of chemotactic-vasoactive leukotrienes. • Histopathology: • minimal change glomerulonephritis +/-interstitial nephritis • Cardinal signs: • edema, elevated creatinine, proteinuria after months of therapy • fever, drug rash, eosinophilia, and eosinophiluria are usually absent • Not seen with acetaminophen

44. NSAIDs: Papillary Necrosis • Acute Renal Papillary Necrosis • Typical candidate: overdose in a dehydrated individual with preexisting normal renal function • Chronic Renal Papillary Necrosis • Typical candidate: abuser of OTC combination analgesic products for 20 to 30 years (Analgesic Abuse Nephropathy) • Histopathology: • Ischemic necrosis due to extremely high local NSAID concentration in the renal papillae. • Cardinal Signs: • Colicky flank pain, Inc. BUN/ Cr, K+, diminished urine volume

45. NSAIDs: Renal Toxicity *National Kidney Foundation recommendation Henrich et al. Am J Kidney Dis 1996; 27:162

46. Selective COX-2 Inhibitors

47. The COX hypothesis • COX 1 • products are responsible for normal homeostasis • COX-2 • Products are responsible for modulating dynamic processes such as inflammation • Inhibition of COX-1  organ-specific toxicity • Selective Inhibition of COX-2 safe anti-inflammatory therapy

48. The COX hypothesis: COX-2 PAIN AND INFLAMATION COX-1 Gastric protection Renal function Platelet Activity

49. The COX Dichotomy

50. COX-2: Inducible “regulatory effects”