1. Chapter 71
Cyclooxygenase Inhibitors: Nonsteroidal Anti-Inflammatory Drugs and Acetaminophen 1

2. Cyclooxygenase Inhibitors
Uses
Suppress inflammation
Relieve pain
Reduce fever
Adverse effects
Gastric ulceration
Bleeding
Renal impairment 2

3. Classification of Cyclooxygenase Inhibitors
Drugs with anti-inflammatory properties
NSAIDs (nonsteroidal anti-inflammatory drugs)
Aspirin, celecoxib, ibuprofen, and naproxen
Drugs without anti-inflammatory properties
Acetaminophen 3

4. First-Generation NSAIDs (aspirin, -profen drugs, naproxyn)
Inhibit COX-1 and COX-2
Used to treat inflammatory disorders (rheumatoid arthritis, osteoarthritis, bursitis)
Alleviate mild to moderate pain
Suppress fever
Relieve dysmenorrhea
Suppress inflammation but have risk of serious harm 4

5. Aspirin Nonselective inhibitor of cyclooxygenase
Irreversible inhibitor of cyclooxygenase (effects last 7 days)
Therapeutic uses
Analgesic, antipyretic, anti-inflammatory
Suppression of platelet aggregation (aspirin is unique for this benefit)
Protects in thrombotic disorders
Dysmenorrhea
Cancer prevention
Prevention of Alzheimer’s disease 5

6. Aspirin Adverse effects Gastrointestinal effects Bleeding
Renal impairment (watch BUN/creatinine, urine output, increasing signs/symptoms of fluid overload esp. in older patients with risk factors)
Salicylism
Reye’s syndrome (avoid in children)
Pregnancy
Anemia, postpartum hemorrhage, may prolong labor, also premature closure of ductus arterious in fetus)
Hypersensitivity reaction- can be very serious, treat with epinephrine 6

7. Aspirin Drug interactions Acute poisonings
Anticoagulants: warfarin and heparin
Glucocorticoids- gastritis
Alcohol- gastritis, bleeding
Ibuprofen –
ACE inhibitors and ARBs- renal impairment
Acute poisonings 7

8. Nonaspirin First-Generation NSAIDs (-profens, naproxyn, ketorolac)
Aspirin-like drugs with fewer GI, renal, and hemorrhagic effects than aspirin
20+ nonaspirin NSAIDs available (all similar, but for unknown reasons, patients tend to do better on one drug or another)
Inhibit COX-1 and COX-2: inhibition is reversible (unlike with aspirin)
Principal indications: rheumatoid arthritis and osteoarthritis, also preferred over aspirin for dysmenorrhea
Do not protect against myocardial infarction (MI) and stroke 8

9. First-Generation NSAIDs
Ibuprofen (Advil, Motrin)
Fenoprofen
Flurbiprofen
Ketoprofen (powerful analgesic, often used post-op, for short-term management of moderate to severe pain, not to exceed 5 days)
Naproxen 9

10. First-Generation NSAIDs
Diclofenac
Diclofenac plus misoprostol
Diflunisal
Etodolac
Indomethacin
Ketorolac
Mefenamic acid
Meclofenamate 10

11. Second-Generation NSAIDs (celecoxib)
Just as effective as traditional NSAIDs in suppressing inflammation and pain
Somewhat lower risk for GI side effects
Can impair renal function and cause hypertension and edema
Increase risks for MI and stroke
In 2005, two coxibs withdrawn from use: rofecoxib (Vioxx) and valdecoxib (Bextra)
Use of celecoxib has sharply declined 11

12. Celecoxib (Celebrex)
Second-generation COX-2 inhibitor—fewer adverse effects than first-generation drugs
Because of cardiovascular risks, last-choice drug for long-term management of pain
Uses
Osteoarthritis
Rheumatoid arthritis
Acute pain
Dysmenorrhea
Familial adenomatous polyposis 12

13. Celecoxib (Celebrex) Adverse effects Dyspepsia Abdominal pain
Renal toxicity
Sulfonamide allergy
Cardiovascular impact (stroke, MI, and other serious events)
Use in pregnancy 13

14. Celecoxib (Celebrex) Drug interactions Warfarin
May decrease diuretic effect of furosemide
May decrease antihypertensive effect of ACE inhibitors
May increase levels of lithium
Levels of celecoxib may be increased by fluconazole 14

15. Acetaminophen (Tylenol)
Therapeutic uses
Analgesic, antipyretic
Does not have any anti-inflammatory or antirheumatic actions
Not associated with Reye’s syndrome
Action
Inhibits prostaglandin synthesis in central nervous system 15

16. Acetaminophen (Tylenol)
Adverse effects
Very few at normal doses (has minimal effects at peripheral sites, acts on cyclooxygenase in the CNS)
Hepatotoxicity
With overdose or in patients with liver failure
Overdose: hepatic necrosis
Signs and symptoms of hepatic failure, coma, death
Early symptoms: nausea and vomiting, diarrhea, sweating, abdominal pain
Treatment for overdose: acetylcysteine (Mucomyst) 16

17. Acetaminophen (Tylenol)
Drug interactions
Alcohol
Warfarin 17

18. AHA Statement on COX Inhibitors
Most COX inhibitors, especially COX-2 inhibitors, increase the risk for MI and stroke
American Heart Association (AHA) recommends a stepped-care approach
AHA = American Heart Association. 18