NSAIDs review

1. Nonsteroidal Anti-
inflammatory Drugs (NSAIDs)
• Common therapeutic indications
• Common adverse effects
• Different pharmacokinetics and potency
• Different chemical families
• Common mechanism of action (cyclooxygenase
inhibition)
• Different selectivities to COX I and II
Similarities more striking than Differences

4. Common Pharmacological
Effects
• Analgesic (CNS and peripheral effect) may
involve non-PG related effects
• Antipyretic (CNS effect)
• Anti-inflammatory (except acetaminophen) due
mainly to PG inhibition.
Some shown to inhibit activation, aggregation, adhesion
of neutrophils & release of lysosomal enzymes
• Some are Uricosuric

5. Common Adverse Effects
• Platelet Dysfunction
• Gastritis and peptic ulceration with bleeding
(inhibition of PG + other effects)
• Acute Renal Failure in susceptible
• Sodium+ water retention and edema
• Analgesic nephropathy
• Prolongation of gestation and inhibition of
labor.
• Hypersenstivity (not immunologic but due to
PG inhibition)

6. NSAID
↑ Leukocyte-Endothelial
Interactions
Capillary
Obstruction
Ischemic
Cell Injury
Proteases +
Oxygen Radicals
Endo/Epithelial
Cell Injury
Mucosal Ulceration
Loss of PGI2 induced inhibition of LTB4 mediated
endothelial adhesion and activation of neutrophils

7. The Salicylates - Aspirin
• Effect on Respiration: triphasic
1. Low doses: uncoupling phosphorylation → ↑
CO2 → stimulates respiration.
2. Direct stimulation of respiratory center →
Hyperventilation → resp. alkalosis → renal
compensation
3. Depression of respiratory center and
cardiovascular center → ↓ BP, respiratory
acidosis, no compensation + metabolic
acidosis also

8. • GI system
1. Dose dependent hepatitis
2. Reye’s syndrome
• Metabolic
1. Uncoupling of Oxid. Phosphorylation
2. Hyperglycemia and depletion of muscle and
hepatic glycogen
• Endocrine: corticosteroids, thyroid
Aspirin

9. • Antipyretic, analgesic
• Anti-inflammatory: rheumatic fever,
rheumatoid arthritis, other rheumatological
diseases. High dose needed (5-8 g/day)
• Prophylaxis of diseases due to platelet
aggregation (CAD, post-op DVT)
• Pre-eclampsia and hypertension of pregnancy
(?excess TXA2)
Aspirin - Therapeutic Uses

10. Generation of Lipoxins by Aspirin

11. Role of Lipoxins in Anti-inflammatory effects of Aspirin

12. Effect of NSAID’s on Platelet-Endothelial Interactions

13. Use of Aspirin in Unstable Angina

14. Use of Aspirin in Unstable Angina

15. • Headache - timmitus - dizziness – hearing
impairment – dim vision
• Confusion and drowziness
• Sweating and hyperventilation
• Nausea, vomiting
• Marked acid-base disturbances
• Hyperpyrexia
• Dehydration
• Cardiovascular and respiratory collapse, coma
convulsions and death
Aspirin Toxicity - Salicylism

16. • Decrease absorption - activated charcoal,
emetics, gastric lavage
• Enhance excretion - alkalinize urine,
forced diuresis, hemodialysis
• Supportive measures - fluids, decrease
temperature, bicarbonate, electrolytes,
glucose, etc…
Aspirin Toxicity - Treatment

17. Other NSAID’s
• Phenylbutazone: additional uricosuric effect.
Aplastic anemia.
• Indomethacin: Common ADR’s. CNS most
common: halucinations, depression, seizures
• Propionic acids: better tolerated. Differ in
pharmacokinetics
• Acetaminophen: differes in effects and ADR’s
from rest. Main toxicity: hepatitis due to toxic
intermediate which depletes glutathione. Treat
with N-acetylcysteine.

19. Attempts to
Decrease
Toxicity of
NSAID’s –
Nitroaspirins

21. Selective COX-II Inhibitors
• Anti-inflammatory with less adverse
effects, especially GI events.
• Potential toxicities: kidney and
platelets - ? increased risk of
thrombotic events
• Role in Cancer prevention
• Role in Alzheimer’s disease

22. VIGOR - Summary of GI Endpoints
†p < 0.001. * p = 0.005.
0
1
2
3
4
5
Confirmed Clinical
Upper GI Events
Confirmed
Complicated
Upper GI Events
All Clinical
GI Bleeding
RR: 0.46†
(0.33, 0.64)
RR: 0.43*
(0.24, 0.78)
RR: 0.38†
(0.25, 0.57)
Rates
per
100
Patient-Years
Rofecoxib
Naproxen
( ) = 95% CI.
Source: Bombardier, et al. N Engl J Med. 2000.

23. Patients with Events (Rates per 100 Patient-Years)
Event Category
Rofecoxib
N=4047
Naproxen
N=4029
Relative Risk
(95% CI)
Confirmed
CV events
45 (1.7) 19 (0.7) 0.42
(0.25, 0.72)
Cardiac
events
28 (1.0) 10 (0.4) 0.36
(0.17, 0.74)
Cerebrovascular
events
11 (0.4) 8 (0.3) 0.73
(0.29, 1.80)
Peripheral
vascular events
6 (0.2) 1 (0.04) 0.17
(0.00, 1.37)
VIGOR - Confirmed Thrombotic
Cardiovascular Events
Source: Data on file, MSD

24. Effect of Celecoxib & Rofecoxib on
PGIM
* p<0.05 vs.
placebo.
0
40
80
120
160
200
Placebo
N=7
Celecoxib
400 mg
N=7
Ibuprofen
800 mg
N=7
Urinary
PGI-M
(pg/mg
creatinine)
(Mean
±
SE)
**
*
Placebo
N=12
Rofecoxib
50 mg QD
N=12
Indomethacin
50 mg TID
N=10
**
**
Single Dose Rx† Two Weeks Rx††
0
40
80
120
160
200
†
Proc. Natl. Acad Sci. USA 1999;96:272-277.
Urinary 2,3 dinor-6-keto-PGF1a (PGIM)
††
J. Pharmacol. Exp. Ther. 1999;289:735-741.
**p<0.01 vs.
placebo.

25. 0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Months of Follow-up
0 2 4 6 8 10 12 14
Cumulative
Incidence
%
Rofecoxib (OA)
Investigator-Reported Thrombotic
Cardiovascular Events in the VIGOR Study
Compared with Phase IIb/III OA Study
Rofecoxib (VIGOR)
Naproxen (VIGOR)
FDA files
Ibuprofen, Diclofenac,
Nabumetone (OA)

26. Treatment of Gout