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
 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
 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)
 NSAID
Loss of PGI2 induced inhibition of LTB4 mediated
endothelial adhesion and activation of neutrophils

Leukocyte-Endothelial
Interactions

Capillary Proteases +
Obstruction Oxygen Radicals

Ischemic Endo/Epithelial
Cell Injury Cell Injury

Mucosal Ulceration
 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
 Aspirin
GI system
1. Dose dependent hepatitis
2. Reyes syndrome
Metabolic
1. Uncoupling of Oxid. Phosphorylation
2. Hyperglycemia and depletion of muscle and
hepatic glycogen
Endocrine: corticosteroids, thyroid
 Aspirin - Therapeutic Uses
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)
Generation of Lipoxins by Aspirin
Role of Lipoxins in Anti-inflammatory effects of Aspirin
Effect of NSAIDs on Platelet-Endothelial Interactions
Use of Aspirin in Unstable Angina
Use of Aspirin in Unstable Angina
 Aspirin Toxicity - Salicylism
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 - Treatment
Decrease absorption - activated charcoal,
emetics, gastric lavage
Enhance excretion - alkalinize urine,
forced diuresis, hemodialysis
Supportive measures - fluids, decrease
temperature, bicarbonate, electrolytes,
glucose, etc
 Other NSAIDs
Phenylbutazone: additional uricosuric effect.
Aplastic anemia.
Indomethacin: Common ADRs. CNS most
common: halucinations, depression, seizures
Propionic acids: better tolerated. Differ in
pharmacokinetics
Acetaminophen: differes in effects and ADRs
from rest. Main toxicity: hepatitis due to toxic
intermediate which depletes glutathione. Treat
with N-acetylcysteine.
Attempts to
Decrease
Toxicity of
NSAIDs
Nitroaspirins
 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 Alzheimers disease
 VIGOR - Summary of GI Endpoints
Rofecoxib
RR: 0.46
Naproxen
(0.33, 0.64)
Rates per 100 Patient-Years

5 RR: 0.38
4 (0.25, 0.57)

3 RR: 0.43*
(0.24, 0.78)
2
1
0
Confirmed Clinical Confirmed All Clinical
Upper GI Events Complicated GI Bleeding
Upper GI Events
p < 0.001. * p = 0.005. ( ) = 95% CI.
Source: Bombardier, et al. N Engl J Med. 2000.
 VIGOR - Confirmed Thrombotic
Cardiovascular Events
Patients with Events (Rates per 100 Patient-Years)
Rofecoxib Naproxen Relative Risk
Event Category N=4047 N=4029 (95% CI)
Confirmed 45 (1.7) 19 (0.7) 0.42
CV events (0.25, 0.72)
Cardiac 28 (1.0) 10 (0.4) 0.36
events (0.17, 0.74)
Cerebrovascular 11 (0.4) 8 (0.3) 0.73
events (0.29, 1.80)
Peripheral 6 (0.2) 1 (0.04) 0.17
vascular events (0.00, 1.37)

Source: Data on file, MSD

 Effect of Celecoxib & Rofecoxib on
PGIM
Urinary 2,3 dinor-6-keto-PGF1a (PGIM)
Urinary PGI-M (pg/mg creatinine)

200 Single Dose Rx 200 Two Weeks Rx

160 160
(Mean SE)

120 120

80 * 80
**
40 ** 40 **

0 0
Placebo Celecoxib Ibuprofen Placebo Rofecoxib Indomethacin
N=7 400 mg 800 mg N=12 50 mg QD 50 mg TID
N=7 N=7 N=12 N=10
* p<0.05 vs.
placebo.
Proc. Natl. Acad Sci. USA 1999;96:272-277.
**p<0.01 vs.
J. Pharmacol. Exp. Ther. 1999;289:735-741.
placebo.
 Investigator-Reported Thrombotic
Cardiovascular Events in the VIGOR Study
Compared with Phase IIb/III OA Study
3.5

3.0
Cumulative Incidence %

Rofecoxib (VIGOR)
2.5 Ibuprofen, Diclofenac,
Nabumetone (OA)
2.0 Rofecoxib (OA)
1.5

1.0 Naproxen (VIGOR)

0.5

0.0
0 2 4 6 8 10 12 14
Months of Follow-up
FDA files
Treatment of Gout