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

ffe ion
e e bi t
ct
Loss of PGI2 induced inhibition of LTB4 mediated

tiv hi
ec in
endothelial adhesion and activation of neutrophils

ot ed
pr a t
to edi
d 2m
an GI

↑ Leukocyte-Endothelial
cy
P
io nd

Interactions
cr 2 a
n
se E
id PG
et
ac of
ss
Lo
of

Capillary Proteases +
Obstruction Oxygen Radicals

Ischemic Endo/Epithelial
Cell Injury Cell Injury

Mucosal Ulceration
 The Salicylates - Aspirin
• Effect on Respiration: triphasic
• Low doses: uncoupling phosphorylation → ↑
CO2 → stimulates respiration.
• Direct stimulation of respiratory center →
Hyperventilation → resp. alkalosis → renal
compensation
• Depression of respiratory center and
cardiovascular center → ↓ BP, respiratory
acidosis, no compensation + metabolic
acidosis also
 Aspirin
• GI system
2. Dose dependent hepatitis
3. Reye’s syndrome
• Metabolic
5. Uncoupling of Oxid. Phosphorylation
6. 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 NSAID’s 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 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.
Attempts to
Decrease
Toxicity of
NSAID’s –
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 Alzheimer’s 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-PGF1α (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