Nonsteroidal Antiinflammatory 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 Obstruction Ischemic Cell Injury

Proteases + Oxygen Radicals

Endo/Epithelial 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

Rates per 100 Patient-Years RR: 0.46 (0.33, 0.64)

Rofecoxib Naproxen
RR: 0.38 (0.25, 0.57) RR: 0.43* (0.24, 0.78)

5 4 3 2 1

Confirmed Clinical Upper GI Events

Confirmed Complicated Upper GI Events

All Clinical GI Bleeding

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)
Event Category Confirmed CV events Cardiac events Cerebrovascular events Peripheral vascular events

Rofecoxib N=4047
45 (1.7) 28 (1.0) 11 (0.4) 6 (0.2)

Naproxen N=4029
19 (0.7) 10 (0.4) 8 (0.3) 1 (0.04)

Relative Risk (95% CI)

0.42 (0.25, 0.72) 0.36 (0.17, 0.74) 0.73 (0.29, 1.80) 0.17 (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) (Mean SE) 200 160 120

Single Dose Rx

200 160 120

Two Weeks Rx

80
40 0

* **
Placebo Celecoxib Ibuprofen N=7 400 mg 800 mg N=7 N=7

80
40 0 Placebo N=12

** **
Rofecoxib Indomethacin 50 mg QD 50 mg TID N=12 N=10

* p<0.05 vs. placebo.

**p<0.01 vs. placebo.

Proc. Natl. Acad Sci. USA 1999;96:272-277. J. Pharmacol. Exp. Ther. 1999;289:735-741.

Investigator-Reported Thrombotic Cardiovascular Events in the VIGOR Study Compared with Phase IIb/III OA Study
3.5 Cumulative Incidence %

3.0
2.5 2.0

Rofecoxib (VIGOR) Rofecoxib (OA)

Ibuprofen, Diclofenac, Nabumetone (OA)

1.5
1.0 0.5

Naproxen (VIGOR)

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

Treatment of Gout