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)
Lo of ss ac of id PG se E cr 2 a et i o nd P n an GI d 2m cy to edi pr a t ot ed ec i n tiv hi e e bi t ffe ion ct
NSAID Loss of PGI2 induced inhibition of LTB4 mediated endothelial adhesion and activation of neutrophils
↑ Leukocyte-Endothelial Interactions
Capillary Obstruction
Proteases + Oxygen Radicals
Ischemic Cell Injury
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. Reye’s 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 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
Rates per 100 Patient-Years
VIGOR - Summary of GI Endpoints
†
5
Rofecoxib Naproxen
RR: 0.46† (0.33, 0.64)
RR: 0.38† (0.25, 0.57)
4 RR: 0.43* (0.24, 0.78)
3 2 1 0
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) Rofecoxib N=4047
Naproxen N=4029
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)
Event Category
Relative Risk (95% CI)
Source: Data on file, MSD
Effect of Celecoxib & Rofecoxib on PGIM Urinary PGI-M (pg/mg creatinine) (Mean ± SE)
Urinary 2,3 dinor-6-keto-PGF1α (PGIM) 200
Single Dose Rx†
200
160
160
120
120
80
* **
40 0
Two Weeks Rx††
80
**
40
Placebo Celecoxib Ibuprofen N=7 400 mg 800 mg N=7 N=7
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 Cumulative Incidence %
3.5 3.0
Rofecoxib (VIGOR)
2.5
Ibuprofen, Diclofenac, Nabumetone (OA)
2.0
Rofecoxib (OA)
1.5
Naproxen (VIGOR)
1.0 0.5 0.0
0
2
4
6 8 10 Months of Follow-up
12
14 FDA files
Treatment of Gout