Nonsteroidal Anti-inflammatory Drugs (nsaids): Inhibition)

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)

ac of id PG se E cr 2 a et io nd P n an GI d 2m cy to edi pr a t ot ed ec in tiv hi e e bi t ffe ion ct

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

of

Lo

ss

↑ Leukocyte-Endothelial Interactions

Capillary Obstruction

Proteases + Oxygen Radicals

Ischemic Cell Injury

Endo/Epithelial 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

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