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

↑ Leukocyte-EndothelialInteractions

Capillary Obstruction

IschemicCell Injury

Proteases +Oxygen Radicals

Endo/EpithelialCell Injury

Mucosal Ulceration

Loss o

f PG

E 2 an

d PG

I 2 m

edia

ted in

hibiti

on

of ac

id se

cret

ion an

d cyto

prote

ctiv

e effe

ct

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

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

• GI system1. Dose dependent hepatitis2. Reye’s syndrome

• Metabolic1. Uncoupling of Oxid. Phosphorylation2. Hyperglycemia and depletion of muscle and

hepatic glycogen

• Endocrine: corticosteroids, thyroid

Aspirin

• 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)

Aspirin - Therapeutic Uses

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

• 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 - Salicylism

• Decrease absorption - activated charcoal, emetics, gastric lavage

• Enhance excretion - alkalinize urine, forced diuresis, hemodialysis

• Supportive measures - fluids, decrease temperature, bicarbonate, electrolytes, glucose, etc…

Aspirin Toxicity - Treatment

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

†p < 0.001. * p = 0.005.

0

1

2

3

4

5

Confirmed Clinical Upper GI Events

ConfirmedComplicated

Upper GI Events

All ClinicalGI Bleeding

RR: 0.46†

(0.33, 0.64)

RR: 0.43*(0.24, 0.78)

RR: 0.38†

(0.25, 0.57)

Ra

tes

per

100

Pat

ien

t-Y

ear

s

RofecoxibNaproxen

( ) = 95% CI.

Source: Bombardier, et al. N Engl J Med. 2000.

Patients with Events (Rates per 100 Patient-Years)

Event CategoryRofecoxibN=4047

NaproxenN=4029

Relative Risk(95% CI)

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)

VIGOR - Confirmed Thrombotic Cardiovascular Events

Source: Data on file, MSD

Effect of Celecoxib & Rofecoxib on PGIM

* p<0.05 vs. placebo.

0

40

80

120

160

200

PlaceboN=7

Celecoxib 400 mg

N=7

Ibuprofen 800 mg

N=7

Urin

ary

PG

I-M

(pg

/mg

crea

tinin

e)

(Mea

n ±

SE

)

***

PlaceboN=12

Rofecoxib50 mg QD

N=12

Indomethacin50 mg TID

N=10

****

Single Dose Rx† Two Weeks Rx††

0

40

80

120

160

200

† Proc. Natl. Acad Sci. USA 1999;96:272-277.

Urinary 2,3 dinor-6-keto-PGF1(PGIM)

†† J. Pharmacol. Exp. Ther. 1999;289:735-741.**p<0.01 vs. placebo.

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Months of Follow-up0 2 4 6 8 10 12 14

Cu

mu

lativ

e In

cid

en

ce %

Rofecoxib (OA)

Investigator-Reported Thrombotic Cardiovascular Events in the VIGOR Study

Compared with Phase IIb/III OA Study

Rofecoxib (VIGOR)

Naproxen (VIGOR)

FDA files

Ibuprofen, Diclofenac, Nabumetone (OA)

Treatment of Gout