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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