Nonsteroidal Antiinflammatory Drugs NSAIDs

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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

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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

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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)

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NSAID
Loss of PGI2 induced inhibition of LTB4 mediated
endothelial adhesion and activation of
neutrophils
Loss of PGE2 and PGI2 mediated inhibition of acid
secretion and cytoprotective effect
? Leukocyte-Endothelial Interactions
Capillary Obstruction
Proteases Oxygen Radicals
Ischemic Cell Injury
Endo/Epithelial Cell Injury
Mucosal Ulceration
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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

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Aspirin

• GI system
• Dose dependent hepatitis
• Reyes syndrome
• Metabolic
• Uncoupling of Oxid. Phosphorylation
• Hyperglycemia and depletion of muscle and hepatic
  glycogen
• Endocrine corticosteroids, thyroid

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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)

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Generation of Lipoxins by Aspirin
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Role of Lipoxins in Anti-inflammatory effects of
Aspirin
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Effect of NSAIDs on Platelet-Endothelial
Interactions
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Use of Aspirin in Unstable Angina
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Use of Aspirin in Unstable Angina
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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

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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

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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.

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Attempts to Decrease Toxicity of NSAIDs
Nitroaspirins
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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

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VIGOR - Summary of GI Endpoints
Rofecoxib
RR 0.46 (0.33, 0.64)
Naproxen
5
RR 0.38 (0.25, 0.57)
4
RR 0.43 (0.24, 0.78)
3
Rates per 100 Patient-Years
2
1
0
Confirmed Clinical Upper GI Events
ConfirmedComplicated Upper GI Events
All Clinical GI Bleeding
p 0.005.
( ) 95 CI.
p lt 0.001.
Source Bombardier, et al. N Engl J Med. 2000.
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VIGOR - Confirmed Thrombotic Cardiovascular Events
Patients with Events (Rates per 100 Patient-Years)
Rofecoxib N4047
Naproxen N4029
Relative Risk (95 CI)
Event Category
45 (1.7)
19 (0.7)
0.42 (0.25, 0.72)
Confirmed CV events
28 (1.0)
10 (0.4)
0.36 (0.17, 0.74)
Cardiac events
8 (0.3)
0.73 (0.29, 1.80)
Cerebrovascular events
11 (0.4)
0.17 (0.00, 1.37)
Peripheral vascular events
6 (0.2)
1 (0.04)
Source Data on file, MSD
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Effect of Celecoxib Rofecoxib on PGIM
Urinary 2,3 dinor-6-keto-PGF1a (PGIM)
Two Weeks Rx
Single Dose Rx
200
200
160
160
120
120
Urinary PGI-M (pg/mg creatinine) (Mean SE)

80
80



40
40
0
0
Placebo N7
Celecoxib 400 mg N7
Ibuprofen 800 mg N7
Placebo N12
Rofecoxib50 mg QDN12
Indomethacin50 mg TIDN10
plt0.05 vs. placebo.
Proc. Natl. Acad Sci. USA 199996272-277.
plt0.01 vs. placebo.
J. Pharmacol. Exp. Ther. 1999289735-741.
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Investigator-Reported Thrombotic Cardiovascular
Events in the VIGOR Study Compared with Phase
IIb/III OA Study
3.5
3.0
2.5
Ibuprofen, Diclofenac, Nabumetone (OA)
2.0
Rofecoxib (OA)
Cumulative Incidence
1.5
1.0
0.5
0.0
0
2
4
6
8
10
12
14
Months of Follow-up
FDA files
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Treatment of Gout