1. Nonsteroidal Anti-inflammatory Drugs (NSAIDs)BY
Dr. Hemant D. Une,
Y. B. Chavan College of Pharmacy,
Dr. Rafiq Zakaria Campus,
Auranagabad

2. 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

3. 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)

4. THE INFLAMMATORY RESPONSE
1. The inflammatory response is a normal (desirable) defense mechanism.
2. The side effects are undesirable.
3. Normal inflammatory response has an on/off switch.
4. In chronic inflammation something has gone wrong with the OFF switch
5. Therefore we need drugs to control the inflammatory reaction.

5. Mediators of the inflammatory response
Complement system
histamine
serotonin
bradykinin - major contributors to symptoms of inflammation
leukotrienes - increase vascular permeability
- increase mobilization of endogenous mediators of inflammation
prostaglandins PGE2 ‑ promote edema and leukocyte infiltration
PGI2 ‑ increase vascular permeability, enhance pain producing properties of bradykinin

6. INFLAMMATORY SITE
 Sensitized lymphocytes release soluble factors ( which recruit & mobilize macrophages to the inflammed tissue.)
Additional activated macrophages produce enhanced levels of enzymes and mediators
Thereby involving macrophages in the defense against microorganisms and foreign antigens
BUT remember that the inflammatory cells have the potential to destroy surrounding tissue.

7. Mediators of inflammation

8. 4 signs of inflammation Redness - due to local vessel dilatation
Heat - due to local vessel dilatation
Swelling – due to influx of plasma proteins and phagocytic cells into the tissue spaces
Pain – due to local release of enzymes and increased tissue pressure

9. MECHANISM OF ACTION Non-steroidal anti-inflammatory drugs (NSAIDs)
All NSAIDs inhibit the cyclooxygenase required for conversion of arachidonic acid to endoperoxide intermediate (PGG2 and PGH2).
NSAIDs inhibit prostaglandin and thromboxane synthesis, they are potent inhibitors of cyclooxygenase and eliminate all prostaglandins and thromboxanes in every cell they reach
Recall that prostaglandins and thromboxanes play crucial roles in: Pain, Inflammation, Fever , Excessive blood clotting

11. Inhibited by NSAIDs

12. COX-2 INHIBITORS
Cyclooxygenase-1 (COX-1):
-constitutively expressed in wide variety of cells all over the body.
-"housekeeping enzyme"
-ex. gastric cytoprotection, hemostasis
Cyclooxygenase-2 (COX-2):
-inducible enzyme
-immediate-early gene product in inflammatory and immune cells
-dramatically up-regulated during inflammation

13. Pathogenesis of fever Infectious agents or toxin ( Endo/Exo)
Mediators of inflammation
Fever
Monocyte/Macrophages
Endothelial cells and other cell type
Increased heat production
Increased heat conservation
Corticosteroid
Pyogenic cytokines
IL –1 alpha and beta
TNF,IL_6, IFNS
Enhanced immunity
Anterior
hypothalamus
Elevation of
Thermoregulatory
Set point
Archidonic
Acid
COX2
Antipyretic
PGF2

14. Tissue damage, release of pyrogens and phospholipids from
MODE OF ACTION
Tissue damage, release of pyrogens and phospholipids from
cell membrane
Archidonic acid
Paracetamol blocks
COX –2 and COX –3 ?
in CNS
NSAID block
COX –1*and COX –2
in periphery and CNS
PG3
PG3
PG3
Fever and Pain
COX –1* is critical to maintain the integrity of
platelets,renal function and gastric mucosa.

15. ↑ Leukocyte-Endothelial
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

16. The Salicylates - Aspirin
Effect on CNS:
Analgesic, Antipyretic
Large dose Anti-inflammatory
(No Sedation)
Blood: Inhibit Platelet Aggregation
ADP
Cox Syn. Of Thromboxane A2
Uricosuric Effect:
Biphasic- 1-2 gm Increases Plsm. Urate
Abov. 5gm Inhibite reabsorption in PT so uricosuric +

17. The Salicylates - Aspirin
GIT:
N/V irritation to stomach mucosa,
PGE2; PGI2 Inhibition – Acid secretion/ ulceration
Unionized → G. mucosa → ionized so indifussable (ion trapping) → Irritation

18. 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

19. Aspirin GI system Metabolic Endocrine: corticosteroids, thyroid
Dose dependent hepatitis
Reye’s syndrome
Metabolic
Uncoupling of Oxid. Phosphorylation
Hyperglycemia and depletion of muscle and hepatic glycogen
Diabetic → Peri Glu Utilization; Inhib Neoglycogenesis
Protein Catabolism → Amino acid Urea
Endocrine: corticosteroids, thyroid

20. 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)

21. Generation of Lipoxins by Aspirin
HETE- hydroxy eicosa tetraeuonic acid

22. Role of Lipoxins in Anti-inflammatory effects of Aspirin

23. Effect of NSAID’s on Platelet-Endothelial Interactions

24. 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

25. Salicylism: Plasma conce. Above 25mg%
Acute intoxication : A-B imbalance, Hyperglycemia, dehydration, hemorrhage, CNS stim., Coma…….
Pregnancy: - delayed labour,
- ↑ blood loss
- close ductus arteriosus.

26. 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…

27. Paracetamol Potent Antipyretic, analgesic; but less- antiinflammatory
Less Effet in peri-PG sys; but Effect.in CNS
OTC – status since 1955.
Consider safer in asthmatic patients.

28. Peak plasma concentration occur between
Pharmacokinetics:
Well absorb orally
Peak plasma concentration occur between
15 mins and 2 hours after ingestion.
PCM bio availability above 80% .
Metabolizm- Liv. C-P Glu. / Sulfu. Conju.
Enhance toxicity in neonate
It has few Pharmacokinetics drug interaction.

29. Side Effects: Meth- haemoglobinaemia. Thrombocytopenia. Anaemia.
Haemostasis
Meth- haemoglobinaemia.
Thrombocytopenia.
Anaemia.
Agranulocytosis.
Hepatotoxicity n-methyl-n-acetyl-p- hydroxy-aniline
Treatment with sulfhydril Gr.- cys, lmethi, n-acet. cys
Nephrotoxicity

30. Your Attention

31. Which sticker should be put on NSAIDs?
Avoid exposure to sunlight. b. Keep refrigerated
Take with food. d. Be sure to complete all medicatio
Mild salicylate intoxiction is charectorized by all except-
Headache b. Ringing in the ears
Dizziness d. Throbbing pain.
The problem with combining alcohol and acetaminophen is-
GI bleeding b. Liver toxicity
Urinary tract Infection d. salicylate toxicity.

32. 4. Write True or False
Salicylate can actually precipitated an attack of Gout.
The only NSAIDs available in parenteral forms are salicylate and paracetamol.
The drug oc choice for acute gout attack is Salicylate
Salicylate are indicated for simple headache, arthritis, pain and fever with flu.
An accepted dose of Aspirin is above 2,000 mg/day
Two NSAIDs that come as ophthalmic are salicylate and paracetamol.

34. 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.