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

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)

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.

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

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.

Mediators of inflammation

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

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  

Inhibited by NSAIDs

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

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

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.

↑ 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

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 +

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

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 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

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 HETE- hydroxy eicosa tetraeuonic acid

Role of Lipoxins in Anti-inflammatory effects of Aspirin

Effect of NSAID’s on Platelet-Endothelial Interactions

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

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

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…

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.

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-P450 Glu. / Sulfu. Conju. Enhance toxicity in neonate It has few Pharmacokinetics drug interaction.

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

Your Attention

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.

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.

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.