1. Non-steroidal Anti-inflammatory Drugs Dr.B.V.Venkataraman Professor in Pharmacology International Medical School Faculti Perubatan, New BEL Rd Bangalore - 560054 Venkataraman_bv@yahoo.com

2. COX

3. Physiological stimulus Inflammatory stimulus COX-1 Constitutive Macrophages/other cells Cox-2 Induced TXA2 Platelets PGI2, endothelium Stomach mucosa etc PGE2, Kidney etc PGs Proteases Other inflammatory mediators INFLAMMATION

5. Classification of NSAID COX-1 and COX-2 inhibitors 1.Salicylates: Aspirin 2.Para-aminophenols: Phenacetin, Paracetamol. 3.Pyrazolons: Phenylbutazone 4.Indoles: Indomethacin, Sulindac, Tolmetin, Ketorolac. 5.Phenylacetates: Diclofenac 6.Propionates: Ibuprofen, Ketoprofen, 7.Fenamates: Flufenamic acid and Mefenamic acid. 8.Oxicams: Piroxicam

6. Classification of NSADs (contd) COX-2 inhibitors (Coxibs) Valdecoxib, etorocoxib COX-3 inhibitors Paracetamol Miscellaneous COX Inhibitors Nimesulide, Meloxicam, Etodolac etc Drugs do not inhibit PGs Nefopam

7. SALYCILATES Source: bark of willow (used in malaria) Now it is commercially synthesised. Salicylic acid Sodium salicylate Acetyl salicylic acid (aspirin) Methyl salicylic acid (oil of winter green) Diflunisal is a derivative of aspirin.

8. SALICYLATES LOCAL ACTIONS Irritants Salicylic acid: Keratolytic, used in ring worm infection Methyl salicylate: counter irritant in relieving joints and muscular pain

9. Aspirin: systemic effects Analgesic Aspirin

10. Types of Analgesis Two types 1.Narcotic analgesics Relieve pain and produce sedative/hypnotic effect e.g. morlphine, pethidine 2.Non-narcotic analgesics Relieve pain with out affecting the consciousness e.g. aspirin, paracetamol

11. Systemic actions of aspirin Antipyretic action: Inhibition of central PG Antiplatelet action:

12. (Anti inflammatory action)

13. Systemic actions of aspirin TxA 2 is present in platelets At any dose anti-platelet aggregation (inhibiting TXA 2 ) At low dose PGI 2 not inhibited At high dose PGI 2 is inhibited. PGI 2 : vasodilator and anti-platelet aggregation. Action is irreversible. Duration 8-10 days (life of platelet)

14. Systemic actions of Salicylates Renal effect: PGE 2 (vasodilator) coordinate with angiotensin-II. Chronic NSAIDs leads to inhibition of PGE 2 and vasoconstriction. Respiration: directly and indirectly. O 2 leads to CO 2 which stimulates respiratory centre. These events leads to hyper ventilation. Low dose decrease the uric acid level. High dose uricosuric effect.

15. Pharmacokinetics Well absorbed from stomach and small intestine Empty stomach and acid medium helps absorption Deacetylation in gut wall, liver, plasma & other tissues after absorption. Protein binding 80% Conjugated with glycine. 1/10 is excreted in active form which can be enhanced with alkalinisation.

16. Side effects of aspirin Intolerance (rare): rashes, urticaria, asthma etc. Gastric irritation Hypoprothrombinemia: Vit K is antidote Reye’s syndrome: Children prescribed for viral fever. Syndrome consists of liver dysfunction (fatal) Salicylism: headache, dizziness, vertigo, difficulty in hearing and dimness of vision. The symptoms are reversible once the drug is withdrawn.

17. Treatment of acute salicylate poisoning Symptomatic treatment Patent airway Hyperthermia: reduced by external cooling. Dehydration should be corrected. Vitamin K should be administered. Metabolic acidosis is corrected by NaHCO3 which also promotes renal excretion of salicylates. Forced diuresis is done by administration of furosemide (40 mg) in the infusion fluid. Dialysis is done in renal failure.

18. Clinical uses of Salicylates Keratolytic and antifungal : salicylic acid Counter irritant: Methyl salicylic acid Acute rheumatic fever: Streptococcal infection induces antibodies reacting with lymphocytes. These antibodies react with heart valves and myocardium. Treatment: a. Penicillin for the streptococcal infection. b. Aspirin (5-8 g in divided doses) for the inflammation. c.corticosteroids can also be given.

19. Clinical uses of aspirin Arthritis and fibromyositis: In rheumatoid arthritis, aspirin at 5-6 g in divided doses is advised. Ischaemic heart disease: In low doses (100 mg daily) aspirin is given to prevent platelet aggregation. Pain: headache, fever, dysmenorrhoea etc. For closure of patent ductus arteriosus.

20. Drug interaction Aspirin displaces oral anticoagulants, oral antidiabetics etc. Interfers with uric acid excretion (analgesic dose inhibit) Decreases the diuretic actions (thiazides and furosemide) Reduces the K+ sparing action of spiranolactone.