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NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) Dr Sasan Zaeri (PharmD, PhD) Department of Pharmacology Inflammatory cascade Triggers Infection Tissue and/or vessel damage Inflammatory Mediators Acute Inflammatory Response Note this is a common & non-specific response - Redness - Heat - Swelling - Pain Drugs block production or effect of inflammatory mediators Tissue and/or vessel damage Infection Inflammatory Mediators o o o o o Vasoactive peptides: Histamine,serotonin The kinin system Coagulation cascade The complement system Arachidonic Acid metabolites NSAIDs Corticosteroids Inflammatory Enzymes: PLA2 & COX 3. Zileuton Montelukast, zafirlukast 1. Steroids Phospholipase A2 2.NSAIDS Arachidonic acid (AA) Lipoxygenase Lipoxygenase products (leukotrienes) Inflammatory effects (esp. in asthma) Cyclooxygenase (COX) Prostaglandins & thromboxanes Inflammatory effects (inducible) Homeostatic Functions (stomach mucus) COX-1 vs. COX-2 NSAIDS- MECHANISM OF ACTION Non –Selective NSAIDs inhibit both COX-1 & COX-2 reversibly Ibuprofen, Diclofenac, Indomethacin, Naproxen, Mefenamic acid etc. Aspirin (irreversible COX inhibitor) Selective NSAIDs inhibit only COX-2 reversibly Celecoxib Pharmacological Actions of NonSelective NSAIDs Analgesic Antipyretic (Drug that lowers the elevated body temperature to normal) Anti-inflammatory Anti-platelet Exceptions: celecoxib, non-acetylated salicylates THERAPEUTIC USES SHARED BY NSNSAIDs Fever Analgesic Headache Migraine Dental pain Common cold THERAPEUTIC USES SHARED BY NSNSAIDs Rheumatoid arthritis Osteoarthritis Myositis or other forms of inflammatory conditions Dysmenorrhea ADVERSE EFFECTS SHARED BY NS-NSAIDS GIT upsets ( nausea, vomiting) GIT bleeding & ulceration Bleeding Hypersensitivity reaction Inhibition of uterine contraction Salt & water retention DOSE DEPENDENT THERAPEUTIC EFFECTS OF ASPIRIN Antithrombotic 0 Antipyretic, Analgesic 1 2 Anti-inflammatory 3 Daily dose of aspirin (g) 4 5 Blood Vessel Wall Endothelial Cell (COX-2) Arachidonic acid PGH2 Prostacyclin (PGI2) cAMP/vessel smooth muscle relaxes Ca2+/vessel smooth muscle constricts Platelet (COX-1) Arachidonic acid PGH2 Thromboxane (TXA2) Ca2+ aggregation cAMP aggregation Normal physiologic interaction between PGI2 and TXA2 in platelet and endothelial cell biology ADDED CLINICAL USES Antiplatelet/Antithrombotic effect Decreases platelet production of TXA2 by COX-1 irreversibly to limit platelet aggregation and vasoconstriction Cardioprotective (reducing the risk of MI) Acute rheumatic fever Prevention Chronic Chronic of pre-eclampsia gouty arthritis with large doses use of small doses , reduce the incidence of cancer colon Adverse Effects Related to : (A) Therapeutic Doses Of Aspirin Aspirin asthma Reye's syndrome Syndrome of hepatic injury & encephalopathy in kids treated with aspirin after a viral illness Aspirin-induced asthma Adverse Effects Related to ( B) LARGE DOSES OR PROLONGED USE OF ASPIRIN Salicylism ( ringing of ear( tinnitus) , vertigo) Hyperthermia GI ulcer and bleeding Metabolic acidosis ADVERSE EFFECTS RELATED TO HIGH DOSES CONTRAINDICATIONS Children with viral infections Patients with GI ulcer or upper GI bleeding Patients with hemophilia Patients with Aspirin-induced asthma PARACETAMOL (acetaminophen) Commonly used as analgesic antipyretic drug CLINICAL USES OF PARACETAMOL Can be used safely in patients with: Peptic or gastric ulcers Bleeding tendency Allergy to aspirin Viral infections in children Pregnancy ADVERSE EFFECTS Mainly on liver due to its active metabolite ( N-acetyl-p-benzoquinone) Large doses cause liver necrosis Treatment Of toxicity of paracetamol: N- acetylcysteine : SH- donor to neutralize the toxic metabolite ACETAMINOPHEN TOXICITY Acetaminophen UDP glucuronosyltransferase Sulfotransferase glucuronide sulfate CYP2E1 induction alcohol Acetylcysteine (antidote) Glutathione-Stransferase glutathione Live r failure protein DICLOFENAC Clinical uses o o o o o Treatment of rheumatoid arthritis , osteoarthritis (accumulates in synovial fluid in Long-term use ) Analgesic Antipyretic Acute gouty arthritis Locally to prevent post-operative ophthalmic inflammation SELECTIVE COX-2 INHIBITORS General advantages : o Adverse effects are slighter than other NSADs o o No effect on platelet aggregation (COX-1) Long-term studies of the incidence of clinically significant gastrointestinal ulcers and bleeding are not yet completed ADVERSE EFFECTS Renal toxicity Cardiovascular (high risk of MI) Rofecoxib and valdecoxib were withdrawn STILL ON THE MARKET GENERAL CLINICAL USES Rheumatoid arthritis Osteoarthritis Acute musculoskeletal pain Dysmenorrhea They can also be used in patients with gastric ulcer , haemophilia for the above indications