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Non Steroidal Anti-Inflammatory Drugs (NSAIDs). Prepared by Prof.Abdulkader El Daibani. Non Steroidal Anti-Inflammatory Drugs (NSAIDs). Non steroidal anti-inflammatory drugs (NSAIDs) Aspirin like drugs and used in treatment of: 1) inflammation (anti-inflammatory). 2) Fever (antipyretic).
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Non Steroidal Anti-Inflammatory Drugs (NSAIDs) Prepared by Prof.Abdulkader El Daibani
Non Steroidal Anti-Inflammatory Drugs (NSAIDs) Non steroidal anti-inflammatory drugs (NSAIDs) • Aspirin like drugs and used in treatment of: 1) inflammation (anti-inflammatory). 2) Fever (antipyretic). 3) Pain (analgesic). • In addition aspirin (used as antithrombotic by inhibiting platelets aggregation. Paracetamol is a weak anti-inflammatory agent.
Non Steroidal Anti-Inflammatory Drugs (NSAIDs) Classification • Heterogeneous compounds and can be classified into three groups: A) Non selective COX-inhibitiors (inhibit COX-1 and COX-2): 1) salicylates • aspirin (acetyl salicylic acid –ASA), sodium salicylate, diflunisal. 2) Indomethacin,sulindac. 3) Diclofenac, tolmetin. 4) Ibuprofen, naproxen, ketoprofen. 5) Mefenamic acid. 6) Piroxicam, tenoxicam. 7) Nabumetone.
Non Steroidal Anti-Inflammatory Drugs (NSAIDs) B) Selective COX-2 inhibitors • e.g. celecoxib. C) Selective COX-3 inhibitors It has been suggested that paracetamol act by inhibiting COX-3. Pharmacokinetics 1) all NSAIDs are weak acids except Nabumetone (prodrug) and metabolized to acidic active metabolite -most are well absorbed from GIT. 2) Most are metabolized by phase I and phase II. 3) most are highly bound to plasma albumin (98%). 4) Some accumulate in synovial fluid e.g. diclofenac and this prolong duration of action.
Non Steroidal Anti-Inflammatory Drugs (NSAIDs) Mode of action: 1) Inhibition of COX-1 and Cox-2 (major mechanism). 2) Chemotaxis effect. 3) ↓ synthesis of interlukin-1. 4) ↓ production of free radicals. 5) Interfere with intracellular Ca++. Side effect: 1) GIT bleeding and ulceration. 2) Inhibit platelet aggregation. 3)↓ uterine motility. 4)Nephrotoxicity.
Non Steroidal Anti-Inflammatory Drugs (NSAIDs) Aspirin (acetyl salicylic acid ASA) • Rarely used now as anti-inflammatory but still used as analgesic, antipyretic and widely used as antithrombotic in small dose (75-100 mg) once daily. Pharmacokinetics: 1) Rapidly absorbed from stomach and S.I with Cmax after 1.5 hr. 2) Hydrolyzed by tissue and plasma esterases to acetic acid and salicylate. • Salicylate is metabolized by phase I oxidation and phase II conjugation in liver to form inactive metabolites.
Non Steroidal Anti-Inflammatory Drugs (NSAIDs) Mode of action: • Irreversible and non specific inhibition of COX1 and COX-2 by acetylation of isoenzymes (COX-1 and COX-2). A) Anti-inflammatory effect 1) Due to inhibition of COX 2, this is the major mechanism. 2) Inhibition of polymorphonuclear neutrophils (PMN). B) Analgesic effect 1) effective in mild and moderate somatic pain but not very effective in visceral pain due to inflammation in periphery. 2) Central effect by inhibiting pain stimuli due to ↓ PGE1 and PGE2 C) antipyretic • may be due to inhibition of COX-1 and COX2 in C.N.S. through inhibition of interleukin-1 leading to ↓ PGE in hypothalamus.
Non Steroidal Anti-Inflammatory Drugs (NSAIDs) Side effect • Some are due to inhibition of COX1. 1)GIT • Epigastric pain , nausea, gastric erosion leading to bleeding due to direct effect and inhibition of PGE1 and PGE2 . 2) ↑ bleeding time due to inhibition of TXA2 in platelet formed by COX1. 3) Tinnitus and hearing loss in high dose . 4) Uricosuric effect (1-2 g/day) • ↓ uric acid tubular secretion in the kidney →↑ plasma uric acid → gout,so aspirin may aggrevate gout.
Non Steroidal Anti-Inflammatory Drugs (NSAIDs) 5) Kidney ↓ PGI2 and PGE2→ decreas blood flow → nephropathy especially in patients with cardiovascular diseases. 6) Metabolic effect Inhibits oxidative phosphorylation in high dose leading to ↓ ATP. 7) Drug interactions Highly bound to plasma protein and may displaces other drugs bound to plasma albumin e.g. Warfarin. 8) Reye's syndrome Rare but sever complication due to encephalopathic disorder and hepatic fatty degradation after viral infection especially influenza or chicken pox. The syndrome may be due to mitochondrial damage.
Non Steroidal Anti-Inflammatory Drugs (NSAIDs) Aspirin Toxicity (10-30g) Characterized by: 1) hyperventilation leading to respiratory alkalosis. 2) metabolic acidosis. 3) Hyperthermia. 4) Dehydration. • If untreated coma and respiratory depression leads to death. Treatment: 1) gastric lavage. 2) I/V infusion of NaHCO3 to correct pH and ↑ excretion.
