10.2 Non steroidal antiinflammatory Drugs -2.pdf

Non-Steroid Anti-inflammatory Drugs (NSAIDs) 2 Dr Khin Thane Oo, Professor, Department of Pharmacology Learning Outcomes 6. Apply the concepts of pharmacological actions of NSAIDs and physiology/pathophysiology to provide basis for the contraindications of non-selective COX inhibitors in the followi...

Non-Steroid Anti-inflammatory Drugs (NSAIDs) 2 Dr Khin Thane Oo, Professor, Department of Pharmacology Learning Outcomes 6. Apply the concepts of pharmacological actions of NSAIDs and physiology/pathophysiology to provide basis for the contraindications of non-selective COX inhibitors in the following: *** a) Patients with peptic ulcer b) Bleeding disorders c) Children below 12 years of age d) Pregnancy 7. Choose an appropriate NSAID for a given clinical condition by comparing their pharmacological properties. *** 8. Explain the manifestations of paracetamol poisoning. *** 9. Apply the toxicokinetics of paracetamol and pathology of paracetamol poisoning to derive principles of management of paracetamol poisoning. *** 10. List topical NSAIDs and analgesic combinations used in pain management. *** 11. List preferred NSAID(s) for the following: *** a) Mild musculoskeletal pain b) Acute musculoskeletal pain c) Dysmenorrhoea d) Patent ductus arteriosus (PDA) e) Rheumatoid arthritis f) Ankylosing spondylitis/ psoriatic arthritis Acute gout Manipalg) University College Malaysia 2 Important NSAIDs Manipal University College Malaysia 3 Aspirin Efficacy - moderate Non-selective COX inhibitor Irreversibly inhibits COX Manipal University College Malaysia 4 Therapeutic uses of aspirin Antiplatelet / antithrombotic in low doses (75-325mg) - Primary & secondary prophylaxis of MI & stroke - To maintain patency of coronary graft - Low dose aspirin inhibits thromboxane A2 synthesis, while PGI2 formation is unaffected. - ↓ Platelet aggregation ↓ thrombi & ↓ MI & stroke Other inflammatory conditions - Rheumatic fever, rheumatoid arthritis, degenerative joint diseases etc. (never in gout) Analgesic - headache, dysmenorrhea, myalgia etc. Miscellaneous: colonic & rectal cancer, Alzheimer ‘s disease, radiation induced diarrhoea Manipal University College Malaysia 5 Aspirin ADR – High - GIT, renal etc. if administered to children having viral fever, aspirin may produce ‘Reye’s syndrome’ (Hepatic failure & encephalopathy with high mortality). Hence, contraindicated in children as antipyretic. Drug interactions –↑efficacy of oral anticoagulants & may lead to haemorrhage. Aspirin overdosage (Acute salicylate poisoning)Accidental poisoning - children Mild form known as salicylism - Nausea, Vomiting, tinnitus, vertigo, hyperventilation and respiratory alkalosis Very high dose : metabolic acidosis, dehydration, hyperthermia, collapse, coma and death 6 Dose related toxicity of aspirin Fever, dehydration & metabolic acidosis Hyperventilation & Resp. alkalosis Antiinflammatory Analgesic Antiplatelet 75 to 325mg 675 -975 mg 3 - 6 gm 5 – 10 gm 10 – 20 gm Shock, coma, respiratory & renal failure and death 20 -30 gm =/>30 - 60 tab > 18 -30 tab 9 - 18 tab 2 - 3 tab 1 0 Treatment of Acute Salicylate poisoning: No specific antidote Gastric lavage followed by administration of activated charcoal Maintain fluid and electrolyte balance Intravenous sodium bicarbonate Forced alkaline diuresis to ↑ excretion External cooling Haemodialysis in severe cases Vitamin K and blood transfusion if there is bleeding. Ibuprofen Standard anti-inflammatory agent. First choice drug, with lowest incidence of adverse effects. Efficacy – Moderate Route – oral, topical Anti-inflammatory dose: 400mg to 800mg three times daily ADR: Low, tolerated better Manipal University College Malaysia 13 Ibuprofen Uses: dental surgery pain, toothache, mild post-operative pain, postpartum use, myalgia fever, fever in children if paracetamol not effective, rheumatoid arthritis, gout, osteoarthritis, Diclofenac Efficacy moderate, preferential COX-2 inhibitor, inhibits lipoxygenase also ADR – High, hepatotoxicity is more Good tissue penetrability and concentration in synovial fluid is maintained for a long period. Extended therapeutic action in joints. Preferred in inflammatory condition of joints Uses: Post operative pain, dysmenorrhea, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, sprain, back ache, renal colic, toothache Route : IM, oral, topical, ophthalmic drops Manipal University College Malaysia 15 Indomethacin Efficacy: very high, most potent non-selective anti-inflammatory agent. Inhibits lipoxygenase also. Additional mechanism: inhibits migration of neutrophils to inflamed area and has immunosuppressant effect. ADR: Never to be prescribed as a simple analgesic & antipyretic in trivial condition due to high toxicity. More GI upset than other NSAIDs, haematological, hepatic, headache, psychiatric disturbances (confusion and hallucinations). Contraindicated in epileptics, psychiatric patients and drivers 11 Indomethacin Uses: Rheumatoid arthritis, gout, ankylosing spondylitis, degenerative joint diseases Pericarditis, pleurisy antipyretic in Hodgkin's disease medical closure of Patent Ductus Arteriosus (PDA) in preterm infants Bartter syndrome (excess PGs leading to hyperreninemia, excess aldosterone and the resultant hypokalaemia Route - Oral, parenteral, eye drops, suppository Ketorolac Analgesic action – Highly effective and potent, almost equal to morphine. Anti-inflammatory – Moderate Drug interactions: Not seen with oral anticoagulants GI toxicity + ve (if given for more than 5 days) Uses: Morphine substitute for short term pain relief. Post operative pain, renal colic, metastatic cancer pain Route: oral, IM, IV, topical Manipal University College Malaysia 20 Piroxicam & Tenoxicam Longest acting due to enterohepatic cycling. GI toxicity – high ↓ PG concentration in synovial fluid. ↓ the production of IgM rheumatoid factor and leucocyte chemotaxis. Uses : Joint diseases, acute gout, musculoskeletal injuries, dental diseases Manipal University College Malaysia 22 Mefenamic acid Non-selective reversible inhibitor of COX inhibits prostaglandin synthesis ↓PG induced uterine contractions ↓myometrium ischaemia -↓menstrual cramps Fever in children -it is used in children not responding to paracetamol treatment. ↓PG synthesis in the hypothalamus thermostat reset the hypothalamic sweating and cutaneous vasodilatation occur ↓the fever Uses: Dysmenorrhoea, fever in children Manipal University College Malaysia 23 Drug Interactions of NSAIDs ❖ NSAIDs with glucocorticoids : increased GI toxicity ❖NSAIDs increases the effects of oral anticoagulants, oral hypoglycemic agents (sulfonyl urea), methotrexate, anti-thyroid drugs by displacing them from plasma protein binding sites and increasing their toxicity ❖ Piroxicam can impair the clearance of lithium leading to toxicity ❖NSAIDs inhibit PG synthesis & promote Na and water retention on chronic use. ❖ They decrease the diuretic efficacy of thiazides and furosemide Manipal University College Malaysia ❖ Aspirin antagonises the uricosuric effects of probenecid 24 Contraindications of Non-selective NSAIDs Patients with peptic ulcer disease Prostaglandin (PGE2) inhibits gastric acid secretion, stimulates mucosal blood flow →↑mucus and bicarbonate secretion →gastroprotective effect NSAIDs inhibit PG production → dyspepsia, epigastric pain, acute gastritis, ulceration and GI bleeding Aspirin(weakly acidic drug)→unionized in the gastric acid juice →enters mucosal cells →gets ionized at pH7.2→trapped(ion-trapping)→Acute ulcers, Erosive gastritis, Hemorrhage 19 Contraindications to Non-selective NSAIDs ❖Bleeding disorders Due to antiplatelet action Long term use →↓proconvertin (factor V) ↓prothrombin levels Contraindicated in bleeding disorders and before surgery ❖ Children below 12 years Children below 12 years of age with viral infection →hepatic damage with fatty infiltration and encephalopathy (Reye’s syndrome) Contraindicated in children below 12 years with fever of unknown origin ❖ Late pregnancy In Pregnancy PGs in uterus →induce labour. Aspirin → delayed or prolonged labour Greater postpartum blood loss →due to antiplatelet effects Hence NSAIDs are avoided in late pregnancy 20 Selective COX-2 Inhibitors Anti-inflammatory action - Moderate Analgesic action - weak ADR: ↑Incidence of thrombo-embolism & MI. It prevents synthesis of PGI2 instead of TXA2 Renal toxicity +ve Drug interactions with anti-hypertensives - + ve Uses: Preferred for elderly - osteoarthritis, post operative pain, rheumatoid arthritis, gout, dysmenorrhoea, musculoskeletal pain Safer than non-selective NSAIDs in peptic ulcer diseases Precautions: Pregnancy, patient with cardiovascular disease 28 Differences between COX-2 inhibitors & non-selective NSAIDs Non-selective NSAIDs Prolong the bleeding time, cardio protective effect (+) Can be safely used in patients with ischaemic heart disease or cerebrovascular disease Contraindicated in patients with bleeding disorders Contraindicated in patients with peptic ulcer Selective COX-2 Inhibitors Do not inhibit platelet aggregation or prolong the bleeding time–devoid of cardioprotective effect. Long term use of selective COX-2 inhibitors can reduce PGI2 production (COX-2 dependent) without affecting TXA2 production by platelets (COX-1 dependent) Avoided in patients with history of ischaemic heart disease or cerebrovascular disease. safely given in patients with bleeding disorders Safe in patients with peptic ulcer - less ulcerogenic 29 Nonselective and selective COX inhibitors KTO 30 Paracetamol (Acetaminophen) Inhibits COX (COX-3) in CNS but not in the peripheral inflamed tissue – No anti-inflammatory activity. Analgesic, antipyretic action - significant Advantages: No ADR on gastric mucosa, kidney, platelets, bleeding time No drug interactions with oral anticoagulants & other drugs Uses: safe analgesic, antipyretic in children (no Reye's syndrome), in patients having gout, haemophilia, aspirin hypersensitivity etc. and where other NSAIDs may not be tolerated. Given along with other NSAID for higher degree of analgesia Route - oral, parenteral Should not be given more than 4g/day. Well tolerated OTC drug. Safe in therapeutic doses in all age groups & during pregnancy & lactation. Rarely may produce skin rash 31 Paracetamol (Acetaminophen) Acetaminophen produces analgesia centrally as a COX-3 inhibitor and via activation of descending serotonergic pathways (Graham and Scott, 2005; Anderson, 2008). It is also thought to produce analgesia as a cannabinoid agonist and by antagonizing NMDA and substance P in the spinal cord (Bertolini et al., 2006). It does not act peripherally at the inflammatory site as it does not act in presence of peroxides which are formed at the site of inflammation. 32 Pharmacokinetics of paracetamol well absorbed from GIT metabolized in the liver by glucuronide and sulfate conjugation (major pathway). small proportion of paracetamol undergoes CYP-mediated N-hydroxylation to form N-acetyl-p-benzoquinoneimine (NAPQI) (minor pathway). NAPQI, a highly reactive intermediate which normally react with thiol (SH Group) in glutathione and rendered harmless KTO 33 PARACETAMOL (ACETAMINOPHEN) CYP 450 oxidation conjugation Nontoxic metabolites Toxic metabolites Glutathione detoxifies the toxic metabolites KTO 34 Paracetamol poisoning Occurs mainly in children and patients with low glucuronide conjugating ability Dose : >10gm Early manifestations - nausea, vomiting, abdominal pain and liver tenderness with no impairment of consciousness. 12-18 hrs later centrilobular hepatic necrosis, renal tubular necrosis and hypoglycaemia Jaundice in 2 days Fulminating hepatic failure and death 35 Mechanism of Paracetamol toxicity N-acetyl-p-benzoquinone-imine (NAPQI) highly toxic minor metabolite formed by CYP450 enzymatic system (minor pathway). At therapeutic doses ↓minor metabolite is formed and detoxified by glutathione conjugation. Hepatic glutathione is limited and exhausted in overdose If amount of paracetamol metabolite is greater than the glutathione available, then the metabolite is able to oxidized thiol (SH Group) in hepatic proteins forms covalent bonding with hepatic and renal cellular proteins causes hepatic necrosis and cell death 36 overdose heavy alcoholics malnutrition KTO Treatment of Paracetamol poisoning Should be started early within 16 hours of paracetamol poisoning Induce vomiting Gastric lavage and administration of activated charcoal to prevent further absorption Administration of I.V. N-acetyl cysteine or oral methionine Both have SH groups like glutathione They replenish the stores of glutathione in liver and conjugate the toxic metabolite which get excreted. Prevents covalent bonding of NAPQI with hepatic and renal cellular proteins Manipal University College Malaysia 28 Topical NSAIDs and analgesic combination ❖ NSAIDs used topically: Ibuprofen, Diclofenac, Piroxicam, Ketorolac ❖ Analgesic combinations Aspirin + Paracetamol Paracetamol + Ibuprofen Paracetamol + Diclofenac Dextropropoxyphene + Paracetamol Paracetamol + Tramadol 29 Specific uses of NSAIDs Specific conditions Preferred NSAID Mild musculoskeletal pain Paracetamol, ibuprofen Moderate to severe musculoskeletal pain Ibuprofen, diclofenac, celecoxib, etoricoxib Dysmenorrhoea Mefenamic acid, ibuprofen Patent ductus arteriosus (PDA) Indomethacin, ibuprofen Rheumatoid arthritis Indomethacin, diclofenac, piroxicam Ankylosing spondylitis/ psoriatic arthritis Indomethacin, piroxicam Acute gout Indomethacin, piroxicam (ASPIRIN CONTRAINDICATED) Manipal University College Malaysia 31