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Nsaids

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Nsaids

  1. 1. DR.UMA KADAM M.B.B.S. MD ASSOCIATE PROFESSOR PHARMACOLOGY SKNMC
  2. 2. I: Pain and Analgesi cs <ul><li>Pain ”an unpleasant sensory and emotional experience with actual or potential tissue damage or described in terms of such damage” </li></ul><ul><li>Analgesia absence of pain </li></ul>
  3. 4. Pain pathways <ul><li>Specialized receptors = free nerve endings </li></ul><ul><li>Stimulation </li></ul><ul><ul><li>Mechanical damage </li></ul></ul><ul><ul><li>Extreme temperature </li></ul></ul><ul><ul><li>Chemical irritation </li></ul></ul><ul><li>Two types of neurons </li></ul><ul><ul><li>A-delta: first pain, sharp </li></ul></ul><ul><ul><li>C: second pain, dull </li></ul></ul><ul><li>Four distinct processes </li></ul><ul><ul><li>Transduction-conduction, transmission, modulation & perception. </li></ul></ul>
  4. 9. Pharmacological treatment of pain <ul><ul><li>Regional Anesthesia </li></ul></ul><ul><ul><li>NSAIDs </li></ul></ul><ul><ul><li>Opioids </li></ul></ul><ul><ul><li>NMDA-receptor agonists </li></ul></ul><ul><ul><li>Alpha-2-receptor agonists </li></ul></ul><ul><ul><li>Other agents </li></ul></ul>
  5. 10. Nonsteroidal Anti-inflammatory Drugs (NSAIDs) <ul><li>Common therapeutic indications </li></ul><ul><li>Common adverse effects </li></ul><ul><li>Different pharmacokinetics and potency </li></ul><ul><li>Different chemical families </li></ul><ul><li>Common mechanism of action (cyclooxygenase inhibition) </li></ul><ul><li>Different selectivities to COX I and II </li></ul><ul><li>Similarities more striking than Differences </li></ul>
  6. 11. NSAIDs: <ul><li>Large and chemically diverse group of drugs with the following properties: </li></ul><ul><ul><li>Analgesic </li></ul></ul><ul><ul><li>Anti-inflammatory </li></ul></ul><ul><ul><li>Antipyretic </li></ul></ul>
  7. 12. NSAIDs: Mechanism of Action <ul><li>Inhibits cyclo-oxygenase (prostaglandin synthase) that is responsible for conversion of arachidonic acid to cyclic endoperoxides </li></ul><ul><li>2 isoforms of enzyme </li></ul><ul><li>- COX-1 : beneficial prostaglandins synthesis </li></ul><ul><li>constitutive, present in platelets, blood vessel, stomach and kidney required for physiological functioning. </li></ul><ul><li>- COX-2 : harmful prostaglandins synthesis </li></ul><ul><li>inducible by cytokines & endotoxins at sites of inflammation e.g. joints, also found in kidney & brain responsible for pain-inflammation-fever. </li></ul>
  8. 13. COX Enzyme:Prostaglandin Effects vasodilation Kidney aggregation Platelets protect mucosa Stomach Modulate pain perception Promote fever (hypothalamus) Brain Inflammation Peripheral injury site COX-2: harmful COX-1: beneficial
  9. 14. Effects of COX Inhibition by Most NSAIDS NSAIDs : anti-platelet—decreases ability of blood to clot COX-1 Gastric ulcers Bleeding Acute renal failure COX-2 Reduce inflammation Reduce pain Reduce fever
  10. 15. CLASSIFICATION OF NSAIDs: <ul><li>Nonselective COX-inhibitors: </li></ul><ul><li>Salicylates: Aspirin </li></ul><ul><li>Propionic acid derivatives: Ibuprofen, Ketoprofen. </li></ul><ul><li>Acetic acid derivatives: Diclofenac, Aceclofenac </li></ul><ul><li>Fenamic acid derivatives: mefenamic acid </li></ul><ul><li>Pyrrolo-pyrrole derivatives: Ketorolac </li></ul><ul><li>Oxicam derivatives: Piroxicam, Meloxicam </li></ul><ul><li>Indole derivatives: Sulindac, Indomethacin </li></ul><ul><li>Pyrazolone derivatives: Phenybutazone </li></ul><ul><li>Selective COX-2 inhibitors: </li></ul><ul><li>Celecoxib, Rofecoxib </li></ul><ul><li>Preferential selective Cox-inhibitors: </li></ul><ul><li>Nimesulide, Meloxicam, Nabumetone </li></ul><ul><li>Analgesic-antipyretic with poor anti-inflammatory effect: paracetamol </li></ul>
  11. 16. PROTOTYPE: Salicylates (Aspirin) <ul><li>More potent effect on platelet aggregation and thermal regulatory center in the brain </li></ul><ul><ul><li>analgesic </li></ul></ul><ul><ul><li>antipyretic </li></ul></ul><ul><ul><li>anti-inflammatory </li></ul></ul><ul><li>Antithrombotic effect: used in the treatment of MI and other thromboembolic disorders </li></ul>
  12. 17. Pharmacokinetics: ASA <ul><li>Absorption : from stomach and intestine </li></ul><ul><li>Distribution : readily, into most fluids/tissues </li></ul><ul><li>Metabolism : primarily hepatic </li></ul><ul><li>ASA contraindicated for use in children with viral fever –can lead to Reye’s Syndrome </li></ul><ul><li>Fatal overdose is possible </li></ul><ul><li>Similar pharmacokinetics for ibuprofen and related NSAIDs </li></ul>
  13. 18. PHARMACOLOGICAL ACTIONS: Aspirin <ul><li>Analgesic: (300-600mg/day) Analgesia by peripheral inhibition of PG synthesis & increased pain threshold by acting on subcortical site . Analgesia without sedation, loss of consciousness or dependence. </li></ul><ul><li>Antipyretic: (300-600mg/day) </li></ul><ul><li>Reset hypothalamic thermostat by inhibition of PG synthesis, promote heat loss by vasodilation & sweating in fever. </li></ul><ul><li>Anti-inflammatory : (4-6 gm/day). Observed at high doses. By inhibition of PG & other mediators synthesis, T-cell modulation & inhibiting chemotaxis </li></ul>
  14. 19. PHARMACOLOGICAL ACTIONS: Aspirin <ul><li>Antiplatelet: </li></ul><ul><li>PGI2 (vasodilation & inhibition of </li></ul><ul><li>platelet aggregation) </li></ul><ul><li>ASPIRIN </li></ul><ul><li>(2-3gm/day) </li></ul><ul><li>TXA2 </li></ul><ul><li>(vasoconstriction & platelet aggregation) </li></ul><ul><li>Low dose aspirin </li></ul><ul><li>(50-325mg/day) </li></ul><ul><li>CVS : Prolonged use cause salt-water retention & precipitation of CCF. </li></ul><ul><li>Acid-base & electrolyte balance: in therapeutic doses compensatory respiratory alkalosis & in toxic doses respiratory acidosis. </li></ul>
  15. 20. PHARMACOLOGICAL ACTIONS: Aspirin <ul><li>Gastrointestinal: </li></ul><ul><li>Urate excretion: </li></ul><ul><li>In therapeutic doses increase plasma Urate levels </li></ul><ul><li>In high doses uricosuric </li></ul>PGs HCl CTZ ASPIRIN SALICYLIC ACID PEPTIC ULCER EMESIS
  16. 21. <ul><li>Effect on Respiration: triphasic </li></ul><ul><li>Low doses: uncoupling Phosphorylation -> ↑ CO 2 -> stimulates respiration. </li></ul><ul><li>Direct stimulation of respiratory center -> Hyperventilation -> resp. alkalosis -> renal compensation </li></ul><ul><li>Depression of respiratory center and cardiovascular center -> ↓ BP, respiratory acidosis, no compensation + metabolic acidosis also </li></ul>PHARMACOLOGICAL ACTIONS: Aspirin
  17. 22. <ul><li>As analgesic: headache, myalgia, neuralgia, toothache, joint pain & dysmenorrhea etc. (300-600mg/day) </li></ul><ul><li>As antipyretic: any fever however paracetamol preferred for the same (300-600mg/day) </li></ul><ul><li>Acute rheumatic fever: first drug of choice </li></ul><ul><ul><li>First 1-3 days 4-6 gm/day for symptomatic relief </li></ul></ul><ul><ul><li>From 4-7 days dose reduction </li></ul></ul><ul><ul><li>2-3 weeks maintenance dose 50mg/kg/day </li></ul></ul><ul><ul><li>Withdrawal slowly over next 2 weeks. </li></ul></ul><ul><li>Rheumatoid arthritis: 3-5gm/day beneficial*; delays progress but does not prevent it. Long-term treatment not tolerated hence other NSAIDs preferred. </li></ul><ul><li>Osteoarthritis: paracetamol is first drug of choice </li></ul><ul><li>Post MI & stroke: low dose i.e. 60-100mg/day prevent reinfarct & lowers incidences of stroke </li></ul><ul><li>Toxemia of pregnancy( preeclampsia): imbalance between TxA2 & PGI2 involved hence 80-100mg/day beneficial </li></ul><ul><li>Patent ductus arteriosus: brings about closure prevent surgery </li></ul><ul><li>Prevention of colonic cancers: since large quantities of COX-2 expressed in colonic tumors </li></ul>ASPIRIN (NSAIDS):THERAPEUTIC USES
  18. 23. NSAIDs: Side Effects <ul><li>Gastrointestinal </li></ul><ul><li>Dyspepsia, heartburn, epigastric distress, nausea </li></ul><ul><li>GI bleeding </li></ul><ul><li>Mucosal lesions (erosions or ulcerations) </li></ul><ul><li>Misoprostol can be used to reduce these dangerous effects. </li></ul><ul><li>Dose dependent hepatitis </li></ul><ul><li>Reye’s syndrome </li></ul><ul><li>Renal </li></ul><ul><li>reductions in creatinine clearance </li></ul><ul><li>acute tubular necrosis with renal failure </li></ul><ul><li>Cardiovascular </li></ul><ul><li>noncardiogenic pulmonary edema </li></ul>
  19. 24. <ul><li>Metabolic </li></ul><ul><li>Uncoupling of Oxid. Phosphorylation </li></ul><ul><li>Hyperglycemia and depletion of muscle and hepatic glycogen </li></ul><ul><li>Endocrine: </li></ul><ul><li>Release of Corticosteroids, thyroid hormone due central stimulation. </li></ul><ul><li>Hypersensitivity: </li></ul><ul><li>Urticaria Skin rashes, Angioedema, Asthma. </li></ul><ul><li>Bleeding & delayed onset of labor </li></ul>Aspirin (NSAIDs): Side Effects
  20. 25. ASPIRIN (NSAIDs) INTERACTIONS: / Diuretics diuretic response& Probencid / NSAIDs inhibit tubular Antagonize uricosuric effect methotrexate uric acid secretion
  21. 26. NSAIDs: Salicylate Toxicity <ul><li>Adults: tinnitus and hearing loss </li></ul><ul><li>Children: hyperventilation and CNS effects </li></ul><ul><li>Effects arise when serum levels exceed 300  g/mL. </li></ul><ul><li>Metabolic acidosis and respiratory alkalosis may be present. </li></ul>
  22. 27. <ul><li>Decrease absorption - activated charcoal, emetics, gastric lavage </li></ul><ul><li>Enhance excretion - alkalinize urine, forced diuresis, hemodialysis </li></ul><ul><li>Supportive measures - fluids, decrease temperature, bicarbonate, electrolytes, glucose, etc… </li></ul>Aspirin Toxicity - Treatment
  23. 28. ASPIRIN vs PARACETAMOL <ul><li>Reversible nonselective Cox-inhibitor </li></ul><ul><li>Analgesic, antipyretic with poor anti-inflammatory* action </li></ul><ul><li>No Gastric irritation, peptic ulcer-bleeding </li></ul><ul><li>No acid-base & electrolyte imbalance </li></ul><ul><li>No Antiplatelet action </li></ul><ul><li>N-acetyl cysteine is antidote </li></ul><ul><li>Preferred analgesic-antipyretic in patient having asthma, peptic ulcer </li></ul><ul><li>Safe in children </li></ul><ul><li>Irreversible nonselective Cox-inhibitor </li></ul><ul><li>Analgesic, antipyretic with potent anti-inflammatory action </li></ul><ul><li>Gastric irritation, peptic ulcer-bleeding common </li></ul><ul><li>Cause acid-base & electrolyte imbalance </li></ul><ul><li>At low doses Antiplatelet action </li></ul><ul><li>No specific antidote </li></ul><ul><li>Contraindicated in patient having asthma, peptic ulcer </li></ul><ul><li>Not given in children: causes Reye’s syndrome </li></ul>Paracetamol (Para-amino phenol derivative) Aspirin (salicylate)
  24. 29. <ul><li>Metabolism </li></ul><ul><li>is conjugated in the liver as the inactive glucuronide and sulphate </li></ul><ul><li>a number of minor oxidation products inc. </li></ul><ul><li>N-acetylbenzoquinoneimine are also formed </li></ul><ul><li>NABQI is highly chemically reactive and is usually inactivated by conjugation with SH (thiol) groups of glutathione </li></ul><ul><li>Supply of glutathione is limited and exhausted in overdose </li></ul><ul><li>NABQI then reacts with cellular macromolecules and causes cell death </li></ul>PARACETAMOL/ acetaminophen (non-NSAID):
  25. 30. PARACETAMOL ( acetaminophen): <ul><li>Paracetamol overdose </li></ul><ul><li>Ingestion of >10g of paracetamol may be fatal </li></ul><ul><li>may be lower in chronic alcoholics or subjects with underlying liver disease. </li></ul><ul><li>Clinical features </li></ul><ul><li>In severe poisoning </li></ul><ul><li>up to 24 hours-none or nausea and vomiting </li></ul><ul><li>> 24 hours-nausea and vomiting, right upper quadrant pain, jaundice, encephalopathy </li></ul>
  26. 31. PARACETAMOL POISONING: <ul><li>Management </li></ul><ul><li>Blood for paracetamol at 4 hours post ingestion </li></ul><ul><li>Emesis, gastric lavage done. Activated charcoal given orally. </li></ul><ul><li>Supportive measures. </li></ul><ul><li>Specific antidote: N-acetylcysteine 150mg/kg infusion over 15 min followed by same dose IV over next 20 hrs. ( if in doubt of severe poisoning, don’t delay). Alternatively 75mg/kg orally 6 hrly for 2-3 days. </li></ul><ul><li>Check prothrombin time and plasma creatinine , pH </li></ul><ul><li>Acute renal (due to acute tubular necrosis) and hepatic failure and occur at 36-72 hours after ingestion </li></ul><ul><li>Indications for referral to liver unit are </li></ul><ul><li>- rapid development of Grade 2 encephalopathy </li></ul><ul><li>- PTT >45 secs at 48 hours or >50 secs at 72 hours </li></ul><ul><li>- rising plasma creatinine </li></ul><ul><li>- Arterial pH <7.3 more than 24 hours after ingestion </li></ul>
  27. 32. PHARMACOLOGICAL BASIS FOR USE OF N-ACETYLCYSTEINE IN TREATMENT OF PARACETAMOL POISONING: <ul><li>N-acetylbenzoquinoneimine (toxic metabolite) usually inactivated by conjugation with SH (thiol) groups of glutathione </li></ul><ul><li>Supply of glutathione is limited and exhausted in overdose </li></ul><ul><li>NABQI then reacts with cellular macromolecules and causes cell death & necrosis </li></ul><ul><li>N-acetylcysteine replenish glutathione stores of liver & prevents binding of toxic metabolites to cellular macromolecules </li></ul>
  28. 33. COMPARATIVE PHARMACOLOGICAL PROFILE OF NSAIDS <ul><li>Nonselective reversible COX-inhibitor </li></ul><ul><li>Potent anti-inflammatory ; poor & slower analgesic-antipyretic, uricosuric. </li></ul><ul><li>Sever GI-CNS-Renal toxic, bone marrow depression-cause fatal agranulocytosis. </li></ul><ul><li>Used in acute gout for short term </li></ul><ul><li>Oral </li></ul><ul><li>Dose:100-200mg bid </li></ul>1.Phenylbutazone/ <ul><li>Nonselective reversible COX-inhibitor </li></ul><ul><li>Potent anti-inflammatory </li></ul><ul><li>Concentrated in jt.spaces hence preferred in arthritis </li></ul><ul><li>More hepatotoxic </li></ul><ul><li>Diclofenac + Misoprostol reduce GI toxicity. </li></ul><ul><li>Oral, IM, rectal, topical, gel & eye drops </li></ul><ul><li>Dose:50-100mg bid </li></ul>Diclofenac <ul><li>Nonselective reversible COX-inhibitor </li></ul><ul><li>Moderate anti-inflammatory </li></ul><ul><li>Better tolerated than aspirin </li></ul><ul><li>Can be used in children* </li></ul><ul><li>Oral, topical </li></ul><ul><li>Dose:400-600mg tid </li></ul>Ibuprofen /Ketoprofen Properties Route & formulations Drug Sr. no
  29. 34. COMPARATIVE PHARMACOLOGICAL PROFILE OF NSAIDS <ul><li>Nonselective reversible COX-inhibitor </li></ul><ul><li>Potent analgesic# modest anti-inflammatory, equally effective as morphine but produce analgesia with out RS depression, hypotension & dependence </li></ul><ul><li>Used in renal colic, postoperative & cancer pain. </li></ul><ul><li>Oral, IM, IV, eye drops, Transdermal patch </li></ul><ul><li>Dose:50-100mg bid </li></ul>Ketorolac <ul><li>Nonselective reversible COX-inhibitor </li></ul><ul><li>Potent anti-inflammatory** </li></ul><ul><li>Long acting </li></ul><ul><li>GIT side effects pronounced* </li></ul><ul><li>Oral, topical gel, IM </li></ul><ul><li>Dose:20 od </li></ul>Piroxicam <ul><li>Nonselective reversible COX-inhibitor </li></ul><ul><li>Potent & promptly acting analgesic-antipyretic but poor anti-inflammatory . </li></ul><ul><li>No uricosuric effect </li></ul><ul><li>Useful as analgesic-antipyretic </li></ul><ul><li>Injection painful, agranulocytosis & GIT side effects.** </li></ul><ul><li>Oral, IM, IV </li></ul><ul><li>Dose:0.5- 1.5gm tid </li></ul>2.Metamizole Properties Route & formulations Drug Sr.no
  30. 35. COMPARATIVE PHARMACOLOGICAL PROFILE OF NSAIDS <ul><li>Preferential COX2-inhibitor* </li></ul><ul><li>Useful in short lasting inflammatory pain e.g. sinusitis, bursitis. </li></ul><ul><li>ADRs Less than other NSAIDs.$ </li></ul><ul><li>Oral </li></ul><ul><li>Dose:100mg bid </li></ul>Nimesulide <ul><li>Nonselective reversible COX-inhibitor </li></ul><ul><li>Central as well as peripheral analgesic. </li></ul><ul><li>Useful in dysmenorrhea, joint & soft tissue pain </li></ul><ul><li>Diarrhea is most common adverse </li></ul><ul><li>Oral </li></ul><ul><li>Dose:250-500mg tid </li></ul>Mephenamic acid <ul><li>Nonselective reversible COX-inhibitor, Potent PGs-I </li></ul><ul><li>Potent anti-inflammatory also Potent & promptly acting analgesic-antipyretic </li></ul><ul><li>Inhibit phospholipase-A & C; Inhibits migration of neutrophils in inflamed area </li></ul><ul><li>Useful in PDA, ankylosing spondilytis, acute gout, rh.arthritis resistant to aspirin </li></ul><ul><li>CNS** & GIT side effects pronounced </li></ul><ul><li>Contraindicated in drivers, machine operators, psychiatrics, epileptics & pregnant women </li></ul><ul><li>Oral, eye drops & suppositories </li></ul><ul><li>Dose:50mg tid </li></ul><ul><li>Indomethacin </li></ul><ul><li>/sulindac (prodrug#) </li></ul><ul><li>Extra MOAs </li></ul><ul><li>Extra uses </li></ul><ul><li>Extra adverse </li></ul>Properties Route & formulations Drug Sr. no.
  31. 36. COMPARATIVE PHARMACOLOGICAL PROFILE OF NSAIDS <ul><li>Selective COX2-inhibitor </li></ul><ul><li>Potent anti-inflammatory analgesic-antipyretic </li></ul><ul><li>No antiplatelet actions. </li></ul><ul><li>Use as other NSAIDs </li></ul><ul><li>GIT side effects less </li></ul><ul><li>Nephrotoxic, Cardiotoxic. </li></ul><ul><li>Oral </li></ul><ul><li>Dose:50mg-200/day </li></ul>Coxibs (etorocoxib, rofecoxib, parecoxib) Properties Route & formulations Drug Sr. no.
  32. 37. Non selective Vs selective COX2 inhibitors <ul><li>↑ risk of cardiovascular adverse events with COX 2 inhibitors </li></ul><ul><li>Rofecoxib was withdrawn from the market </li></ul><ul><li>Higher BP, incidence of myocardial infarction, stroke </li></ul><ul><li>Mechanism _ ? Unopposed effect of Cox 1 action </li></ul><ul><li> - ? Block protective effect of COX2 on </li></ul><ul><li> ischemic myocardium or atherogenesis </li></ul>
  33. 38. NSAIDs: Nursing Implications <ul><li>Before beginning therapy, assess for conditions that may be contraindications to therapy, especially: </li></ul><ul><ul><li>GI lesions or peptic ulcer disease </li></ul></ul><ul><ul><li>Bleeding disorders </li></ul></ul><ul><li>Assess also for conditions that require cautious use. </li></ul><ul><li>Perform lab studies as indicated (cardiac, renal, liver studies, CDC, platelet count). </li></ul>
  34. 39. NSAIDs: Nursing Implications <ul><li>Perform a medication history to assess for potential drug interactions. </li></ul><ul><li>Several serious drug interactions exist: </li></ul><ul><ul><li>alcohol </li></ul></ul><ul><ul><li>heparin </li></ul></ul><ul><ul><li>phenytoin </li></ul></ul><ul><ul><li>oral anticoagulants </li></ul></ul><ul><ul><li>steroids </li></ul></ul><ul><ul><li>sulfonamides </li></ul></ul>
  35. 40. NSAIDs: Nursing Implications <ul><li>Salicylates are NOT to be given to children under age 12 because of the risk of Reye’s syndrome. </li></ul><ul><li>Because these agents generally cause GI distress, they are often better tolerated if taken with food, milk or an antacid to avoid GI irritation. </li></ul><ul><li>Explain to patients that therapeutic effects may not be seen for 3 to 4 weeks. </li></ul>
  36. 41. NSAIDs: Nursing Implications <ul><li>Educate patients about the various side effects of NSAIDs, and to notify their physician if these effects become severe or if bleeding or GI pain occur. </li></ul><ul><li>Patients should watch closely for the occurrence of any unusual bleeding, such as in the stool. </li></ul><ul><li>Enteric-coated tablets should not be crushed or chewed. </li></ul>
  37. 42. NSAIDs: Nursing Implications <ul><li>Monitor for therapeutic effects, which vary according to the condition being treated: </li></ul><ul><ul><li>decrease in swelling, pain, stiffness, and tenderness of a joint or muscle area </li></ul></ul>
  38. 43. Summary
  39. 44. NSAIDs: Drug Effects <ul><li>Analgesic (mild to moderate) </li></ul><ul><li>Antigout </li></ul><ul><li>Antiinflammatory </li></ul><ul><li>Antipyretic </li></ul><ul><li>Relief of vascular headaches </li></ul><ul><li>Platelet inhibition (ASA) </li></ul>
  40. 46. NSAIDs: Therapeutic Uses <ul><li>Relief of mild to moderate pain </li></ul><ul><li>Acute gout </li></ul><ul><li>Various bone, joint, and muscle pain </li></ul><ul><li>Osteoarthritis </li></ul><ul><li>Rheumatoid arthritis </li></ul><ul><li>Juvenile rheumatoid arthritis </li></ul><ul><li>Dysmenorrhea </li></ul><ul><li>Fever </li></ul>
  41. 47. THANK YOU

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