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Non steroidal anti inflammatory drugs (NSAIDS)

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pharmacology of NSAIDs

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Non steroidal anti inflammatory drugs (NSAIDS)

  1. 1. NonSteroidalAntiInflammatoryDrugs (NSAIDs) Girmay F. girmaytg@yahoo.com 1
  2. 2. Presentation outline  Introduction  Mechanism of Action  Pharmacokinetics  Clinical Effects  Drug interaction  Diclofenac  Ketorolac  Aspirin(Acetyl Salicyclic Acid) 2
  3. 3. Introduction  A heterogeneous class of drugs grouped together by their common Anti-inflammatory , Analgesic and Anti- pyretic properties.  Used for Rx of  Mild-to moderate pain  Chronic inflammation  Post –op pain where they have an opioid sparing effect. 3
  4. 4.  Most are organic acids.  conventional NSAIDs can be grouped according to their chemical structure 4
  5. 5. Mechanisms of Action  Inhibition of the enzyme cyclooxygenase.  Reduce the production of :  Prostaglandin synthesis (PGH2, PGE2, PGF2).  Leukotrienes, prostacyclins.  Thromboxanes . 5
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  7. 7. Prostaglandins (PGs) : PGE2,PGD2,PGF2 o present in all organs and are synthesised in most cells of the body. o Act locally producing many diverse effects via GPC membrane receptors. oThey have a variety of effects on Glandular secretions, Renal function , Peripheral blood vessels and Smooth muscles. 7
  8. 8.  Involved in the modulation of pain both at peripheral and central sites.  PGs sensitize primary nerve endings in the periphery to the algesic action of agents (such as bradykinin, histamine and serotonin) produced as part of the inflammatory response to tissue injury. 8
  9. 9.  Spinal and Supra spinal analgesic effects are due to modulation of the spinal actions of NMDA and Substance P.  NSAIDs may also have direct inhibitory effects on neutrophils activation and function in inflamed tissues. 9
  10. 10. Mechanism of action antipyretic: 1. Inhibition of production of prostaglandins induced by interlukin-1 (IL-1) and interlukin-6 (IL-6) in the hypothalamus 2. the resetting of the thermoregulatory system, leading to vasodilatation and increased heat loss. 10
  11. 11.  The COX enzyme has two distinct isoforms termed COX-1 and COX-2.  These two enzymes are coded for by two genes and expressed differentially in various tissues. 11
  12. 12.  COX-1:  being “constitutive” .  is expressed continuously in many tissues, for example kidneys, stomach, lung liver and platelets.  It is involved in various protective homeostatic Mechanisms, for example Renal blood flow, Gastric mucosal integrity and platelet aggregation. 12
  13. 13.  COX-2:  being “inducible”, such that it is not normally present in any appreciable quantity in tissues.  its production is induced in sites of inflammation and tissue injury by cytokines (e.g. interleukin-1) and tumor necrosis factor alpha. 13
  14. 14.  Conventional NSAIDs inhibit both enzymes; inhibition of COX-1 accounting for most of the unwanted side effects of NSAIDs and inhibition of COX-2 accounting for the therapeutic effects.  In theory the ‘perfect’ NSAID would therefore only inhibit COX-2, leaving COX-1 to continue with normal homeostatic processes. 14
  15. 15.  Selective COX2 Inhibitor( coxibs)  Celecoxib  Etoricoxib  parecoxib.  Rofecoxib 15
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  17. 17.  effective against pain associated with integumental structures (pain of muscular and vascular origin, arthritis, and bursitis) than with pain associated with the viscera.  Have an opioid -sparing effect after abdominal, thoracic and orthopaedic surgery.  less sedation, improved respiratory function, less urinary retention 17
  18. 18. Pharmacokinetics  NSAIDs are weak organic acids(pKa=3-5)  Rapidly absorbed in the acid environment of the stomach.  Low first-pass metabolism and a high oral bio- availability.  Exception: Diclofenac has a high hepatic metabolism resulting in a bio availability of 60%. 18
  19. 19.  highly protein-bound and have the potential to displace other drugs from plasma proteins so potentiating the effects these drugs (oral anti coagulants ,anti convulsants ,lithium and oral hypoglycemic agents).  In general , NSAIDs are eliminated by Hepatic Biotransformation followed by Renal excretion 19
  20. 20. Clinicaleffects/Sideeffects 1. Gastrointestinal tract  PGE2 have a ‘Gastro-protective effect’  a decrease in gastric acid production  an increase in production of the protective gastric mucosal barrier and an increase in local gastric mucosal blood flow.  NSAIDs : Decrease prostaglandin production and may also cause damage to the gastric mucosa by a direct contact physiochemical effect. 20
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  23. 23.  Aspirin, acts in a non-competitive manner by irreversibly inactivating COX. Platelets cannot synthesis proteins de novo, and are therefore unable to produce “new” COX enzyme, thereby rendering them ineffective for their lifespan of up to ten days.  It is for this reason that aspirin must be discontinued for (1-2 weeks) prior to elective surgery. 23
  24. 24.  PGI2, produced by normal endothelium,  inhibit platelet aggregation, antithrombotic properties of intact blood vessels.  vasodilatation of vascular beds exception the pulmonary vasculature where they cause vasoconstriction.  PGI2 is COX-2 dependent, higher risk of cardiovascular side effects seen with some COX-2 selective NSAIDs. 24
  25. 25.  A small increase in MI risk is associated with the long-term use of certain NSAIDs (e.g. Diclofenac), others confer no increased risk (ibuprofen) or perhaps even slightly reduce the risk (Naproxen).  The greatest risk appears to be with the long-term use of COX-2 inhibitors, this has been shown to be associated with 25
  26. 26. 3. Renal:  In patients with heart failure, chronic renal failure and/or Hypovolaemia, renal blood flow is much more dependent on prostaglandin-induced vasodilatation .  NSAID induced reduction in prostaglandin levels can precipitate acute renal failure. 26
  27. 27.  prostaglandins normally inhibiting ADH hormone production leads to excretion sodium and water.  NSAIDS increase retention with the risk of oedema and/or hypertension.  All NSAIDs are contraindicated in patients with heart failure and renal failure. 27
  28. 28. 4. Obstetrics  PGs are important for initiating labour .  NSAID usage can lead to prolonged labour and a NSAID (commonly rectal Indometacin) is sometimes used as a tocolytic in premature labour.  potentially serious side effects including fetal oligiuria, and premature closure of the ductus arteriosus. 28
  29. 29.  NSAID-induced closure in utero can lead to pulmonary hypertension and myocardial infarction.  It may increase the risk if miscarriage. The effect seems to be greatest if NSAIDs are used for more than a week and around the time of conception. 29
  30. 30. 5.Respiratorysystem:  Bronchospasm in susceptible individuals. ’Aspirin- induced asthma ‘ affects between 10 and 20% of adults with asthma, and bronchospasm can be severe and fatal.  Hyper sensitivity reactions ,urticaria ,rashes and angio- oedema have been reported. 30
  31. 31.  These Rxns are due to COX inhibition w/c increase arachidonic acid levels and increases metabolism via lipoxygenase pathway to form of leukotrienes. 31
  32. 32. Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000) 32
  33. 33. Summery Common Adverse Effects Gastritis and peptic ulceration with bleeding (inhibition of PG + other effects)  GIT bleeding and perforation o Platelet Dysfunction  Acute Renal Failure in susceptible  Sodium+ water retention and edema  Analgesic nephropathy  Prolongation of gestation and inhibition of labor.  Hypersensitivity (not immunologic but due to PG inhibition) 33
  34. 34. Drug interactions  can interact with other drugs in various ways.  Firstly, as a result of their potential effect on renal function the plasma levels of other drugs may be affected (e.g. lithium).  NSAIDs may compound the effects of another drug. For example, patients taking an NSAID and Warfarin are at greater risk of severe hemorrhage  an elevated INR which may occur in patients taking warfarin and a concomitant NSAID. 34
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  36. 36. DICLOFENAC KETOROLAC ASPIRIN(ASA) 36
  37. 37. DICLOFENAC  A phenylacetic acid derivatives.  Potent anti inflammatory and analgesic properties.  It has a great affinity for COX than other NSAIDs.  Potent inhibitors of PGs synthesis.  A central analgesic action is mediated by endogenous opioids .  Higher therapeutic ratio than most NSAIDs. 37
  38. 38.  Indication:  mild to moderate pain.  For relief of signs and symptoms of osteoarthritis, rheumatoid arthritis and  For acute or long-term use in the relief of signs and symptoms of ankylosing spondylitis. 38
  39. 39. Pharmacokinetics  Absorption  Diclofenac is 100% absorbed after oral administration compared to IV administration as measured by urine recovery.  Due to first-pass metabolism, only about 50% of the absorbed dose is systemically available 39
  40. 40.  Distribution  More than 99% bound to human serum proteins, primarily to albumin.  Serum protein binding is constant over the concentration range (0.15 to 105 mcg/mL) achieved with recommended doses. 40
  41. 41.  Excretion: eliminated via metabolism and subsequent urinary and biliary excretion of the glucuronides and the sulfate conjugates of the metabolites.  Little or no free unchanged diclofenac is excreted in the urine  65% of the dose is excreted in the urine and approximately 35% in the bile as conjugates. 41
  42. 42.  Metabolism:  Five diclofenac metabolites have been identified in human plasma and urine. The metabolites include  4'-hydroxy-, 5-hydroxy, 3'-hydroxy-, 4',5-dihydroxy- and 3'- hydroxy-4'-methoxy Diclofenac.  Diclofenac metabolites undergo further glucuronidation and sulfation followed by biliary excretion. 42
  43. 43.  Dose:  Paediatric ; PO/PR:1mg/kg tds, maximum 3mg/kg/day(>1yr).  Adult : PO/PR: 25-50mg tds(or 100mg 18-hourly)  Maximum 150 mg/day  Onset of action: 30 minutes.  Duration of action: up to 8 hours. 43
  44. 44.  Cautions C/I :  Hypersensitivity to aspirin  Asthma  Severe renal impairment  Peptic ulceration 44
  45. 45. KETOROLAC  A pyrrole acetic acid derivatives  More effective as analgesic than as anti inflammatory and anti pyretic drug.  The trimethamine salt possesses sufficient water solubility to allow it to be given IV or IM injection  Dose:10-30mg 45
  46. 46. ASPIRIN(ASA)  Derivative of salicylic acid  Weak organic acids , Pka of 3.5  Rapid absorption in the stomach mainly in the unionized form.  Salicylate anion trapping can occur in the alkaline env’t of the stomach and absorption may occur in the small intestine . 46
  47. 47. MOA: Irreversible, non-selective COX inhibitor(causes acetylation of COX) .  Low dose- analgesic-antipyretics,300-600mg,6-8 hourly  inhibition of PGs in the periphery and has some central action.  Standard anti inflammatory agent, Most potent  High dose-anti inflammatory(3to 6g). 47
  48. 48.  Pharmacokinetics:  Rapidly absorbed from the stomach and upper GI.  Peak plasma level within 2hrs.  Hydrolyzed by plasmaesterasein blood ,liver and tissue to: Acetic acid and salicylates .  Salicylates are mainly metabolized in the liver to salicyluric acid and glucuronides . there fore Readily excreted by the kidney. 48
  49. 49. Clinical application A. Anti inflammatory Action: • Aspirin irreversibly inactivates COX-1 and COX-2 by acetylation of a specific serine residue.  prevent PG(PGE and PGF) synthesis.  Inhibits migration PMNL and Macrophages into sites of inflammation.  Inhibits granulocytes adhesion. 49
  50. 50.  used to treat:  rheumatoid arthritis ,Rheumatic fever ,juvenile arthritis , osteoarthritis and other inflammatory disorders. B. Cardio protective; Low dose aspirin (75mg/day) has been shown to reduce the risk of TIA secondary to MI. 50
  51. 51. C.Prevention of pre- eclampsia D. As analgesic : 300 to 600 mg during 6 to 8 h for headache, backache, pulled muscle, toothache, neuralgias.  Aspirin is a weaker analgesic than morphine-type drugs  Aspirin 600 mg < Codeine 60 mg < 6 mg Morphine 51
  52. 52. Side effects  Platelet dysfunction  GI problems  Acute Renal Failure in susceptible ,Sodium+ water retention and edema.  Hypersensitivity reaction ,aspirin induced asthma in susceptible individuals. 52
  53. 53. C/I andCautions  should not be given to children under 15 years unless specifically indicated, e.g. for juvenile arthritis (paracetamol is preferred).  Reyes syndrome  liver dysfunction and Encephalopathy following an acute viral illness which has a mortality rate of 20-40%. 53
  54. 54.  C/I  in patients with bleeding disorders  Salicylates are not recommended during pregnancy; they may induce:  postpartum hemorrhage  premature closure of the fetal ductus arteriosus. 54
  55. 55. Salicylism o Chronic ingestion of large dose of aspirin /Over dose (toxicity) when the amount of aspirin ingested is >150- 175mg/kg.  Characterized by ; o Tinnitus , dizziness, ,deafness, sweating and Hyperthermia . o CNS stimulation – agitation, confusion and convulsion o CNS depression –stupor, coma. 55
  56. 56.  Effect on Respiration: triphasic 1. Low doses: uncoupling phosphorylation → ↑ CO2 → stimulates respiration. 2. Direct stimulation of respiratory center → Hyperventilation → resp. alkalosis → renal compensation 3. Depression of respiratory center and cardiovascular center → ↓ BP, respiratory acidosis, no compensation + metabolic acidosis also 56
  57. 57. Treatment of Aspirin Toxicity 1. Correction of acid—base disturbances 2. Replacement of electrolytes and fluids 3. Cooling 4. Alkalinization of urine with bicarbonate to reduce salicylate reabsorption 5. Forced diuresis, hemodialysis 6. Gastric lavage or emesis 57
  58. 58. NSAID Therapy Guidelines  The lowest dose for the shortest duration of therapy that accomplishes the therapeutic goal should be used  Most NSAIDs are not used in children, however ibuprofen is an exception 58
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