NSAIDS

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NSAIDS

  1. 1. PGs and Eicosanoid antagonists Remaining portion of lec
  2. 3. EFFECTS OF PGs LT C4 & LTD4 BRONCHOCONSTRICTION LTB4 CHEMOTACTIC FACTOR PGE2 & PROSTACYCLIN VASODILATION PGE1 & DERIVATIVES PROTECTION ON GASTRIC MUCOSA PGE1 & PGE2 RELAX VASCULAR & OTHER SMOOTH MUSCLE THROMBOXANE PLATELET AGGREGATION
  3. 4. DRUGS <ul><li>PGE2 – dinoprostone, used at term before induction of labour with oxytocin </li></ul><ul><li>PGE1 – misoprostol, safest abortifacient and also to maintain patency of the ductus arteriosus in infants & to prevent peptic ulcers </li></ul><ul><li>PG12 – epoprostenol, in severe pulmonary hypertension & to prevent platelet aggregation in dialysis machines </li></ul>
  4. 5. <ul><li>PGE1 – alprostadil, in tx of impotence </li></ul><ul><li>PGF2a – latanoprost, used in glaucoma </li></ul><ul><li>bimatoprost, travoprost, noprostine </li></ul>
  5. 6. THERAPEUTIC EFFECTS <ul><li>Obstetrics </li></ul><ul><li>Pediatrics </li></ul><ul><li>Pulmonary hypertension & dialysis </li></ul><ul><li>Peptic ulcer associated with NSAID use </li></ul><ul><li>Urology </li></ul><ul><li>Ophthalmology </li></ul>
  6. 7. EICOSANOID ANTAGONISTS <ul><li>Corticosteroids_inhibit the synthesis of COX-2 </li></ul><ul><li>NSAIDS _inhibit cyclooxygenase and also thromboxane, prostaglandin, prostacyclin </li></ul><ul><li>Leukotriene antagonists_enzyme inhibitor drug, ZILEUTON and receptor blocker, ZAFIRLUKAST & MONTELUKAST_____used for ASTHMA </li></ul>
  7. 8. ANTI-INFLAMMATORY DRUGS NSAIDS RHEUMATOID ARTHRITIS GOUT
  8. 9. <ul><li>The inflammatory response is complex, involving immune system and various endogenous agents like PGs, bradykinin, histamine, chemotactic factors, superoxide free radicals formed by the action of lysosomal enzymes </li></ul>
  9. 10. ANTI-INFLAMMATORY DRUGS <ul><li>NSAIDS </li></ul><ul><li>COX-2 INHIBITORS </li></ul><ul><li>ACETAMINOPHEN </li></ul><ul><li>DRUGS FOR ARTHRITIS </li></ul><ul><li>DRUGS FOR GOUT </li></ul>
  10. 12. NSAIDS <ul><li>ASPIRIN & OTHER SALICYLATE DRUGS </li></ul><ul><li>PROPIONIC ACID DERIVATIVES </li></ul><ul><li>Ibuprofen </li></ul><ul><li>Naproxen </li></ul><ul><li>Fenoprofen </li></ul><ul><li>Ketoprofen </li></ul><ul><li>Flurbiprofen </li></ul><ul><li>Oxaprozin </li></ul>
  11. 13. <ul><li>ACETIC ACID DERIVATIVES </li></ul><ul><li>Indomethacin </li></ul><ul><li>Sulindac </li></ul><ul><li>Etodolac </li></ul><ul><li>OXICAM DERIVATIVES </li></ul><ul><li>Piroxicam </li></ul><ul><li>Meloxicam </li></ul>
  12. 14. <ul><li>FENAMATES </li></ul><ul><li>Mefenamic </li></ul><ul><li>meclofenamate </li></ul><ul><li>OTHER AGENTS </li></ul><ul><li>Diclofenac </li></ul><ul><li>Ketorolac </li></ul><ul><li>Tolmetin & Nabumetone </li></ul><ul><li>Diflunisal </li></ul>
  13. 15. COX-2 SELECTIVE NSAIDS <ul><li>Celecoxib </li></ul><ul><li>Valdecoxib </li></ul><ul><li>Rofecoxib </li></ul>
  14. 16. OTHER ANALGESICS OR NON-NARCOTIC ANALGESICS <ul><li>Acetaminophen </li></ul><ul><li>Phenacetin </li></ul>
  15. 17. ASPIRIN
  16. 18. <ul><li>Pharmacodynamics </li></ul><ul><li>Effects on different organ, tissue or cells </li></ul><ul><li>Pharmacokinetics </li></ul><ul><li>Therapeutic uses </li></ul><ul><li>Adverse effects </li></ul><ul><li>Toxicity by aspirin and treatment </li></ul><ul><li>Prescription to medically compromised patients </li></ul>
  17. 19. NSAID ↑ Leukocyte-Endothelial Interactions Capillary Obstruction Ischemic Cell Injury Proteases + Oxygen Radicals Endo/Epithelial Cell Injury Mucosal Ulceration Loss of PGE 2 and PGI 2 mediated inhibition of acid secretion and cytoprotective effect Loss of PGI 2 induced inhibition of LTB 4 mediated endothelial adhesion and activation of neutrophils
  18. 20. MECHANISM OF ACTION OR PHARMACODYNAMICS <ul><li>ANTI-INFLAMMATORY EFFECT </li></ul><ul><li>ANALGESICS EFFECT </li></ul><ul><li>ANTIPYRETIC EFFECT </li></ul>
  19. 21. ANTI-INFLAMMATORY EFFECT <ul><li>Is due to the inhibition of the enzyme prostaglandin H synthase ( cyclooxygenase or COX), which converts arachidonic acid to prostaglandins and to TXA2 & prostacyclin </li></ul><ul><li>Aspirin irreversibly inactivates COX-1 and COX-2 by acetylation of a specific serine residue. Its an important difference b/w other NSAIDS, which reversibly inhibit COX-1 and COX-2 </li></ul>
  20. 22. <ul><li>NSAIDS have no effect on lipoxygenase and thus do not inhibit the production of leukotrienes </li></ul>
  21. 23. ANALGESIC EFFECT <ul><li>It is related to the peripheral inhibition of prostaglandin production and it may also be due to the inhibition of pain stimuli at a subcortical site </li></ul><ul><li>NSAIDS prevent the potentiating action of PGs on endogenous mediators of peripheral nerve stimulation (eg, bradykinin) </li></ul>
  22. 24. ANTIPYRETIC EFFECT <ul><li>Its related to inhibition of the interlukin-1 & interlukin-6-induced production of PGs in the hypothalamus & the resetting of thermoregulatory system, leading to vasodilation and increased heat loss </li></ul>
  23. 25. PHARMACOKINETIC PROPERTIES <ul><li>Salicylates are weak organic acids, aspirin has a pKa of 3.5 </li></ul><ul><li>These agents are rapidly absorbed from the intestine as well as from the stomach, where low pHfavors absorption. The rate of absorption is increased with rapidly dissolving (buffered) or predissolved (effervescent) dosage forms </li></ul>
  24. 26. <ul><li>Salicylates are hydrolyzed rapidly by plasma and tissue esterases to acetic acid and the active metabolite salicylic acid </li></ul><ul><li>Half life 3-6 hrs after acute administration & chronic administration of high doses or toxic overdose increases the t1/2 to 15-30hrs – enzymes for glycine and glucuronide conjugation become saturated </li></ul><ul><li>Unmetabolized salicylates are excreted by the kidney </li></ul>
  25. 27. Actions of aspirin <ul><li>Anti-inflammatory – inhibits inflammation in arthritis </li></ul><ul><li>Analgesic action – repress sensation of pain, combination of opioids and NSAIDS are effective in treating pain caused by a malignancy </li></ul><ul><li>Antipyretic action- anterior hypothalamic thermoregulatory centre is elevated </li></ul>
  26. 28. <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>
  27. 29. <ul><li>GI system </li></ul><ul><li>PGI2 inhibits gastric acid secretion & PGE2 and PGF2a stimulate synthesis of protective mucus in stomach and small intestine </li></ul><ul><li>prostanoids are not formed, resulting in increased gastric acid secretion & diminished mucus protection – epigastric distress, ulceration or hemorrhage </li></ul><ul><li>Dose dependent hepatitis </li></ul><ul><li>Reye’s syndrome </li></ul>
  28. 30. <ul><li>Effect on platelets </li></ul><ul><li>Aspirin can irreversibly inhibit thromboxane production in platelets without affecting TXA2 production in the endothelial cells of the blood vessel </li></ul><ul><li>Platelet aggregation is reduced, producing an anticoagulant effect with a prolonged bleeding time </li></ul>
  29. 31. <ul><li>Actions on the kidney </li></ul><ul><li>Decreased synthesis of PGs can result in retention of sodium & water and may cause edema and hyperkalemia </li></ul><ul><li>Interstitial nephritis can also occur with all NSAIDS except aspirin </li></ul>
  30. 32. <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>
  31. 33. THERAPEUTIC USES <ul><li>Inflammation </li></ul><ul><li>NSAIDS are first-line drugs used to arrest inflammation & the accompanying pain of rheumatic and nonrheumatic diseases, including rheumatoid arthritis, juvenile arthritis, osteoarthritis, psoriatic arthritis, ankylosing spondylitis, Reiter’s syndrome, dysmennorhea </li></ul><ul><li>Bursitis & tendonitis also respond to NSAIDS </li></ul>
  32. 34. <ul><li>2. Analgesia-alleviate mild-moderate pain but less effective than opioids </li></ul><ul><li>more effective against pain associated with integumental structures than that associated with viscera </li></ul><ul><li>3. Antipyresis-reduce elevated body temperature </li></ul><ul><li>4. Miscellaneous uses </li></ul><ul><li>reduces formation of thrombi </li></ul><ul><li>is used prophylactically to reduce recurrent transient ischemia, unstable angina, incidence of thrombosis after coronary artery bypass grafts </li></ul>
  33. 35. <ul><li>5. Topically to treat corns, calluses & epidermophytosis </li></ul><ul><li>methyly salicylate- cutaneous counterirritant in liniments </li></ul><ul><li>6. Chronic use of aspirin reduces the incidence of colorectal cancer </li></ul>
  34. 36. ADVERSE EFFECTS <ul><li>Platelet Dysfunction </li></ul><ul><li>Gastritis and peptic ulceration with bleeding (inhibition of PG + other effects) </li></ul><ul><li>Acute Renal Failure in susceptible </li></ul><ul><li>Sodium+ water retention and edema </li></ul><ul><li>Analgesic nephropathy </li></ul><ul><li>Prolongation of gestation and inhibition of labor. </li></ul><ul><li>Hypersenstivity (not immunologic but due to PG inhibition) </li></ul>
  35. 37. <ul><li>Hypersensivity – urticaria, bronchoconstriction or angioedema, fatal anaphylactic shock (rare) </li></ul><ul><li>Reye syndrome (is an often fatal, fulminating hepatitis with cerebral edema), aspirin is given during viral infections and this occurs in children instead of aspirin, given acetaminophen to reduce fever </li></ul>
  36. 38. <ul><li>Drug interactions </li></ul><ul><li>The action of anticoagulants may be enhanced by their displacement by aspirin from binding sites on serum albumin. Aspirin displaces tolbutamide, phenytoin & others </li></ul><ul><li>Antacids may alter the absorption of aspirin </li></ul><ul><li>Aspirin competes for tubular reabsorption with penicillin G& prolongs its half life </li></ul><ul><li>Alcohol may increase GI bleeding when taken with alcohol </li></ul>
  37. 40. <ul><li>Headache - timmitus - dizziness – hearing impairment – dim vision </li></ul><ul><li>Confusion and drowziness </li></ul><ul><li>Sweating and hyperventilation </li></ul><ul><li>Nausea, vomiting </li></ul><ul><li>Marked acid-base disturbances </li></ul><ul><li>Hyperpyrexia </li></ul><ul><li>Dehydration </li></ul><ul><li>Cardiovascular and respiratory collapse, coma convulsions and death </li></ul>Aspirin Toxicity - Salicylism
  38. 41. <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
  39. 42. OTHER NSAIDS
  40. 43. PROPIONIC ACID DERIVATIVES <ul><li>DRUGS </li></ul><ul><li>Ibuprofen </li></ul><ul><li>Naproxen </li></ul><ul><li>Ketoprofen anti-inflammatory </li></ul><ul><li>Fenoprofen analgesic </li></ul><ul><li>Flurbiprofen antipyretic activity </li></ul><ul><li>oxaprozin </li></ul>
  41. 44. <ul><li>Used in chronic treatment of rheumatoid arthritis & osteoarthritis </li></ul><ul><li>Reversible inhibitors of cyclooxygenases </li></ul><ul><li>Well absorbed on oral administration </li></ul><ul><li>Bound to serum albumin </li></ul><ul><li>Hepatic metabolism & are excreted by the kidney </li></ul><ul><li>Adverse effects – GI; dyspepsia to bleeding; </li></ul><ul><li>CNS, headache, tinnitus, dizziness </li></ul>
  42. 45. ACETIC ACID DERIVATIVES <ul><li>DRUGS </li></ul><ul><li>Indomethacin anti-inflammatory </li></ul><ul><li>Sulindac analgesic </li></ul><ul><li>Etodolac anti-pyretic activity </li></ul><ul><li>Reversibly inhibiting </li></ul><ul><li>Cyclooxygenase </li></ul><ul><li>Generally not used to lower </li></ul><ul><li>fever </li></ul>
  43. 46. <ul><li>Indomethacin – use to treat acute gouty arthritis, ankylosing spondylitis , osteoarthritis </li></ul><ul><li>Sulindac – used in the treatment of rheumatoid arthritis, ankylosing spondylitis, osteoarthritis , acute gout ( less potent than indomethacin) </li></ul>
  44. 47. OXICAM DERIVATIVES <ul><li>DRUGS </li></ul><ul><li>Piroxicam used to treat rheumatoid </li></ul><ul><li>Meloxicam arthritis, ankylosing </li></ul><ul><li>spondylitis, osteoarthritis </li></ul>
  45. 48. FENAMATES <ul><li>DRUGS </li></ul><ul><li>Mefenamic acid </li></ul><ul><li>Meclofenamate </li></ul><ul><li>Side effects: diarrhea </li></ul><ul><li>hemolytic anemia </li></ul>
  46. 49. OTHER AGENTS <ul><li>DICLOFENAC </li></ul><ul><li>Long term use in the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis </li></ul><ul><li>More potent than indomethacin or naproxen </li></ul><ul><li>Ophthalmic preparation available </li></ul><ul><li>Diclofenac stimulates in synovial fluid </li></ul><ul><li>Route of excretion for drug and its metabolites in urine </li></ul>
  47. 50. <ul><li>KETOROLAC </li></ul><ul><li>Administered intramuscularly- tx of postoperative pain </li></ul><ul><li>Topically for allergic conjunctivitis </li></ul><ul><li>Hepatic metabolism </li></ul><ul><li>Metabolites eliminated via urine </li></ul><ul><li>TOLMETIN & NABUMETONE </li></ul><ul><li>Treating adult or juvenile rheumatoid arthritis or osteoarthritis </li></ul><ul><li>DIFLUNISAL </li></ul><ul><li>More potent than aspirin </li></ul>
  48. 51. COX-2-SELECTIVE NSAIDs <ul><li>CELECOXIB </li></ul><ul><li>More selective for inhibition of COX-2, its time-dependent & reversible </li></ul><ul><li>Used for the treatment of osteoarthritis & rheumatoid arthritis </li></ul><ul><li>Readily absorbed </li></ul><ul><li>Extensively metabolized in liver by cyt P450 </li></ul><ul><li>Excreted in the feces & urine </li></ul><ul><li>Half-life, 11 hrs </li></ul>
  49. 52. <ul><li>Adverse effects: </li></ul><ul><li>Abdominal pain </li></ul><ul><li>Diarrhea </li></ul><ul><li>Dyspepsia </li></ul><ul><li>Gastrointestinal ulcers </li></ul><ul><li>Chronic renal insufficiency </li></ul><ul><li>Severe heart disease shd be </li></ul><ul><li>Volume depletion avoided </li></ul><ul><li>Hepatic failure </li></ul><ul><li>Anaphylactoid reactions </li></ul><ul><li>CI , allergic to sulfonamides </li></ul>
  50. 53. <ul><li>Drug interactions </li></ul><ul><li>Inhibitors of CYP2C9, such as fluconazole, fluvastatin, zafirlukast, increse serum levels of celecoxib </li></ul><ul><li>It could elevate the level of some B-blockers, antidepressants, antipsychotic drugs </li></ul>
  51. 54. OTHER ANALGESICS <ul><li>ACETAMINOPHEN </li></ul><ul><li>Do not cause physical dependence or tolerance </li></ul><ul><li>It is a substitute for aspirin to treat mild to moderate pain for selected pts who are intolerant to aspirin, with gastric complaints </li></ul><ul><li>Acetaminophen does not antagonize the uricosuric agent probenecid, & may be used in pts with gout who are taking that drug </li></ul>
  52. 55. <ul><li>Rapidly absorbed </li></ul><ul><li>First pass metabolism – in luminal cells of intestine & hepatocytes </li></ul><ul><li>Is conjugated in liver to form inactive glucuronidated or sulfated metabolites </li></ul><ul><li>It is hydroxylated to form N-acetylbenzoiminoquinone – a highly reactive & potentially dangerous metabolites that reacts with sulfhydryl gps </li></ul><ul><li>At normal doses – forming nontoxic substance </li></ul><ul><li>Excretion in urine </li></ul>
  53. 56. <ul><li>ADVERSE EFFECTS </li></ul><ul><li>Skin rash </li></ul><ul><li>Minor allergic reactions </li></ul><ul><li>Alterations in leukocyte count </li></ul><ul><li>Renal tubular necrosis & hypoglycemic coma – rare </li></ul><ul><li>Hepatic necrosis </li></ul>
  54. 57. DISEASE-MODIFYING ANTIRHEUMATIC AGENTS
  55. 58. <ul><li>Methotrxate </li></ul><ul><li>Leflunomide </li></ul><ul><li>Chloroquine & hydroxychloroquine </li></ul><ul><li>D-Penicillamine </li></ul><ul><li>Gold salts </li></ul><ul><li>Anticytokine drugs in rheumatoid arthritis </li></ul>
  56. 59. Methotrexate <ul><li>Methotrexate – It is an immunopressant agent. used in rheumatoid or psoriatic arthritis, have not responded to aspirin </li></ul><ul><li>Adverse effects: mucosal ulceration & nausea, cytopenias, cirrhosis of liver, acute pneumonia like syndrome </li></ul>
  57. 60. Chloroquine & Hydroxychloroquine <ul><li>Used in rheumatic arthritis & malaria </li></ul><ul><li>Mechanism uncertain- inhibiting NA synthesis, they stabilize lysosomal membranes & trap free radicals </li></ul><ul><li>These drugs- slow progression of erosive bone lesions & may induce remission </li></ul>
  58. 61. Adverse effects <ul><li>Low doses- chemosuppression of malaria </li></ul><ul><li>Higher doses- GIT upset, pruritus, headaches, visual disturbances </li></ul><ul><li>Discoloration of nail beds & mucus memb. </li></ul><ul><li>Cautiously in pts with hepatic dysfunction or severe GI problems or in pts with neurologic or blood disorders </li></ul><ul><li>Dermatitis </li></ul><ul><li>Psoriasis or porphyria </li></ul>
  59. 62. LEFLUNOMIDE <ul><li>Immunomodulatory agent –causes cell arrest of autoimmune lymphocytes thru its action on dihydroorotate dehydrogenase (DHODH) </li></ul>
  60. 63. <ul><li>Dihydroorotate dihydroorotate orotate </li></ul><ul><li>dehydrogenase </li></ul><ul><li>Orotidine 5’monophosphate UMP </li></ul>
  61. 64. <ul><li>Well absorbed </li></ul><ul><li>Extensively bound to albumin </li></ul><ul><li>Half-life, 14-18 hrs </li></ul><ul><li>Rapidly metabolized </li></ul><ul><li>Excretion in urine and feces </li></ul><ul><li>Adverse effects, headache, nausea, diarrhea, weight loss, allergic reactions-flu like syndrome, skin rash, alopecia, hypokalemia </li></ul><ul><li>CI: in pregnancy & women of child bearing potential </li></ul><ul><li>Caution in pts with liver disease </li></ul>
  62. 65. <ul><li>D-Penicillamine – aacid of cysteine </li></ul><ul><li>Used in rheumatoid arthritis </li></ul><ul><li>Slow progress of bone destruction & rheumatoid arthritis </li></ul><ul><li>Adverse effects, dermatologic problems to nephritis, aplastic anemia </li></ul><ul><li>Chelating agent in tx of poisoning by heavy metals & also in treating cystinuria </li></ul>
  63. 66. <ul><li>GOLD SALTS , gold sodium thiomalate, aurothioglucose </li></ul><ul><li>Taken up by macrophages & suppress phagocytosis and lysosomal enzyme activity- retards progression of bone & articular destruction </li></ul>
  64. 67. ANTICYTOKINE THERAPIES IN RHEUMATOID ARTHRITIS <ul><li>Etanercept </li></ul><ul><li>Infliximab </li></ul><ul><li>Adalimumab </li></ul><ul><li>Anakinra </li></ul>
  65. 68. <ul><li>Etanercept </li></ul><ul><li>Tx in rheumatoid & psoriatic arthritis </li></ul><ul><li>Combination with methotrexate, more effective than alone </li></ul>
  66. 69. <ul><li>Infliximab </li></ul><ul><li>Monoclonal antibody </li></ul><ul><li>For Crohn’s disease & rheumatoid arthritis </li></ul><ul><li>Used in combination with Methotrxate </li></ul><ul><li>Adverse effects: </li></ul><ul><li>-Long term used, antibodies developed </li></ul><ul><li>-Infusion reactions, fever chill pruritus urticaria </li></ul><ul><li>-Leading to pneumonia & cellulitus </li></ul><ul><li>-Leukopenia, neutropenia, thrombocytopenia, pancytopenia </li></ul><ul><li>-Lymphoma </li></ul>
  67. 70. <ul><li>Adalimumab </li></ul><ul><li>Tx of rheumatoid arthritis </li></ul><ul><li>Recombinant monoclonal antibody –TNFa receptor site </li></ul><ul><li>Reaction ,rash, headache, nausea </li></ul><ul><li>Predisposed injection – pneumonia </li></ul><ul><li>Anakinra </li></ul><ul><li>Receptor antagonists to IL-1 </li></ul><ul><li>Tx of rheumatoid arthritis </li></ul>
  68. 71. GOUT
  69. 72. DRUGS USED IN THE TREATMENT OF GOUT <ul><li>Is a metabolic disorder – high levels of uric acid in the blood </li></ul><ul><li>Hyperuricemia results in the deposition of sodium urate crystals in tissues (kidney & joints) </li></ul><ul><li>Sodium urate is the end product of purine metabolism </li></ul><ul><li>Deposition of urate crystals initiates an inflammatory process involving infiltration of granulocytes that phagocytize urate crystals </li></ul>
  70. 73. <ul><li>Process generates oxygen metabolites, which damage tissue, release of lysosomal enzymes that evoke an tissues increases </li></ul>
  71. 74. Preventing deposition of urate crystals <ul><li>Interfering with uric acid synthesis with allopurinol </li></ul><ul><li>Increasing uric acid excretion with probenecid or sulfinpyrazone </li></ul><ul><li>Inhibiting leukocyte entry into the affected joint with colchicine </li></ul><ul><li>Administration of NSAIDs </li></ul>
  72. 75. <ul><li>DRUGS </li></ul><ul><li>Colchicine </li></ul><ul><li>Allopurinol </li></ul><ul><li>Uricosuric agents – Probenecid & </li></ul><ul><li>Sulfinpyrazone </li></ul>
  73. 76. COLCHICINE <ul><li>Treatment of acute gouty attacks </li></ul><ul><li>It binds tubulin, causes depolarization. Disrupts cellular functions, mobility of granulocytes, decreasing migration into affected area </li></ul><ul><li>Also inhibits synthesis and release of the leukotrienes </li></ul><ul><li>Adverse effects: nausea, vomiting, abdominal pain, diarrhea. Chr adm; myopathy, agranulocytosis, aplastic anemia, alopecia </li></ul>
  74. 77. <ul><li>CI: not be used in pregnancy </li></ul><ul><li>Caution in pts with hepatic, renal or CV disease </li></ul>
  75. 78. ALLOPURINOL <ul><li>Reduces production of uric acid by competitive inhibits – xanthine oxidase </li></ul><ul><li>Treatment of primary hyperuricemia of gout & secondary to other conditions, like malignancies or in renal disease </li></ul><ul><li>Alloxathine (oxypurinol) – xanthine oxidase inhibitor </li></ul><ul><li>Adverse effects; hypersensitivity reactions, nausea, diarrhea, </li></ul>
  76. 79. <ul><li>Drug interaction; interferes with metabolism of anti-cancer agent 6-mercaptopurine & azathioprine (immunosuppressant), requiring a reduction in dosage </li></ul>
  77. 80. Probenecid & Sulfinpyrazone <ul><li>Are organic weak acids that reduce urate levels by acting at anionic transport site in the renal tubule to prevent reabsorption of uric acid </li></ul><ul><li>Used for chronic gout </li></ul><ul><li>Undergo rapid oral absorption </li></ul><ul><li>Inhibit excretion of other drugs (penicillin, NSAIDs, cephalosporins, methtrexate) that are actively secreted by renal tubules </li></ul>
  78. 81. <ul><li>Increased urinary concentration of uric acid - urolithiasis. This risk is decreased with ingestion of large volumes of fluid or alkalinization of urine with potassium citrate </li></ul><ul><li>Low doses of uricosuric agents & salicyltes inhibit uric acid secretion. </li></ul><ul><li>Aspirin is CI in gout </li></ul><ul><li>Adverse effects; GI disturbances, dermatiitis, blood dyscrasias (rare) </li></ul>
  79. 82. Tx – ACUTE GOUT <ul><li>Excessive alcohol consumption, diet rich in purines, kidney disease </li></ul><ul><li>Tx – indomethacin; decrease movement of granulocytes into affected area & NSAIDs ; decrease pain and inflammation </li></ul>
  80. 83. Tx – CHRONIC GOUT <ul><li>Genetic defect- increase in rate of purine synthesis, renal deficiency, lesch-nyhan syndrome, increase synthesis of uric acid with cancer chemotherapy </li></ul><ul><li>Tx – uricosuric drugs, allopurinol </li></ul>
  81. 84. ANTITUSSIVES
  82. 85. COUGH <ul><li>Cough receptors, specialized stretch receptors in the trachea & bronchial tree, send vagal afferents to cough centre & trigger the cough reflex </li></ul>
  83. 86. ANTITUSSIVE AGENTS <ul><li>Codeine, Hydrocodone, Hydromorphone </li></ul><ul><li>Dextromethorphan </li></ul><ul><li>Benzonatate </li></ul><ul><li>Diphenhydramine </li></ul>
  84. 87. Codeine, Hydrocodone, Hydromorphone <ul><li>Decrease sensitivity of central cough centre to peripheral stimuli & decrease mucosal secretions </li></ul><ul><li>Actions occur at doses lower than those required for analgesia </li></ul><ul><li>Produce constipation, nausea , respiratory depression </li></ul>
  85. 88. DEXTROMETHORPHAN <ul><li>L-isomer opioid </li></ul><ul><li>Active as an antitussive </li></ul><ul><li>Devoid of analgesic or addictive liability </li></ul><ul><li>Less constipating than codeine </li></ul>
  86. 89. BENZONATE <ul><li>Glycerol derivative chemically similar to procaine </li></ul><ul><li>Reduces activity of peripheral cough receptors </li></ul><ul><li>Also reduce threshold of central cough centre </li></ul>
  87. 90. DIPHENHYDRAMINE <ul><li>Antitussive activity is not mediated at H1 receptor </li></ul><ul><li>Acts centrally to decrease the sensitivity of cough centre to afferents </li></ul>
  88. 91. LEVOPROPOXYPHENE <ul><li>Weak opioid agonist dextropropoxyphene </li></ul><ul><li>Sedation as a side effects </li></ul><ul><li>50-100mg every 4 hrs </li></ul>
  89. 92. DEXTROMETHORPHAN <ul><li>Methylated derivative of levorphanol </li></ul><ul><li>Free of addictive properties & produces less constipation than codeine </li></ul>

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