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Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
Nsai Ds, Dmar Ds & Antigout1
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Nsai Ds, Dmar Ds & Antigout1

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  • 1. Nonsteroidal Anti-inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout Florencia D. Munsayac, MD, MBA, RMT
  • 2. The Inflammatory Response <ul><li>3 Phases of Inflammation: </li></ul><ul><li>Acute Inflammation/acute phase </li></ul><ul><li>The Immune Response/sub-acute or delayed phase </li></ul><ul><li>Chronic Inflammation/chronic proliferative phase </li></ul>
  • 3. Some of the mediators of acute inflammation & their effects - +++ - Leukotrienes + +++ +++ Prostaglandins +++ - +++ Bradykinin - - +/- Serotonin - - ++ Histamine Pain Chemotaxis Vascular Permeability Vasodilation Mediators
  • 4. Some of the Mediators of Chronic Inflammation Fibroblast chemotaxis, proliferation Macrophages, endothelial cells, fibroblasts, platelets PDGF Many Macrophages, endothelial cells, T lymphocytes Interferons PG production Macrophages TNF-alpha Macrophage & granulocyte activation T lymphocytes, endothelial cells, fibroblast GM-CSF Lymphocyte activation, PG production Macrophages, T lymphocytes Interleukins-1, -2, and -3 Primary Effects Sources Mediators
  • 5. Rheumatoid arthritis <ul><li>Chronic inflammation -> pain & destruction of bone & cartilage </li></ul><ul><li>An autoimmune disease </li></ul>
  • 6. Goals of Therapy <ul><li>- Relief of pain </li></ul><ul><li>Reduction of inflammation </li></ul><ul><li>Protection of articular structures </li></ul><ul><li>Maintenance of function </li></ul><ul><li>Control of systemic involvement </li></ul>
  • 7. 5 General Approaches <ul><li>NSAIDs and simple analgesics </li></ul><ul><ul><li>to control the s/s of local inflammatory process </li></ul></ul><ul><ul><li>Minimal effect on the progression of the disease </li></ul></ul><ul><ul><li>Groups of NSAIDs </li></ul></ul><ul><li>Salicylic acid derivatives (Aspirin, Na salicylate, choline Mg++ trisalicylate, salsalate, diflunisal, sulfasalazine) </li></ul><ul><li>Para-chlorobenzoic acid derivatives or indoles (Indomethacin, Sulindac) </li></ul><ul><li>Pyrazolone derivatives (Phenylbutazone) </li></ul><ul><li>Arylpropionic acid (Ibuprofen, Flurbiprofen, Ketoprofen, Fenoprofen, Naproxen, Oxaprozin) </li></ul>
  • 8. 5 General Approaches <ul><li>NSAIDs and simple analgesics </li></ul><ul><ul><li>to control the s/s of local inflammatory process </li></ul></ul><ul><ul><li>Minimal effect on the progression of the disease </li></ul></ul><ul><ul><li>Groups of NSAIDs </li></ul></ul><ul><li>Fenamates/Anthranilic acids (Mefenamic Acid, Meclofenamic acid) </li></ul><ul><li>Enolic acids/Oxicams (Piroxicam) </li></ul><ul><li>Heteroaryl/Penylacetic acids (Diclofenac Sodium, Tolmetin, ketorolac) </li></ul><ul><li>Alkalones (Nabumetone) </li></ul><ul><li>Selective COX-2 inhibitors (Celecoxib, Rofecoxib, Meloxicam) </li></ul><ul><li>Para-aminophenol (Acetaminophen) </li></ul>
  • 9. 5 General Approaches <ul><li>Glucocorticoids </li></ul><ul><ul><li>To suppress s/s of inflammation </li></ul></ul><ul><ul><li>Retard the development & progression of bone erosions </li></ul></ul><ul><li>DMARDs </li></ul><ul><ul><li>Methotrexate, sulfasalazin, hydroxychloroquine, gold salts, or D-penicillamine </li></ul></ul><ul><ul><li>Have the capacity to decrease elevated levels of acute phase reactants -> modify inflammatory component & its destructive capacity </li></ul></ul>
  • 10. 5 General Approaches <ul><li>Biologics </li></ul><ul><ul><li>TNF-neutralizing agents: infliximab, etanercept, & adalimumab </li></ul></ul><ul><ul><li>IL-1 neutralizing agents: anakinra </li></ul></ul><ul><ul><li>Depletes B cells: rituximab </li></ul></ul><ul><ul><li>Interferes T cell activation: abatacept </li></ul></ul><ul><li>Immunosuppressive & Cytotoxic agents </li></ul><ul><ul><li>Leflunomide, cyclosporine, azathioprine, cyclophosphamide </li></ul></ul><ul><ul><ul><li>Shown to ameliorate the disease process </li></ul></ul></ul>
  • 11.  
  • 12. Types of Cyclooxygenases / Prostaglandin G/H synthase <ul><li>COX 1 - involved in tissue hemeostasis </li></ul><ul><li>COX 2 - responsible for the production of the prostanoid mediators of inflammation (IL-1 and TNF-  ) </li></ul><ul><li>COX 3 </li></ul>
  • 13. Three major types of effects of NSAIDs <ul><li>Anti-inflammatory </li></ul><ul><li>Analgesic </li></ul><ul><li>Antipyretic </li></ul><ul><ul><li>related to their primary action: inhibition of arachidonate cyclooxygenase, -> inhibition of prostaglandin and thromboxanes. </li></ul></ul>
  • 14. Other Effects of NSAIDs <ul><li>Strong O2-radical scavenging effects decrease tissue damage </li></ul><ul><li>Inhibit platelet aggregation except COX 2 selective inhibitors </li></ul><ul><li>Gastric irritants </li></ul><ul><li>Nephrotoxicity </li></ul><ul><li>Hypertensive complications </li></ul><ul><li>hepatotoxicity </li></ul>
  • 15. NSAIDs: Pharmacokinetics <ul><li>Weak organic acid, except Nabumetone </li></ul><ul><li>Well absorbed </li></ul><ul><li>food does not change their bioavailability, except Fenoprofen & Piroxicam </li></ul><ul><li>Highly metabolized: CYP3A or CYP2C </li></ul><ul><li>Renal excretion: most important route of final elimination </li></ul><ul><li>Biliary excretion & reabsorption (enterohepatic circulation) </li></ul><ul><li>Highly protein bound (~ 98%): albumin </li></ul><ul><li>Found in synovial fluid </li></ul>
  • 16. Aspirin or Acetylsalicylic Acid (ASA) <ul><ul><li>Comes from the family of salicylates </li></ul></ul><ul><ul><li>derived from salicylic acid </li></ul></ul><ul><ul><li>Prototype drug </li></ul></ul><ul><ul><li>Developed in 1899 by Adolph Bayer </li></ul></ul><ul><ul><li>The oldest anti-inflammatory agent </li></ul></ul><ul><ul><li>Rarely used as an anti-inflammatory medication </li></ul></ul>
  • 17. Aspirin or Acetylsalicylic Acid (ASA) Pharmacokinetics <ul><li>Rapidly absorbed from the stomach & upper small intestine </li></ul><ul><li>Peak plasma level: 1-2 hrs </li></ul><ul><li>80-90% protein bound </li></ul><ul><li>t1/2: 15 minutes </li></ul><ul><li>Cross BBB & placental barrier </li></ul><ul><li>Undergoes hepatic metabolism </li></ul><ul><li>Excretion: kidneys </li></ul>
  • 18. Aspirin or Acetylsalicylic Acid (ASA) Mechanisms of Action <ul><li>- Inhibits prostaglandin synthesis </li></ul><ul><li>- Irreversibly blocks the enzyme cyclooxygenase (PG synthase) </li></ul><ul><li>. Pharmacological Properties & Therapeutic indications: </li></ul><ul><li>- anti-inflammatory effects </li></ul><ul><li>- analgesic effects </li></ul><ul><li>- antipyretic effects </li></ul><ul><li>- Platelet effects </li></ul><ul><li>- Uricosuric effects </li></ul><ul><li>. Dosage: children: 50-75mg/kg/day </li></ul><ul><li> adult: 325-650mg p.o. q 4 hrs </li></ul>
  • 19. Aspirin or Acetylsalicylic Acid (ASA) Adverse Effects <ul><li>Gastric upset </li></ul><ul><li>Salicylism  vomiting, tinnitus, decreased hearing, & vertigo </li></ul><ul><li>Hyperpnea </li></ul><ul><li>Respiratory alkalosis  later acidosis supervenes </li></ul><ul><li>Glucose intolerance </li></ul><ul><li>Cardiotoxicity </li></ul><ul><li>Increases uric acid levels </li></ul><ul><li>Elevation of liver enzymes, hepatitis, decreased renal function, bleeding, rashes, asthma </li></ul><ul><li>Reye’s syndrome </li></ul>
  • 20. Aspirin or Acetylsalicylic Acid (ASA) Contraindications <ul><li>Pregnancy </li></ul><ul><li>Severe hepatic damage </li></ul><ul><li>Vitamin K deficiency </li></ul><ul><li>Hypoprothrombinemia </li></ul><ul><li>Hemophilia </li></ul><ul><li>PUD </li></ul><ul><li>Viral (chickenpox & influenza) </li></ul>
  • 21. Aspirin or Acetylsalicylic Acid (ASA) Drug Interactions <ul><li>Indomethacin, Naproxen </li></ul><ul><li>Ketoprofen, Fenoprofen </li></ul><ul><li>Warfarin </li></ul><ul><li>Sulfonylureas, Methotrexate </li></ul><ul><li>Spironolactone </li></ul><ul><li>Penicillin </li></ul>
  • 22. COX-2 Selective Inhibitors <ul><li>Were developed in an attempt to inhibit PG synthesis by the COX-2 iso-enzyme without affecting the action of COX-1 found in the GIT, kidneys & platelets </li></ul><ul><li>At usual dose: no impact on platelet aggregation </li></ul><ul><li>Do not offer cardio-protective effects </li></ul><ul><li>Suggested a higher incidence of CV thrombotic events: rofecoxib & valdecoxib </li></ul>
  • 23. COX-2 Selective inhibitors Inc BP, MI, inc transaminases MI, CVA/HTN, CHF, Stevens-Johnson syndrome Slightly less ulcerogenic dyspepsia Side Effects 40% decreased in elderly kidney Affected by hepatic impairment Excretion liver CYP2C9 Metabolism 1-3 hrs Peak Plasma concentration high Protein binding 24 hrs 8-11 hours 20% 20-26% 11 hrs Half-life Rapid & well absorbed 15 minutes (IV, IM) 1-2 hours Slowly absorb 83% 20-30% (affected by food) Absorption Lumiracoxib Parecoxib Valdecoxib/ Rofecoxib Meloxicam Etoricoxib Celecoxib Drugs
  • 24. Non-selective COX inhibitors (Heteroacyl/Phenylacetic acid derivative) Somnolence, dizziness, HA, dyspepsia, nausea pain at injection site GI distress, Occult GI bleeding, Gastric ulceration,  amino-transferases Side effects Urine (90%) Biliary (30%) & urine (65%) Excretion CYP3A4 & CYP2C9 Metabolism 80% 80% 30-70% Bioavailability 30-50 min. Peak Plasma Concentration 99% 99% 99% Protein-binding 4-6 hours 7 hours 1-2 hours Half-life Rapid (oral, IM), IV, oral rinse, topical Rapid, well absorbed rapid Absorption Ketorolac Etodolac Diclofenac Drugs
  • 25. Non-selective COX inhibitors (Salicylic acid derivative) Diflunisal <ul><li>Derived from salicylic acid </li></ul><ul><li>Not metabolized to salicylic acid or salicylate </li></ul><ul><li>Undergoes enterohepatic cycle with reabsorption of its glucoronide metabolite </li></ul><ul><li>T1/2: 13 hours </li></ul><ul><li>Uses: cancer pain with bone metastases & pain control in dental (3 rd molar) surgery </li></ul><ul><li>Preparation: 2% oral ointment </li></ul><ul><li>dosage: 500-1000mg daily in 2 divided doses </li></ul>
  • 26. Non-selective COX inhibitors (Propionic acid derivative) Probenecid Drug Interactions GIT & CNS (30%) GI irritation & bleeding Interstitial nephritis, GI irritation, tinnitus, rash pruritus Side effects urine urine Excretion CYP2C8 & CYP2C9 Extensive hepatic Extensive hepatic Metabolism 1-2 hours 1-2 hours 2 hours Peak Plasma Concentration 99% 99% 99% Protein-binding 1-3 hours 1-2 hours 0.5-4 hours 2-4 hours Half-life Well absorbed Rapid, incomplete Absorption Ketoprofen Ibuprofen Flurbiprofen Fenoprofen Drugs
  • 27. Non-selective COX inhibitors (Propionic acid derivative) UGIB, allergic pneumonitis, leukocytoclastic vasculitis, pseudoporphyria Side effects Excretion CYP2C9, less in CYP1A2 & CYP2C8 Metabolism Bioavailability Peak Plasma Concentration high Protein-binding 50-60 hours 10-16 hours 1-2 hours, 2-4 hours (elderly) 12 hours Half-life Absorption Oxaprozin Caprofen Tiaprofen Naproxen Drugs
  • 28. Non-selective COX inhibitors (Para-chlorobenzoic acid derivative or indole) Indomethacin <ul><li>Introduced in 1963 </li></ul><ul><li>A more potent analgesic, antipyretic & anti-inflammatory agent than ASA </li></ul><ul><li>May also inhibit phospholipase A & C </li></ul><ul><li>Reduce PMN migration </li></ul><ul><li>Decrease T & B cells proliferation </li></ul>
  • 29. Non-selective COX inhibitors (Para-chlorobenzoic acid derivative or indole) Furosemide, thiazide, beta blockers, ACEI, probenecid Drug interaction GIT, CNS, hematologic, renal, allergic reactions GIT, CNS, hematologic, psychosis w/ hallucination Side effects Urine, bile, feces Urine, bile, feces Excretion First pass hepatic, sulfide, active metabolite Liver Metabolism 1 hour, t1/2: 7 hours 2 hours Peak concentration 90% absorption Rapid & almost complete Absorption Sulindac Indomethacin Drugs
  • 30. Non-selective COX inhibitors (Fenamates/Anthranilic Acid) Meclofenamate & Mefenamic acid <ul><li>Inhibit both COX & phospholipase A2 </li></ul><ul><li>Peak plasma level: 30-60 min </li></ul><ul><li>t1/2: 1-3 hrs </li></ul><ul><li>SE: LBM, abdominal pain (meclofenamate) </li></ul><ul><li>CI: pregnancy, children </li></ul><ul><li>DI: oral anticoagulants </li></ul><ul><li>Indications: Primary Dysmenorrhea </li></ul>
  • 31. Non-selective COX inhibitors (Alkalones) Nabumetone <ul><li>The only nonacid NSAID, causes less gastric damage </li></ul><ul><li>Converted to the active metabolites in the liver, 6-methoxy-2 naphthylacetic acid </li></ul><ul><li>Given as a ketone prodrug </li></ul><ul><li>Dose: 1000 mg </li></ul><ul><li>t1/2: > 24 hrs </li></ul><ul><li>Does not undergo enterohepatic circulation </li></ul><ul><li>Causes pseudoporphyria & photosensitivity </li></ul>
  • 32. Non-selective COX inhibitors (Pyrazolone derivative) aplastic anemia, agranulocytosis Toxicities 12-16 hours Half-life Structurally related to phenylbutazone Withdrawn from the market Properties Azapropazone Phenylbutazone Drugs
  • 33. Non-selective COX inhibitors (Oxicams/Enolic acid) 19. Piroxicam <ul><li>Inhibits PMN leukocyte migration, decreases O2 radical production, & inhibits lymphocyte function </li></ul><ul><li>Inhibits proteoglycanase & collagenase </li></ul><ul><li>Mean t1/2: 50-60 hrs </li></ul><ul><li>Dosing: o.d. or every other day </li></ul>
  • 34. Non-selective COX inhibitors (Oxicams/Enolic acid) 19. Piroxicam <ul><li>Pharmacokinetics: </li></ul><ul><ul><li>Rapidly absorbed from the stomach & upper intestine </li></ul></ul><ul><ul><li>Peak plasma concentration: 1 hr </li></ul></ul><ul><ul><li>Extensively metabolized to inactive metabolites </li></ul></ul><ul><ul><li>99% protein bound </li></ul></ul><ul><ul><li>Elimination: renal – 5% unchanged </li></ul></ul><ul><ul><li>Toxicity: GI symptoms, dizziness, tinnitus, HA & rash, increased incidence of PUD and bleeding </li></ul></ul>
  • 35. Non-selective COX inhibitors (Oxicams/Enolic acid) 20. Tenoxicam <ul><li>Half-life: 72 hours </li></ul><ul><li>Similar to piroxicam </li></ul>
  • 36. Other analgesics ACETAMINOPHEN <ul><ul><li>Active metabolite of phenacetine </li></ul></ul><ul><ul><li>A weak PG inhibitor </li></ul></ul><ul><ul><li>No significant anti-inflammatory effect </li></ul></ul><ul><ul><li>For the treatment of mild to moderate pain </li></ul></ul><ul><ul><li>Antipyretic effect </li></ul></ul>
  • 37. Other analgesics ACETAMINOPHEN <ul><li>Pharmacokinetics: </li></ul><ul><ul><li>Administered orally </li></ul></ul><ul><ul><li>Absorption: related to rate of gastric emptying </li></ul></ul><ul><ul><li>Peak blood concentration: 30-60 min </li></ul></ul><ul><ul><li>Slightly protein bound </li></ul></ul><ul><ul><li>Partially metabolized by hepatic microsomal enzyme  acetaminophen SO4 & glucuronide </li></ul></ul><ul><ul><li>Excretion: unchanged < 5% </li></ul></ul><ul><ul><li>A minor but highly active metabolite (N-acetyl-p-benzoquinone) is important  liver & kidney toxicity </li></ul></ul><ul><ul><li>t1/2: 2-3 hrs </li></ul></ul>
  • 38. Other analgesics ACETAMINOPHEN <ul><li>Adverse effects: </li></ul><ul><ul><li>Mild increase in hepatic enzymes </li></ul></ul><ul><ul><li>Dizziness, excitement & disorientation </li></ul></ul><ul><ul><li>Ingestion of 15gm: fatal  death caused by hepatotoxicity with centrilobular necrosis & sometimes with acute renal tubular necrosis </li></ul></ul><ul><ul><li>Symptoms of early hepatic damage: N/V, diarrhea, abdominal pain </li></ul></ul><ul><ul><ul><li>Antidote: N-acetylcysteine (sulfhydryl groups) </li></ul></ul></ul><ul><li>Caution: liver disease </li></ul><ul><li>Dosage: 325-500mg q.i.d. </li></ul>
  • 39. CORTICOSTEROID DRUGS <ul><li>Capable of slowing the appearance of new bone erosions </li></ul><ul><li>Known to inhibit phospholipase A2 </li></ul><ul><li>Shown to selectively inhibit the expression of COX-2 </li></ul><ul><li>SE: fracture, infections, cataracts </li></ul><ul><li>Prep: oral, intra-articular </li></ul>
  • 40. DISEASE-MODIFYING ANTIRHEUMATIC DRUGS (DMARDS) <ul><li>Might arrest or at least slow the progression of bone & cartilage destruction </li></ul><ul><li>Effects may take 6 weeks to 6 months to become evident </li></ul><ul><li>Exert minimal direct nonspecific anti-inflammatory or analgesic effects </li></ul><ul><li>Frequent improvement in serologic evidence of disease activity, titers of RF & CRP and ESR decline </li></ul>
  • 41. METHOTREXATE <ul><li>MOA: inhibition of aminoimidazolecarboxamide ribonucleotide (AICAR) transformylase & thymidylate synthase, with secondary effects on PMN chemotaxis plus enhanced adenosine release </li></ul><ul><li>Absorption: 70% after oral administration </li></ul><ul><li>Excretion: urine & bile </li></ul><ul><li>Dose: 7.5 - 25mg/wk (oral, SC or IM) </li></ul><ul><li>Toxicities: nausea, mucosal ulcers, dose-related hepatotoxicity, “hypersensitivity” lung reaction, pseudolymphomatous reaction </li></ul><ul><li>Folic acid & leucovorin </li></ul>
  • 42. SULFASALAZINE <ul><li>Consists of sulfapyridine & 5-amino-salicylic acid connected by diazo bond </li></ul><ul><li>Metabolized by bacteria in the colon </li></ul><ul><li>Have some anti-inflammatory action by O2 radical scavenging & inhibition of prostanoids and inhibit immune reactivity </li></ul><ul><li>t1/2: 6-17 hrs </li></ul><ul><li>Dose: 2-3g/d </li></ul><ul><li>Uses: RA, juvenile arthritis & ankylosing spondylitis </li></ul>
  • 43. CHLOROQUINE, HYDROXYCHLOROQUINE <ul><li>Used for the treatment of RA & SLE </li></ul><ul><li>MOA: unclear </li></ul><ul><ul><li>They suppress the responsiveness of T lymphocytes to nitrogens </li></ul></ul><ul><ul><li>decrease leukocyte chemotaxis </li></ul></ul><ul><ul><li>stabilize lysosomal membranes </li></ul></ul><ul><ul><li>inhibit DNA & RNA synthesis and trap free radicals </li></ul></ul><ul><li>Effects are seen after 12-24 weeks </li></ul><ul><li>Other indications: juvenile chronic arthritis, Sjogren’s syndrome </li></ul><ul><li>Toxicity: ocular, dyspepsia, N/V, abdominal pain, rashes, nightmares </li></ul>
  • 44. GOLD <ul><li>Prep: auranofin – oral </li></ul><ul><li> aurothiomalate & aurothioglucose – parenteral </li></ul><ul><li>95% protein-bound </li></ul><ul><li>Concentrate in synovial membrane, liver, kidney, spleen, adrenal glands, LN, & BM </li></ul><ul><li>Peak serum level: 2-6 hrs </li></ul><ul><li>Excretion: 40% within a week = 2/3-urine; 1/3-feces </li></ul><ul><li>Total body t1/2 (IM) – 1 year </li></ul>
  • 45. GOLD <ul><li>Mechanisms of action: </li></ul><ul><ul><li>alters the morphology and functional capabilities of human macrophages </li></ul></ul><ul><ul><li>inhibition of lysosomal enzyme activity </li></ul></ul><ul><ul><li>reduction of histamine release from mast cells </li></ul></ul><ul><ul><li>suppression of phagocytic activity of the PMN leukocytes </li></ul></ul><ul><ul><li>Aurothiomalate reduces the number of circulating lymphocytes </li></ul></ul><ul><ul><li>Auranofin inhibits the release of PGE2 from synovial cells and the release of leukotrienes B4 & C4 from PMN leukocytes </li></ul></ul>
  • 46. GOLD <ul><li>Indications: </li></ul><ul><ul><li>Active RA </li></ul></ul><ul><ul><li>Active inflammation & erosive changes </li></ul></ul><ul><ul><li>RA with Sjogren’s syndrome </li></ul></ul><ul><ul><li>Juvenile RA </li></ul></ul><ul><li>CI: history of previous toxicity from the drug, pregnancy, serious liver & renal impairment & blood dyscrasia </li></ul>
  • 47. GOLD <ul><li>Adverse effects: </li></ul><ul><ul><li>Dermatitis - 15-20% (most common) </li></ul></ul><ul><ul><li>Thrombocytopenia, leukopenia, pancytopenia – 1-10% </li></ul></ul><ul><ul><li>Aplastic anemia – rare but fatal </li></ul></ul><ul><ul><li>Proteinuria  nephrotic syn – 8-10% </li></ul></ul><ul><ul><li>Stomatitis, metallic taste, skin pigmentation, enterocolitis, cholestatic jaundice, peripheral neuropathy, pulmonary infiltrates, & corneal deposition of gold </li></ul></ul><ul><ul><li>Nitritoid reaction (sweating, faintness, flushing, & headache) </li></ul></ul><ul><ul><li>GI disturbances (LBM) </li></ul></ul>
  • 48. PENICILLAMINE <ul><li>Pharmacodynamics: </li></ul><ul><ul><li>Interact with lymphocytes membrane receptors </li></ul></ul><ul><ul><li>Interfere with the synthesis of DNA, collagen, & mucopolysaccharides </li></ul></ul><ul><li>Parmacokinetics: </li></ul><ul><ul><li>A metabolite of penicillin </li></ul></ul><ul><ul><li>Is an analog of amino acid cysteine </li></ul></ul><ul><ul><li>Absorption: half of the orally administered, enhanced after 1.5 hrs p.c. </li></ul></ul><ul><ul><li>Excretion: urine & feces in 24 hrs </li></ul></ul><ul><ul><li>Dose: 125-250mg daily for 1-3 months, 1.5 hrs p.c. </li></ul></ul>
  • 49. PENICILLAMINE <ul><li>Adverse effects: </li></ul><ul><ul><li>Decrease RF titer </li></ul></ul><ul><ul><li>Impedes absorption of many drugs </li></ul></ul><ul><ul><li>Inhibition of wound healing, muscle & blood vessel damage </li></ul></ul><ul><ul><li>Proteinuria – 20% </li></ul></ul><ul><ul><li>Immune complex nephritis – 4% </li></ul></ul><ul><ul><li>Leukopenia & thrombocytopenia  aplastic anemia </li></ul></ul><ul><ul><li>Skin & mucosal membrane reactions </li></ul></ul><ul><ul><li>Drug fever associated with cutaneous eruption </li></ul></ul><ul><ul><li>Any of these maybe seen: myasthenia gravis, hemolytic anemia, thyroiditis, Goodpasture’s syndrome & SLE </li></ul></ul><ul><ul><li>Loss of taste perception or metallic taste, anorexia, N/V </li></ul></ul><ul><ul><li>Mammary hyperplasia, alopecia, & psychologic changes </li></ul></ul>
  • 50. PENICILLAMINE <ul><li>Contraindications: </li></ul><ul><ul><li>Pregnancy </li></ul></ul><ul><ul><li>Renal insufficiency </li></ul></ul><ul><li>Drug Interactions: </li></ul><ul><ul><li>Gold </li></ul></ul><ul><ul><li>Cytotoxic drugs </li></ul></ul><ul><ul><li>Phenylbutazone </li></ul></ul>
  • 51. Biologics <ul><li>Bind & neutralize TNF </li></ul><ul><ul><li>Etanercept – a TNF type II receptor fused to IgG1 </li></ul></ul><ul><ul><li>Infliximab – a chimeric mouse/human antibody to TNF </li></ul></ul><ul><ul><li>Adalimumab – a fully human antibody to TNF </li></ul></ul><ul><li>L-1 neutralizing agent </li></ul><ul><ul><li>Anakinra </li></ul></ul><ul><li>Depletes B cells </li></ul><ul><ul><li>rituximab </li></ul></ul><ul><li>Interferes with T cell activation </li></ul><ul><ul><li>abatacept </li></ul></ul>
  • 52. Biologics that bind & neutralize TNF Opportunistic infections, leukopenia, vasculitis, lupus Upper RTI, nausea, headache, sinusitis, rash & cough with MTX Injection site reactions, activation of latent pulmonary tuberculosis Side Effects 10-20 days 8-12 days Half-life 40mg every other week SC 3 or 10mg/kg at 0, 2 & 6 weeks I V infusion 25mg SC b.i.d. Route of Administration 72 hour Peak Serum Concentration Adalimumab Infliximab Etanercept Drugs
  • 53. Biologics increased risk of infection, hypersensitivity reactions related to transfusion reaction injection site reaction Side Effects 13-16 days, May or may not be combined with MTX, but not with anti-TNF May be combined with MTX Not recommended to combined with anti-TNF Half-life/Drug interaction I V infusion, 3 initial dose (day 0, week 2, week 4), then followed by monthly infusion 2 I V infusions 2 weeks apart Route/Dose Inhibits the activation of T cells by inhibiting the binding to CD28 and CD80/86 A chimeric monoclonal antibody that targets CD20 B lymphoctyes A recombinant IL-1 receptor antagonist that competitively blocks the binding of IL-1 β & IL-1  MOA Abatacept Rituximab Anakinra Drugs
  • 54. Immunosuppressive Therapy <ul><li>These drugs have been reserve for patients who have clearly failed therapy with DMARDs and biologics </li></ul><ul><li>Effective in the treatment of RA </li></ul>
  • 55. AZATHIOPRINE <ul><li>Acts through its major metabolite, 6-thioguanine suppresses inosinic acid synthesis and B & T cell functions, immunoglobulin production & IL-2 secretion </li></ul><ul><li>Dosage: 2mg/kg/d </li></ul><ul><li>Other indications: SLE, Behcet’s syndrome, psoriatic arthritis, reactive arthritis, polymyositis </li></ul><ul><li>Toxicities: BM suppression, GI disturbances, increased in risk for infections and malignancy </li></ul>
  • 56. LEFLUNOMIDE <ul><li>A77-1726 (active metabolite) inhibits dihydroorotate dehydrogenase  decrease de novo RNA synthesis and lower levels of rUMP  translocation of p53 to nucleus  inhibits autoimmune T cell proliferation & production of autoantibodies by B cells </li></ul><ul><li>Increases the mRNA level of IL-10 receptor, decreases IL-8 receptor type A mRNA concentrations & blocks TNF-dependent nuclear factor-kappa B activation </li></ul>
  • 57. LEFLUNOMIDE <ul><li>Pharmacokinetics: </li></ul><ul><ul><li>Orally active molecule </li></ul></ul><ul><ul><li>MW: 270 </li></ul></ul><ul><ul><li>Absorption: rapidly & nearly 100% </li></ul></ul><ul><ul><li>plasma t1/2: 15 days </li></ul></ul><ul><ul><li>Strong protein binding </li></ul></ul><ul><ul><li>Enterohepatic circulation </li></ul></ul><ul><ul><li>Excretion: bile </li></ul></ul><ul><li>DI: cholestyramine </li></ul><ul><li>SE: diarrhea, elevation of liver enzymes </li></ul>
  • 58. CYCLOSPORINE <ul><li>Acts through IL-2 & TNF-a suppression, mediated through T cell effects </li></ul><ul><li>Absorption: erratic </li></ul><ul><li>Bioavailability: 30%, grape fruit juice increases by 62% </li></ul><ul><li>Metabolized in the liver </li></ul><ul><li>Dosage: 3-5mg/kg/d </li></ul><ul><li>Toxicities: nephrotoxicity, HTN, hyperkalemia, hepatotoxicity, gingival hyperplasia, & hirsutism </li></ul>
  • 59. CYCLOPHOSPHAMIDE <ul><li>MOA: through it active metabolite, phosphoramide mustard, cross-links DNA & prevents cell replication, it suppresses T & B cell functions by 30-40% </li></ul><ul><li>Metabolized in the liver </li></ul><ul><li>Given orally at 2mg/kg/d </li></ul><ul><li>Toxicities: infertility, BM suppression, hemorrhagic cystitis, bladder Ca  acrolein </li></ul><ul><li>Other indications: SLE </li></ul>
  • 60. Mycophenolate mafetil <ul><li>Active form: mycophenolic acid </li></ul><ul><li>Inhibits cytosine monophosphate dehydrogenase </li></ul><ul><li>Inhibits T-cell lymphocyte proliferation </li></ul><ul><li>Interferes with leucocyte adhesion to endothelial cells through inhibition of E-selectin, P-selectin, & IC adhesion molecule1 </li></ul><ul><li>Indication: SLE, vasculitis, Wagener’s granulomatosis, RA </li></ul><ul><li>Dosage: 2 g/day </li></ul><ul><li>Adverse effects: GI, hematopoietic & hepatic </li></ul>
  • 61. IMMUNOADSORPTION APHERESIS <ul><li>Mechanism of action: </li></ul><ul><ul><li>Down-regulation of B cell function through the release of small amounts of staphylococcal protein A complexed with immunoglobulins </li></ul></ul><ul><li>Median duration of response: 6 months </li></ul><ul><li>SE: chills – 30%, musculoskeletal pain – 15%, HA & nausea – 20-30%, joint pains & swelling – 30% </li></ul>
  • 62. DRUGS USED IN GOUT (COLCHICINE) <ul><li>Dramatically relieves pain, by binding to IC protein tubulin  preventing polymerization into microtubules  inhibition of leukocyte migration & phagocytosis </li></ul><ul><li>Absorption: readily, oral </li></ul><ul><li>Peak serum level: 2 hrs </li></ul><ul><li>Excretion: intestinal tract & urine </li></ul>
  • 63. DRUGS USED IN GOUT (COLCHICINE) <ul><li>Indication: gouty arthritis, acute Mediterranean fever, sarcoid arthritis, hepatic cirrhosis </li></ul><ul><li>Dosage: 0.5-1 mg q 2 hrs </li></ul><ul><li>SE: LBM, N/V, abdominal pain, hair loss, BM depression, peripheral neuritis, myopathy </li></ul><ul><li>Acute intoxication: burning throat pain, bloody LBM, shock, hematuria, oliguria, CNS depression </li></ul>
  • 64. NSAIDs in GOUT <ul><li>Inhibit urate crystal phagocytosis </li></ul><ul><li>Indomethacin is the agent most often used – 50 mg q 6 hrs  reduced to 25mg t.i.d or q.i.d. for 5 days </li></ul><ul><li>ASA, salicylates, tolmetin are not effective for gouty episodes </li></ul><ul><li>Oxaprozin, lowers serum uric acid, but not given to patients with uric acid stone </li></ul>
  • 65. URICOSURIC AGENTS ( Probenecid & Sulfinpyrazone) <ul><li>Act at the anionic transport sites of the renal tubule </li></ul><ul><li>Employed to decrease the body pool of urates </li></ul><ul><li>Reabsorption of uric acid in the proximal tubule is decreased </li></ul><ul><li>Probenecid: completely reabsorbed by renal tubules & metabolized slowly </li></ul><ul><li>Sulfinpyrazone: rapidly excreted by the kidneys </li></ul>
  • 66. Probenecid & Sulfinpyrazone Adverse Effects, CI & Cautions <ul><li>AE: GI irritation, allergic dermatitis, nephrotic syndrome (probenecid), aplastic anemia </li></ul><ul><li>CI & C: stone formation </li></ul><ul><li>Dosage: probenecid – 0.5 gm orally in divided doses, sulfinpyrazone – 200 mg daily </li></ul>
  • 67. ALLOPURINOL <ul><li>Reduce uric acid synthesis by inhibiting xanthine oxidase and increasing uric acid excretion </li></ul><ul><li>Absorption: 80%, oral </li></ul><ul><li>Given o.d. </li></ul><ul><li>Indications: chronic tophaceous gout, uric acid urine (24hrs) > 600-700mg, allergic reactions to probenecid & sulfinyrazone, renal impairment, grossly elevated serum uric acid levels </li></ul><ul><li>AE: N/V, diarrhea, peripheral neuritis, necrotizing vasculitis, BM depression, aplastic anemia, hepatic toxicity, interstitial nephritis, allergic skin reaction, cataracts </li></ul>
  • 68. Febuxostat <ul><li>First non-purine inhibitor of xanthine oxidase </li></ul><ul><li>More than 80% absorbed following oral administration </li></ul><ul><li>Maximum concentration: 1 hour </li></ul><ul><li>Extensively metabolized in the liver </li></ul><ul><li>Excreted in the urine </li></ul>
  • 69. Febuxostat <ul><li>Pharmacodynamics: </li></ul><ul><ul><li>Potent & selective inhibitor of xanthine oxidase -> reduces the formation of xanthine & uric acid </li></ul></ul><ul><li>Dose: 80mg, 120mg, 300mg daily </li></ul><ul><li>Adverse effects: liver function abnormalities, diarrhea, headache nausea </li></ul>
  • 70. Thank You & God Bless...

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