Nsai Ds, Dmar Ds & Antigout1

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Nsai Ds, Dmar Ds & Antigout1

  1. 1. Nonsteroidal Anti-inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout Florencia D. Munsayac, MD, MBA, RMT
  2. 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. 3. Some of the mediators of acute inflammation & their effects - +++ - Leukotrienes + +++ +++ Prostaglandins +++ - +++ Bradykinin - - +/- Serotonin - - ++ Histamine Pain Chemotaxis Vascular Permeability Vasodilation Mediators
  4. 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. 5. Rheumatoid arthritis <ul><li>Chronic inflammation -> pain & destruction of bone & cartilage </li></ul><ul><li>An autoimmune disease </li></ul>
  6. 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. 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. 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. 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. 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>
  12. 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>
  13. 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>
  14. 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>
  15. 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>
  16. 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>
  17. 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>
  18. 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>
  19. 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>
  20. 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>
  21. 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>
  22. 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
  23. 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
  24. 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>
  25. 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
  26. 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
  27. 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>
  28. 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
  29. 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>
  30. 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>
  31. 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
  32. 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>
  33. 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>
  34. 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>
  35. 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>
  36. 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>
  37. 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>
  38. 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>
  39. 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>
  40. 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>
  41. 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>
  42. 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>
  43. 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>
  44. 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>
  45. 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>
  46. 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>
  47. 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>
  48. 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>
  49. 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>
  50. 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>
  51. 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
  52. 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
  53. 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>
  54. 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>
  55. 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>
  56. 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>
  57. 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>
  58. 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>
  59. 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>
  60. 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>
  61. 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>
  62. 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>
  63. 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>
  64. 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>
  65. 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>
  66. 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>
  67. 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>
  68. 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>
  69. 70. Thank You & God Bless...
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