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