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Drugs used in joint diseases

Drugs used in joint diseases. Dr Sanjeewani Fonseka Department of Pharmacology. OBJECTIVES. List the classes of drugs that are used in the treatment of RA Describe the mechanism of action, pharmacokinetics and adverse effects of the above drugs Explain the basis of disease modifying drugs

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Drugs used in joint diseases

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  1. Drugs used in joint diseases Dr Sanjeewani Fonseka Department of Pharmacology

  2. OBJECTIVES • List the classes of drugs that are used in the treatment of RA • Describe the mechanism of action, pharmacokinetics and adverse effects of the above drugs • Explain the basis of disease modifying drugs • Explain the basis of drug treatment of OA and gout

  3. Rheumatoid arthritis • Chronic synovial inflammation • Autoimmune • Cytokine networks are responsible for inflammation & joint destruction • Tumor Necrosis Factor-α (TNF-α) • Interleukins - 1,6,17

  4. Disability in Early RA • Inflammation • Swollen • Stiff • Sore • Warm • Fatigue • Potentially Reversible

  5. Periarticular OsteopeniaJoint Space NarrowingErosionsMal-Alignment

  6. Disability in RA • Most of the disability in RA is a result of the INITIAL burden of disease • People get disabled because of: • Inadequate control • Lack of response • Compliance • GOAL: control the disease early on!

  7. Drugs for RA • Nonsteroidal anti-inflammatory drugs (NSAIDs) • Disease-modifying anti-rheumatic drugs (DMARDs) • Synthetic • Biologic • Glucocorticoids

  8. NSAIDs • Cyclo-oxygenase inhibitors • Do not slow the progression of the disease • Provide partial relief of pain and stiffness

  9. NSAIDs • Non-selective COX inhibitors • Ibuprofen • Diclofenac sodium • COX–2 inhibitors • celecoxib

  10. COX-2 Inhibitors • COX-2 inhibitors appear to be as effective NSAIDs • Associated with less GI toxicity • However increased risk of CV events

  11. Read Side effects of • non selective NSAID • COX – II inhibitors

  12. Drugs for RA • Nonsteroidal anti-inflammatory drugs (NSAIDs) • Disease-modifying anti-rheumatic drugs (DMARDs) • Synthetic • Biologic • Glucocorticoids

  13. 90% of the joints involved in RA are affected within the first year SO TREAT IT EARLY

  14. Disability in Late RA (Too Late) • Damage • Bones • Cartilage • Ligaments and other structures • Fatigue • Not Reversible

  15. DMARDs Disease Modifying Anti-Rheumatic Drugs • Reduce swelling & inflammation • Improve pain • Improve function • Have been shown to reduce radiographic progression (erosions)

  16. DMARDs • Synthetic • Biologic

  17. Synthetic DMARDs • Methotrexate • Sulphasalazine • Chloroquine • Hydroxychloroquine • Leflunomide

  18. Synthetic DMARDs • Methotrexate • Sulphasalazine • Chloroquine • Hydroxychloroquine • Leflunomide

  19. Methotrexate (MTX) • Dihydrofolate reductase inhibitor • ↓ thymidine & purine nucleotide synthesis • “Gold standard” for DMARD therapy • 7.5 – 30 mg weekly • Absorption variable • Elimination mainly renal

  20. MTX adverse effects • Hepatotoxicity • Bone marrow suppression • Dyspepsia, oral ulcers • Pneumonitis • Teratogenicity • Folic acid reduces GI & BM effects • Monitoring • FBC, ALT, Creatinine

  21. Synthetic DMARDs • Methotrexate • Sulphasalazine • Chloroquine • Hydroxychloroquine • Leflunomide

  22. Sulphasalazine • Sulphapyridine + 5-aminosalicylic acid • Remove toxic free radicals • Remission in 3-6 month

  23. Elimination hepatic • Dyspepsia, rashes, BM suppression

  24. Synthetic DMARDs • Methotrexate • Sulphasalazine • Chloroquine /Hydroxychloroquine • Leflunomide

  25. Chloroquine, Hydroxychloroquine • Mechanism unknown • Interference with antigen processing ? • Anti- inflammatory and immunomodulatory • For mild disease

  26. Chloroquine cont • Take a month to see the effect

  27. Chloroquine cont Side effects • Irreversible Retinal toxicity, corneal deposits • Ophthalmologic evaluation every 6 months

  28. Synthetic DMARDs • Methotrexate • Sulphasalazine • Chloroquine • Hydroxychloroquine • Leflunomide

  29. Leflunomide • Competitive inhibitor of dihydroorotate dehydrogenase (rate-limiting enzyme in de novo synthesis of pyrimidines) • Reduce lymphocyte proliferation

  30. Leflunomide cont • Oral • T ½ - 4 – 28 days due to EHC • Elimination hepatic • Action in one month • Avoid pregnancy for 2 years

  31. Side effects of leflunomide • Hepatotoxicity • BM suppression • Diarrhoea • rashes

  32. Combination therapy (using 2 to 3) DMARDs at a time works better than using a single DMARD

  33. Common DMARD Combinations • Triple Therapy • Methotrexate, Sulfasalazine, Hydroxychloroquine • Double Therapy • Methotrexate & Leflunomide • Methotrexate & Sulfasalazine • Methotrexate & Hydroxychloroquine

  34. DMARDs • Synthetic • Biologic

  35. BIOLOGIC THERAPY • Complex protein molecules • Created using molecular biology methods • Produced in prokaryotic or eukaryotic cell cultures

  36. Biologics • Monoclonal Antibodies to TNF • Infliximab • Adalimumab • Soluble Receptor Decoy for TNF • Etanercept • Receptor Antagonist to IL-1 • Anakinra • Monoclonal Antibody to CD-20 • Rituximab

  37. Tumour Necrosis Factor (TNF) • TNF is a potent inflammatory cytokine • TNF is produced mainly by macrophages and monocytes • TNF is a major contributor to the inflammatory and destructive changes that occur in RA • Blockade of TNF results in a reduction in a number of other pro-inflammatory cytokines (IL-1, IL-6, & IL-8)

  38. Macrophage TNF Receptor How Does TNF Exert Its Effect? Any Cell Trans-Membrane Bound TNF Soluble TNF

  39. Strategies for Reducing Effects of TNF Monoclonal Antibody (Infliximab & Adalimumab) Trans-Membrane Bound TNF Macrophage Soluble TNF

  40. Side Effects • Infection • Common (Bacterial) • Opportunistic (Tb) • Demyelinating Disorders • Malignancy • Worsening CHF

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