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Understanding Drugs for Joint Diseases Management

Explore different drug classes used in Rheumatoid Arthritis treatment. Learn about mechanisms of action, side effects, and disease-modifying drugs. Delve into drug therapy for Osteoarthritis and Gout.

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Understanding Drugs for Joint Diseases Management

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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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