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RA.ppt
- 1. Drugs used injoint diseases Dr Sanjeewani Fonseka Department of Pharmacology
- 2. OBJECTIVES • List theclasses 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 • Chronicsynovial inflammation • Autoimmune • Cytokine networks are responsible for inflammation & joint destruction – Tumor Necrosis Factor-α (TNF-α) – Interleukins - 1,6,17
- 7. Disability in EarlyRA • Inflammation – Swollen – Stiff – Sore – Warm • Fatigue • Potentially Reversible
- 10. Periarticular Osteopenia Joint SpaceNarrowing Erosions Mal-Alignment
- 11. 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!
- 12. Drugs for RA •Nonsteroidal anti-inflammatory drugs (NSAIDs) • Disease-modifying anti-rheumatic drugs (DMARDs) – Synthetic – Biologic • Glucocorticoids
- 13. NSAIDs • Cyclo-oxygenase inhibitors •Do not slow the progression of the disease • Provide partial relief of pain and stiffness
- 15. NSAIDs • Non-selective COXinhibitors – Ibuprofen – Diclofenac sodium • COX–2 inhibitors – celecoxib
- 16. COX-2 Inhibitors • COX-2inhibitors appear to be as effective NSAIDs • Associated with less GI toxicity • However increased risk of CV events
- 17. Read Side effects of •non selective NSAID • COX – II inhibitors
- 18. Drugs for RA •Nonsteroidal anti-inflammatory drugs (NSAIDs) • Disease-modifying anti-rheumatic drugs (DMARDs) – Synthetic – Biologic • Glucocorticoids
- 19. 90% of thejoints involved in RA are affected within the first year SO TREAT IT EARLY
- 20. Disability in LateRA (Too Late) • Damage – Bones – Cartilage – Ligaments and other structures • Fatigue • Not Reversible
- 21. DMARDs Disease Modifying Anti-RheumaticDrugs • Reduce swelling & inflammation • Improve pain • Improve function • Have been shown to reduce radiographic progression (erosions)
- 22.
- 23. Synthetic DMARDs • Methotrexate •Sulphasalazine • Chloroquine • Hydroxychloroquine • Leflunomide
- 24. Synthetic DMARDs • Methotrexate •Sulphasalazine • Chloroquine • Hydroxychloroquine • Leflunomide
- 25. Methotrexate (MTX) • Dihydrofolatereductase inhibitor • ↓ thymidine & purine nucleotide synthesis • “Gold standard” for DMARD therapy • 7.5 – 30 mg weekly • Absorption variable • Elimination mainly renal
- 27. MTX adverse effects •Hepatotoxicity • Bone marrow suppression • Dyspepsia, oral ulcers • Pneumonitis • Teratogenicity • Folic acid reduces GI & BM effects • Monitoring – FBC, ALT, Creatinine
- 28. Synthetic DMARDs • Methotrexate •Sulphasalazine • Chloroquine • Hydroxychloroquine • Leflunomide
- 29. Sulphasalazine • Sulphapyridine +5-aminosalicylic acid • Remove toxic free radicals • Remission in 3-6 month
- 30. • Elimination hepatic •Dyspepsia, rashes, BM suppression
- 31. Synthetic DMARDs • Methotrexate •Sulphasalazine • Chloroquine /Hydroxychloroquine • Leflunomide
- 32. Chloroquine, Hydroxychloroquine • Mechanismunknown – Interference with antigen processing ? – Anti- inflammatory and immunomodulatory • For mild disease
- 33. Chloroquine cont • Takea month to see the effect
- 34. Chloroquine cont Side effects •Irreversible Retinal toxicity, corneal deposits • Ophthalmologic evaluation every 6 months
- 36. Synthetic DMARDs • Methotrexate •Sulphasalazine • Chloroquine • Hydroxychloroquine • Leflunomide
- 37. Leflunomide • Competitive inhibitorof dihydroorotate dehydrogenase (rate-limiting enzyme in de novo synthesis of pyrimidines) • Reduce lymphocyte proliferation
- 38. Leflunomide cont • Oral •T ½ - 4 – 28 days due to EHC • Elimination hepatic • Action in one month • Avoid pregnancy for 2 years
- 39. Side effects ofleflunomide • Hepatotoxicity • BM suppression • Diarrhoea • rashes
- 41. Combination therapy (using2 to 3) DMARDs at a time works better than using a single DMARD
- 42. Common DMARD Combinations • TripleTherapy – Methotrexate, Sulfasalazine, Hydroxychloroquine • Double Therapy – Methotrexate & Leflunomide – Methotrexate & Sulfasalazine – Methotrexate & Hydroxychloroquine
- 43.
- 44. BIOLOGIC THERAPY • Complexprotein molecules • Created using molecular biology methods • Produced in prokaryotic or eukaryotic cell cultures
- 45. Biologics • Monoclonal Antibodiesto TNF – Infliximab – Adalimumab • Soluble Receptor Decoy for TNF – Etanercept • Receptor Antagonist to IL-1 – Anakinra • Monoclonal Antibody to CD-20 – Rituximab
- 46. 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)
- 47. Macrophage Any Cell Trans-Membrane Bound TNF TNFReceptor Soluble TNF How Does TNF Exert Its Effect?
- 49. Trans-Membrane Bound TNF Soluble TNF Strategiesfor Reducing Effects of TNF Macrophage Monoclonal Antibody (Infliximab & Adalimumab)
- 50. Side Effects • Infection –Common(Bacterial) –Opportunistic (Tb) • Demyelinating Disorders • Malignancy • Worsening CHF
- 51. Drugs for RA •Nonsteroidal anti-inflammatory drugs (NSAIDs) • Disease-modifying anti-rheumatic drugs (DMARDs) – Synthetic – Biologic • Glucocorticoids
- 52. Glucocorticoids • Potent anti-inflammatorydrugs • Serious adverse effects with long-term use • To control the diaseas • Indications – As a bridge to effective DMARD therapy – Systemic complications (e.g. vasculitis)
- 53. Route of steroid •Oral • Intra- articular • IM - depot
- 54.
- 55. Osteoarthritis • Most commonjoint disorder worldwide • Diagnosed on clinical presentation and supported by radiography.
- 57. Clinical Features • Ageof Onset > 40 years • Commonly Affected Joints
- 58. Goals of Treatment •Control pain and swelling • Minimize disability • Improve the quality of life • Prevent progression
- 59. NSAIDs • Tend toavoid for long-term use • Indomethacin should be avoided for long- term use in patients with hip OA –associated with accelerated joint destruction
- 60. • Read –different classes of NSAID that can be used in OA
- 61. Topical NSAIDs • Effectwas not apparent at three to four weeks • Topical NSAIDs were generally inferior to oral NSAIDs • Topical route was safer than oral use • Topical Diflofenac (1% gel or patch)
- 62. • Corticosteroid –intra- articular injections
- 63. Glucosamine Sulfate • Glycoproteinderived from marine exoskeletons or produced synthetically • Found - tendons, ligaments, cartilage, synovial fluid • ? disease modifying agent in osteoarthritis.
- 64. • orally, intravenously,intramuscularly, and intra-articularly • provide pain relief, reduce tenderness, and improve mobility in patients with OA
- 65. Hyaluronic acids – Injectedinto the joint capsule to reduce friction and improves articulation (act as synovial fluid)
- 66.
- 68.
- 69. TREATMENT GOALS • Rapidlyend acute flares • Protect against future flares
- 70. Acute Flare • NSAIDS •Colchicine • Corticosteroids
- 71. Colchicine Colchicine- reduces pain,swelling, and inflammation; pain subsides within 12 hrs and relief occurs after 48 hrs Prevent migration of neutrophils to joints
- 72. Side effects • Nausea •Vomiting • Diarrhea • Rahes
- 73. TREATMENT GOALS • Rapidlyend acute flares Protect against future flares
- 75. URICOSURIC AGENTS • Probenecid •Increased secretion of urate into urine • Reverses most common physiologic abnormality in gout ( 90% pt.s are underexcretors)
- 77. • Hypoxanthine • Xanthine •Uric acid XO
- 78. • Hypoxanthine • Xanthine •Uric acid XO ALLOPURINOL
- 79. XANTHINE OXIDASE INHIBITOR • Allopurinol •Effective in overproducers • May be effective in underexcretors • Can work in pt.s with renal insufficiency
- 80.
- 81. Drugs for RA •Nonsteroidal anti-inflammatory drugs (NSAIDs) • Disease-modifying anti-rheumatic drugs (DMARDs) – Synthetic – Biologic • Glucocorticoids
- 82.
- 83. OA • Pain relief •Glucosamine Sulfate • Hyaluronic acids injections • Surgery
- 84. TREATMENT OF GOUT •Colchicine, NSAID, steroids – acute attack • Allopurinol- decreases the production of uric acid • Probenecid - prevent absorption of uric acid in the tubules of kidney
- 85. OBJECTIVES • List theclasses 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