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Locomotion disorders

Locomotion disorders

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Locomotion disorders

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  1. Locomotion disorders Martin Votava

  2. Treatment of locomotion disorders ØSkeletal Muscle Relaxants ØAnxiolytic Agents Nonsteroidal anti-inflammatory drugs ØAnalgetics ØSlow-acting anti-rheumatic drugs ØGlucocorticoid drugs ØChondroprotective drugs ØDrugs used in gout

  3. Rheumatoid Arthritis • A chronic, systemic autoimmune disease of unknown etiology • Characterized by symmetric, erosive, joint synovitis • Can be Palindromic, Relapsing, or Malignant • May involve multiple organ systems:cardiovascular, pulmonary, renal, skin and eyes

  4. Epidemiology: • Affects 1% of U.S. adults • 150,000 new cases annually • 80% of cases occur between 35-50 years • Female-to-male ratio of ~ 3:1 • Gender predisposition decreases with increasing age • Costs/year ~$8.74 billion (1994 dollars)

  5. RA Joint • Pannus formation • Tendon and ligament instability • Invasion of cartilage and bone surface • Erosion of bone and cartilage • Joint instability • Eventual destruction of the joint

  6. What diseases are considered in the differential diagnosis of RA? • Osteoarthritis • Spondyloarthritis • Gout and Pseudogout • Fibromyalgia • Polymyalgia Rheumatica • Systemic Lupus Erythematosus • Reactive Arthritis

  7. Functional Classification • Class I: capable of all activities without handicap • Class II: Able to conduct normal activities despite discomfort or limited mobility of one or more joints • Class III: Functional capacity only adequate to perform a few of the normal duties of usual occupation • Class IV: Confined to bed or wheelchair; capable of little or no self-care

  8. Rheumatoid Arthritis:Extra-articular Manifestations • Dermatologic: subcutaneous nodules • Hepatic: elevated transaminases • Cardiac: pericarditis • Pulmonary: fibrosis, nodules, pleural effusion • Ocular: keratoconjunctivitis, scleritis

  9. Rheumatoid Arthritis:Laboratory Abnormalities • Serologic Findings:Anemia, thrombocytosis, mild leukocytosis, positive RF, elevated ESR, C-reactive protein • Synovial Fluid Findings:Straw-colored and slightly cloudy fluid, leukocytosis 5,000 to 25,00/mm3, 85% polymorphonuclear cells

  10. What laboratory data is consistent with a diagnosis of RA • Anemia • Thrombocytosis • (+) Rheumatoid Factor

  11. Rheumatoid Arthritis:Treatment • Goal: • Prevent disease progression to irreversible joint damage • Maintain Quality of life • Multidisciplinary approach: • Patient education: treatment plan, compliance, understanding of disease • Psychotherapy: manage pain and stress • Rehabilitation: exercise, joint protection

  12. Non-Pharmacologic Interventions: • Goal: • Reduce pain, disability and protect mobility • Physical Therapy • Occupational Therapy • Psychological support for the patient and family • Surgical Alternatives • Synovectomy • Joint replacement

  13. Pharmacologic Interventions • Early aggressive treatment: • Control swelling and pain • Reduce the probability of irreversible joint damage • Agents: • Glucocotricoids • NSAID’s • DMARDs • Biologic response modifiers • Chondroprotective agents

  14. NSAIDs NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

  15. are among the most widely used drugs • major type of effects: • antiinflammatory • analgesic (reduction of somatic pain) • antipyretic (lowering of a raised temperature) • mechanisms of action: • inhibition of arachidonate cyclooxygenase (COX) • inhibition of biosynthesis of PGs and TXs • COX-1 = enzyme expressed in most tissues • involved in cell-cell signalling and in tissue homeostasis • COX-2= enzyme induced in inflammatory cells when they are activated , responsible for the production of prostanoid mediators of inflammation

  16. Nonselective NSAIDs Selective and nonselective NSAIDs arachidonic acid inflammation physiological activation COX-1 COX-2 (constitutive form) Endoperoxides (inducible form) proinflammatory prostanoids prostanoids ensuring physiological functions Results from inhibition of prostanoids biosynthesis COX-2 inhibition COX-1 inhibition) Unwanted effects mainly on the GIT and kidney, decrease in pl.aggregation Antiinflammatory, analgesic and antipyretic effects

  17. Regulation and Expression of COX-1 and COX-2 COX-1 • Constitutive (Protective) • Found in all tissues • Important role in • GI tract • Kidneys • Platelets COX-2 • Induced at site of inflammation(Inducible) • Produced by macrophages, synoviocytes during inflammatory process Vane JR, Botting RM. Semin Arthritis Rheum. 1997;26:2-10.

  18. the antiinflammatory action of NSAIDs is mainly related to their inhibition of COX- 2 and it is probable that their unwanted effects are largery due to their inhibition of COX-1 All NSAIDsare analgesics and antipyretics but the degree of anti-inflammatory activity varies. OTC drugs (over the counter)

  19. Analgesic effect-- mechanisms in the periphery against pain associated with inflammation or tissues damage because of decrease in PGs production that sensitises nociceptors to inflammatory mediators (bradykinin) centralmechanisms (in the spinal cord) NSAIDs are effective in: arthritis pain of muscular and vascular origin headache, toothache, dysmenorrhoea in combination with opioids : decrease in postoperative pain

  20. Antiinflammatory effect • NSAIDs reduce mainly components of the inflammatory and immune response in which the products of COX-2 action play a significant part: • vasodilatation • oedema • pain

  21. THE SALICYLATES natural products that contain precursors of salicylic acid such as willow bark (glycoside salicin) acetylsalicylic acid sodium salicylate methylsalicylate used in topical applications diflunisal ASPIRIN (acetylsalicylic acid) pharmacokinetics well absorbed, highly bound to plasma proteins first-pass effect--converted to salicylic acid in low dose t1/2 = 4 h, first-order kinetics in high doses >4 g/day saturation pharmacokinetics (danger of overdosage !)pH of urine

  22. Unwanted effects: • gastritis with focal erosions and bleeding • salicylism with repeated ingestion of large doses of s: • tinnitus, vertigo, decreased hearing • Reye´s syndrom in children: encephalopathy and • hepatopathy that can follow an acute viral illness (treated with • aspirin). RS has a 20-40% mortality • allergic reactions: skin rashes, worsening of asthma • IND: • antiplatelet effects: 0.1 g/day • analgesic effects: 0.5 g 4-6times/day • for short-term analgesia • antiinflammatory effects: 3.5 - 4 g/day • for long-term treatment

  23. IBUPROFEN • analgesic, antipyretic and antiinflammatory action • without gastric toxicity • ind: acute pain for short-term analgesia • OTHER NSAIDs • for antiinflammatory effects in acute or chronic • inflammatory conditions (e.g. rheumatoid arthritis and related • connective tissue disorders) • are given in higher doses then that for simple analgesia and • treatment may need to be continued for long period • indomethacin, naproxen can also be used for severe pain • unrelated to inflammation • flurbiprofen, diclofenac • more selective for COX-2: nimuselide, celecoxib (treatment of arthritis)

  24. COX Isoform Selectivity of Commercially Available NSAIDs and Investigational COX-2 Selective Inhibitors Highly Relatively Relatively HighlyCOX-1 COX-1 Equally COX-2 COX-2Selective Selective Selective Selective SelectiveFlurbiprofen Fenoprofen Aspirin Diclofenac Celecoxib Ketoprofen Piroxicam Ibuprofen Etodolac Rofecoxib Indomethacin Meloxicam L-743,337 Ketorolac Nabumetone NS-398 Naproxen Nimesulide Valdecoxib Oxaprozin Parecoxib Tolmetin Vane JR et al. Annu Rev Pharmacol Toxicol. 1998;38:97-120.

  25. Unwanted effects • gastrointestinal disturbances • dyspepsia, diarrhoea, nausea, vomiting • one in five chronic users: gastric damage (risk of • serious hemorrhage and/or perforation) • PGs inhibit acid secretion and have protecting action on • the gastric mucosa • skin reactions (from mild rashes, urticaria to more serious • reactions) • renal reactions • acute renal insufficiency reversible on stopping the drug • (due to inhibition of PGE2 mediated compensatory vasodilatation • that occurs in response to NORA and ANG II) • chronic NSAIDs consumption: analgesic nephropathy • chronic nephritis, renal papillary necrosis (renal hypertension, • malignancies)

  26. NSAID-Induced Upper GI Toxicity • Estimated prevalence of dyspepsia is 10%-60% • Use of nonselective COX-2 NSAIDs is associated with a significantly increased risk of gastric and duodonal ulcers • Endoscopic ulcer point prevalence is 10%-30% • Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs appears to occur in 2%-4% of patients treated for 1 year • Majority of patients hospitalized for NSAID-induced ulcer complications have no warning symptoms Singh G. Am J Med. 1998;105(suppl 1B):31S-38S. (cont)

  27. NSAID-Induced Upper GI Toxicity • NSAID use is associated with significant morbidity and mortality • Approximately 107,000 hospitalizations per year • More than 16,500 deaths per year • Relative risk does not decline with long-term therapy Singh G. Am J Med. 1998;105(suppl 1B):31S-38S.

  28. Prevention of NSAID-Induced Gastropathy • Is inflammation present? • Misoprostil • Omeprazole • Not H2-Blockers • COX-2 selective NSAIDs

  29. Criteria for NSAID Selection • Record of efficacy and safety (experience, length of time on the market) • Patient characteristics and concomitant disease states (minimize risks in high risk patients) • Pharmacodynamic/pharmacokinetic profiles • Dose - Dosing interval • Price

  30. Pros and Cons of NSAID Therapy Cons • Does not affect disease progression • GI toxicity common • Renal complications (eg, irreversible renal insufficiency, papillary necrosis) • Hepatic dysfunction • CNS toxicity Pros • Effective control of inflammation and pain • Effective reduction in swelling • Improves mobility, flexibility, range of motion • Improve quality of life • Relatively low-cost

  31. Rheumatoid Arthritis: Disease-Modifying Antirheumatic Drugs • DMARDs can alter the progression of RA • May be initiated within the first 3 months of diagnosis if: • Ongoing inflammation despite treatment with NSAIDS • Glucocorticoid dose 7.5 mg prednisone/day (or equiv) • Radiographic evidence of joint destruction • Presence or development of extra-articular disease • May take 2wks - 6 months for a response

  32. Rheumatoid disease (one of commonest chronic inflammatory conditions) is a common cause of disability. • The primary inflammatory cytokines, interleukin-1 and tumour necrosis factor-α , have a major role in pathogenesis • DMARDs improve symptoms and can reduce disease activity • as measured by: • reduction in number of swollen and tender joints • pain score • disability score • radiology • serum concentration of acute-phase proteins

  33. The effects : • probably result from inhibition of excessive cytokine • liberation • are slow in onset • only have a part to play in progressive disease • are also toxic (the patient must be monitored) IND: rheumatoid + psoriatic arthritis

  34. Drugs Unwanted effects Comments --------------------------------------------------------------------------- Immunosuppressantsblood dyscrasias MTX is usual methotrexate(MTX) carcinogenesis first-choice azathioprin opportunistic inf. DMARD cyclosporin MTX: cirrhosis mucositis cycl.: nephrotoxicity hypertension --------------------------------------------------------------------------------------- sulphasalazine blood dyscrasias s. is also used for (combination of rashes chronic inflammatory sulphonamidecolours urine/tearsbowel disease with a salicylate)orange

  35. Drugs Unwanted effects Comments Gold compounds skin rashses inhibit mitogen- sodium aurotiomalate mouth ulcerations induced concentrated in macrophages lymphocyte and synovial cells in joints, proliferation effects appear slowly (in months) (maximum effects in 3-4months) penicillamine in 40% is known to have nauzea, vomiting, metal-chelating propert proteinuria and decreases IL-1 gener. chloroquine blurring of vision decreases leukocyte retinopathies chemotaxis, lyozomal enzyme release

  36. Rheumatoid Arthritis: Choice of DMARDs Drug Side Effects hydroxychloroquine retinal toxicity, diarrhea sulfasalazine bone marrow suppression, GI intolerance • Can be used as initial therapy in milder disease • Semiannual eye exam for HCQ (macular damage) • Dosing: • SAS - 1 gram bid or tid • HCQ - 200 mg bid (maintenance)

  37. Rheumatoid Arthritis: Choice of DMARDs Drug Side Effects methotrexate bone marrow suppression, hepatic and pulmonary toxicity, GI intolerance, stomatitis, rash • Most rapid onset and sustained benefit • Weekly dose 7.5-15 mg PO • Close monitoring required

  38. Rheumatoid Arthritis: Choice of DMARDs Drug Side Effects gold salts bone marrow suppression, rash, stomatitis, proteinuria diarrhea, edema • Administered IM (50 mg) on a weekly basis for 3-5 months, followed by less frequent dosing • Requires close monitoring of bone marrow and renal toxicity • PO dosing 3-6 mg qd (auranofin)

  39. Rheumatoid Arthritis: Choice of DMARDs Drug Side Effects azathioprine bone marrow suppression, hepatotoxicity, GI symptoms • AZA is used when disease activity persists on other DMARDs • May be safer than MTX for patients > 65 years with renal insufficiency • PO dose: 50-100 mg qd (max 2.5 mg/kg/day)

  40. Rheumatoid Arthritis: Choice of DMARDs Drug Side Effects D-penicillamine bone marrow suppression, rash, stomatitis, dysgeusia, proteinuria, autoimmune disease • d-Penicillamine is used if disease activity persists on other DMARDs • Associated with high incidence of lupus, myasthenia gravis • PO dose: 125-250 mg qd (max. 1 gram/day)

  41. Rheumatoid Arthritis: Choice of DMARDs Drug Side Effects cyclophosphamide bone marrow suppression hemorrhagic cystitis, malignancy, infertility • Oral immunosuppressive agent with significant toxicity profile • Used in severe vasculitis and other extra-articular involvement • PO dose: 50-100 mg qd (max 2.5 mg/kg/day)

  42. DMARD Combinations • MTX + sulfasalazine • MTX + hydroxychloroquine (HCQ) • MTX + sulfasalazine + HCQ • MTX + gold • MTX + Azathioprine + HCQ • MTX + Penicillamine

  43. Rheumatoid Arthritis:Choice of DMARDs • Cost • Dosing regimen • Compliance • Comorbid disease states • Toxicity profile and monitoring requirements • Severity and prognosis of patient

  44. Rheumatoid Arthritis : Glucocorticoids • Potent rapidly acting anti-inflammatory agents • Used as “bridge therapy” until DMARD’s become effective; local injection is efficacious and less toxic than DMARD’s • Low dose systemic therapy may slow the rate of joint damage and is effective in refractory RA

  45. Rheumatoid Arthritis: Glucocorticoids • Side effects: • Osteoporosis, Cushingoid state, hypertension, premature athersclerosis, infection • Reducing the risk of osteoporosis: • Regular exercise, estrogen therapy, supplemental calcium and vitamin D • Calcitonin or bisphosphonates in patients with low bone mass

  46. Pros and Cons of Corticosteroid Therapy Cons • Does not conclusively affect disease progression • Tapering and discontinuation of use often unsuccessful • Low doses result in skin thinning, ecchymoses, and Cushingoid appearance • Significant cause of steroid-induced osteopenia Pros • Anti-inflammatory and immunosuppressive effects • Can be used to bridge gap between initiation of DMARD therapy and onset of action • Intra-articluar injections can be used for individual joint flares

  47. New Pharmacologic Agents • Immunomodulator: • Leflunomide • Biologic Response Modifiers • Etanercept • Infliximab • Antibiotics: • Minocycline

  48. Leflunomide/A77 1726 Primary Mechanism of Action DHODH Salvage Dihydroorotate Orotate pathway Leflunomide Extracellular Glutamine UMP pyrimidines + HCO 3 + Aspartate Pyrimidine nucleotides DNA/RNA synthesis; glycosylation

  49. Leflunomide: • Hepatic metabolism: • Active metabolite inhibits cell proliferation in activated lymphocytes; results in cell cycle arrest • t 1/2 ~14 days • Dose: 100 mg/day x3 days then 20 mg qd • Side effects: • Diarrhea 27%,  LFT’s 10%, rash 8%, alopecia 7%

  50. Etanercept: • soluble receptor for TNFα • Indication: • To reduce signs/symptoms of moderate to severe active RA in patients who have had an inadequate response to one or more DMARD’s • Dose: • 10 mg or 25 mg SC twice a week • Kinetics: • t 1/2 of 25 mg dose ~5 days • Response rate: • 50-70% in moderate or severe RA