Rheumatoid Arthritis Management PDF

Shereen Elsaid Elkholy Lecturer of clinical pharmacology Chronic synovial inflammation Autoimmune Cytokine networks are responsible for inflammation & joint destruction Tumor Necrosis Factor-α (TNF-α) Interleukins - 1,6,17 The inflammatory process results in damage to cartilage & bone ...

Shereen Elsaid Elkholy Lecturer of clinical pharmacology Chronic synovial inflammation Autoimmune Cytokine networks are responsible for inflammation & joint destruction Tumor Necrosis Factor-α (TNF-α) Interleukins - 1,6,17 The inflammatory process results in damage to cartilage & bone Inflammation Swollen Stiff Sore Warm Fatigue Potentially Reversible  smalljoints of hands and feet affected first, larger joints later  Desired Outcomes The goals of treatment in RA are to:  (1) reduce or eliminate pain  (2) protect articular structures  (3) control systemic complications  (4) prevent loss of joint function  (5) improve or maintain quality of life.  The following medication classes are prescribed commonly for the treatment of RA:  (1) non-steroidal anti-inflammatory drugs (NSAIDs).  (2) glucocorticoids.  (3) Nonbiological DMARDs.  (4) Biological DMARDs. Cyclo-oxygenase inhibitors Do not slow the progression of the disease Provide partial relief of pain and stiffness Pharmacological effect of NSAIDS: 1. antipyretic effects: Effect: reduction of body temperature in patients with fever no effect on normal body temperature Mechanism: reduction of PGs biosynthesis via inhibition of cyclo-oxygenase pathway for PGs synthesis to lower body temperature in patients with fever. * Use: high fever. Antipyretics decreases only high body temperature by inhibition of PGs biosynthesis and has no effect on normal body temperature. 2. analgesic effect Effect: weak, only effective on mild to moderate dull pain little effect on colicky pain and sharp pain (intense pain) no narcotic. Mechanism: relieving pain via inhibition of PGs biosynthesis* Use: common dull pains. e.g. headache, toothache, neuralgia, muscular pain, arthralgia and dysmenorrhea etc. 3. anti-inflammatory effect Effect: relieving inflammatory symptoms (pain and swelling). Mechanism: inhibition of PG synthesis.* 【classification I】 1. salicylates aspirin 2. aminophenol derivatives acetaminophen 3. pyrazolon phenylbutazone 4. other organic acids indomethacin etc. 【classification II】 1. non-selective COX inhibitors: aspirin, diclofenac etc. antipyretic analgetic antiinflammatory antiplatelet 2. COX-2 selective inhibitors: celecoxib,etoricoxib,meloxicam antipyretic analgetic antiinflammatory  Acetylsalicylic acid (ASA, aspirin) 【pharmacokinetics】  metabolized in liver by the hydrolyzation to salicylate and acetic acid by esterases.  half life is 3.5 h, 【pharmacologic effects】 Aspirin is rapidly deacetylated by esterases in body, producing salicylate which has anti-inflammatory, analgesic,and antipyretic effects. Aspirin irreversibly acetylates cyclooxygenase to inhibit the enzyme activity. 1. antipyretic action: rapid and moderate in potency. 2. analgesic effects: effective for mild, moderate dull pain. 3. antiinflammatory effects: to treat rheumatoid and rheumatic arthritis, symptomatic relief. 4.antiplatelet effects: to inhibit platelet aggregation 5.other effects: increasing gastric acid secretion and diminishing mucus protection to cause epigastric distress, ulceration, hemorrhage resulting in retention of sodium and water to cause edema and hyperkalemia 【therapeutic uses】 DOSAGE 1. hyperpyrexia: middle dose. 2.dull pain: e.g. headache, arthritis, dysmenorrhea etc. middle dose. 3.rheumatic fever and rheumatoid arthritis (first-line drugs) in relatively large dose. 4. prevention of thromboembolism, stroke, myocardial infarction in small dose. decreasing incidence of transient ischemic attack and unstable angina as well as that of coronary artery thrombosis. 5.chronic use of aspirin reduces incidence of colorectal cancer.* 【adverse effects】 1.gastrointestinal reaction: epigastric distress, nausea, vomiting, gastric ulceration and bleeding. taking aspirin with meal or with sodium bicarbonate, taking enteric- coated aspirin. 2. hepatic damage: mild, reversible. 3. prolonging bleeding time due to inhibition of platelet functions in small dose and reduction of plasma prothrombin level in large dose. 4.hypersensitivity or allergy. 6.Reye’s syndrome: seen during viral infections fatal, especially in children manifestations: fulminating hepatitis with cerebral edema children should use acetaminophen instead. 7.Salicylate toxication (salicylism): mild toxication: headache, mental confusion, drowsiness, difficulty in hearing, vomiting severe toxication: hyperventilation, severe CNS disturbulance, respiration depression and marked alteration in acid-base balance Medication: discontinuation of salicylates, gastric lavage, relieving symptoms, intravenous infusion of NaHCO3 and dialysis.  Acetaminophen Acetaminophen inhibits prostaglandin synthesis in CNS,but less effect on peripheral cyclooxygenase.  antipyretic and analgesic effects are similar to aspirin in potency  no anti-inflammatory activity. Use: dull pain and hyperpyrexia., choice for children with viral infections or chicken pox. Adverse effects: skin rash and drug fever, hypoglycemic coma, renal tubular necrosis and renal failure in long- term administration, acute hepatic necrosis in large dose.  Ⅳ Other Organic Acids Indomethacin 【pharmacologic effects】 anti-inflammatory, analgesic and antipyretic effects more potent than aspirin as an anti-inflammatory agent inferior to the salisylates at dose tolerated by patients with rheumatoid arthritis. 【therapeutic uses】 rheumatoid and rheumatic arthritis, not routinely for analgesia and antipyresis because of its toxicity and side effects. 【adverse effects】 35%-50% of patients report some adverse effects and most adverse effects are dose-related. 1. gastrointestinal complaints. 2. CNS effects: frontal headache, dizziness, vertigo, mental confusion etc. 3. hematologic effects: neutropenia, thrombocytopenia, inpaired platelet functions, rare aplastic anemia. 4. contraindication: in pregnancy or nursing women, patients with psychiatric disorders, epilepsy, parkinsonism, renal diseases, peptic ulcers  Ibuprofen anti-inflammatory, analgesic and antipyretic activity. chronic treatment of rheumatoid and osteoarthritis. less intense of gastrointestinal effects than that of aspirin. Potent anti-inflammatory drugs Serious adverse effects with long-term use To control the diasease Indications As a bridge to effective DMARD therapy Systemic complications (e.g. vasculitis) Route of steroid Oral Intra- articular IM - depot Disease Modifying Anti-Rheumatic Drugs Reduce swelling & inflammation Improve pain Improve function Have been shown to reduce radiographic progression (erosions)  Methotrexate Sulphasalazine Chloroquine Hydroxychloroquine Leflunomide Dihydrofolate reductase inhibitor “Gold standard” for DMARD therapy 7.5 – 30 mg weekly Absorption variable Elimination mainly renal Hepatotoxicity Bone marrow suppression Dyspepsia, oral ulcers Pneumonitis Teratogenicity Folic acid reduces GI & BM effects Sulphapyridine + 5-aminosalicylic acid Remove toxic free radicals Remission in 3-6 month Elimination hepatic Dyspepsia, rashes, BM suppression Mechanism unknown  Anti- inflammatory and immunomodulatory  For mild disease  take a month to see effects  Side effects - Irreversible Retinal toxicity, corneal deposits - Ophthalmologic evaluation every 6 months  Competitive inhibitor of dihydroorotate dehydrogenase (rate- limiting enzyme in de novo synthesis of pyrimidines)  Reduce lymphocyte proliferation  Oral T ½ : 4 – 28 days Elimination hepatic  Action in one month  Avoid pregnancy for 2 years Hepatotoxicity BM suppression Diarrhoea rashes ❖ T-cell modulating drug ( abatacept ) ❖ B-cell cytotoxic agent ( rituximab ) ❖ Anti-IL-6 receptor antibody ( tocilizumab) ❖ TNF- blocking agents ( infliximab)