Inflammation Page 4


Overview: antimalarials Efficacious in management of rheumatoid arthritis and systemic lupus erythematosus with long-term chloroquine use: rheumatoid factor levels decreased no evidence of eeffect on progressivein erosive bone lesions Possible Mechanisms of Action: reduced T lymphocyte mitogen responsiveness reduced leukocyte chemotaxis stabilization of lysosomal membranes trapping free radicals Clinical Indications:antimalarials Used for patients not responding adequately salicylate/NSAIDs return to main menu I - return to main menu II Gold and Rheumatoid Arthritis Overview:gold Parenteral gold reduces: symptoms slows disease progression may reduce bone/articular cartilage destruction Toxicities: reduce likelihood of long-term use Chemistry:available gold preparations Aurothiomalate-- parenteral (intramuscular; water-soluble gold salts (50% elemental gold) Aurothioglucose--parenteral (intramuscular; water-soluble gold salts (50% elemental gold) Auranofin -- substitute gold thioglucose derivative-- oral route administration Pharmacokinetics:gold highly plasma protein-bound concentrated synovial membranes also concentrates in liver, kidney, spleen, lymph nodes, bone marrow, adrenal glands body half-life: about one-year oral administration: 25% absorption return to main menu I - return to main menu II Pharmacodynamics:gold Mechanism of action: uncertain Gold affects macrophage function/morphology Many other effects including: reduced lysosomal enzyme activity decreased mast cell histamine released inactivation of first component of complement suppression of phagocytosis by polymorphonuclear leukocytes reduced macrophage function inhibition of Shwarzman phenomenon return to main menu I - return to main menu II Clinical Use/contraindications: gold May be used for active rheumatoid arthritis Gold may be used for patients showing active inflammation/erosive changes Gold for rheumatoid arthritis in patients with Sjogren's syndrome or juvenile rheumatoid arthritis Major Contraindications: gold previous history toxicity pregnancy significant liver or renal function impairment blood dyscrasia return to main menu I -return to main menu II Adverse Effects:gold Frequency of adverse effects: 33% Most common: pruritus -- frequency 15%-20% and gastrointestinal disturbances (diarrhea) Hematologic: frequency 1%-10%: thrombocytopenia leukopenia pancytopenia aplastic anemia (rare) -- but potentially fatal Proteinuria: frequency -- 8% -- 10%; some cases progressed to nephrotic syndrome Diverse, other adverse effects: stomatitis metallic taste skin pigmentation enterocolitis cholestatic jaundice peripheral neuropathy pulmonary infiltrates corneal gold deposition return to main menu I - return to main menu II Penicillamine Overview:penicillamine metabolite of penicillin; analog of cysteine D-form (isomer) is used clinically Pharmacokinetics:penicillamine 50% absorption following oral Route of Administration 60% of drug excreted in 24 hours Pharmacodynamics: penicillamine Mechanism of action:penicillamine uncertain interacts with lymphocyte membrane receptors may interfere with DNA synthesis, collagen, mucopolysaccharides long latency (3-4 months) Clinical Indications:penicillamine Active, progressive erosive rheumatoid disease-uncontrollable by more conservative treatment mainly prescribed for patients not responsive to gold therapy not useful for seronegative arthropathies Caution: penicillamine significantly interferes with absorption of many other drugs return to main menu I - return to main menu II Adverse Effects:penicillamine Proteinuria: frequency 20% Immune complex nephritis: frequency 4% (reversible) Leukopenia and thrombocytopenia -- may occur at any time, may be preceding aplastic anemia Most common adverse effects: skin/mucous membrane reactions Autoimmune Diseases associated with penicillamine use:(requires immediate cessation of drug) Goodpasture's syndrome lupus erythematosus hemolytic anemia thyroiditis Diverse adverse effects: reduced taste perception, anorexia, nausea, vomiting, mammary hyperplasia, alopecia, psychological changes Contraindications:penicillamine pregnancy renal insufficiency concurrent treatment with: gold, cytotoxic drugs, phenylbutazone Frequency of adverse effects requiring discontinuation of penicillamine treatment: 40% return to main menu I - return to main menu II Sulfasalazine Overview:sulfasalazine First introduced for management of ulcertive colitis Effective in management of rheumatoid arthritis Pharmacokinetics:sulfasalazine Main metabolites: 5-acetylsalicyclic acid (5-ASA), sulfapyridine Active drug for inflammatory bowel disease: 5-ASA Active drug for rheumatoid arthritis: either sulfapyridine or sulfapyridine + sulfasalazine Pharmacodynamics:sulfasalazine Mechanism of action: probably NOT dihydrofolate inhibition Sulfasalazine does have effects on B lymphocyte function FDA approved for rheumatoid arthritis Adverse Effect:sulfasalazine In rheumatoid arthritis patients: Most common side effects -- gastrointestinal disturbance rashes dizziness photosensitivity neutropenia (rare)-May require drug withdrawal; hypersensitivity pneumonitis (rare); sterility (rare) return to main menu I - return to main menu II Glucocorticoids Overview:glucocorticoids Very effective in treating rheumatoid arthritis Prednisone and related agents may slow development of new bone erosions Pharmacodynamics:glucocorticoids Inhibition: phospholipase A₂: causes liberation of membrane lipid arachidonic acid glucocorticoids: selective inhibition of COX-II expression return to main menu I - return to main menu II Adverse Effects:glucocorticoids Prolonged Use: fractures infections cataracts in certain patients, with prolonged use: diabetes, hypertension, accelerated atherosclerotic heart disease Clinical Uses:glucocorticoids Extra-articular presentations: pericarditis eye involvement exacerbations Intra-articular corticosteroids: pain reduction preferable to increasing systemic dosage return to main menu I - return to main menu II Diet Eating unpurified eicosapentaenoic acid: reduced platelet aggregation reduced chemotactic activity-- caused by leukotriene B4 reduced polymorphonuclear adherence-- caused by leukotriene B4 Eicosapentaenoic acid treatment: reduces morning stiffness decreases number of painful joints in rheumatoid arthritis patients reduces erythema associate with psoriasis may be beneficial as an adjunct to traditional management return to main menu I - return to main menu II Acetaminophen Overview:acetaminophen Important drug for management of mild/moderate pain AF anti-inflammatory effect is not required Phenacetin (prodrug, more toxic)® metabolized to acetaminophen Weak prostaglandin inhibitor No appreciable anti-inflammatory actions return to main menu I - return to main menu II Pharmacokinetics:acetaminophen Oral administration Peak plasma levels: 30-60 minutes Partial hepatic metabolism:-- inactive metabolites acetaminophen sulfate acetaminophen glucuronide < 5% excreted unchanged Toxic, minor metabolite: N-acetyl-p-benzoquinone liver, kidney toxicity a concern at high doses return to main menu I - return to main menu II Clinical Uses:acetaminophen Comparable to aspirin analgesia and antipyretic effect; No anti-inflammatory effects No effect on uric acid levels No platelet inhibition Effective in management of mild/moderate pain due to: headache myalgia postpartum pain For analgesia, acetaminophen preferable if: patient allergic to aspirin salicylates -- poorly tolerated patient has hemophilia peptic ulcer disease present aspirin induces bronchospasm no antagonism of probenecid (uricosuric drug); may be used with probenecid for management of gout in children with viral infection: preferable to aspirin (Reye's syndrome concern) return to main menu I - return to main menu II Adverse Effects:acetaminophen Small increase in hepatic enzymes (reversible) -- occurs at therapeutic doses Larger doses: dizziness, excitement, this orientation Very high doses: (15 grams): maybe fatal due to: severe hepatotoxicity -- central lobular necrosis symptoms of hepatic damage: nausea, diarrhea, abdominal pain, vomiting acute renal tubular necrosis renal pathology may occur or in the absence of hepatic damage Management of overdosage: supportive sulfhydryl groups: may neutralize toxic metabolites (acetylcysteine) cautious use in patients with liver disease return to main menu I - return to main menu II