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Mechanism Intra-articular crystals (gout = monosodium urate monohydrate; pseudogout = calcium pyrophosphate dihydrate, & basic calcium phosphates); Urate tends to crystallize in colder & more acidic conditions. Neutrophils ingesting crystals secrete inflammatory mediators that lower pH & lead to further urate precipitation Analog of hypoxanthine metabolized to active oxypurinol. Both agents ↓ uric acid production & ↑ purine excretion via inhibition of xanthine oxidase (at low doses: competitive; at high doses & any dose of oxypurinol: non-competitive) Arrests mitosis in metaphase by binding to tubulin & prevents mitotic spindle formation in granulocytes & other motile cells. Inhibits migration of granylocytes into inflamed areas & ↓ their metabolic & phagocytic activities. Prevents elaboration of urate-induced glycoprotein in joints Intra-articular steroids (methylprednisolone), systemic (oral prednisone) or IM triamcinolone, hexacetonide, & corticotrophin Anti-inflammatory via inhibition of COX (mainly ↓ PGE2, which plays a major role in crystal induced inflammation, & acts synergistically w/other mediators (bradykinin, LTB4) to enhance dilatation, pain sn, & neutrophil chemotaxis)
Activity/Use Prompt commencement impt
Side Effects/Toxicities Recurrent attacks usual
For hyperuricemia, gout, prevention of hyperuricemia in pts. receiving antineoplastic drugs Prevention & tx of gout. No analgesia. Give within 24 hrs. Best when neither NSAIDs or colchicine are recommended (elderly w/renal or hepatic dz, cardiac failure, PUD, hypersn) Non-salicylate NSAIDs are DOC for acute crystal induced arthritis
Hypersn rxn, rash if w/ampicillin; risk of bone marrow suppression if w/cyclophosphamide GI upset from chronic exposure to drug & its metabolites due to enterohepatic circulation (↑ turnover of jejunal mucosal cells), diarrhea. Short duration of tx & rare side effects
↑ t1/2 for probenecid & enhances its uricosuric effect (probenecid ↑ clearance of oxypurinol); ↑ levels of mercaptopurine & theophylline Long-term use: hair loss, bone marrow depression, peripheral neuritis, myopathy (↑ CPK) Avoid if joint sepsis not excluded & in those prone to hypoglycemia
NSAIDS: nonselective = Naproxen, Sulindac, Indomethacin; selective for COX2 = Rofecoxib, Celecoxib Avoid in pts. w/nephrolithiasis or w/overproduction of uric acid. Also inhibits tubular secretion of other drugs like methotrexate & NSAIDs Mostly excreted unchanged in urine, but To avoid precipitating an early attack 10% eliminated as N-p-hydroxyphenyl of gout, give w/colchicine. Risk of GI metabolite which has potent uricosuric irritation, hypersn, ↓ hematopoeisis, effects. May induce hypoglycemia inhibition of platelet aggregation, (inhibits metabolism of sulfonylurea oral renal stones (↑ fluid intake) hypoglycemic agents) Methemoglobinemia, acute renal failure, anaphylaxis Renal urate stones (↑ fluid intake to avoid). Mild GI irritation & acute gouty arthritis attack possible (give NSAIDs & colchicine)
Used to tx gout & also to inhibit the Inhibits uric acid reabsorption (via competition for the anion exchanger) active secretion of PCN G in pts. where in the proximal tubule, resulting in ↑ secretion or uric acid (action is PCN resistance is an issue or in pts. tx blunted by salicylates). Also moderately analgesic & anti-inflammatory w/neurosyphilis or gonorrhea infection Inhibits uric acid reabsorption in the proximal tubule. Small doses inhibit uric acid secretion.
For chronic gout
A recombinant urate-oxidase that catalyzes the enzymatic oxidation of uric acid into the soluble & inactive metabolite allantoin Potent uricosuric agent used in Europe TNF-α plays a central role in the immune response seen in rheumatoid arthritis Recombinant human anti-TNF monoclonal Ab that complexes w/soluble TNF-α & prevents its interaction w/p55 & p75 cell surface receptors. Macrophage & T cell fxn are downregulated.
Lowers urate levels more effectively than allopurinol - initial mgmt in peds pts. Efficacy ↓ by production of Abs w/leukemia, lymphoma & solid tumor against drug. Hemolysis in G6PDmalignancies on chemo (tumor lysis deficient syndrome) Effective in pts. w/renal dz
TNF-α Blocking Agents Adalimumab Infliximab Get PPD before tx!! Used to decrease rate of formation of new erosions in RA Risk of macrophage-dept. infections (i.e.: TB or other opportunistic infections)
Chimeric (25% mouse, 75% human) monoclonal Ab that binds to Used to tx RA & ulcerative colitis in combo Infusion rxns, development of Abs to soluble & membrane-bound TNF-α - similar mechanism to adalimumab w/methotrexate drug, infections Fusion protein of two soluble TNFp75 receptor moieties linked to Fc portion of human IgG1. Binds TNF-α molecules & also inhibits lymphotoxin-α Converted in plasma & intestines to active agent A77-1726. Inhibits dihydroorotate dehydrogenase leading to a ↓ in ribonucleotide synthesis & arrest of stimulated cells in G1 phase of cell growth. Inhibits T cell proliferation & B cell production of auto-Abs Recombinant humanized anti-CD11a monoclonal Ab that inhibits the interaction of LFA-1 on all lymphocytes w/ICAM-1, thereby inhibiting adhesion, activation, & migration of lymphocytes into skin Active agent is metabolite 6-thioguanine, which suppresses the synthesis of inosinic acid, B & T cell fxn, Ig production, & IL-2 secretion Suppress T lymphocytes' response to mitogens, ↓ leukocyte chemotaxis, stabilize lysosomal enzymes, inhibit DNA & RNA Metabolite of PCN & analog of cystine Agents include Auranofin, Gold sodium thiomalate, Aurothioglucose. Probable mechanism: alter morphology & fxn of macrophages & inhibit IL-8, IL-1β, & VEGF. Auranofin inhibits release of PGE2 & LB4. Metabolized to phenylacetic acid mustard which cross-links DNA & prevents cell replication Active metabolite is phosphoramide mustard which inhibits cells repln by cross-linking DNA. Suppresses T & B cell fxn. Active vs. RA (only oral, not if IV). Useful for SLE, vasculitis, wegener's granulomatosis Used for joint pains of SLE & Sjogren's syndrome (dryness of mucus membrane, D isomer used to tx RA Slows radiologic progression of RA. Also used for Sjogren's & juvenile RA Retinal damage, dyspepsia, N/V, abd pain, rashes, nightmares Rarely used due to toxicity Chrysiasis (gray-blue skin pigmentation) of GI tract mucus membranes & skin, exfoliative dermatitis, renal damage, thrombocytopenia Dose-dept. bone marrow suppression, infertility w/azoospermia & amenorrhea Dose-related infertility in men/women, bone marrow suppression, alopecia Used to tx RA, juvenile chronic arthritis, Risk of activation of latent TB & psoriatic arthritis, ankylosing spondylitis. ↓ opportunistic infections, also injection rate of formation of new erosions but site rxns ineffective for ulcerative colitis! As effective as methotrexate in tx RA Approved for tx of adult pts. w/severe psoriasis Diarrhea & elevation in liver enzymes are main side effects. Also mild alopecia, weight gain, HTN Excretion & clearance enhanced by colestyramine
Efalizumab others Azathioprine Chloroquine Hydroxychloroquine d-Penicillamine Gold Salts
Contraindicated w/renal/hepatic dz, infectious hepatitis, hematologic disorders High risk of leukemia after 3 yrs of use! Hemorrhagic cystitis, rare bladder carcinoma, pulmonary fibrosis
At low doses used to tx RA, anti-inflammatory mechanisms Nausea, mucosal ulcers, dose-dept. predominate rather than the anti-proliferative ones. MTX inhibits 5hepatotoxicity & rare lung hypersn. Reabsorption in proximal jejunum, aminoimidazole-4-carboxamide ribonucleotide (AICAR) Contraindicated in pregnancy, enters cells via active (folate receptors formylotransferase resulting in accumulation of adenosine which DMARD of choice to tx RA alcoholism, liver/kidney dz, untreated α&β), passive & facilitated diffusion. binds to A2 α receptors to ↑ cAMP, which then ↓ secretion of TNF, IFNfolate deficiency, pancytopenia, Polyglutamate metabolites stored in γ, IL-12, IL-6, & inhibits phagocytosis. Also induces apoptosis, immunodeficiency, concurrent liver & RBCs for a long time suppresses neutrophil chemotaxis, ↓ ICAM & VCAM in synovial tissue, trimethoprim tx inhibits dihydrofolate reductase, etc. Inhibits calcineurin, a phosphatase that normally dephosphorylates the cytoplasmic subunit of nuclear factor of activated T cells (NFAT) allowing NFAT to translocate to the nucleus & augment tcr of several Significant nephrotoxicity made worse Drug retards the appearance of new Hyperkalemia, HTN, hepatotoxicity, cytokines. In T cells, calcineurin inhibition blocks IL-2 gene tcr & by other meds that inhibit CYP3A. bony erosions in RA gingival hyperplasia, hirsutism release, & ultimately inhibits T cell activation. Also inhibits macrophageGrapefruit juice ↑ bioavailability 62%. T cell interactions & T cell responsiveness; affects T cell-dept. B cell fxn. Active agent is mycophenolic acid which inhibits enzyme inosine monophosphatase dehydrogenase (IMPDH), w/resultant depletion of guanosine nucleotides needed for DNA & RNA synthesis. 5x more potent inhibitor of IMPDH type II isoform found in B- & T-cells, thus GI intolerance, bone marrow Used to tx renal dz due to SLE specifically inhibits lymphocyte activation & proliferation. May also suppression, hepatotoxicity enhance apoptosis. Inhibits E-selectin, P-selectin, & intercellular adhesion molecule 1, thereby interfering w/leukocyte adhesion to endothelial cells Metabolized to sulfapyridine & 5-aminosalicylic acid. ↓ rate of Hemolytic anemia, appearance of new joint damage. Inhibits IgA & IgM rheumatoid Sulfapyridine is active moiety when tx RA methemoglobinemia, N/V, headache factor production