Drug

Anti-Gout

Allopurinol

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

Other Cautions

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

Colchicine

Steroids

NSAIDs

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)

Probenecid

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.

Sulfinpyrazone

For chronic gout

Rasburicase
Benzbromarone

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- plays a central role in the immune response seen in rheumatoid arthritis Recombinant human anti-TNF monoclonal Ab that complexes w/soluble TNF- & 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

Anti-Rheumatic
TNF- 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- - 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- molecules & also inhibits lymphotoxin- 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-1, & 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

Etanercept

Leflunomide

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

Chlorambucil Cyclophosphamide

Methotrexate

Cyclosporine

Mycophenolate mofetil

Sulfasalazine

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 &), passive & facilitated diffusion. binds to A2 receptors to cAMP, which then secretion of TNF, IFNfolate deficiency, pancytopenia, Polyglutamate metabolites stored in , 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