Arthritis and Gout Flashcards
(24 cards)
Indomethacin; Naproxen
Non-selective NSAIDs
Risk of gastric and duodenal ulcers
Indomethacin: Most potent NSAID and used in acute gout
COX-2 Inhibitors
e.g. Celecoxib
Use is superseding convention NSAIDs because they decrease the incidence of gastric and duodenal ulcers by 50%
Prednisone
Glucocorticoid
1) . Inhibit phospholipase A2 activity -> inhibits release of arachidonic acid –> inhibits prostaglandin synthesis
2) . Inhibit cytokines –> prevent induction of COX-2
Hyperglycemia, osteoporosis, poor wound healing
Chloroquine and Hydroxychloroquine
Antimalarial Drugs/Quinolones (treat Lupus too)
Act by inhibiting chemotaxis**
Chloroquine can cause irreversible retinal damage during long-term treatment (hydroxychloroquine is better tolerated)
Hydroxychloroquine: First line treatment for mild RA. Stabilizes lysosomes and decreased chemotaxis. Known to have VERY little side effects
Quinine derivative –> GI distress and visual disfunction (cinchonism), hemolysis in G6PD deficiency**
Sulfasalazine
Works in less than a month (quick acting, commonly used in Europe)
Retards progression of RA by inhibiting IL-1 and TNF-alpha**
Nausea, vomiting, headaches, skin rashes and neutropenia cause about 30% of patients to discontinue
Methotrexate
Gold standard DMARD
Folate analog that inhibits a reaction catalyzed by dihydrofolate reductase which is essential for DNA synth
RA: Low dose inhibits of aminoimidazolecarboxamide (AICAR) transformylase and thymidylate syntheses with secondary effects on poly chemotaxis
- -> AMP accumulates and is converted to adenosine which inhibits inflammation
- -> SE: Nausea and stomatitis but hepatotoxicity** can occur
Leflunomide
Prodrug taken orally
Inhibits dihydroorotate dehydrogenase (DHODH) the RLE required for de novo synthesis of pyrimidine (UMP) –> low ribonucleotides –> arrests lymphocytes in G1 –> Reduces T and B cell populations and release of cytokines
SE: Alopecia, diarrhea and hepatotoxicity**
Better efficacy but worse side effects
Etanercept
TNF-alpha antagonist (Biological response modifiers)
Fusion protein made up of two recombinant soluble TNF RECEPTORS fused with the Fc portion of human IgG1.
Twice weekly subQ. Significant improvement and well tolerated
Infliximab
TNF-alpha antagonist
Chimeric (mouse/human hybrid) monoclonal IgG1 ANTIBODY against TNF-alpha. Positive effects within a week
SE: Antigenic again mouse ab
Adalimumab
TNF-alpha antagonist
Fully human monoclonal anti-TNF-alpha ab
As effective as etanercept but more convenient dosing (twice monthly)
Golimumab
TNF-alpha antagonist
Human monoclonal ab that binds to membrane-bound and soluble TNF-alpha
Once monthly (advantage)
SE: Serious infections (TB, fungal and opportunistic infections) - THIS IS THE CASE FOR ALL TNF-ALPHA BLOCKERS**
Certolizumab
TNF-alpha antagonist
Humanized ab Fab fragment conjugated to polyethylene glycol to delay its metabolism and elimination
Anakinra
IL-1 RECEPTOR ANTAGONIST**
Short (6 hr) half life in plasma = frequent daily treatment with high doses
Tocilizumab
IL-6 RECEPTOR ANTAGONIST**
SE: TB, fungal, viral and other opportunistic infections
Abatacept
Inhibits T-cell activation and induces T-cell apoptosis
SE: Headaches, infectiosn
Rituximab
Anti-CD20 mAb that reduces circulating B-cells (apoptosis of B cells)
SE: Infections, hypsensitivity reactions; decrease with repeated dosing
Tofacitinib
Inhibitor of the enzyme (JAK) 1 and 3 involved in intracellular signaling –> inhibits production of inflammatory cytokines
The drug enters the cell and inhibits tyrosine kinase
Colchicine
Used to treat acute gouty arthritis
Binds to tubulin** –> prevents polymeriziation –> inhibition of leukocyte migration, mitosis** (M phase specific) and phagocytosis
SE: Nausea, vomiting, abdominal pain and diarrhea** (inhibition of epithelial cell proliferation), peripheral neuropathy or neutropenia and low TI**
NSAIDs
Initial treatment of acute gouty arthritis
Inhibit eicosanoid-mediated pain and inflammation
Indomethacin, naproxen, sulindac and celecoxib are effective. Doses at higher end of therapeutic range are often needed.
Corticosteroids
Used to treat acute gouty arthritis
Intraairticular injections at the site of acute monoarticular gout are effective
Used when other treatment are not working
Probenecid
Uricosuric agent: Increase the rate of excretion of uric acid
Used to treat chronic tophaceous gout
Competes with uric acid at the anionic transport sites of the renal tubule and inhibit reabsorption
SE: GI, nausea, UA mobilization –> acute gouty arthritis (paradoxical), and reduced secretion of some weak acids (e.g. penicillin –> prolonged effect)**. Aspirin may decrease effects by competing.
Allopurinol
Reduces the synthesis of uric acid
Used to treat chronic tophaceous gout
Inhibits xanthene oxidase (replaced uricosuric agents, probenecid) by competitive inhibition
Metabolized by xanthine oxidase –> alloxantlhine which acts as a non-competitive inhibitor of xanthine oxidase (suicide inhibitor: inhibits the enzyme that made it active in the first place) while allopurinol itself acts as a competitive inhibitor –> inhibits hypoxanthine –> xanthine –> uric acid
DRUG INTERACTION**: 6-Mercaptopurine (inactive) –> via HGPRT 6-Mercaptopurine (active nucleotide) –> requires xanthine oxidase (which is now inactive) to be metabolized into inactive form –> if taken with allopurinol leads to enhanced effects
Can be seen as a good thing because you can take less (2/3 the amount) 6-MP and get the same effect with a smaller dose –> less side effects
SE: maculopapular rash in 2% of patients, rare hypersensitivity syndrome, acute attacks of gouty arthritis due to mobilization of uric acid
Febuxostat
Novel, non-purine, non-competitive antagonist of xanthine oxidase
SE: nausea, rash, arthralgias, expensive
currently being studied for cadiovascular safety
Pegloticase
Recombinant form of uricase bound to polyethylene glycol
Used to treat chronic tophaceous gout
Used for patients who aren’t responding to other therapies
