Arthritis & Gout Flashcards
Chronic inflammation of the synovial membrane with infiltration by blood derived cells that produce inflammatory cytokines
Rheumatoid Arthritis
Name the general classes of the disease modifying anti-rheumatic drugs (DMARDs)
Gold salts, anti-malarials, immunosuppressives
At what point in the progression of RA is joint damage most rapid (early, intermediate, or late)?
Early! Once damage is done, it is irreversible
How are indomethacin and naproxen useful for treating RA? What are the drawbacks of using these drugs? What class of NSAID are they getting replaced by?
Used to treat the pain and reduce the inflammation but does NOT slow disease progression. Being replaced by COX-2 inhibitors, as there is less GI toxicity.
How do glucocorticoids work to treat RA and in what context are they often used today?
Suppress inflammation by inhibiting PLA2 activity and inhibiting the production of cytokines. Used in conjunction with the initiation of a DMARD, because DMARDs are slower acting and take weeks to start having an effect.
Your patient is experiencing an acute gout attack in his thumb that just won’t go away, and it is impairing his ability to perform at his job as a mechanic. He’s in great distress and is begging you for a joint injection. What do you inject?
Intraarticular glucocorticoid injection
How does gold work as an immunosuppressant?
inhibits the funcational capabilities of the macrophages
What is the likely MOA of sulfasalazine as an immunosuppressant and what is unique about this drug when comparing to other DMARDs?
Inhibitions of IL-1 and TNF-a release. Acts more quickly than the other DMARDs
How do the doses of methotrexate when used for RA compare to the doses used for cancer? How does the difference in doses change the mechanism of action of the drug?
The RA doses are lower than those used for cancer. Works by inhibition of aminoimidazolecarboxamide (AICAR) transformylase and thymidylate synthetase, causing AMP to accumulate, be converted to adenosine, and inhibit inflammation. Methotrexate is the GOLD STANDARD of RA therapy.
Tell me about Leflunomide.
Prodrug DMARD, works by inhibiting DHODH and essentially inhibits T-lymphocyte response to stimuli. Side effects are diarrhea and hepatotoxicity.
How does etanercept work?
Blocks binding of TNF to TNF receptors.
What is the major difference between infliximab and adalimumab?
Inflixumab is chimeric and adalimumab is fully human, so adalimumab is better tolerated! No antigenic response.
What is a major side effect of golimumab (and of all TNF-a blockers)?
Increased risk of serious infections by opportunistic pathogens (TB, fungal, etc)
What is unique about certolizumab when compared to other TNF-a blockers?
conjugated to polyethylene glycol, so metabolism and elimination is delayed
How does anakinra work to treat RA?
IL-1 receptor antagonist
How does tocilizumab work to treat RA?
IL-6 receptor antagonist
How does abatacept work to treat RA?
inhibits T cell activation and induces T cell apoptosis
How does rituximab work to treat RA?
anti-CD20 MAB that reduces circulating B cells, often used for RA refractory to TNF-a inhibitors
- recurrent episodes of acute arthritis
- local infiltration by macrophages and neutrophils
- lactate production and local decrease in pH
- presence of urate crystals in joint/cartilage
What is the diagnosis?
Gout
How is uric acid produced?
Hypoxanthine –> xanthine (catalyzed by xanthine oxidase)
Xanthine –> uric acid (catalyzed by xanthine oxidase)
Purine catabolism
What are the 4 treatment strategies for approaching gout management?
- decrease synthesis of uric acid
- increase excretion of uric acid
- decrease mobility of leukocytes
- symptomatic relief with NSAIDs or corticosteroids
Where is uric acid reabsorbed and secreted?
Middle segment of proximal tubule
What are some instances that would increase the rate of urate production in a patient?
- disease states associated with rapid production and destruction of cells
- antineoplastic agents and radiation therapy
- alcohol use
- lots of animal muscle, seafood, beer, and high fructose corn syrup in diet
What are some instances that would decrease the rate of urate excretion in a patient?
- renal problems
- low urine volumes
- drugs, such as thiazide diuretics
What is the term for deposits of urate in tissues or joints?
Tophi, or tophaceous gout
How does colchicine work to treat acute gout?
binds to tubulin and prevents polymerization, which leads to the inhibition of leukocyte migration and release of proinflammatory autacoids
What are the serious side effects of colchicine?
peripheral neuropathy and neutropenia
How does probenecid work when treating chronic gout? What is an interesting side effect?
Competes with urate at the anionic transport sites of renal tubule to inhibit reabsorption of gout. Sometimes, reduced urate levels may cause urate crystal mobilization and acute gouty arthritis!
How does allopurinol work to treat chronic gout?
Competitive inhibitor of xanthine oxidase, and is metabolized to alloxanthine which is a non competitive inhibitor of xanthine oxidase
How does febuxostat work to treat chronic gout?
non-competitive antagonist of xanthine oxidase
How does pegloticase work to treat chronic gout?
recombinant form of uricase, converts uric acid to allantoin
