Pharmacology - Drugs - Rheumatoid Arthritis and Gout Flashcards
What is indomethicin used for?
Like naproxen, NSAID Long-term relief of symptoms in RA and other musculoskeletal disorders
Why are COX-2 inhibitors being used more than NSAIDs?
Cox-2 inhibitors decrease the incidence of gastric and duodenal ulcers by 50% as compared with traditional NSAIDs Provide therapeutic relief until a DMARD takes effect.
What is sulfasalazine used for?
Oldest DMARD Fast-acting (1 month) Mechanism not understood, may inhibit IL-1 and TNF-alpha release Adverse effects - nausea, rashes, headaches, neutropenia
What is one advantage of using antimalarials to treat rheumatic disorders?
Less efficacious than other DMARDs but also less toxic
What is the gold-standard DMARD therapy?
Methotrexate
Why is cyclosporine A not used more often as a DMARD?
Toxic
What is leflunomide?
Similar effects to sulfasalazine and methotrexate DMARD Newest prevents de novo pyrimidine synthesis Side effects are diarrhea, alopecia and hepatotoxicity
What is the mechanism of action of prednisone?
Glucocorticoids in general: inhibit phospholipase A2 activity –> inhibits release of arachadonic acid from cell membranes –> inhibits formation of prostaglandins Glucocorticoids also inhibit production of numerous cytokines which prevent induction of COX-2.
What are the long term effects of glucocorticoid use?
Hyperglycemia Osteoporosis Poor wound healing Though usually benefits outweigh complications Use glucocorticoids to induce remission while slower-acting DMARD takes effect
What are examples of antimalarials in use as DMARDs?
Chloroquine (can cause irreversible retinal damage if used long term) Hydroxychloroquine (better tolerated) for RA, lupus Overall, less efficacious than other DMARDs Act by inhibiting chemotaxis
What is the most commonly used DMARD (is also immunosuppressive)?
Methotrexate Folate analog Inhibits reaction catalyzed by dihydrofolate reductase that is essential for DNA synthesis Also used as anticancer agent Major complication is hepatotoxicity At low doses (for rheumatic diseases) –> inhibition of aminoimidazolecarbomide transformylase and thymidylate synthetase with secondary effects on polymorphonuclear chemotaxis –> AMP then accumulates and is converted to adenosine, which inhibits inflammation
What are the TNF-alpha antagonists?
Etanercept Infliximab Adalimumab Golimumab Certolizumab
How does Etanercept (Enbrel) work?
TNF-alpha antagonist –> less inflammation systemically Binds to TNF and prevents its binding to receptors example of an antagonist that binds a receptor but does not activate it SubQ 2x/wk
What is Infliximab (Remicade)?
TNF-alpha antagonist –> less inflammation systemically Monoclonal antibody (chimeric mouse-human) TNF-alpha antagonist Effective within 1 week of injection Antigenic
Why is Adalimumab favored over etanercept?
TNF-alpha antagonist –> less inflammation systemically More convenient dosing regimen (2x/monthly) Fully human anti-tnf-alpha mab Not antigenic
How does Golimumab work?
TNF-alpha antagonist –> less inflammation systemically Once monthly dosing human mab, binds to both membrane bound and soluble tnf-alpha Opportunistic pathogen infection risk is increased (ie TB) **which is generally true of all TNF-alpha blockers
How is Certolizumab different from other TNF-alpha antagonists?
TNF-alpha antagonist –> less inflammation systemically It’s a humanized Fab fragment congugated to polyethylene glycol to delay metabolism and elimination
What is Anakinra?
Cytokine antagonist (IL-1) Soluble human IL-1 receptor antagonist Short half life necessitates frequent daily treatment in high doses
What IL-6 receptor antagonist has had serious issues with opportunistic infections?
Tocilizumab Approved as “Actemra”
What is the MOA of Abatacept?
Inhibits T-cell activation and induces T-cell apoptosis Name brand: Orencia approved for RA refractory to TNF-alpha inhibitors Side effects - headaches, infections
What is Rituximab?
Anti-CD20 mAb that reduces circulating B cells considered a “costimulation modulator” approved for RA refractory to TNF-alpha inhibitors
What signaling pathway inhibitor is used for RA treatment?
Tofacitinib inhibitor is JAK kinase 1 and 3 inhibits production of inflammatory mediators
RA is characterized by chronic inflammation of the synovial membrane and infiltration by blood-derived cells, for example….
CD4+ T-cells, which produce inflammatory cytokines
T/F: TNF-alpha and IL-1 play a central role in RA.
True IL-6 also plays a role in pro-inflammatory plathways.
