Pharm RA and Gout. Flashcards
Rheumatoid Arthritis
chronic, inflammatory, autoimmune disease - more frequent in women 4-6th decade of life - inflammation of the synovial lining of the joints which causes pain, stiffness, swelling
Which cytokines play a central role in rheumatoid arthritis?
TNF-a and IL-1 produced by macrophage
What does production of TNF-a and IL-1 lead to?
recruitment of other inflammatory cells to joint and release of metalloporteinases which results in bone and cartilage degradation
What leads to the development of the rheumatoid pannus?
hypertrophy and hyperplasia and development of new blood vessels in synovium
What does the panes do?
invades and damages cartilage and bone due to cytokine induction of destructive enzymes (esp matrix metalloproteinases)
What are the differences between early RA and established RA?
early: synovial membrane beings to invade the cartilage established: synovial membrane becomes transformed into inflammatory tissue (pannus) which invades and destroys adjacent cartilage and bone
What is the purpose of aspirin and NSAIDS in RA treatment?
relieve pain and inflammation
What is given when aspirin and NSAIDS became ineffective? examples?
DMARD - disease-modifying anti-rheumatic drugs (ex. gold salts and antimalarial drugs)
Which NSAIDS are given to treat RA?
indomethacin, naproxen (relieve symptoms) and COX2 inhibitors (like conventional NSAIDS but decrease incidence of gastric and duodenal ulcers)
What is the problems with NSAIDS in RA treatment?
eliminate pain and some inflammation - but do not slow progression of the disease “bridge therapy” - provide symptomatic relief until therapeutic effect of DMARD is observed
DMARD
drugs that retard or halt the progression of the disease - can take 2 weeks to 6 months to become clinically evident
What are DMARDS used for RA treatment?
- glucocorticoids (no longer) 2. antimalarial drugs 3. sulfasalazine 4. immunosuppressive drugs (methotrexate and leflunomide)
Glucocorticoids (example and mechanism)
prednisone: inhibit phospholipase A2 activity which inhibits release of arachidonic acid from cell membranes, blocks formation of prostaglandins - also prevents induction of COX-2
Why are glucocorticoids no longer used in treatment of RA?
serious adverse effects (hyperglycemia, osteoporosis, poor wound healing)
Antimalarial drugs (examples and mechanism)
chloroquine and hydroxychloroquine - act by inhibiting chemotaxis (t cell activation) - less efficacious than other DMARDS
Sulfasalazine (mechanism)
sulfasalazine acts more quickly than antimalarials - retards radiographic progression of RA - inhibits IL-1 and TNF-a release
Immunosuppressive drugs (examples and mechanism)
methotrexate and leflunomide (reduce both pain and swelling as well as slow the progression of destruction) - need to be given early in course of disease
What is the most commonly used DMARD?
methotrexate and leflunomide (reduce both pain and swelling as well as slow the progression of destruction) - need to be given early in course of disease
Methotrexate mechanism
folate analog - inhibits reaction by dihydrofolate reductase which is essential for DNA synthesis (used as anticancer treatment as well) - at low doses in RA - inhibition of AICAR trnsformylase and thymidylate synthetase which have effects on chemotaxis
What is the newest member DMARD for RA treatment? What is its mechanism?
leflunomide - active metabolite - inhibits dihydroorotate dehydrogenate which is the rate limiting step for de novo synthesis of pyrimidine so t-lymphocyte response to stimuli is inhibited
Biological response modifiers - What do they do and what are the 4 groups?
highly specific therapeutics that target molecules involved in pro-inflammatory roles and surface molecules on different cells involved in pathogenesis of RA Groups: 1. TNF-a antagonists 2. other cytokine antagonists 3. co-stimulation modulators 4. signaling pathway inhibitors
What are the TNF-a antagonists?
etanercept, infliximab, adalimumab, golimumab, certolizumab
Etanercept
fusion molecule with anti-TNF activity - binds TNF and prevents its binding to receptors - 2x weekly SC injections
Infliximab
chimeric monoclonal antibody against TNF-a - antigenic because chimeric
Adalimumab
fully human monoclonal anti-TNF-a - 2x monthly SC injection
Golimumab
human monoclonal - binds TNF-a, 1x monthly
What is side effect of TNFa antagonists?
blocking TNF so become susceptible to opportunistic pathogens
Certolizumab
humanized antibody Fab fragment conjugated to polythylene glycol to delay its metabolism and elimination
What are the other cytokine antagonists?
anakinra and tocilizumab
Anakinra
IL-1 receptor antagonist, short half life (daily injection) - not really used anymore
Tocilizumab
IL-6 receptor antagonist - opportunistic infections occur
What are co-stimulation modulators?
abatacept and rituximab
Abatacept
inhibits T-cell activation and induces T cell apoptosis
Rituximab
anti-CD20 mAb that reduces B cells
What is the signaling pathway inhibitor? What is its mechanism?
tofacitinib - inhibitor of JAK1 and 3 tyrosine kinases - inhibits production of inflammatory mediators - WORKS INSIDE CELL (different from other biological response modifiers)
What is the current approach to therapy for patients with early RA and low disease activity?
treated with non biologic DMARD mono therapy (hydroxychloroquine, minocycline, lefunomide, methotrexate, sulfasalazine)
What is the current approach to therapy for patients with moderate or high RA but without poor prognostic features?
initial treatment with DMARD mono therapy or the combination of methotrexate and hydroxychloroquine
What is the current approach to therapy for patients with moderate or high disease activity and evidence of poor prognostic features?
combination therapy with mehtotrexate/hydroxychloroquine, methotrexate/sulfasalazine, or methotrexate/sulfasalazine/hydroxychloroquine
What is the current approach to therapy for patients with high disease activity and features of poor prognosis?
Anti-TNF therapy with or without methotrexate
Gout
acute arthritis mediated by crystallization of uric acid within the joints - associated with hyperuricemia
What is gout associated with?
high serum levels of uric acid - poorly soluble and major end product of purine metabolism
What is normal serum uric acid concentration? When does it begin forming crystals?
normal: 40-50 mg/L crystals: >100 mg/L
Where is uric acid reabsorbed and secreted? What amount is excreted?
middle segment of the proximal tubule. 10% excreted of filtered
What is the general mechanism of drugs that treat gout?
compete with urate for the transporters in proximal tubule, inhibiting reabsorption of uric acid and increase its secretion
What are the causes of hyperuricemia?
high rate of urate production (disease states, metabolism, drug induced, diet) and low rate of urate excretion (renal problems, suboptimal urine volumes, drugs)
What drugs are capable of inhibiting urate secretion?
thiazide diuretics
What is the recommended therapy for patients with acute gouty arthritis?
lifestyle changes (weight loss, diet control, reduced alcohol intake) or altering drug intake will be sufficient to control BOTH forms of gout
Which drugs are used to treat acute gout?
colchicine, NSAIDs, corticosteroids
Colchicine mechanism
an alkaloid isolated from plant autumn crocus - alleviates inflammation by binding to cytoskeletal protein tubule, preventing its polymerization and leads to inhibition of leukocyte activity
What is an adverse side effect of colchicine?
low therapeutic index
NSAIDs in gout
inhibit eicosanoid-mediated pain and inflammation - doses at higher end of therapeutic range often needed
Corticosteroids in gout
intraarticular injection - pain relief - used when colchicine and NSAIDS ineffective
What types of drugs are used in chronic gout?
uricosuric agents (probenecid - increase rate of excretion of uric acid) and allopurinol and febuxostat which reduce synthesis of uric acid
Probenecid
compete with urate at the anionic transport sites of the renal tubule - inhibit reabsorption
What is a side effect of probenecid?
secretion of weak acids, esp penicillin, is reduced
Allopurinol
reduces synthesis of uric acid - competitive inhibitor of xanthine oxidase - metabolized by xanthine oxidase to alloxantlhine which is a non-competitive inhibitor of xanthine oxidase
febuxostat
non-purine, non-competitive antagonist of xanthine oxidase - newer, still be studied
Pharmacologic intervention for acute gout
NSAIDs, colchicine, glucocorticoids
Pharmacologic intervention for asymptomatic hyperuricemia
none
Pharmacologic intervention for chronic gout?
allopurinal, probenecid, febuxostat
