RA Flashcards
Initial therapy
DMARD (i.e. Methotrexate) w/ NSAID and corticosteroid
Initial therapy if mild
Hydroxychloroquine instead of methotrexate b/c less toxic
If initial treatment failure…
Biological agents (TNF-alpha inhibitors) used as monotherapy or with methotrexate
If not good response to TNF-a inhibitor…
non-TNF-a drugs (anakinra, rituximab, toclizumab)
What kind of treatment can lead to longer disease-free remission, less joint destruction, and better quality of life?
Early, aggressive treatment w/ MTX and/or biological agent
AMPLE trial
Triple therapy (i.e. MTX + Sulfasalazine + Hydroxychloroquine) is just as good and much cheaper than using a biological agent (i.e. MTX + etanercept)
TEAR trial
trial was done in pts w/ early, poor-prognosis RA
First study to demonstrate that initial MTX monotherapy w/ option to step-up combination therapy results in similar outcomes to immediate combo therapy (and not all pts ended up needing any combo therapy)
DMARDs–non-biological agents
Methotrexate
Hydroxychloroquine
Leflunomide
Sulfasalazine
Common property of all DMARDs
ability to improve inflammatory symptoms and slow progression of joint erosions
What usually limits use of non-biological DMARDs
toxicity and inadequate response
MTX–MOA
immunosuppression
inhibition of AICAR transformylase–> AICA riboside accumulation–> inhibition of adenosine deaminase–> increased circulating adenosine concentrations–> inhibition of lymphocyte proliferation; suppression of IL-1, IFN-y, and TNF secretion; increased secretion of IL-4; impaired release of histamine from basophils; decreased chemotaxis of neutrophils
MTX–>adenosine
increases
adenosine–>lymphocytes
inhibits proliferation
decreases
adenosine–>IL-1
decreases
adenosine–>IFN-y
decreases
adenosine–>TNF
decreases
adenosine–>IL-4
increases
adenosine–>release of histamine from basophils
decreases
adenosine–>chemotaxis of neutrophils
decreases
MTX metabolism
undergoes polyglutamation when enters cell (so retained intracellularly)
Hepatic
(contraindicated in alcoholism, hepatic disease,etc.)
Enterohepatic recirculation (increases terminal half-life)
MTX elimination
renal (caution in renal failure; alkalinization and hydration reduce renal damage and aid elimination)
involves tubular secretion
(competition w/ weak acids and probenecid)
MTX adverse effects
Myelosuppresion
Pulmonary toxicity
–can be fatal, acute/chronic interstitial pneumonitis, pulmonary fibrosis
Cat. X teratogen
contraindicated in breast feeding
Vaccination
Malignant lymphomas in low dose MTX
Severe and sometimes fatal derm rxns
GI toxicity in pts w/ PUD/ulcerative colitis (esp. when given w/ NSAIDs)
Sulfasalazine indications
pt responded inadequately to salicylates or other NSAIDs
Sulfasalazine MOA
anti-inflammatory properties of mesalamine (metabolic product)… an inhibitor of PG and LT production
Sulfasalazine metabolism
metabolized to active components (sulfapyridine and mesalamine) by bacteria in colon
further metabolyzed via acetylation and hydroxylation in liver
Sulfasalazine elimination
Renal
Caution in pts w/ renal dysfunction
Sulfasalazine Contraindications
hypersensitivity to 5-aminosalicylate, salicylate, sulfonamide drugs
Sulfasalazine Toxicities
Hematotoxicity
potentially fatal blood dyscrasias…infrequent
Leflunomide MOA
active primary metabolite (A77 1726) inhibits dihydroorotate dehydrogenase (DHODH), an enzyme in cell mitochondria that catalyzes key step in de novo pyrimidine synthesis–> in T and B cells, cell cyle progression is arrested and collaborative interaction interrupted–> immunoglobulin production suppressed
Cytostatic (not toxic) at normal doses
Leflunomide Elimination
Major metabolite (A77 1726) has uricosuric effect and is eliminated in feces primarily
other metabolites and conjugates also eliminated
Hepatic metabolism and thus toxicity w/ chronic use
Leflunomide contraindications
pts w/ severe immunosuppression
Cat. X teratogen
Hydroxychloroquine
usually associated w/ treatment of malaria
also can be for RA and SLE
Different MOA and is pretty slow acting
(since very different MOA, compliments combo therapy)
Hydroxychloroquine MOA
increases intracellular vacuole pH and alters protein degredation by acidic hydrolases in lysosome, assembly of macromolecules in endosomes, and post-translation modification of proteins in golgi.
acidic cytoplasmic compartments required for antigenic protein to be digested and for peptides to assemble w/ alpha and beta chains of MHC class II proteins. So…
drug diminishes formation of MHC protein complexes required to stimulate CD4+ T cells and results in down regulation of immune response
Hydroxychloroquine Elimination
Renal
Extensive and slow
Hydroxychloroquine metabolism
partial Hepatic
Hydroxychloroquine cautions and contraindications
Ocular disease (b/c drug–> corneal opacities, keratopathy, retinopathy)
Hepatic disease or alcoholism
Blood dyscrasias
CNS toxicity (polyneuritis, ototoxicity, seizures, neuromyopathy)
Which drugs must be monitored w/ CBCs?
all non-biological DMARDs
Which drugs must be monitored w/ LFTs?
MTX
Sulfasalazine
Leflunomide
Which drugs must be monitored w/ serum creatinine/BUN?
MTX
Sulfasalazine
Which drugs must be monitored w/ serum uric acid?
MTX
Which drugs must be monitored w/ urinalysis?
Sulfasalazine
Which drugs must be monitored w/ pregnancy testing?
Leflunomide
Which drugs must be monitored w/ serum electrolytes
Leflunomide
Which drugs must be monitored w/ opthalmalogic exam?
Hydroxychloroquine
