DMARDs Flashcards
first line therapy for RA
methotrexate if preferred, NSAIDs for rapid symptom relief, important to start DMARDs immediately to avoid permanent joint damage.
combination therapy for patient who do not reach remission within 3 to 6 months
glucocorticoids - chemistry
lipophilic and well absorbed from GI tract, hepatic metabolism to active component
mimics the actions of endogenous cortisol
intracellular receptor - induces transcription - causes transrepression of inflammatory genes
drug use leads to feedback inhibition of the HPA axis which decreases the release of cortisol. Abrupt cessation of glucocorticoids can cause a cortisol deficit
cortisol- effects
maintain metabolic homeostasis: carbs, protein, lipid metabolism and electrolyte balance
cardiovascular, skeletal muscle and CNS effects
suppression of the immune system - inhbits PG and leukotriene synthesis, reduces macrophage activity, reduce numbers of circulating WBC and inhibition of neutrophil release of collagenase and lysosomal enzymes
certain hormones only work in the presence of cortisol
Glucocorticoid use in RA
bridging therapy - low-dose for immediate symptom control while waiting for the effects of DMARDs
intra-articular therapy - injection into joint, limited to few joints. used for management of acute exacerbation of RA and control of extra-articular manifestations.
general effects of glucocorticoid therapy
pallative - not curative or specific
dosing is trial and error, start large and taper down until minimally effective dose is achieved
duration is administration influences toxicity, dosing accumulates
In life-threatening disease - large dose with tapering
exhibits withdrawal
Glucocorticoids adverse effects
dose dependent - cumulative
hypertension, hyperglycemia, central obesity with cervical fatpad and moon face with erythema
skeletal muslce wasting and thin fragile skin
menstrual irregularties and hirsiutism
increased ocular pressure -> cataracts
causes growth retardation in children
osteoporosis
euphoria or depression
increased risk of infection and impaired wound healing
peptic ulcers
(CUSHING)
what are the complications of abrupt glucocorticoid withdrawal?
abrupt adrenal insufficiency - severe abdominal pains, vomiting, diarrhea, profound muscle weakness, hypotension, hyponatremia, hyperkalemia and shock
shock leads to death
disease flare ups
General charateristics of DMARDs
They have little anti-inflammatory or analegesic effects
clinical benefit is delayed for weeks to months
serology titers decrease with treatment (RF, CRP, ESR)
Retards the development of bone erosion
Methotrexate - PK
folate antimetabolite - used for anticancer and in smaller doses RA - can be given orally for RA
50% protein binding with narrow therapeutic window
polyglutamated within cell into active form then renally excreted
Methotrexate - mech of effect
DHFR inhibition - blocks DNA/RNA synthesis
TYMS inhibition - blocks formation of thimydylate which impairs DNA synthesis and repair
AICAR formyl transferase inhibition - accumulation of AICAR. AICAR inhibits adenosine and AMP deaminases - produces antiinflammatory affect mediation by of adenosine
Methotrexate anti-inflammatory affects
suppression of neutrophils, macrophages, DCs, lymphocytes and PMN chemotaxis
Methotrexate antiproliferation
direct inhibitory effect on proliferation, stimulation of apoptosis, inhibits pro-inflammatory cytokines linked to rheumatoid synovitis
methotraxate therapy in RA
oral - once weekly
long term efficacy
toxicites are well understood and managed
combination with other agents increase efficacy
approved for idiopathic juvenile arthritis
methotraxate adverse effects
GI toxic - hepatotoxicity: can be reduced with folate rescue
bone marrow toxicitiy
nephrotoxicity
lymphomas
pneomonitis
dermatologic
phototoxicity
opportunistic infection
infertility and menstrual irregulatities
contraindicated in pregnancy or breast feeding
folate rescue
taken once daily to reduce incidence of GI and liver function abnormalities
not working? leucovorin, weekly (5,10-MTFH)
methotraxate drug interactions
inhibitors of OAT and p-GP increases MTX concentration
OAT - NSAIDS, aspirin, penecillins, sulfonamindes, probenecid
p-GP - cyclosporine
plasma protein binding drugs displace MTX and increase free MTX
all increasing risk of toxicitie
warfarin - increased risk of bleeding
leflunomide and azathioprine - additive - hepatotoxicity
Sulfasalazine
azo-linked and cleaved -> sulfapyridine + 5-aminosalicylic acid
sulfapyridine is the active form in RA
metabolism is rate dependent on N-acetyltransferase
sulfonamides displace MTX
onset: 6 weeks – 3 months
MOA is unknown but supresses T cells, inhibits B cell proliferation, inhibits release of cytokine release and decreases formation of RF
higher efficacy in combination therapy but can be used alone if patients done tolerate MTX
SAFE IN PREGNANCY
approved for juvenile idiopathic arthritis
Sulfasalazine - AEs
common - headache, GI effects and rash, folate def. reversible infertility
hemolytic anemia in G6PD def patients
stevens-johnson syndrome - toxis epidermal necrolysis in predisposed individuals
hepatotoxicity, agranulocytosis, neutropenia, pulmonary toxicity and hypersensitivity reactions
discontinues at first sign of rash or severe side effects
Sulfasalazine Drug Interactions
plasma protein binding - competes
additive effects - dermatological, hepatotoxicity, blood dyscrasias and pulmonary toxicity
mesalamine - can interfere with absorption of digotoxin, increased risk of bruising or bleeding when given with heparin
Hydroxychloroquine
rapidly absorbed from GI tract, high volume of distribution - especially in melanin-containing tissues
hepatic metabolism - nonCYP
30-50 day half life, onset 6 weeks – 3 months
concentrates inside acidic vesicles, lysosomes, increases pH and disrupts T cell function.
decreases leukocyte chemotaxis, inhibits DNA and RNA synthesis
combination therapy
Hydroxychloroquine - adverse effects
common - GI: nausea, vomiting, cramping and diarrhea, headache and lightheadedness
serious - skin reactions, psychosis, seizures. myopathy, retinal damage
retinopathy is irreversible and requires ophthalmic monitoring, corneal deposits is reversible
Hydroxychloroquine and pregnancy
considered safe at recommended doses
inters breast milk
contraindicated in children
Leflunomide
prodrug similar to MTX, metabolite enters enterohepatic circulation which causes a longer half life
high protein binding
18 day half life - can be longer, takes 4 to 8 weeks to be effective
competitive inhibitor of dihydroorate dehydranase - inhibits pyrimidine synthesis
not approved for use in children or pregnancy, excreted in breast milk
Leflunomide - effects in RA
inihbits T cell proliferation
interfers with DC function
reduces production of autoantibodies
inhbits leukocyte adhesion to endothelium
decreased synovial infiltration by lymphocytes
blocks NF-kB
used for people who do not respond to MTX and are not eligible for other Rx
Leflunomide - toxicities
fulminant liver failure, hepatic necrosis and cirrhosis
diarrhea and nausea
bone marrow suppression - pancytopenia, agranulocytosis, thrombocytopenia
concurrent use with MTX or other immunosuppressants increases risk
increased risk of lymphoma
increased risk of infection
steven-johnson syndrome
remedy for severe Leflunomide toxicity
cholestrramine will sequester in the gut for more rapid elimination
Leflunomide - drug interactions
with any drug which also causes these toxicities :
Hepatotoxicity Myelosuppression Immunosuppression Pulmonary toxicity Peripheral neuropathy Skin reactions
inhibits CYP2C9
Class Properties of Targeted Immunosuppressants
given paraentally - IV and SubQ
tofacinitinib - oral
Target specific mediators of inflammation or receptors
used with non-biologic DMARDs but not together
adverse effects - myelosuppression; hepatic injury; lupuslike
syndrome; hypertension, heart failure; immunological
reactions
immunization before administration
screen for TB, HBV, HCV, PML
excretion in breast milk
Infliximab
Chimeric Monoclonal Antibody
Binds to both soluble and membrane-bound TNFα preventing the cytokine from binding to its receptor
IV - every 8 weeks
uses - Rheumatoid arthritis, psoriatic arthritis, active alkylosing spondylitis, Crohn’s disease, plaque psoriasis, JIA in children ≥ 4yo
HBV / TB reactivation, hypersensitivity - IR can be mouse portion of drug, infection, hepatic toxic
Etanercept
Fusion Protein - Binds to soluble TNFα preventing the cytokine from binding to its receptor
RA - SubQ 1-2x weekly, uses - Rheumatoid arthritis, psoriatic arthritis, active alkylosing spondylitis,
plaque psoriasis, JIA in children ≥ 2yo
AE - infection, HBV/TB reactivation, injection site reaction, hypersensitivity
Abatacept
fusion protein CTLA-4 to IgG
blocks costimulatory action → inhibits T cell activation
used for RA w or w/o MTX and for JIA in children
AE - typical of class (adverse effects - myelosuppression; hepatic injury; lupuslike
syndrome; hypertension, heart failure; immunological reactions)
Rituximab
Depletes CD20+ B cells
IV infusion, 24 weeks, half life 18 days
use - CD20+ B cell lymphomas, autoimmune diseases, RA
AE - Infusion/hypersensitivity reactions; rash; hypo- or hypertension; arrhythmia; reactivation of HBV infection; PML
not for pregnancy or children
Tocilizumab
Inhibition of IL-6 receptor
I.V. q4 weeks; t½terminal up to 13 days
use - RA treatment as monotherapy or combined with methotrexate Adults and JIA in children ≥ 2yo
AE - infection risk, neutropenia, thrombocytopenia, increased liver enzymes, increased LDL and GI perforation
Anakinra
IL-1 receptor antagonist
SubQ times daily, half-life 4 to 6 hours
downregulates inflammatory response
uses - RA, JIA, neonatal-onset multisystem inflammatory disease, mediterranean fever, gout, pericarditis
AE - typical of class
TOFACITINIB
oral JAK3 enzyme inhibitor
moderate protein binding and hapatic metabolism CYP 3A4 and C19
AE - Lymphocytopenia and neutropenia; gastrointestinal perforation; hepatotoxicity; lipid abnormalities
CYP mediated and biologics drug interactions
inhibition prevents - intracellular activity of immune cells, reduction of NK cells, serum IgG, IgM, IgA and CRP and increased B cells.
Rx RA during pregnancy
Low-dose glucocorticoid
Hydroxychloroquine and sulfasalazine
