Immunosuppressants Flashcards
what are some of the cells responsible for the pathogenesis of RA?
T cells, B cells, anti CCP antibodies, RF, macrophages, cytokines, metalloproteinases, neuropeptides
how do corticosteroids work and what are their side effects?
they prevent IL-1 & IL-6 production by macrophages and prevent all stages of T cell activation
CUSHINGOID
cataracts, ulcers, skin, hypertension, infection, necrosis, GI upset, osteoporosis/obesity, insomnia, diabetes
azothioprine - uses, mechanism, test before prescribing, adverse effects
SLE&vasculitis, used in IBD also
cleaved to 6-MP and this is metabolised by TPMT to antimetabolites which decrease DNA&RNA synthesis
the TPMT gene is highly polymorphic so do a test before prescribing
bone marrow suppression, increased risk of malignancy, increased his of infection, hepatitis
calcineurin inhibitors - names, uses, mechanism, adverse effects
ciclosporin & tacrolimus
widely used in transplantation and for atopic dermatitis and psoriasis
active against T helper cells, preventing the production of IL-2 via calcineurin inhibition
- ciclosbrin binds to cyclophilin protein and tacrolimus binds to tacrolimus binding protein
- the drug/protein complexes bind calcineurin which stops the phosphatase activity
can cause gum swelling, not often used due to renal toxicity, multiple drug interactions due to CYP450
mycophenolate mofetil - uses, mechanism, adverse effects
primarily in transplantation, good efficacy as induction and maintenance for lupus nephritis/vasculitis
it is a pro drug which inhibits inosine monophosphate dehydrogenase (req. for guanine synthesis), impairs B&T cell proliferation and spares other rapidly dividing cells
n&v, diarrhoea, myelosuppression, cancer risk, ulcers in mouth
cyclophosphamide - uses, mechanism, pharmacodynamics, pharmacokinetics, considerations
lymphoma, leukaemia, solid cancers, lupus nephritis, Wegener’s granulumatosis
alkylating which cross links DNA so it cannot replicate and suppress T&B cell activity
pro drug converted by CYP450, main active metabolite is 4-hydroxycyclophosphamide (this exists in eqm. with its tautomer - aldophosphamide)
- most of aldophosphamide is oxidised to carboxyphophamide, and a small proportion is converted to phosphor amide mustard (main active metabolite)
excreted by kidney, acrolein is toxic to bladder so can cause haemorrhage cystitis (prevented through aggressive hydration and mesna)
significant toxicity, infertility, monitor FBC, adjust dose in renal impairment
methotrexate - uses, mechanisms, pharmacokinetics, adverse effects
gold standard for RA, also used in malignancy, psoriasis, Crohns, ectopic pregnancy
competitively inhibits dihydrofolate reductase
- DHFR usually catalyses conversion of dihydrofolate to active tetrehydrofolate which is the key carrier of 1C units in purine and thymidine synthesis
- it acts during DNA synthesis hence is cytotoxic during S phase of the cell cycle. Greter toxic effect on rapidly dividing cells
- in non malignancy - mechanism unclear
oral bioavailability = 33%, IM = 76%, weekly dosing, prescribe with folic acid, 50% is protein bound so NSAIDs displace, renal excretion
mucositis, marrow suppression, hepatitis, cirrhosis, pneumonitis, infection risk, highly teratogenic, abortifacient
sulfasalazine - what is it a conjugate of, use, mechanism, adverse effects
conjugate of salicylate and a sulfapyridine molecule, designed to relieve pain and fight infection
inhibition of T cell proliferation, inhibition of IL-2 production, cleaved in large bowel so effective in IBD
myelosuppression, hepatitis, rash, n&v
what are the effects of blocking TNF-a with biologicals and what is a key risk when prescribing?
decreased inflammation by cytokine cascade, decreased angiogenesis, decrease joint destruction, MMPs, bone resorption and cartilage breakdown
TB reactivation is a risk as TNFa essential for development and maintenance of granulomatas, so screen for latent TB
rituximab - mechanism, use
binds specifically to CD20 which is found on a subset of B cells but not on stem cells, pro B cells, plasma cells or any other cell types
- causes B cell apoptosis
effective in RA and good safety data
