Immunosuppression & Arthritis Flashcards
Disease-Modifying Anti-Rheumatic Drugs (DMARDs): 2 main types
Methotrexate
Sulfasalazine
Methotrexate: mechanism of action route of administration ADRs DDIs
folic acid antagonist
a DMARD and an immunosuppressant
works differently in malignant and non-malignant disease
Malignant:
inhibits synthesis of DNA and RNA proteins: allosterically inhibits dihydrofolate reductase (normally catalysing dihydrofolate to tetrahydrofolate, used in thymidine and purine base synthesis)
Non-malignant (incl RA):
inhibits enzymes involved in purine metabolism = accumulation adenosine in cell; release and acts on GPCRs of inflammatory and immune cells to reduce activity of T cells
oral, SC, IM
mucositis, bone marrow suppression, hepatitis, cirrhosis, increased risk infection, teratogenic
(give with folic acid supplement)
interacts with other immunosuppressants, anti-cancer drugs, auto-immune drugs
reduce renal blood flow and elimination
affect plasma protein binding (incl aspirin)
requires toxicity monitoring (CXR, FBC, LFTs, U&E, creatinine)
Sulfasalazine: a combination of which 2 drugs what it is used for mechanism of action ADRs
5-aminosalicylate acid (5-ASA) - active component
and sulfapyridine - poorly absorbed in GIT but broken down in lower GIT - allows 5-ASA to reach intended area
used in RA & IBD
in RA: inhibits T cell proliferation and IL2 production
(mechanism in IBD unknown)
sulfapyridine causes the ADRs: nausea, fatigue, headaches, myelosuppression, hepatitis, allergic rash
do not use if allergic to aspirin
Immunosuppressants:
main mechanism of action
5 main types
reduce lymphocyte proliferation
corticosteroids azithioprine cyclophosphamide mycophenolate mofetil (MMF) calcineurin inhibitors (ciclosporin and tacrolimus)
Corticosteroids:
mechanism of action
ADRs
immunosuppressants: inhibitors of gene expression (prevent IL1 and 6 production by macrophages, inhibit all stages of T cell activation)
cushingoid ADRs: weight gain, fat redistribution, growth retardation, glucose intolerance, adverse lipid profile
osteoporosis, AVN, infection risk
Azithoprine:
mechanism of action
ADRs
immunosuppressant:
inhibits purine synthesis, reducing DNA and RNA synthesis
acts on cells with high mitotic rates (used in RA, IBD, leukaemia)
steroid sparing
bone marrow suppression, increased risk infection, emergence malignant line cells, hepatitis (monitor LFTs)
Cyclephosphamine:
mechanism of action
ADRs
active form (4-hydroxycyclophosphamide) forms DNA crosslinks between and within DNA strands, preventing replication acts on cells with high mitotic rates (so also used in cancer therapy)
increased risk bladder cancer (toxic metabolite to bladder epithelium produced), lymphoma, leukaemia, infertility, teratogenesis
need to monitor FBCs and adjust dose if renal impairment
Mycophenolate Mofetil (MMF): mechanism of action ADRs
immunosuppressant:
increases oral bioavailability of mycophenolic acid (MPA), which inhibits enzyme inosine monophosphate dehyrdogenase, which is required for guanine synthesis
results in impaired B and T cell proliferation, whilst sparing other rapidly dividing cells
agent of choice in transplant immunosuppression
myelosuppression (incl neutropenia), increased risk infection, nausea, vomiting, diarrhoea
calcineurin inhibitors:
mechanism of action
ADRs
immunosuppressant:
active against T helper cells by preventing production of IL2 via calcineurin inhibition
used in transplant immunosuppression and treatment inflammatory skin conditions
nephrotoxicity, Htn, hyperlipidaemia, nausea, vomiting, diarrhoea, hyperuriciemia
elimination kinetics affected by CYP450 inhibitors and inducers
broadly outline the treatment pathway for Rheumatoid Arthritis
Disease-Modifying Anti-Rheumatic Drugs (DMARDs): halt & reverse response to inflammation (T cell activation, production rheumatic factor, stimulating macrophages via IgG Fc receptors, forming immune complex and creating more inflammatory response)
(alongside NSAIDs: reduce symptoms)
Immunosuppressants: with worsening disease
