Session 10 Immunosupressants Flashcards
What is rheumatoid arthritis?
An autoimmune multi-system disease
It is initially localised to synovium followed by inflammatory change and proliferation (of the synovium) leading to dissolution of cartilage and bone
When diagnosing rheumatoid arthritis - what are the clinical criteria?
Morning stiffness >1 hour Arthritis of 3 or more joints Arthritis of hand joints Symmetrical arthritis Rheumatoid nodules
When diagnosing rheumatoid arthritis, what are the non-clinical criteria?
Serum rheumatoid factor / anti CCP antibodies
X ray changes
What are the goals of treatment for rheumatoid arthritis?
Symptomatic relief
Prevention of joint destruction
What is the treatment STRATEGY for RA?
Early use of disease modifying drugs
Aim to achieve good disease control
Use of adequate dosages
Use of combination of drugs
Avoidance of long term corticosteroids
What are the goals of treatment in SLE and vasculitis?
Symptomatic relief e.g.arthralgia, Raynaud’s phenomenon
Reduction in mortality
Prevention o organ damage
Reduction in long term morbidity caused by disease and by drugs
What is the general MoA for corticosteroids?
Prevent interleukin IL-1 and IL-6 production by macrophages
Inhibit all stages of T-cell activation
What are two examples of disease-modifying anti-rheumatic drugs (DMARDs) that are NON-biologics?
Sulphasalazine
Hydroxychloroquine
hat are two examples of disease-modifying anti-rheumatic drugs (DMARDs) that are biologics?
Anti-TNF agents
Rituximab
IL-6 inhibitors, JAK inhibitors
What can azathioprine be used for?
SLE and vasculitis
RA (weak evidence)
IBD
= ‘steroid sparing’ drug
Pharmacodynamics of Azathioprine?
Metabolised by?
6-MP is metabolised by thiopurine methyltransferase (TPMT)
TPMT gene is highly polymorphic THEREFORE Individuals vary markedly in TPMT activity
If you have low TPMT levels - risk of myelosupression
SO need to test TPMT activity before prescribing
Aziothioprine MoA?
Cleaved to 6-mercaptopurine (6-MP) then to 6-MeMP (inactive) / TIMP (active) or 6-TU (inactive)
TIMP > 6-MeMPN = inhibition of de novo purine synthesis
TIMP > 6-TGN = incorporation into DNA
Anti-metabolite decrease DNA and RNA synthesis
ADR of azathioprine?
Bone marrow suppression (need to monitor FBC)
Increased risk of malignancy
Increased risk of infection
Hepatitis (need to monitor LFTs)
What are Ciclosporin and tacrolimus examples of?
Calcineurin inhibitors
What are ciclosporin and tacrolimus widely used for?
In transplantation
But also for atopic dermatitis and psoriasis
Lots of drug interactions!!
Ciclosporin and tacrolimus MoA?
Active against helper T cells, preventing production of IL-2 via calcineurin inhibition
Ciclosporin binds to cyclophilin protein
Tacrolimus binds to tacrolimus-binding protein
Drug/protein complexes bind calcineurin
Calcineurin exerts Phosphatase activity of activated T-cells then nuclear factor migration starts IL-2 transcription
When would you use mycophenolate mofetil in practice?
Transplantation
Good efficacy as induction and maintenance therapy for lupus nephritis / vasculitis maintenance
Mycophenolate mofetil MoA?
Prodrug
Inhibits inosine monophosphate dehydrogenase (required for guanosine synthesis)
Impairs B and T cell proliferation
Spaces other rapidly dividing cells
How does mycophenolate mofetil spare other rapidly dividing cells? I.e. only impairs B- and T- cell proliferation?
Due to guanosine salvage pathways in other cells
What are the adverse effects associated with mycophenolate mofetil?
Nausea, vomiting, diarrhoea = most common
Myelosuppression = most serious
How does cyclophosphamide work?
It is an alkylation agent that cross links DNA so that it cannot replicate
It suppresses T and B cell activity
When would you use cyclophosphamide?
Lymphoma, leukaemia, solid cancers
Lupus nephritis
Wegener’s granulomatosis (ANCA-vasculitis)
Describe the pharmacodynamic of cyclophosphamide
Prodrug
Converted in the liver (cytochrome P450) to active forms
Main active metabolite = 4-hydroxycyclophosphamide
(This exists in equilibrium with its tautomer - aldophosphamide)
Most of the aldophosphamide is oxidised to make carboxyphosphamide
A small portion of aldophosphamide is converted into phosphoramide mustard (main active metabolite)
Describe the pharmacokinetics of cyclophosphamide
Excreted by the kidney
Acrolein (another metabolite) is toxic to the bladder epithelium and can lead to haemorrhagic cystitis
This can be prevented through the use of aggressive hydration
How can we prevent acrolein from causing Haemorrhagic cystitis (as is toxic to bladder epithelium) ?
Aggressive hydration and/or mesna
When prescribing cyclophosphamide - what are some important considerations?
It is significantly toxic
- increased risk of bladder cancer, lymphoma and leukaemia
- infertility
- monitor FBC
- adjust dose in renal impairment
What is safer and just as effective in treating lupus nephritis?
(When compared to cyclophosphamide)
Mycophenolate mofetil
Describe the pathogenesis of RA
there is an imbalance of autoinflammatory cytokines
i.e. more pro-inflammatories than anti-inflammatories
what are some examples of pro-inflammatories?
IL1
IL6
TNF-a
what are some examples of anti-inflammatories?
IL4
TGF-b
What is the gold standard treatment for RA?
methotrexate
other indications
- malignancy
- psoriasis
- crohn’s disease
- ectopic pregnancy
methotrexate MoA?
it competitively and reversibly inhibits dihydrofolate reductase
normally: dihydrofolate reductase catalyses the conversion of dihydrofolate to the active tetrahydrofolate
tetrahydrofolate = key carrier of C units in purine and thymidine synthesis
therefore, methotrexate inhibits synthesis of DNA, RNA and proteins
Which stage of the cell cycle is methotrexate cytotoxic to?
S-phase
acts during DNA and RNA synthesis
greater toxic effect on rapidly dividing cells which replicate their DNA more frequently
Oral bioavailability of methotrexate =
IM bioavailability =
how should it be taken and why?
excreted by?
oral = 33% IM = 76%
weekly dosing NOT daily
- has a long half life
- taken with folic acid
renal excretion
adverse effects of methotrexate?
mucositis marrow suppression hepatitis, cirrhosis pneumocitis infection risk
HIGHLY teratogenic
effects of sulfasalazine?
T cell
- inhibition of proliferation
- apoptosis
- inhibition of IL-2 production
neutrophil
* reduce chemotaxis and degranulation
adverse effects of sulfasalazine?
these are mainly due to the sulfapyridine moiety
- myelosuppression
- hepatitis
- rash
- nausea
- abdo pain and vomiting
what are the benefits associated with sulfasalazine use in practice?
effective favorable toxicity long term blood monitoring not needed few drug interactions no carcinogenic potential safe in pregnancy!!
what are the effects of blocking TNF-a (through using anti TNF)?
decreased inflammation
decreased angiogenesis
decreased joint destruction
what is a major risk when using anti TNF therapy?
TB reactivation!
TNFa is released by macrophages in response to TB infection and is essential for development and maintenance of granulomata
need to screen for latent TB before prescribing anti-TNF treatment
what does rituximab cause?
B cell apoptosis
NB: v effective in RA
how does rituximab work?
binds to CD20 (a unique cell surface marker)
CD20 is found on a subset of B cells but not on stem cells, pro-B cells, plasma cells or any other cell so is v specific! - good safety data
