Immunosuppressants Flashcards
What are some examples of immunosuppressants?
Corticosteroids Methotrexate Azathioprine Ciclosporin Tacrolimus Cyclophosphamide
What is the method of action for corticosteroids?
Prevent IL-1 and IL-6 production by macrophages
Inhibit all stages of T cell activation
Not targeted, so produce many side effects
What is azathioprine used for?
SLE and vasculitis maintenance therapy
IBD
Describe the pharmacodynamics of azathioprine
6-MP is metabolised by TPMT
TPMT gene is highly polymorphic
Low/absent TPMT => risk of myelosupression
What is the mechanism of action of azathioprine?
Cleaved to 6-MP which decreases DNA and RNA synthesis
What are some adverse effects of azathioprine?
Bone marrow suppression - need to monitor FBC
Inc risk of malignancy - esp in transplant pts
Inc risk of infection
Hepatitis - monitor LFTs
What are some examples of calcineurin inhibitors?
Ciclosporin
Tacrolimus
What are calcineurin inhibitors used for?
Transplantation
Atopic dermatitis
Psoriasis
What are some adverse effects of calcineurin inhibitors?
Renal toxicity - check BP and eGFR
Inhibits cytochrome P-450
What is the mechanism of action of calcineurin inhibitors?
Active against helper T cells => prevent IL-2 production
Drug-protein complexes bind to calcineurin
Ciclosporin - binds to cyclophilin protein
Tacrolimus - binds to tacrolimus binding protein
What is mycophenolate mofetil used for in practice?
Primarily in transplantation
Also good for induction and maintenance therapy in lupus nephritis/vasculitis
What is the mechanism of action of mycophenolate mofetil?
Inhibits inosine monophosphate dehydrogenase => reduced guanosine synthesis
Impairs B and T cell proliferation
Spares other rapidly dividing cells
What are some adverse effects of mycophenolate mofetil?
Nausea, vomiting and diarrhoea
Myelosuppression
What is the method of action of cyclophosphamide?
Alkylating agent - cross links DNA
Unable to replicate
Suppress T and B cell activity
What are some indications for cyclophosphamide?
Lymphoma, leukaemia
Lupus nephritis
Wegener’s granulomatosis; ANCA-vasculitis
Lower dose used for non-cancer
Describe pharmacodynamics of cyclophosphamide
Converted in liver - CYP P450
Describe pharmacokinetics of cyclophosphamide
Excretion - kidney
Produces a metabolite which is toxic to the bladder => haemorrhagic cystitis
What are some important considerations for cyclophosphamide?
Significant toxicity =>
Inc risk of bladder cancer, lymphoma and leukaemia
Risk of infertility
Adjust dose with renal impairment
What are some indications for methotrexate use?
Good standard treatment for RA
Malignancy
Psoriasis
Crohn’s disease
What is the mechanism of action of methotrexate?
Reversible competitive inhibition of dihydrofolate reductase
Therefore inhibits purine and thymidine synthesis
Inhibition of DNA, RNA and protein synthesis
What is the mechanism of action of methotrexate for non-malignant disease?
Not really clear
Not through anti-folate action
Possibly:
Inhibits accumulation of adenosine
Inhibits T cell activation
Suppresses expression of intracellular adhesion molecules
Describe pharmacokinetics of methotrexate
Oral bioavailability 33%
Long half life therefore weekly dosing
Renal excretion
How is methotrexate used in practice?
Well tolerated
Improved QoL
Retardation of joint damage
What are some adverse effects of methotrexate?
Mucositis Marrow suppression Hepatitis and cirrhosis Pneumonitis Inc risk of infection
Highly teratogenic, can cause abortion
What is the mechanism of action go sulphasalazine?
Relieves pain and stiffness
Fight infection
What are the immunological effects of sulphasalazine?
T cells:
Inhibit proliferation
Apoptosis
Inhibit IL-2 production
Neutrophils:
Reduced chemotaxis
Reduced degranulation
What are some adverse effects of sulphasalazine?
Myelosuppression
Hepatitis
Rash
Nausea and vomiting
Abdo pain
How is sulphasalazine used in practice?
Effective
V few drug interactions
No carcinogenic potential
Safe in pregnancy
How are immunosuppressant “biologicals” produced?
Extracted from living systems eg whole blood, blood components, stem cell therapy
Recombinant DNA technology produces substances that are nearly identical to key signalling proteins eg growth hormone, EPO
Monoclonal antibodies block substances in the body or target a specific cell type
What are the effects of blocking TNF-α?
Decreased inflammation
Decreased angiogenesis
Decreased joint destruction
What are some risks of blocking TNF-α activity?
TB reactivation
TNF-α released by macrophages in response to TB infection
Essential for development and maintenance of a granuloma
Therefore need to screen for latent TB before anti-TNF treatment
What is the mechanism of action of rituximab?
Immunosuppressant
Binds to specific cell-surface markers on B cells
Causes B cell apoptosis
V effective in RA
