Immunosuppresants (RA) Flashcards
What are DMARDS?
Disease-modifying anti-rheumatic drugs
What do corticosteroids do?
- prevent IL-1 and IL-6 production by macrophages
- inhibits all stages of T-cell activation
- has many many side effects
Azathioprine
- good for lupus and vasculitis as maintenance therapy
- very weak evidence of it helping RA
- good for IBD
- non-biological that helps to limit steroid side effects
- is a “steroid sparing” drug
Pharmacodynamics
- 6MP metabolised by TPMT
- TPMT is highly polymorphic
- low/absent TPMT levels= risk of myelosuppresion
- must test TPMT activity before prescribing
Mechanism of action
- is cleaved to 6MP
- which is an anti-metabolic that decreases DNA and RNA synthesis to limit inflammatory response
Adverse effects
- bone marrow suppression
- increases malignancy risk
- increased risk of infection
- hepatitis
Calcineurin inhibitors (ciclosporin and tacrolimus)
- ciclosporin: causes gum swelling
- tacrolimus: good for transplant
- used in atopic dermatitis and psoriasis
- not often used in rheumatology because it can cause renal toxicity
- must check BP and eGFR regularly since it can decrease their levels
- multiple drug interactions possible (i.e. CYP 450)
Mechanism of Action
- 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 phosphates activity of activated T-cells then nuclear factor migration starts IL-2 transcription
Mycophenolate mofetil
- primarily in transplantation
- good efficacy as induction and maintenance therapy for lupus nephritis/vasculitis
- side effect: can cause cancer
Mechanism of action
- is a prodrug
- inhibits inosine monophosphate dehydrogenase (required for guanosine synthesis)
- impairs B-cell and T-cell proliferation
- spares other rapidly dividing cells
Adverse effects
- nausea, vomiting, diarrhoea
- myelosuppresion
- mouth ulcers
Cyclophosphamide
- cancer drug
- alkylation gets agent that cross links and breaks DNA so it cannot replicate
- suppresses T cell activity and B cell activity
- very good for lupus
Indications
- lymphoma, leukaemia, solid cancers
- lupus nephritis
- wegener’s granulomatosis
- is a prodrug
- converted by CYP450 to active forms
- main active metabolite is 4HC
- 4HC exist is in equilibrium with its tautomer: aldophosphamide
- excreted by kidney
- side effect: acrolein (another metabolite) which is toxic to bladder and can cause hemorrhagic cystitis
- can be prevented through hydration and managing doses
Considerations
- significant toxicity: increased risk of bladder cancer, infertility, monitor FBC, adjust dose in renal impairment
- mycophenolate mofetil is safe and as effective in lupus
Methotrexate
Gold standard for RA
- also helps with malignancy, psoriasis and Crohn’s disease
- can be used as an abortion drug and cancer drug
- helps in inflammatory myopathies, vasculitis, steroid-sparing agent in asthma
Mechanism of action
-competitively and reversibly inhibits DHFR
1000x more affinity than folate
-inhibits the conversion of dihydrofolate to tetrahydrogolate which is the key carrier of one-carbon units
-inhibits synthesis of DNA, RNA and proteins
-cytotoxic during the S-phase of cell cycle and has greater toxic effect on rapidly dividing cells
-possible mechanism: inhibition of accumulation of adenosine, inhibition of T-cell activation
-lower oral bioavailability compared to intramuscular but can be given both ways
-give a weekly dosing not daily because it is metabolised to polyglutamates which have long half lives
-50% protein bound but NSAIDS can displaces them
-Renally excreted
-well tolerated, improves QoL
Adverse effects
- muositis
- marrow suppression
- hepatitis, cirrhosis
- pneumonitis
- infection risk
- teratogenic
Sulfasalazine
- conjugate of a salicylate and a sulfapyridine molecule
- designed to relieve pain and stiffness in RA
- and to fight infection
- less effective than methotrexate
- if someone allergic to aspirin dont give this drug because similar structure
Immunological effects
- T cell: inhibition of proliferation, possible T-cell apoptosis, inhibition of IL-2 production
- Neutrophil: reduced chemotaxis, reduced degranulation
- but need to give a lot of tablets per day
- effective in IBD
Adverse effects
- myelosuppresion
- hepatitis
- rash
- nausea, vomiting, abd pain
MUCH SAFER IN PREGNANCY
Rituximab
- binds specifically to CD20 which is found only on a subset f B cells
- this drug causes B cell apoptosis
- very effective in RA and good safety data
