8 - Immunosuppressants Flashcards
What is the pathogenesis of rheumatoid arthritis and how do we treat it?
- Autoimmune disease causing inflammation to joints destroying cartilage and bone
- Associated with morning stiffness, rheumatoid nodules, symmetrical, arthritis of more than three joints (mainly hands)
- Can look at x-ray changes and serum rheumatoid factor
What is the treatment goals with RA?
- Symptomatic relief
- Prevent joint destruction
- Avoid long term corticosteroids
What are some of the symptoms of systemic lupus erythematosus? (SLE)
- Autoimmune disease where body attacks own health tissue over a number of systems
- Joint pain, rash, mouth ulcers, swollen lymph nodes
What is vasculitis?
- Autoimmune condition causing inflammation of blood vessels (can occur as a result of SLE)
- Leads to things like temporal arteritis (need corticosteroids like prednisolone) that causes headache, tiredness, stiff jaw and pain wose on touch
What are some examples of immunosupressants?
- Glucocorticoids
- Calcineurin inhibitors
- Antiproliferative
- Biologics
What is the mechanism of action of systemic corticosteroids, what are some examples of this drug and what are the side effects?
- Prevent IL-1 and IL6 production by macrophages stopping T cell activation and inflammation
- Prednisolone, Hydrocortisone, Dexamethasone, Betamethasone
- Can cause osteoporosis, diabetes, hypertension, weight gain, glaucoma, cataracts (accelerated old age)
What are the side effects of corticosteroids?
What is the mechanism of action of Azathioprine and what is it used to treat?
- Treatment of SLE and Vasculitis (not good for RA) and sometimes atopic dermatitis, IBS and organ transplants
- TPMT is an enzyme that breaks down this drug and activates it to 6-mercaptopurine so individual needs high TPMT activty (highly polymorphic)
- 6-MP metabolite blocks purine synthesis and therefore DNA synthesiswhich helps as lupus activates temporal and humoral cell division so stops them dividing
What are some adverse drug reactions associated with azathioprine use?
- Bone marrow suppression
- Cancer risk (especially skin)
- Hepatitis (deranged LFTs)
- Infections
- Thrombocytopenia
Need to monitor FBCs and LFTs as the longer you use the drug the more the risk
What are some examples of antiproliferative immunosupressants?
- Azathioprine
- Cyclophosphamide
- Mycophenolate mofetil
What are some of the side effects of calcineurin inhibitors?
- Ciclosporin and Tacrolimus
- Used for organ transplant rejection, atopic dermatitis, psoriasis, RA, Crohn’s
- Renal toxicity so check BP and eGFR frequently
- Gingival hyperplasia can occur
- Lots of drug interactions as uses CYP450
- Eye discomfort
- Hepatitis
What is the mechanism of action of calcineurin inhibitors as immunosuppressants?
- Prevent IL-2 production by helper T cells (more targeted than corticosteroids)
- Ciclosporin bids to cyclophilin protein and tacrolimus binds to tacrolimus-binding proteins and the drug complexes bind to calcineurin inhibiting it
- Calcineurin usually exerts force on activated helper T cells by starting IL2 transcription
What are some CYP450 inhibitors and inducers?
What is mycophenolate mofetil used for and what is it its mechanism of action?
- Used in lupus nephritis to induce remission (which azathioprine can’t do) and transplantation
- Prodrug from fungus and inhibits inosine monophosphate dehydrogenase which is needed for guanosine synthesis so impairs B and T cell proliferation
- Spares other rapidly dividing cells by guanosine salvage pathways
What are some adverse effects of mycophenolate mofetil?
- Mucositis
- Long term cancer risk (especially skin)
- Bone marrow suppression
- N+V and diarrhoea
(less immunosuppression than azithioprine)
What is cyclophosphamide used for and what is its mechanism of action?
- Used in lupus (nephritis), vasculitis and lymphomas/leukaemias
- Supresses B and T cell activity as it is an alkylating agent so cross links DNA so it cannot replicate
- Prodrug converted in the liver by CYP450 and excreted by kidney. Active metabolite 4-hydroxycyclophosphamide (4HC)
What are the side effects of cyclophosphamide?
- Acrolein is a toxic metabolite which can cause haemorraghic cystitis and bladder cancer (rehydrate!!)
- Risk of lymphomas, leukaemia and bladder cancer
- Renal impairment
- Infertility (measure FBC)
What is the safest antiproliferative immunosuppressant to use in lupus nephritis?
- Mycophenolate mofetil as less renal impairment and no hair loss at low doses
What is methotrexate used for and what is it’s dosing schedule?
- Gold standard for RA
- Chemotherapy
- Psoriasis arthritis
- Crohn’s disease
- Abortion
Given weekly due to long half life (30 hours) of its polyglutamate metabolites
What is the mechanism of action of methotrexate in cancer treatment and as a DMARD?
- Competitive and reversible Dihydrofolate reductase inhibitor (in cancer treatment)
- Uses up all the folate which is needed for thymidine and puring synthesis so cannot do DNA, RNA and protein synthesis
- Greater effect on rapidly dividing cells in S phase
- In RA it works by reducing pyrimidines
What are some adverse drug reactions with methotrexate?
- Highly protein bound but NSAIDs can displace
- Low oral bioavailability
- If nausea swap to SC
- Can cause pneumonitis, hepatitis and stomatitis
What is the mechanism of action of sulphasalazine and what is it used for?
- Used for RA as a DMARD and IBD as main activity in the gut
- Inhibits T cell and neurotrophils by reducing chemotaxis by being a 5-aminosalicyclic acid donor
- Antiinflammatory and fights infection
What are some adverse effects of sulfasalazine?
- Hepatitis
- N+V
- Abdo pain
- Rash
- Myelosuppression/Leucopenia
- Dizziness
- Arthralgia
Mainly due to sulfapyridine moiety
What are some TNF-a inhibitors (biologics), what are they used for and what is their mechanism of action?
Infliximab and Adalimumab
- Used for RA, psoriasis, crohn’s
- Monoclonal antibody that binds TNFa which is nomally proinflammatory so stops inflammation, angiogenesis and joint destruction
What is the mechanism of action of rituximab and what is it used for??
- B-lymphocyte lytic monoclonal antibody
- Binds to CD20 on specific subset of B cells and causes B cell apoptosis
- Effective in RA
What are the side effects of anti-TNF agents?
- Risk of TB activation as TNFa is needed for stabilisation of granulomas
- Need to test for latent TB before giving these drugs
Why do we need to wean people off of steroids?
When given steroids, adrenal glands decrease their cortisol production so an immediate withdrawal is dangerous as adrenal glands do not have time to adjust so may have Addison’s crisis
What is the treatment goal in SLE and vasculitis?
What are ‘biologicals’ used in the treatment of RA?
- Extracted from living systems e.g stem cell therapy
- Very few side effects because they are ‘sniper like’
What is a steroid sparing drug?
Immunosuppresive medications given in addition or instead of steroids to limit side effects when low doses of steroids (prednisolone) cannot be used
What is the mechanism of action of hydroxychloroquinine and what is it used to treat?
RA, Lupus and Malaria
Increase pH inside macrophage lysosomes which stops antigen processing and MHC II presentation, therefore decreasing T-Cell activation
