L15 - Immunosuppressants Flashcards
Rheumatoid arthritis
Autoimmune multi systemic diseases initially causing inflammation localised to the synovium (joints) leading to dissolution of cartilage and bone
Pannus
Tissues and inflammatory cells involved in inflammation and proliferation of the synovium
Juvenile idiopathic arthritis
Rheumatoid arthritis that occurs in children aged 3+
Diagnostic criteria for rheumatoid arthritis
Morning stiffness - for more than 1 hour
Arthritis of 3+ joints including hands and wrist
Symmetrical arthritis
Rheumatoid nodules
Investigations:
- serum rheumatoid factor/ anti -CCP antibodies
- X - ray changes due to joint damage
Pathogenesis
Antibodies (anti-CCP) against self antigens cause more pro-inflammatory mediators to be produced than anti-inflammatory mediators
Pro inflammatory mediators
IL-1 and 6
TNF - alpha
Metalloproteinases - causes joint damage and inflammation
Anti- inflammatory mediators
IL-4
TGF- beta
SLE
Prevalent in African Caribbean ladies
Multi systemic
Treat with steroids (anabolic)
Characteristic face rash
Vasculitis
Vessel inflammation Can causes: - nephritic syndrome - purpuric ulcers - pulmonary haemorrhage
Immunosuppressant examples
Corticosteroids Methotrexate Azathioprine Cyclosporin Tacrolimus Mycophenolate mofetil Leflunomide Cyclophosphamide Monoclonal antibodies - biologics
Corticosteroid mechanism of action
- Lipophilic so passes through the plasma membrane
- Binds to a glucocorticoid receptor in the cytoplasm and forms a complex
- Translocates into the nucleus forming a homodimer
- Prevents gene transcription of interleukin 1 and 6 (inflammatory mediators) therefore not produced by macrophages
- Inhibits all stages of T cell activation
Side effects of corticosteroids
- Weight gain
- Thrush ( candidiasis)
- Immunosuppression if used for 3+ months
- Glaucoma
- Cataracts
- Causes accelerated old age - osteoporosis, muscle weakness and bruising
DMARDs - disease modifying anti rheumatic drugs
Non biologics:
- hydroxychloroquine
- sulphasalazine
Biologics:
- anti TNF agents
- rituximab
- IL-6 inhibitors
- JAK inhibitors
Azathioprine use
Steroid sparing drug
SLE and vasculitis - maintenance therapy RA - not as effective Inflammatory bowel disease Atopic dermatitis - rarely used Bulbous skin disease
Azathioprine pharmacodynamics
Is a prodrug of 6MP given orally
- TPMT (thiopurine methyltransferase) metabolises (cleaves) azathioprine into 6-MP
- 6-MP is converted to 6MeMP via TPMT
- decreases DNA and RNA synthesis by inhibiting de novo purine synthesis
- apoptosis of activated lymphocytes
What should be done before prescribing azathioprine?
Test TPMT activity before prescribing as the TPMT gene is highly polymorphic therefore there is varied activity in individual
- low or absent TPMT increases the risk of myelosupression
Azathioprine ADRs
- Bone marrow suppression - suppresses RBCs, WBCs and platelets - therefore monitor FBC
- Increased risk of malignancy especially in transplanted patients
- increased risk of infection
- drug induced hepatitis - monitor LFTs
Calcineurin
Calcium and calmodulin
- exerts phosphates activity of activated T cells
- nucleus factor migrates
- IL-2 is transcribed
Calcineurin inhibitors examples
Cyclosporin
Tacrolimus
Uses of calcineurin inhibitors
Used in:
- transplantation
- atopic dermatitis and psoriasis