Immunosuppression Flashcards
What is autoimmune disease?
Autoimmune disease – immune system produces antibodies against self-antigens (may be a viral trigger) and the cells of the immune system attack your own tissue. Autoimmune disease is fairly common – the prevalence of RA is 1%.
Describe RA. What are diagnostic features?
In RA the inflammation is initially localised to the synovium, which is inflamed and proliferates, and then cartilage and bone becomes involved. The joints involved are the wrist and metacarpophalangeal joints – you get subluxation and rheumatoid nodules and get the characteristic appearance of rheumatoid.
RA is diagnosed by: • Morning stiffness lasting longer than one hour • Arthritis affecting more than 3 joints • Arthritis of hand joints • Symmetrical arthritis • Rheumatoid nodules • Serum rheumatoid factor • X-ray changes
What is the strategy of treatment in RA?
Symptomatic relief, and prevention of joint destruction.
Broadly the strategy is:
• Use DMARDs early & aim to achieve good disease control
• Use high enough doses and combinations of drugs
• Avoid long term corticosteroids
What is the strategy of treatment in SLE and vasculitis?
- Symptomatic relief (e.g. of arthralgia and Raynaud’s phenomenon in SLE)
- Reduction in mortality (by inducing remission and then maintaining)
- Preventing organ damage (e.g. renal failure in SLE)
- Reduction in long term morbidity caused by both the disease itself and the treatment
What are examples, indication, MOA and ADRs for corticosteroids?
Hydrocortisone, prenisolone
PMR, GCA, vasculitis, SLE, RA
MOA
Bind intracellular receptors and modify gene expression – reduce production of IL-1 and IL-6 by macrophages and inhibit T cell activation
Anti-proliferative effects - inhibit DNA synthesis
ADR CUSHINGOID FAM Cushing's syndrome Ulcers -PUD Skin - striae, thinning, bruising HTN Infection Necrosis Growth restriction Osteoporosis Obesity (central/buffalo hump) Immunosuppression - infection Diabetes - glucose intolerance Fluid retention Acute pancreatitis Myopathy
Central adiposity, bruising, moon face & buffalo hump, abdominal striae, hypertension, acne, hair growth, osteoporosis, glucose intolerance and dyslipidaemia, infection, cataracts
What are indication, MOA and ADR and CI of azathioprine?
Rheumatoid arthritis, Inflammatory Bowel Disease, transplantation and leukaemia. The drug is “steroid sparing” – reduces use of steroids
MOA
Prodrug which is activated to form 6-mercaptopurine
Inhibition of purine metabolism (antimetabolite) which reduces DNA and RNA synthesis.
Immunosuppression
ADR Bone marrow suppression Hypersenstivity reaction Infection Emergence of malignant cell lines Hepatitis Hair loss Cholestatic jaundice
CI:
Hypersensitivity
Breastfeeeding
Pregnancy
What are indication, MOA and ADR of cyclophosphamide?
Immunosupression and chemotherapy. Specifically: Lymphoma and leukaemia Lupus nephritis Wegener’s granulomatosis Polyarteritis nodosum
MOA
Prodrug activated by CYP450 to produce alkylating cytotoxic metabolites, selective for cells with a higher mitotic rate
ADR Concentration of acrolein (metabolite) in urine leads to bladder cancer Infertility Teratogenesis Lymphoma Leukaemia
What are indication, MOA, ADR of mycophnolate?
Transplant immunosuppression/RA
MOA
Prodrug used to increase oral bioavailability of mycophenolic acid. Highly selective non-competitive inhibition of an enzyme needed in guanosine synthesis – selective for B and T lymphocytes as other cells can salvage guanosine
ADR Leukopenia Neutropenia Myelosuppression Infection (especially viral) GI - Nausea, vomiting and diarrhoea, mouth ulcers
What are indication, MOA, ADR, DDI of calcineurin inhibitors? Examples?
Ciclosporin/Tacrolimus
Transplant patients
Inflammatory skin conditions
Rheumatoid arthritis – not commonly used due to toxicity
MOA
Ciclosporin binds to the cyclophilin protein, tacrolimus binds to tacrolimus binding pathway. They then have a common pathway – the drug-protein complex binds calcineurin. Calcineurin usually acts as a phosphatase on a nuclear factor in activated T cells, which then causes IL-2 transcription, but its binding by the drug protein complex inhibits this.
ADR Nephrotoxicity No clinical effect on bone marrow so can be used in cytopenias Hypertension Hyperlipidaemia Nausea, vomiting and diarrhoea Hypertrichosis (excessive hair growth) Gingival hyperplasia Hyperuricaemia
What are DDIs in calcineurin inhibitors? What should you advise patients before taking tacrolimus/ciclosporin?
Elimination is affected by CYP inhibition or induction.
Inducers: rifampicin, carbamazepine, phenytoin, omeprazole
Inhibitors: ciprofloxacin, antifungals, fluoxetine, paroxetine, HIV antivirals.
Should avoid grapefruit juice in the hour before taking the tablet, and avoid high potassium foods (bananas, tomatoes, dried fruit)
What are indications for methotrexate? What is the MOA?
Cancer
Autoimmune disease
Transplantation
MOA
Inhibits purine synthesis by inhibiting dihydrofolate reductase and hence impairing recycling of folate, this prevents DNA synthesis. It is selective during S phase, in cells with high mitotic rates (so in cancer, autoimmune disease, or the immune system post-transplantation)
What are ADRs and DDIs of methotrexate?
ADR GI mucositis Bone marrow suppression Hepatitis Pneumonitis Cirrhosis Infection Teratogenesis
DDI
Therapeutic interactions with other immunosuppressants, anti-cancer drugs and autoimmune drugs
Adverse DDIs with drugs that affect renal blood flow, renal elimination and plasma protein binding, examples include:
NSAIDs
Phenytoin
Tetracyclines
Penicillin
(as this can lead to increased risk of myelosuppression)
Also can interact with any drug that causes renal or hepatic ADRs to increase the risk of ADRs – including azathioprine and sulfasalazine
How often is methotrexate dosed? What should you give alongside it?
Dosing once per week, give folic acid to reduce toxicity
How is methotrexate monitored?
Must carry out clinical monitoring of toxicity – chest x-ray at baseline along with baseline and regular FBC, LFT, U+E and creatinine.
Describe oral bioavailability, elimination of methotrexate
Oral bioavailability is widely variable and dose dependent so it is often given IV.
Its binding to plasma proteins is about 50%
Elimination depends on the dose, at high doses the half-life is 8-10 hours.
It also undergoes intracellular and hepatic metabolism to polyglutamates which accumulate cells and also bind to dihydrofolate reductase – they can be retained in cells for weeks to months and may require a review of dosing.
Methotrexate is eliminated renally – by glomerular filtration and tubular secretion
