Rheumatology Flashcards
What is the mechanism of action of Corticosteroids?
- Prevent interleukin 1 and IL-6 production by macrophages
- Inhibits all stages of T-cell activation
When are Corticosteroids used?
- Malignancy
- Psoriasis/Psoriatic arthritis
- Crohn’s disease
- Vasculitis
- Maintenance therapy in vasculitis
- Steroid sparing agent in asthma
What is the mechanism of action of Methotrexate?
- Competitively and reversibly inhibits dihydrofolate reductase
- Inhibits purine and thymidine synthesis so therefore inhibits DNA, RNA and proteins
- Cytotoxic in the S-phase of the cell and has a greater toxic effect on rapidly dividing cells.
When is methotrexate used?
- Cancer
- Non-malignant disease such a R.A psoriasis. Mechanism is not via anti-folate action
Well tolerated and 50% of patients continue drug for more than 5 years. Improved QOL. Retardation of joint damage
What are the side effects of Methotrexate?
- Mucositis (response to folic acid supplementation)
- Marrow suppression (respond to folic acid supplementation)
- Hepatitis
- Cirrhosis
- Pneumonitis
- Infection Risk
- High tetragenic and abortifacient
What are the pharmacokinetics of Methotrexate?
- Oral bioavailability is 33% and intramuscular is 76%
- Administered PO, IM or S/C
- Weekly dosing.
- 50% protein bound so NSAIDs can displace
What is the mechanism of action of Sulfasalazine?
- Inhibition of T cell proliferation
- T cell apoptosis
- Inhibition of IL-2 production
- Reduced chemotaxis of neutrophil
- Reduced degranulation of neutrophils
What are the uses of Sulfasalazine?
- Relief of pain and stiffness in RA and to finght infection
- Used for Inflammatory arthritis
- Effective in IBD (activity in intestine)
What are the side effects of Sulfasalazine?
Mainly due to sulfapyridine moiety
- Myelosuppression
- Hepatitis
- Rash
Other
- Nausea
- Abdominal pain/vomiting
What are the features of Sulfasalazie in practice?
- Effective and favorable toxicity
- Very few interactions
- Long term blood monitoring not always needed
- No carcinogenic potential and safe in pregnancy
What is the mechanism of action of Azathioprine?
Cleaved to 6-mercatopurine
Anti-metabolite decreases DNA and RNA synthesis
What are the use of Azathioprine?
- SLE & Vasculitis - as maintenance
- Rheumatoid arthritis
- Inflammatory bowel disease
- Atopic dermatitis
- Bullous skin disease
What are the side effects of Azathioprine?
- Bone marrow suppression (monitor FBC)
- Increased risk of malignancy (Esp transplanted patients)
- Increased risk of infection
- Hepatitis (monitor LFT)
What are the features of the metabolism of Azathioprine?
- Metabolised by thiopurine methyltransferase
- TPMT gene is highly polymorphic
- Individuals vary markedly in TPMT activity
What can result from low/absent TPMT level?
- Risk of myelosuppression
- Test TPMT activity before prescribing
What is the mechanism of action of Mycophenolate mofetil?
- Inhibits inosine monophosphate dehydrogenanse
- Impairs B- and T-cell proliferation
- Spares other rapidly dividing cells
When is Mycophenolate mofetil used?
- Primary in transplantation. Induction and maintenance therapy
- Lupus nephritis
What are the side effects of Mycophenolate mofetil?
- Nausea
- Vomiting
- Diarrhoea
- Myelosuppression
What is the mechanism of action of Cyclophosphamide?
- Alkylating agent - cross links DNA so that it cannot replicate
- May immunological effects
- Suppresses T cell activity
- Suppresses B cell activity
When is Cyclophosphamide used?
- Lymphoma
- Leukaemia
- Solid cancers
- Lupus nephritis
- Wegener’s granulomatosis
How is Cyclophosphamide activated in the body?
- Pro drug converted in the liver to active form.
- Main active metabolite is 4-hydroxycyclophosphamide.
- This exist in equilibrium with it tautomer, aldophosphosphamide.
What are the possible routes of damage during the excretion of cyclophosphamide?
- Excreted by the kidney
- Acrolein, another metabolite is toxic to the bladder epithelium and can lead to haemorrhagic cystitis.
- This is prevented through the use of aggressive hydration and/or mensa
What is the mechanism of action of Anti-TNF?
- Decreased inflammation by affecting the cytokine cascade.
- Decrease recruitment of leukocytes to join and elaboration of adhesion molecules and production of chemokines
- Decrease angiogenesis and VEGF levels
- Decrease Joint destruction MMPs and other destructive enzymes.
- Decrease in bone resorption and erosion and cartilage breakdown.
What is the risk of Anti-TNF use?
- TB reactivation is a risk
- TNF-alpha is released by macrophages in response of a TB infection
What is the mechanism of action of Rituximab?
- Binds specifically to unique cell-surface marker CD20 which is found on subset of B cells but not on stem cell, pro-B cells, plasma cells any other cell type.
- Causes B cell apoptosis
When is Rituximab used?
-Effective in RA (stops B cells presenting antigen to T cells, to prevent cytokines releasing and antibodies)
What is the mechanism of action of Calcinerium inhibitors?
-Active against helper T cells, preventing production of IL-2 calcineurin inhibition
What are the examples of calcinerium inhibitors?
- Ciclosporin
- Tacrolimus
What are examples of corticosteroids?
- Fludrocortisone
- Hydrocortisone
- Betamethasone
- Prednisolone
- Dexamethasone
