Pharmacology: Immunosuppression and disease modifying therapy in rehaumatology Flashcards
Give some examples of diseases managed by rheumatology
- Rheumatoid arthritis
- Systemic lupus erythematosus (severe joint pain, malar rash on face, headaches, raynauds)
- Systemic vasculitis
- Systemic sclerosis (excess production of collagen in the CT, affects skin, blood vessels, joints, etc)
What is the pathology of rheumatoid arthritis?
Initially localised to the synovium which thickens (then called a pannus). The pannus releases lots of cytokines causing inflammation and damage to the cartilage and bone.
What is the target for dugs treating rheumatoid arthritis?
The pro-inflammatory cytokines eg IL-1 inhibitors, TNF inhibitors
How is rheumatoid arthritis diagnosed?
- morning stiffness lasting more than 30mins (the longer the stiffness the more significant)
- arthritis of 3 or more joints (small joints)
- symmetrical arthritis
- rheumatoid nodules (late stage and shouldnt be left that long)
- xray changes (shouldnt be left til that stage but may see some)
Whats the difference between arthritis and arthralgia?
Arthritis is joint pain with swelling
Arthralgia is joint pain without swelling
What is the mechanism of action of corticosteroids?
They inhibit all stages of T cell activation across all systems - therefore they have lots of side effects
Prevent IL-1 and IL6 production by macrophages
List some common side effects of steroids
- cataracts
- hypertension
- immunocompromised
- peptic ulcers
- osteoporosis
- weight gain
- increased body hair
- easy bruising
- thinning of the skin
What is azathioprine used for in practice?
An immunosuppressant used to treat:
- lupus and vasculitis (v effectice)
- RA but weak evidence
- IBD in severe cases
- atopic dermatitis
What is a ‘steroid sparing drug’? Give some examples
A medication that allows the stopping of steroids early to avoid side effects
eg Azathioprine, methotrexate
What is the mechanism of action of azathioprine?
It is broken down by the TPMT enzyme, the action of the metabolites is to inhibit purine and therefore DNA and RNA synthesis
(Individuals low in TMPT are at risk of myelosupression so need to test TMPT levels before prescribing)
What are side effects of immunosuppressants?
- Myelosuppression is the main concern (need regular blood tests to monitor)
- Increased risk of malignancy
- Increased risk of infection
- Hepatitis
Name some calcineurin inhibitors
Ciclosporin and tacrolimus
What are some uses for calcineurin inhibitors?
- widely used in transplantation
- atopic dermatitis
- severe psoriasis
What are the risks of ciclosporin?
Can cause renal toxicity
Raised potassium
Hypertension
Lots of drug interaction (CYP P450)
What is the mechanism of action of calcineurin inhibitors?
Inhibit T helper cells (needed to communicate with B cells) which prevents production of IL2
What is mycophenolate used to treat?
- primarily transplantation (but needs to be well monitored for risk of myelosuppression)
- good efficacy for treating new onset lupus
What is the mechanism of action of mycophenolate?
Inhibits B cell and T cell proliferations selectively
Spares other rapidly dividing cells - more accurate rather than steroids
What is cyclophosphamide used for?
- initially chemotherapy for solid cancers, lymphomas and leukaemias
- found to also treat lupus
- vasculitis
(quickest acting drug - starts to work in 10 days vs 4-6weeks)
How does cyclophosphamide work?
Cross links DNA to prevent replication
Suppresses both B and T cell activity
What are the side effects of cyclophosphamide?
- one of the metabolites causes haemorrhagic cystitis of the bladder therefore need to give with mesna to bind up the metabolite and encourage drinking lots of water
- increases risk of bladder cancers long term
- infertility (doses changing so becoming less of an issue, but still 10-25%) may offer to freeze the eggs to have IVF
What is methotrexate used to treat?
- v high doses for malignancy
- gold standard for RA
- psoriasis
- crohns disease
Unlicensed: myopathies, steroid sparing in asthma
What is the mechanism of action of methotrexate in malignancy?
Inhibits dihydrofolate reductase (competes against folate)
Inhibits the s phase of the cell cycle - cytotoxic to rapidly dividing cells such as malignany, GI mucosa
What is the mechanism of action of methotrexate in non malignant diseases?
Mechanism not clear, but it is NOT via anti-folate action like it is in malignancy.
What are the methods of administering methotrexate?
Orally - oral bioavailability is 35%
IM - bioavailability is 75%
Sub cutaneous - used if they cannot tolerate oral eg nausea aside effects
