Anti-Proliferative Immunosuppressants
Examples
- Azathioprine
- Mycophenolate mofetil
- (Cyclophosphamide)
Indications
Both
Azathioprine
- Inflammatory bowel disease
- Rheumatoid arthritis (unlicensed indication)
- Other auto-immune diseases as a steroid-sparing agent
Contraindications
Contraindications
- Hypersensitivity to azathioprine / mercaptopurine
- Pregnancy and breast-feeding
Caution
- Renal impairment
- Hepatic impairment
- Elderly
- Active GI bleeding (mycophenolate)
Mechanism
Azathioprine is metabolised to mercaptopurine, which is then metabolised to a nucleoside analogue which prevents the formation of purines required for DNA synthesis. As immune cells such as lymphocytes are rapidly proliferating, the production of these will be reduced providing an immunosuppressant effect.
Mycophenolate is more specifically targetted than azathioprine, giving it greater efficacy and safety. It acts as an inhibitor of ionsine monophosphate dehydrogenase, blocking production of guanoside phosphate, a key component of DNA.
Administration
Oral
Adverse Reactions
These are mainly due to bone marrow suppression.
Bone marrow suppression causes: anaemia, thrombocytopenia and reduced immune response.
Other problems include hepatic impairment, pancreatitis and pneumonitis.
Hypersensitivity to Azathioprine can cause: nausea/vomiting, diarrhoea, fever, flu-like symptoms, hypotension and interstitial nephritis.
Mycophenolate can also cause GI side effects, renal impairment and increased incidence of malignancy, particularly lymphoma and skin cancer.
Interactions
Azathioprine is involved in a number of important drug-drug interactions.
Allopurinol significantly inhibits the metabolism of azathioprine. A 75% reduction in azathioprine dose is recommended if the two are used together (common in chemotherapy regimes).
Other drugs such as aminosalicylates may increase the risk of leucopenia with azathioprine.
ACE inhibitors can increase the risk of anaemia and leucopenia with azathioprine, particularly in patients with renal impairment.
Co-trimoxazole and azathioprine can increase the risk of haematological toxicity.
In patients taking warfarin, the INR may be reduced by azathioprine.
Mycophenolate has far fewer interactions, mainly with antibiotics such as metronidazole and rifampicin which reduce mycophenolate concentrations.
Education
Patients should be warned about exposure to infection and to report signs of illness (bleeding, bruising or infection) quickly.
Frequent monitoring of full blood count is needed.
Pharmacokinetics
Azathioprine is absorbed by the oral route, unlike it's active metabolite mercaptopurine. Azathioprine is quickly metabolised and the metabolite produced is renally excreted.
Mycophenolate is also well absorbed and rapidly metabolised to its active metabolite. It is also renally cleared.
Other Systems
