What is azathioprine and mercaptopurine?
Azathioprine is an antimetabolite thiopurineanaloguedrug that interferes withDNAsynthesisand suppresses the immune system response.
Azathioprine is metabolised in the liver to mercaptopurine, also known as 6-mercaptopurine (6-MP) which is also commercially available as a drug. Mercaptopurine is then converted intothioguaninenucleotideswhichinhibitcell growth.
Who uses azathioprine and mercaptopurine?
Azathioprine is more often used in practice than mercaptopurine for the treatment of skin conditions, however they are closely related.
Approved azathioprine indications may include:
- Prevention of organtransplantrejection,rheumatoidarthritis,Crohn disease
- Dermatology-approved indications in some countries include:systemiclupus erythematosus,dermatomyositis,polyarteritis nodosa.
Azathioprine may be approved to treat these skin conditions
Off-label uses in dermatology with good evidence include:
- Behçet disease
- Cutaneouspolyarteritis nodosa
- Pemphigus vulgaris
- Relapsing polychondritis
Limited evidence is available for many other dermatologic conditions.
What are thecontraindicationsand precautions with azathioprine and mercaptopurine?
- Drug orexcipientallergy
- Pregnancy (relativecontraindication— see below)
- Very low thiopurine methyltransferase (TPMT) activity (relative contraindication — see below)
- Concomitantuse of allopurinol or febuxostat (relative contraindication)
- Live vaccines [seeImmunisation inimmunosuppresseddermatology patients]
- Phototherapydue to skincancerrisk
Pregnancy and breastfeeding
Treatment with azathioprine and mercaptopurine during all stages of pregnancy should be avoided except where benefits outweigh risks.
Females of childbearing potential should be advised of the risks involved and use effective contraception where appropriate.Teratogenicityis unclear in men taking azathioprine or mercaptopurine and adequate contraception may also be advised in this case.
Although low concentrations of 6-mercaptopurine may be found in breastmilk, there has been no evidence to suggest harm. Potential benefits should outweigh risks; for further information, seeLactation and medications used in dermatology.
Tell me more about azathioprine and mercaptopurine
Mechanism of action
Azathioprine has been widely prescribed since the 1960s, however its mechanism of action as well as that of itsmetabolite6-MP is not fully understood. There are a number of proposed mechanisms including:
- Reduction in cell division through self-incorporation into DNA andRNAas a falsenucleotide
- Immunosuppressionoccurs after mercaptopurine crosses cell membranes and becomes intracellularly activated.
Drug forms and dosing
Azathioprine and mercaptopurine may be available as an oral tablet, oral liquid, or intravenous injection (azathioprine only).
The dose of azathioprine is generally 1–3 mg/kg/day, however the individualised dose isdependenton several factors including indication, age, response, and TPMT activity (see below). Thebioavailabilitymay vary between differentformulations. Dose reduction may be required in patients withhepaticandrenalimpairment.
Effects of azathioprine and mercaptopurine may take up to several months to be seen — this should be considered when reviewing treatment.
What are the benefits of azathioprine and mercaptopurine?
- Potential steroid-sparing effect
- 多个剂型和strengths, allowing for easy dose titration
What are the disadvantages of azathioprine and mercaptopurine?
- May take several months for the full benefits to be seen
- Metabolismvaries between individuals (see TPMT monitoring below)
- Regular blood test monitoring is required
What are the side effects and risks of azathioprine and mercaptopurine?
Azathioprine and mercaptopurine usually cause mild side effects but may occasionally be severe enough to stop treatment. These include:
- Mucocutaneousside effects
Mucocutaneous side effects that may be caused by azathioprine
- Common side effects
- nausea and dose-related bone marrow suppression
- Less common side effects
- diarrhoea, vomiting, infections, liver impairment, andpancreatitis.
If the use of an interacting drug combination is unavoidable, dose adjustment may be required and blood counts should be monitored carefully. Interactions include:
- Warfarin dose requirement may increase 3-4 fold when given with azathioprine [seeAnticoagulants and antiplatelet agents]
- Trimethoprim + sulfamethoxazole
- Neuromuscular blocking agents eg, rocuronium, atracurium
- Sulfasalazine and other benzoic acid derivatives
Monitoring during treatment
Before starting treatment:
- Testing forlatenttuberculosis,hepatitisB and C
- Checking immunity status eg, measles and varicella [seeImmunisation in immunosuppressed dermatology patients]
- Baselineblood tests and skin check.
- Regular full blood counts are checked weekly at first for the first 4–8 weeks, then at longer intervals.
- Liver and kidney function tests — baseline and periodically
- Regular skin checks — patients should practiceself skin examination.
Thiopurine methyltransferase (TPMT)
Azathioprine and mercaptopurine is primarily metabolised by theenzymeTPMT. Some people have ageneticmutationcausing them to have either low enzyme activity (approximately 11% of the population) or a lack of enzyme activity (1 in 300 people). Those with bothgenesare at severe risk of bone marrow suppression. Conversely, some other individuals have high levels of enzyme activity and may require a higher dose than normal.
TPMT levels should be measured to determine a patient's level of risk before starting treatment. Low levels are < 5 U/mL, intermediate levels are 5–13.7 U/mL, and high levels are > 13.8 U/mL.
Discontinuation of treatment
Azathioprine should be stopped and promptly managed jointly with ahaematologistif:
- Neutrophilcount < 1.0x109/L
- Lymphocytecount < 0.5x109/L
- Plateletcount < 50x109/L.
我们建议你参考国家药品approval agency such as the AustralianTherapeutic Goods Administration (TGA),USFood and Drug Administration (FDA),UKMedicines and Healthcare products regulatory agency (MHRA)/emc, and NZMedsafe,or a national or state-approved formulary eg, theNew Zealand Formulary(NZF) andNew Zealand Formulary for Children(NZFC) and theBritish National Formulary(BNF) andBritish National Formulary for Children (BNFC).