Azathioprine Flashcards
Azathioprine - Mechanism of Action
Immunosupressant
Purine antimetabolite
Metabolised to 6-mercaptopurine
This is incorporated into DNA
Causes cell damage and death
Azathioprine - dose
1 - 3 mg / kg per day
Dose is dependant on TPMT activity
Azathioprine - pregnancy status
Category D
“have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage”
Azathioprine - Contraindications
Pregnancy
Hypersensitivity
Low TPMT activity
Active clinically significant infection
Azathioprine - Relative Contraindications
Breastfeeding
Allopurinol Use
Prior use of alkylating agents (theoretical increased risk of malignancy)
Azathioprine - Adverse effects
Myelosuppression
- Correlates with TPMT activity
- Neutropenia
- Agranulocytosis and pancytopenia (rare)
- Cease if WCC < 3.5-4 (neut < 1, lymph < 0.5), Hb < 100, Plt < 100)
Hypersensitivity syndrome
- Develop between 1-4 weeks after starting therapy
- More common in those also on concurrent CyA or MTX
- ○ Cutaneous: morbilliform, pustules/vesicles, petechial lesions, purpura, EM, urticaria, angioedema, EN
○ Systemic: cardiovascular collapse, fever, leukocytosis, nausea, hepatotoxicity, pancreatitis, arthralgias, myalgias, rhabdomyolysis, headache, renal insufficiency, pneumonitis
○ Absolute contraindication to re-exposure
Immunosuppression carcinogenesis (but no clear evidence in dermatologic use)
- lymphoproliferative malignancies (non-Hodgkin’s lymphoma) and SCC, and less commonly gynaecologic SCC
Infection
- HSV, HPV, Scabies
- True opportunistic infections are uncommon in dermatologic indications
GI (most common)
- Nausea, vomiting, diarrhoea
- Present day 1-10 of therapy
- Reduce dose, divide dose, take with food
- Rarely pancreatitis
Hepatic
- Elevated transaminases
- Severe hepatocellular toxicity (rare)
What is Azathioprine Hypersensitivity syndrome
Rare adverse reaction
Occurs in ~2% of patients
constitutional symptoms with or without a cutaneous reaction
Less commonly, liver and renal dysfunction, hypotension, and shock may occur
Lab abnormalities: neutrophilia, leukocytosis, anemia, elevated inflammatory markers, and rarely, positive antineutrophilic cytoplasmic antibodies
What are the cutaneous manifestations of Azathioprine Hypersensitivity syndrome?
Most common = neutrophilic dermatoses / sweets syndrome
Small vessel vasculitis
AGEP
Non-specific exanthem
Azathioprine - pre commencement Ix
FBC, UEC, LFTs
TPMT
NUDT-15
beta HCG
Immunosuppression screen
Ensure up to date with age-appropriate malignancy screens
Azathioprine monitoring Ix
FBC, UEC, LFTs
Every 2 weeks until 2 months, then every 2 - 3 months
FSE including LN examination every year
Azathioprine pre-commencement counselling
What it is and why we use it - oral medication, immunosuppressant, taken once daily
Common ADRs - GI side effects
Serious but less common - myelosuppression, hypersensitivity, organ dysfunction, increase risk of malignancy
Pregnancy risk for women
Importance of up to date malignancy screen and annual FSE / LN check
To contact derm if having any S/E or concerns - easy bruising, fever, malaise etc etc
Azathioprine Drug interactions
Allopurinol: inhibits xanthine oxidase, increases risk of myelosuppression
ACE inhibitors (captopril): may increase the risk of leukopenia
Warfarin: may need to dose increase warfarin as azathioprine decreases anticoagulant effect
Sulfasalazine: inhibits TMPT enzyme activity, and thus may potentate azathioprine toxicity
MTX: plasma levels of 6-MP may increase
CyA: plasma levels may be decreased of CyA
Neuromuscular blockers (pancuronium): may require an increased dose of this paralytic agent for appropriate control
Given that azathioprine is myelosuppressive, concomitant use of other known myelosuppressive agents, such as co-trimoxazole and penicillamine, should be avoided
May decrease effectiveness of intrauterine contraceptive devices
