Azathioprine

Author: Prof. Dr. med. Peter Altmeyer

Last updated on: 22.04.2021

Definition
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Active substance belonging to the immunosuppressive group (originally developed as a cytostatic drug). Imidazole derivative of 6-mercaptopurine (6MP), which is metabolized in the liver to 6MP by a thiopurine methyltransferase (TPMT) (TPMT has a known polymorphism that can lead to both increased inactivation and increased toxicity of AZT; about 10% of the normal population are heterozygous carriers of an allele with low TPMT activity. In homozygous carriers, AZT can lead to severe myelosuppression). In terms of effect, 100 mg of azathioprine corresponds to about 60 mg of 6MP. Both drugs are degraded as purine analogues (via xanthine oxidase) to uric acid, a metabolic pathway that can be inhibited by allopurinol. Allopurinol causes an accumulation of azathioprine or 6MP with the risk of severe bone marrow toxicity. If purine analogues and allopurinol are administered simultaneously, the dose of azathioprine must therefore be adjusted, see table.

Half-life
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4,5–5 h

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Pharmacodynamics (Effect)
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Inhibition of DNA and RNA synthesis, immunosuppression, anti-inflammatory effect, inhibition of humoral and cell-mediated immune response, inhibition of B-cell proliferation as well as IgG and IgM synthesis, suppression of CD4 cells, stimulation of CD8 cells.

Indication
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Azathioprine is the most frequently used immunosuppressive after glucocorticoids ( glucocorticoids, systemic). Its advantage is that it can be combined with other immunosuppressants, e.g. methotrexate or ciclosporin A.

Absolute indications: Systemic lupus erythematosus, mixed collagenosis (overlap syndrome), polymyositis/dermatomyositis, panarteritis nodosa, pemphigus vulgaris, bullous pemphigoid.
Azathioprine 2nd choice: Wegener's granulomatosis, Behçet's disease, Pyoderma gangraenosum, polymyalgia rheumatica, systemic scleroderma, primary Sjögren's syndrome, rheumatoid arthritis, psoriatic arthritis, juvenile chronic arthritis, essential cryoglobinemia.
Exceptional indications of azathioprine therapy: persistent erythema exsudativum multiforme, ankylosing spondylitis, infectious arthritis (e.g. Lyme arthritis, reactive arthritis), degenerative diseases, fibromyalgia syndrome.

Limited indication
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Liver and kidney diseases (careful haematological controls, possible dose reduction), Lesch-Nyhan syndrome (reduced efficacy), simultaneous or recently completed cytostatic/myelosuppressive therapy, thiopurine methyltransferase (TMPT) deficiency (rapid onset of myelosuppression). DNA strand breaks can be detected when azathioprine is ingested and exposed to UVA radiation (the azathioprine metabolite 6-thioguanine is incorporated into the cellular DNA where it acts as a UVA-sensitive chromophore!)

Dosage and method of use
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adults: 1-2,5 mg/kg bw/day p.o.
children from 1 year: 50-150 mg/day p.o.
children from 12 years: 100-200 mg/day p.o.

Remember! The daily dose can be divided into three doses (e.g. 3 times/day 50 mg). The onset of effect can be expected after 3-4 weeks, this is recognizable by a "steroid-saving effect"!

Undesirable effects
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In the case of severe side effects such as nausea, vomiting, hepatotoxicity, bone marrow depression and mucosal ulcerations, thiopurine-methyltransferase deficiency should be excluded. This enzyme is responsible for the metabolism of azathioprine.

Interactions
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S. Tab.

Contraindication
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Severe liver, kidney and bone marrow damage, pancreatitis, vaccinations with live vaccines (mumps, measles, rubella, polio, BCG), severe infections (system mycoses, toxoplasmosis, tuberculosis), pregnancy, lactation, hypersensitivity to the active substance or 6-MP.

Preparations
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Imurek, Zytrim

Note(s)
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Remember! During the treatment and up to 6 months afterwards, effective contraception must be carried out on both men and women! Blood tests (BB and liver values) in the 1st month weekly, in the 2nd and 3rd month every 14 days, then monthly!
The therapy can be continued without problems for 4-6 years (after that the risk of hepatocellular carcinoma increases dramatically!)
The degradation product of azathioprine, 6-thioguanine, is incorporated into the DNA and acts as a UVA-sensitive chromophore, which induces chromosome strand breaks upon UVA irradiation (see also DNA repair).
It is recommended to have the TPMT status determined before starting!

Literature
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Brem R et al (2010) DNA breakage and cell cycle checkpoint abrogation induced by a therapeutic thiopurine and UVA radiation. Oncogene 29:3953-3963
Meggitt SJ et al (2011) Association of Dermatologists' guidelines for the safe and effective prescribing of azathioprine. Br J Dermatol 165:711-734.

Tables
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Side effects of Azathioprine

Respiratory Organs	Alveolitis, dyspnea, flu-like symptoms, cough, rarely interstitial pneumonia.
Blood/Lymph	Dose-dependent blood formation disorder, leukopenia (up to 50%), thrombocytopenia, anemia, pancytopenia, eosinophilia, leukocytosis, bleeding tendency, megaloblastic anemia (administration of leukoverin!), acute myeloid leukemia, non-Hodgkin's lymphoma (0.5%)
Electrolytes, metabolism, endocrinium	Hyperbilirubinemia, reticulum cell Ca, mamma Ca
GIT	Nausea, vomiting, gastrointestinal disturbances, loss of appetite (12%), diarrhea (depending on source: 5-20% of pat.), steatorrhoea, intrahepatic cholestasis with elevation of AP, GPT, GOT (reversible), intestinal perforation, diverticulitis, dysphagia, toxic hepatitis (1-5%, reversible after discontinuation), Budd-Chiari syndrome (in kidney transplant patients), pancreatitis (reversible), parotitis, primary hepatocellular carcinoma (after long-term therapy)
Skin	Urticaria (2-8% of patients, depending on source), exanthema (2%), alopecia (reversible), mucosal ulcers, bacterial skin infections, verrucae vulgares, herpes zoster and herpes simplex, and spinocellular carcinoma (especially at higher doses).
Cardiovascular	cardiac arrhythmias, RR drop, hypotension up to circulatory collapse
Nervous system	Neuritis, paresthesias, rigor, dizziness, aggravation of myasthenia gravis up to myasthenic crisis
Kidney	Renal dysfunction
Other	Fever, increased tendency to infection, chromosomal changes (reversible after discontinuation), teratogenicity
Musculoskeletal system	arthralgias, arthritis, myalgias, myositis

Interactions of azathioprine

ACE inhibitors	severe leukopenia
Allopurinol	Azathioprine levels ↑, allopurinol effects ↓ (common metabolic pathway via xanthine oxidase).
Live virus vaccines	Risk of atypical reactions, avoid combination
Pancuronium	Pancuronium effect ↓
Penicillamine	Penicillamine toxicity ↑
Suxamethonium	neuromuscular blockade ↑
Dead vaccines	Inactivated vaccine effect ↓, immune response ↓
Trimethoprim sulfonamides	Antifolate activity ↑, trimethoprim-sulfonamide toxicity ↑, renal damage
Tubocurarine	Tubocurarine action ↓