Azathioprine is a purine analog with cytotoxic and immunosuppressive activity. Azathioprine is a prodrug that is converted by hepatic xanthine oxidase to its active metabolite 6-mercaptopurine (6-MP). 6-MP is further metabolized by hypoxanthine-guanine phosphoribosyltransferase (HGPRT) into 6-thioguanosine-5′-phosphate (6-thio-GMP) and 6-thioinosine monophosphate (6-thio-IMP), both inhibit nucleotide conversions and de novo purine synthesis. This leads to inhibition of DNA, RNA, and protein synthesis. As a result, cell proliferation may be inhibited, particularly in lymphocytes and leukocytes.
Azathioprine(AZA) is an immunosuppressive medication used in rheumatoid arthritis, Crohn’s disease, ulcerative colitis, and in kidney transplants to prevent rejection. It is taken by mouth or injected into a vein. An immunosuppressive antimetabolite pro-drug. It is an imidazolyl derivative of 6-mercaptopurine and many of its biological effects are similar to those of the parent compound. Azathioprine is converted into 6-mercaptopurine in the body where it blocks purine metabolism and DNA synthesis.
Mechanism of Action of Azathioprine
Azathioprine antagonizes purine metabolism and may inhibit synthesis of DNA, RNA, and proteins. It may also interfere with cellular metabolism and inhibit mitosis. Its mechanism of action is likely due to the incorporation of thiopurine analogs into the DNA structure, causing chain termination and cytotoxicity. Azathioprine is a chemotherapy drug, now rarely used for chemotherapy but more for immunosuppression in organ transplantation and autoimmune diseases such as rheumatoid arthritis or inflammatory bowel disease or Crohn’s disease. It is a pro-drug, converted in the body to the active metabolite 6-mercaptopurine. Azathioprine acts to inhibit purine synthesis necessary for the proliferation of cells, especially leukocytes and lymphocytes. It is a safe and effective drug used alone in certain autoimmune diseases, or in combination with other immunosuppressants in organ transplantation. Its most severe side effect is bone marrow suppression, and it should not be given in conjunction with purine analogs such as allopurinol. The enzyme thiopurine S-methyltransferase (TPMT) deactivates 6-mercaptopurine. Genetic polymorphisms of TPMT can lead to excessive drug toxicity, thus the assay of serum TPMT may be useful to prevent this complication.
Indications of Azathioprine
- Azathioprine is an immunosuppressive agent used in combination with cyclophosphamide and hydroxychloroquine in the treatment of rheumatoid arthritis.
- Rheumatoid Arthritis
- Psoriatic Arthritis
- Renal Transplant
- Autoimmune Hepatitis
- Crohn’s Disease
- Atopic Dermatitis
- Behcet’s Disease
- Biliary Cirrhosis
- Bullous Pemphigoid
- Chronic Active Hepatitis
- Chronic Inflammatory Demyelinating Polyradiculoneuropathy
- Cogan’s Syndrome
- Crohn’s Disease, Acute
- Crohn’s Disease, Maintenance
- Idiopathic Thrombocytopenic Purpura
- Inflammatory Bowel Disease
- Multiple Sclerosis
- Myasthenia Gravis
- Nephrotic Syndrome
- Organ Transplant, Rejection Prophylaxis
- Systemic Lupus Erythematosus
- Takayasu’s Arteritis
- Ulcerative Colitis
- Wegener’s Granulomatosis
- Disseminated Sclerosis
- Immune Thrombocytopenia
- Kidney Transplant Rejection
Contra Indication of Azathioprine
- Severe infection
- Severe anemia
- Decreased Blood Platelets
- Severe Decrease in White Blood Cells
- A Blood Clot in a Vein of the Liver
- Acute Inflammation of the Pancreas
- Malignant Lymphoma
- Moderate to Severe Kidney Impairment
- Thiopurine S-Methyltransferase Deficiency
- Hepatosplenic T-cell Lymphoma
- Allergies to Mercaptopurine Analogues
Dosage of Azathioprine
Strengths : 50 mg
- Initial dose: 1 mg/kg (50 to 100 mg) orally or IV per day given in 1 to 2 divided doses
- Maintenance dose: Lowest effective dose
- Maximum dose: 2.5 mg/kg orally or IV per day
- Duration: At least 12 weeks
- 1.5 to 4 mg/kg per day for 10 days up to 52 weeks
- 1.5 to 4 mg/kg per day for 10 days up to 52 weeks in maintenance dose
- 2.5 mg/kg orally once a day, in the morning, for 3 months
- Initial dose: 2 mg/kg per day in combination with prednisolone 0.6 to 0.8 mg/kg per day, with prednisolone reduced to 0.1 mg/kg within 2 to 3 months
- Maintenance dose: 2 mg/kg per day with prednisolone 0.1 mg/kg per day for 21 to 22 months.
Chronic Active Hepatitis
- Autoimmune hepatitis: 1 to 2 mg/kg per day, concomitantly with prednisolone (5 to 15 mg/day) for a minimum of 1 year (average 5 years)
- Treatment of choroidal neovascularization: 1 to 1.5 mg/kg orally per day, in combination with prednisolone and cyclosporine
- IV: 20 to 40 mg/kg via IV infusion over 36 hours or 40 mg/kg as three 8-hour infusions over 3 days followed by oral azathioprine
- Oral: 2 mg/kg orally per day beginning the day after completion of the IV loading dose
- Initial dose: 3 to 5 mg/kg orally or IV once a day, beginning at the time of transplant
- Maintenance dose: 1 to 3 mg/kg orally or IV once a day
- Greater than 17 years: 2.5 mg/kg orally once a day, in the morning, for 3 months
- Greater than 6 years: 2.5 to 3.5 mg/kg per day in patients with normal levels of thiopurine methyltransferase
Side Effects of Azathioprine
The most common
- stomach pain, especially if it comes along with fever and diarrhea or constipation
- yellowing of the skin or eyes
- loss of appetite
- sleepiness or unusual drowsiness
- clumsiness or unsteadiness
- dry mouth
- false sense of well-being
- increased watering of mouth
- vision changes;
- breast swelling (in men or women); or
- decreased sex drive, impotence, or difficulty having an orgasm.
- blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights;
- restless muscle movements in your eyes, tongue, jaw, or neck;
- Drowsiness and lightheadedness the day after taking the medicine.
- Numbed emotions.
- Visual disturbances such as blurred vision or double vision.
- Shaky movements and unsteady walk (ataxia).
- Loss of memory (amnesia).
- Muscle weakness.
- Skin rashes.
- Disturbances of the gut such as diarrhoea, constipation, nausea, vomiting or abdominal pain.
- Difficulty in passing urine (urinary retention).
- Changes in sex drive.
- Low blood pressure (hypotension).
- Blood disorders.
- Unexpected aggression, restlessness or irritability (tell your doctor if you experience this).
- Nightmares or hallucinations (tell your doctor if you experience this).
- behavioural changes, including aggressiveness, angry outbursts, bizarre behaviour, or decreased inhibitions
- increased trouble sleeping
- memory problems
- muscle spasms
- shortness of breath
Drug Interactions of Azathioprine
Azathioprine may interact with following drugs, supplyments, & may change the efficacy of drugs
- anti-tumor necrosis factor agents (e.g., adalimumab, etanercept, infliximab, )
- “azole” antifungals (e.g., itraconazole, ketoconazole, voriconazole)
- beta-blockers (e.g., carvedilol, metoprolol, propranolol)
- corticosteroids (e.g.dexamethasone, hydrocortisone, prednisone)
- macrolide antibiotics (e.g., clarithromycin, erythromycin)
Pregnancy & Lactation of Azathioprine
FDA Pregnancy Category D
Animal studies have revealed evidence of teratogenicity. There are no controlled data in human pregnancy. Congenital anomalies, including polydactyly, plagiocephaly, congenital heart disease, hypospadias, and bilateral talipes equinovarus have occurred. Leucopenia and/or thrombocytopenia have been reported in a proportion of neonates whose mothers took azathioprine throughout their pregnancies
Studies in women taking azathioprine at doses up to 200 mg per day for immunosuppression in inflammatory bowel disease, systemic lupus erythematosus, or transplantation have found either low or undetectable levels of its active metabolites in milk and infant serum.