Usage
Azathioprine is prescribed as an immunosuppressant to prevent organ rejection after transplantation (e.g., kidney, heart, liver) and to treat autoimmune diseases like rheumatoid arthritis, lupus nephritis, Crohn’s disease, ulcerative colitis, and other inflammatory conditions like vasculitis, systemic lupus erythematosus (SLE/lupus), and polymyositis. Its pharmacological classification is antimetabolite/immunosuppressant. The drug works by suppressing the immune system by interfering with the synthesis of DNA and RNA, which reduces the proliferation of immune cells (like lymphocytes) involved in the immune response.
Alternate Names
Azathioprine is also known as 6-[(1-methyl-4-nitro-1H-imidazol-5-yl)thio]purine. Brand names include Imuran, Azasan, Azamun, Azapin, and Thioprine.
How It Works
Pharmacodynamics: Azathioprine acts as a prodrug, converting to 6-mercaptopurine (6-MP), which is then metabolized into active metabolites, including 6-thioguanine nucleotides (6-TGNs). These 6-TGNs are incorporated into DNA and RNA, disrupting cell replication and function, primarily targeting rapidly dividing cells like lymphocytes, thus suppressing the immune system.
Pharmacokinetics: Azathioprine is well-absorbed orally. It undergoes extensive hepatic metabolism via various enzymes, including thiopurine S-methyltransferase (TPMT). TPMT activity is crucial as it influences the balance between the production of active metabolites (6-TGN) and inactive metabolites (6-methylmercaptopurine or 6-MMP). The drug is primarily excreted through the kidneys as metabolites. Genetic polymorphisms affecting TPMT activity can lead to varied responses and toxicity risks.
Mode of Action: Azathioprine’s mode of action involves blocking purine synthesis and inhibiting DNA and RNA synthesis. Its immunosuppressive effect is mediated through the incorporation of 6-TGN into the DNA, which impairs cell division and causes cell death of lymphocytes. It does not bind to specific receptors, but primarily exerts its effects through metabolic interference with purine synthesis pathways.
Elimination Pathways: Azathioprine undergoes complex hepatic metabolism through various pathways, including TPMT, xanthine oxidase, and hypoxanthine-guanine phosphoribosyl transferase (HGPRT). Metabolites are primarily excreted through the kidneys.
Dosage
Standard Dosage
Adults:
The initial dose is typically 1 mg/kg/day, administered orally or intravenously once daily or in two divided doses. After 6-8 weeks, the dose can be increased by 0.5 mg/kg/day every 4 weeks, not exceeding 2.5 mg/kg/day. The maintenance dose is adjusted based on therapeutic response and tolerance, usually between 1 and 3 mg/kg/day.
Children:
Similar to adult dosing, the initial dose is usually 1 mg/kg/day, with adjustments based on response and tolerance, not exceeding 2.5 mg/kg/day. Pediatric use requires close monitoring due to increased vulnerability to side effects.
Special Cases:
- Elderly Patients: Dosages should be at the lower end of the range, with careful monitoring for toxicity due to age-related decline in renal and hepatic function.
- Patients with Renal Impairment: Dose reduction is necessary, guided by renal function assessment.
- Patients with Hepatic Dysfunction: Lower doses are indicated due to impaired metabolism, and hepatic function should be monitored.
- Patients with Comorbid Conditions: Dosage adjustment and close monitoring may be required based on the specific comorbid condition, such as diabetes or cardiovascular disease.
Clinical Use Cases
The dosing of azathioprine varies with indication. For kidney transplantation, the starting dose is 3-5 mg/kg/day at the time of transplant, followed by a maintenance dose of 1-3 mg/kg/day. For rheumatoid arthritis, the usual starting dose is 1 mg/kg/day, and it can be increased gradually. Azathioprine is not typically used for intubation, surgical procedures, mechanical ventilation, ICU use, or in emergency situations like status epilepticus or cardiac arrest.
Dosage Adjustments
Dose modifications are based on patient-specific factors, such as renal or hepatic dysfunction, TPMT enzyme activity, concomitant medications, and other metabolic disorders. TPMT genotyping or phenotyping is recommended to assess the risk of myelosuppression, and doses should be reduced in patients with low or absent TPMT activity.
Side Effects
Common Side Effects:
Nausea, vomiting, loss of appetite, diarrhea, abdominal pain, unusual bruising or bleeding, fatigue, hair loss, skin rash, increased sensitivity to sunlight, mouth sores.
Rare but Serious Side Effects:
Pancytopenia (decreased red blood cells, white blood cells, and platelets), liver toxicity, pancreatitis, infections (due to immunosuppression), allergic reactions, increased risk of malignancy (lymphoma and skin cancers).
Long-Term Effects:
Prolonged use can increase the risk of infections and certain cancers.
Adverse Drug Reactions (ADR):
Severe bone marrow suppression, life-threatening infections, hepatitis, pancreatitis, allergic reactions requiring immediate medical intervention.
Contraindications
Hypersensitivity to azathioprine or 6-mercaptopurine, pregnancy (unless benefits outweigh risks), breastfeeding (though generally considered acceptable at low doses with precautions), known malignancy, active severe infections, very low or absent TPMT activity, previous treatment with alkylating agents in patients with rheumatoid arthritis.
Drug Interactions
Azathioprine interacts with numerous medications. Allopurinol, febuxostat, and other xanthine oxidase inhibitors should be avoided or used at significantly reduced doses, as they increase the risk of myelosuppression. Concomitant use with other immunosuppressants (e.g., ciclosporin, tacrolimus, rituximab, tofacitinib) increases the risk of infections and other side effects. Live vaccines are contraindicated, and responses to killed vaccines may be diminished. Interactions with certain medications (e.g., warfarin, aminosalicylates, some antibiotics) can alter their effects. Food and lifestyle factors like milk/dairy products (reduce azathioprine absorption) and alcohol (may increase liver toxicity) should be considered.
Pregnancy and Breastfeeding
Azathioprine is generally considered acceptable during breastfeeding with appropriate precautions. It passes into breast milk at low levels, which are considered generally safe for infants. Monitoring the infant’s blood counts and liver function is advised in certain situations. It is recommended to discard breast milk for 4 hours after taking azathioprine to minimize infant exposure. Although data suggests low risk in pregnancy, it can increase the risk of miscarriage, low birth weight, and preterm delivery. Contraception is recommended during treatment.
Drug Profile Summary
- Mechanism of Action: Immunosuppressant antimetabolite; interferes with DNA synthesis.
- Side Effects: Nausea, vomiting, bone marrow suppression, increased infection risk, liver toxicity, pancreatitis, malignancy risk.
- Contraindications: Hypersensitivity, pregnancy (unless benefits outweigh risks), breastfeeding (with precautions), very low/absent TPMT, active infection, malignancy.
- Drug Interactions: Allopurinol, febuxostat, other immunosuppressants, live vaccines, warfarin, milk/dairy.
- Pregnancy & Breastfeeding: Generally acceptable during breastfeeding with precautions; use contraception during treatment; low risk in pregnancy.
- Dosage: 1-3 mg/kg/day, adjust based on response and tolerance; renal/hepatic impairment requires dose reduction.
- Monitoring Parameters: Complete blood counts, liver function tests, renal function, TPMT activity.
Popular Combinations
Azathioprine is sometimes used in combination with corticosteroids in certain conditions like lupus nephritis and organ transplantation. It can also be used with other immunosuppressants, but careful monitoring for toxicity is crucial. Its use with biologics for Inflammatory Bowel Disease is established, and often used at lower doses (e.g., 1.3 mg/kg).
Precautions
Pre-screening is essential for assessing TPMT activity, renal/hepatic function, and potential drug interactions. For pregnant women, the risks and benefits must be carefully considered. For breastfeeding mothers, monitor infant’s health and consider discarding breast milk for 4 hours after the dose. For children and the elderly, close monitoring is needed due to their vulnerability to adverse effects. Alcohol consumption should be limited. Regular monitoring of blood counts, liver and renal function is essential throughout treatment.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Azathioprine?
A: The initial dose is typically 1 mg/kg/day, with adjustments every 4 weeks as needed, not exceeding 2.5 mg/kg/day. Dosing varies by condition and requires careful monitoring.
Q2: How does Azathioprine work?
A: Azathioprine inhibits DNA synthesis, leading to suppression of the immune system, particularly affecting rapidly dividing cells like lymphocytes.
Q3: What are the major side effects of Azathioprine?
A: Major side effects include nausea, vomiting, bone marrow suppression, increased risk of infections, liver toxicity, pancreatitis, and a potential increased risk of malignancies.
Q4: Is Azathioprine safe during pregnancy and breastfeeding?
A: It can be used with careful consideration of risks and benefits, with precautions during breastfeeding.
Q5: What are the contraindications to using Azathioprine?
A: Contraindications include hypersensitivity, pregnancy (unless benefits outweigh risks), active severe infection, low or absent TPMT activity, and some types of prior cancer treatment.
Q6: What are the key drug interactions with Azathioprine?
A: Key interactions include allopurinol, febuxostat, other immunosuppressants, and live vaccines. Milk/dairy products can also reduce absorption.
Q7: How should TPMT activity be addressed when prescribing Azathioprine?
A: TPMT genotyping or phenotyping is recommended. Dose reduction or avoidance is required for individuals with low or absent activity due to increased myelosuppression risk.
Q8: What are the important monitoring parameters during Azathioprine treatment?
A: Monitor complete blood counts, liver and renal function, and TPMT activity.
Q9: What are some specific examples of conditions Azathioprine treats?
A: Azathioprine is used to prevent organ rejection and treat autoimmune diseases like rheumatoid arthritis, lupus nephritis, and inflammatory bowel diseases (Crohn’s disease and ulcerative colitis).
Q10: What should patients be advised regarding lifestyle while taking Azathioprine?
A: Patients should avoid or limit alcohol, avoid excessive sun exposure, and take precautions to prevent infections. They should inform all healthcare providers about their Azathioprine use. They should also discuss diet, particularly dairy product intake around medication timing, as these can affect absorption.
