Azathioprine - A Game-Changer in Autoimmune Therapy

Overview:

Azathioprine is an immunosuppressant drug widely prescribed to treat rheumatoid arthritis and to prevent the chances of organ transplant in patients who have undergone kidney transplantation. It is available as an oral tablet and an injection (administered by a healthcare professional only). Azathioprine works by suppressing the immune system.

The active ingredient in Azathioprine is Azathioprine sodium. Make sure to wear sunscreen and protective clothing, and avoid tanning booths while taking this drug, as it may lead to serious side effects. If symptoms of infections (fever, chills, nasal congestion, shortness of breath, sore throat, burning sensation while urinating) arise while administering the drug, report to the doctor immediately.

For Patients:

Drug Group:

Azathioprine belongs to the antimetabolites class under the broader division of immunosuppressant drugs. The medications of this class act by weakening the immune system. The other drugs of the immunosuppressant group include Mycophenolate Mofetil (MMF), Mycophenolate Sodium, etc.

What Is Azathioprine Used For?

Azathioprine is used to treat the following conditions:

• Prevention of Kidney Transplant Rejection: A kidney transplant is a surgical procedure in which a healthy kidney is from a donor (living or deceased) into a person with end-stage kidney disease. Transplant rejection happens when the immune system recognizes the transplanted organ as a foreign body and fights against it.

• Rheumatoid Arthritis: It is a condition characterized by the inflammation of the joints of the hands, legs, and feet. It is a long-term condition caused by an abnormal immune response in one's body.

Never take Azathioprine or any other medication without talking to the doctor first.

How Does Azathioprine Work?

The exact mechanism of how Azathioprine causes immunosuppressive action is unknown. However, it is thought to suppress the cell-mediated hypersensitivity reactions (exaggerated response of the immune system) and by causing alterations in the antibody production of the body.

Onset of Action:

Azathioprine is given as an intravenous (through veins) injection. It reaches its maximum concentration in blood almost immediately. Azathioprine is converted into its active forms by liver enzymes. A major portion of the drug is excreted through urine. The onset of action is observed only slowly within a few weeks after the therapy is initiated.

Habit-Forming:

Azathioprine has not been reported to have shown any habit-forming tendencies in people taking the drug.

Expiry Date:

Avoid taking the medication past its expiry date, which will be given or printed on the back of the drug packet.

How to Use Azathioprine?

Tablets:

• Take the medication as a single daily dose or in divided doses or with food to reduce irritation to the stomach.

• For any queries, contact the pharmacist or refer to the leaflet provided with the drug.

Injection:

• Azathioprine will be administered by a healthcare professional in a clinical setting.

• In case of side effects, contact the doctor immediately.

Missed Dose:

Tablet:

Take the drug as soon as the patient remembers about missing the tablet. However, if it is already time for the next dose, do not take two tablets together, as it might result in severe adverse reactions. Just skip the missed dose and take the next dosage.

Injection:

If an appointment is missed, immediately contact the clinic or the physician to reschedule the consultation at the earliest.

Overdose:

Tablet:

If the drug is taken more than the recommended amount and unwanted symptoms arise, seek medical help or contact the nearest poison control center immediately.

Injection:

The chances of overdose with Azathioprine are unlikely since it is administered under medical supervision. However, the healthcare team will immediately take the required intervention if it happens.

What Are the Drug Warnings and Precautions?

Inform the physician if any of the following medical conditions are present:

• Gastric Conditions: Azathioprine may cause hypersensitivity reactions in the stomach leading to symptoms like severe nausea and vomiting, and possibly diarrhea, rash, fever, malaise, and muscle pain. Report to the doctor if these symptoms arise.

• Skin Conditions: Azathioprine has the potential to develop malignant tumors. Hence, limit the exposure to direct light. Wear sunscreens and protective clothing while on therapy with the drug.

• Blood Disorders: Azathioprine may cause reduced blood cell counts. Monitoring is required while taking the drug.

• Infections: Since Azathioprine suppresses the immune system, patients are at high risk for bacterial, viral, and fungal infections. Always check for the symptoms of infection and report to the doctor immediately.

• Vaccines: Do not take vaccines without a doctor's approval while taking this drug, as it may lead to serious adverse effects.

• Pregnancy and Breastfeeding: Azathioprine can cause potential harm to the fetus and feeding baby. Hence, avoid using drugs during pregnancy and breastfeeding.

What Are the Side Effects of Azathioprine?

The common side effects of Azathioprine include,

• Nausea.

• Vomiting.

• Hair loss.

These symptoms usually resolve over time. However, if they worsen or become persistent over time, contact the doctor immediately.

The more severe side effects include,

• Drug Allergy: Symptoms of drug allergies like rashes, itching, swelling, or breathlessness.

• Pain: Worsening of joint or muscle pain.

• Liver Damage: Symptoms include dark urine, yellowing skin or eyes, abdominal pain, vomiting, etc.

• Brain Infection: Symptoms include memory loss, vision changes, seizure, confusion, lack of coordination, etc.

If these symptoms arise, seek immediate medical help.

What Are the Interactions of Azathioprine?

Various medications that interact with other drugs, supplements, food, or beverages can result in unwanted side effects.

The common interactions of Azathioprine are as follows:

1. With Other Drugs:

• Alacepril.

• Alfalfa.

• Allopurinol.

• Benazepril.

• Black Cohosh.

• Captopril.

• Cilazapril.

• Doxorubicin.

• Enalaprilat.

• Enalapril Maleate.

• Fosinopril.

• Lisinopril.

• Mercaptopurine.

• Moexipril.

• Mycophenolic Acid.

• Olsalazine.

• Oxypurinol.

• Pentopril.

• Perindopril.

• Quinapril.

• Ramipril.

• Ribavirin.

• Ruxolitinib.

• Spirapril.

• Sulfamethoxazole.

• Sulfasalazine.

• Tofacitinib.

• Trandolapril.

• Trimethoprim.

• Vaccines.

• Zofenopril.

2. With Alcohol: Intake of alcohol may facilitate liver damage when taking Azathioprine. Hence, heavy consumption of alcoholic beverages is not recommended.

3. With Food: No specific food-drug interactions are reported for Azathioprine.

For Doctors:

Indication

The FDA-labeled indications:

• Prophylaxis of renal transplant rejection.

• Rheumatoid arthritis.

Dosing:

The doctor determines the dosage of Azathioprine based on the condition, age, and weight. The alterations in dose may be adjusted by the physician based on the response to the drug.

Azathioprine is commonly available as a 100 mg powder for injection and 50 mg, 65 mg, and 100 mg tablets.

The general dosing information of the drug is as follows:

Prevention of Kidney Transplant Rejection:

• Adult Dosing (18 to 64 Years): Starting with 3 to 5 mg/kg intravenously, as a single daily dose starting at the time of transplant, the doctor further adjusts.

• Child Dosing: The safety and efficacy of Azathioprine are not yet established in children.

Rheumatoid Arthritis:

Adult Dosing (18 to 64 Years): 1 mg/kg/day (50 to 100 mg) intravenously as a single dose or divided twice daily.

Maximum Dose: 2.5 mg/kg/day.

The drug dose will be adjusted by the physician for patients with kidney impairment.

Dosing Considerations:

• Renal Impairment: Patients with reduced urine output, particularly those who have experienced damage to the kidney tubules in the period following a transplant from a deceased donor, may require lower doses of this medication due to the possibility of delayed clearance and increased sensitivity to the drug.

• Hematologic Toxicity: If a patient experiences a sudden decrease in white blood cell counts or persistent low counts or shows any other signs of bone marrow depression, consider reducing the dosage or suspending treatment altogether. If abnormalities in complete blood count results persist despite dose reduction, it may be necessary to discontinue the medication entirely.

• Hepatic Impairment: There are no specific recommendations available regarding the use of this medication in patients with impaired liver function.

Pharmacology:

Mechanism of Action:

The mechanism of action of Azathioprine is not yet fully understood, however, it could be linked to its ability to block the production of purines and impede the function of B and T cells.

Azathioprine breaks down into 6-thioguanine triphosphate, which can trigger the death of T cells by regulating the activation of rac1 when combined with CD28. This effect may occur through rac1's influence on mitogen-activated protein kinase, NF-kappaB.

Pharmacodynamics:

Azathioprine is an immunosuppressive medication that operates by adjusting rac1 activity to trigger T cell death, in addition to other unexplained immunosuppressive effects. It has a lengthy period of activity since it is administered daily and has a narrow range of effectiveness. Patients must be informed of the potential for skin malignancies and lymphomas.

Pharmacokinetics:

Absorption:

Post oral administration Azathioprine is rapidly and almost completely absorbed from the gastrointestinal tract. The bioavailability of the drug is around 45 to 65 percent, and peak plasma concentrations are achieved within one to two hours of oral administration.

Distribution:

Azathioprine is widely distributed throughout the body, and it binds extensively to plasma proteins (approximately 30 percent). It crosses the placenta and is also found in breast milk.

Metabolism:

Azathioprine is extensively metabolized in the liver. It is converted to its active metabolites, 6-mercaptopurine (6-MP) and 6-thiouric acid (6-TU), by the enzyme thiopurine methyltransferase (TPMT). The active metabolites are responsible for the therapeutic effects of Azathioprine.

Excretion:

Azathioprine and its metabolites are excreted primarily in the urine. The elimination half-life of Azathioprine is approximately three to five hours, while the half-life of its active metabolites is around one to two hours. The drug and its metabolites are also excreted in the feces, but this route of excretion is less significant.

Toxicity:

Warnings and Precautions:

Dermatological: Limit exposure to sunlight and UV light as patients taking Azathioprine are at an increased risk of developing lymphoma and other malignancies, particularly of the skin.

Gastrointestinal: A gastrointestinal hypersensitivity reaction, which may include severe nausea and vomiting, diarrhea, rash, fever, malaise, myalgias, liver enzyme elevations, and hypotension, has been reported. This reaction typically occurs within the first few weeks of therapy and may recur on rechallenge.

Hematologic: Dose-related hematologic toxicities, including severe bone marrow suppression, leukopenia, thrombocytopenia, or anemias, including macrocytic anemia, may occur. These toxicities may be more severe in renal transplant patients during homograft rejection. Delayed hematologic suppression may also occur.

Monitoring is recommended, and prompt dose adjustment or interruption may be required. Patients with thiopurine S-methyl transferase or nucleotide diphosphatase deficiency may be at an increased risk of severe, life-threatening, and sometimes fatal myelotoxicity. Monitoring is recommended, and dose modification or alternative therapies should be considered.

Immunologic: Aggressive and sometimes fatal hepatosplenic T-cell lymphoma has been reported, particularly in patients with Crohn disease or ulcerative colitis, and in adolescent or young adult males. Patients are at an increased risk of bacterial, viral, fungal, protozoal, reactivation of latent infections, and opportunistic infections, which may be serious or fatal. Progressive multifocal leukoencephalopathy (PML) associated with JC virus infection, including fatalities, has been reported. Consider diagnosing PML with new onset neurological manifestations. Adjusting the amount of immunosuppression and weighing the risk of reduced immunosuppression in transplant patients should be considered.

Malignancies: Patients taking Azathioprine are at an increased risk of post-transplant malignancies, predominantly skin cancer, reticulum cell, or lymphomatous tumors. The risk of lymphomas may be increased with aggressive treatment with immunosuppressive drugs. Maintain immunosuppression at the lowest effective levels. Acute myelogenous leukemia and solid tumors have been reported in patients with rheumatoid arthritis.

Reproductive: Azathioprine can cause fetal harm. It should be avoided in pregnant patients whenever possible, and administration during pregnancy should not occur without carefully weighing the risks versus benefits.

Contraindications:

Azathioprine is contraindicated in the following conditions:

• Known history of allergy to any drug components.

• Pregnant women with rheumatoid arthritis.

• Along with the drug Febuxostat.

• Rheumatoid arthritis patients who have been on therapy with drugs including Melphalan, Cyclophosphamide, Chlorambucil melphalan, or any drug belonging to this class as it may potentiate the risk of development of tumors.

Other Specifications:

Azathioprine in Pregnant Women: Azathioprine is classified as a pregnancy category D drug, which means that there is evidence of potential risk to the developing fetus, but the benefits of the drug may outweigh the risks in certain situations. Azathioprine should be used with caution during pregnancy and only if the potential benefits to the mother outweigh the potential risks to the fetus. It is recommended that women who are pregnant or planning to become pregnant discuss the risks and benefits of taking Azathioprine with their healthcare provider.

Azathioprine in Lactating Women: It is recommended that women who are taking Azathioprine should not breastfeed their infants. If a woman must take Azathioprine while breastfeeding, close monitoring of the infant for potential adverse effects is recommended.

Azathioprine in Geriatrics: Azathioprine is cleared from the body primarily through the kidneys, and the pharmacokinetics of the drug may be altered in geriatric patients due to changes in renal function. Geriatric patients may also be more susceptible to adverse effects. Close monitoring of geriatric patients taking Azathioprine is recommended, and dosage adjustments may be necessary based on renal function.