IMMUNOSUPPRESSANTS AZATHIOPRINE

Chemical structure: Azathioprine, a mercaptopurine analog of adenine and hypoxanthine, was developed in the 1950s as an antineoplastic agent.

Chemical structure:    

Physical Properties: Azathioprine ,is available in tablet form for oral administration. Its molecular weight is 277.26 and it is insoluble in water.

Pharmacodynamics: Mechanism of action: It is a prodrug that is converted first to 6-mercaptupurine (6-MP) which in turn can be converted to 6- mercaptopurine nucleotides leading to an inhibition of denovo purine synthesis.

Pharmacological effects: Azathioprine is antiproliferative and affects predominantly rapidly dividing cells such as precursor cells in the bone marrow. Azathioprine has strong anti-inflammatory properties. It reduces the numbers of circulating monocytes by inhibition of proliferation.

Pharmacokinetics: Absorption: Rapidly absorbed orally within 1-2 hours after administration Distribution:Distributed in all tissues but does not cross the blood–brain barrier.

Metabolism: Three enzymes play major roles in the metabolism of azathioprine and mercaptopurine 1-     xanthine oxidase(XO) 2-     thiopurine methyltransferase (TPMT) 3- purine pathway salvage enzyme hypoxanthine–guanine phosphoribosyltransferase (HGPRT). Azathioprine is initially converted in the liver to mercaptopurine by an undefined process.

Metabolism:

Excretion: The parent drug and its metabolites are excreted by the kidney

Uses: Azathioprine is now widely used as an adjunctive immunosuppressive agent in patients receiving solid-organ transplants, and in rheumatology, dermatology, and gastroenterology as an immunosuppressant and a corticosteroid-sparing agent.

Contraindications: Azathioprine should not be given to: 1- women of child bearing potential 2- pregnant women 3- lactating mothers 4- Pts. who have shown hypersensitivity to the drug

Adverse Effects: 1-Hematopoietic toxicity, including neutropenia, anemia, and thrombocytopenia, is the most common dose-limiting adverse effect. 2-Liver adverse effects are the second most common 3- increased incidence of neoplasia and opportunistic infections.

Drug Interactions: 1-Use with Allopurinol: The XO pathway is inhibited by Allopurinol. Patients receiving azathioprine and allopurinol concomitantly should have a dose reduction of azathioprine to approximately 1/3 to 1/4 the usual dose.

Drug Interactions: 2-Derivatives of benzoic acid can inhibit the TPMT pathway. 3-sulfasalazine and salicylic acid derivatives inhibit TPMT activity and can therefore augment azathioprine action.

Drug Interactions: 4-Use with Other Agents Affecting Myelopoesis: Drugs which may affect leukocyte production, including co-trimoxazole, may lead to exaggerated leukopenia, especially in renal transplant recipients.

Pharmacutical formulations: Brand name:Imuran AZASAN® Tablets, USP are available in: 25 mg, oval-shaped, yellow, scored tablets.

Mycophenolate Mofitel Azathioprine DRUG USES ADVERSE EFFECTS Cyclosporine prevention of graft rejection renal dysfunction, hepatotoxicity , HTN,anaphylaxis. Tacrolimus prevent rejection in transplant. nephrotoxicity, neurotoxicity Sirolimus reduce rejection episodes Haematopoietic toxicity & hypertriglyceridemia. Mycophenolate Mofitel Solid organ transplant. Azathioprine solid-organ transplantation& rheumatology, Hematopoietic toxicity Liver adverse effects and allergies.