1. IMMUNOSUPPRESSANTS
AZATHIOPRINE

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

3. Chemical structure:

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

5. 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.

6. 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.

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

8. 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.

9. Metabolism:

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

11. 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.

12. 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

13. 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.

14. 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.

15. 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.

16. 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.

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

18. 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.