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Immunosuppressant drugs by Pankaj Maurya

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Immunosuppressant drugs by Pankaj Maurya

  1. 1. Submitted by: Pankaj Kumar Maurya M.Pharm ( Pharmacology) Roll No. 1888024002 Submitted to: Dr. Saurabh Sharma Head of the School Department Of Pharmacology IMMUNOSUPRESSANT DRUGS ADVANCED PHARMACOLOGY-II – MPL 201T SCHOOL OF PHARMACEUTICAL AND HEALTH CARE SCIENCES
  2. 2. Contents • Syllabus • Introduction • Cascade of immune response • Classification of immunosuppressant agents • References 2/38
  3. 3. Syllabus Module 3 :- Chemotherapy • Drugs used in Protozoal Infections • Drugs used in the treatment of Helminthiasis • Chemotherapy of cancer • Immunopharmacology • Cellular and biochemical mediators of inflammation and immune response. • Allergic or hypersensitivity reactions. • Pharmacotherapy of asthma and COPD. • Immunosuppressants and Immunostimulants 3/38
  4. 4. Introduction • Immunosuppressant drugs inhibit cellular/humoral or both immune response and have their major use in organ transplantation and autoimmune diseases. • Steroids were the first immunosuppressant identified, but side effects limited its use. • Azathioprine was identified in 1960, but it was the discovery of cyclosporin in 1980. • These drugs have met high degree of success in organ transplant and autoimmune diseases. 4/38
  5. 5. Cascade of immune response 5/38
  6. 6. Cascade of immune responses 6/38
  7. 7. Classification of immunosuppressant agents 1. Calcineurin inhibitors Cyclosporine , Tacrolimus. 2. m-TOR inhibitors Sirolimus, Everolimus. 3. Antiproliferative drugs Azathioprine, Methotrexate, Cyclophosphamide, Chlorambucil, Mycophenolate mofetil (MMF). 4. Glucocorticoids Prednisolone. 7/38
  8. 8. Classification of immunosuppressant agents 5. Biological agents. (a) Anti CD-3 antibody: Muromonab CD3. (b) IL-2 receptor antagonists: Daclizumab, Basiliximab. 8/38
  9. 9. Calcineurin inhibitors 9/38
  10. 10. 10/38 • Cyclosporine is a cyclic polypeptide with 11 amino acids obtained from a fungus and introduced in 1997. • Cyclosporine is a second line drug in autoimmune diseases, like severe rheumatoid arthritis, uveitis, bronchial asthma, inflammatory bowel disease, dermatomyositis, etc • Used in organ transplantation:- Kidney, liver, bone marrow, and other transplant. • It selectively inhibits T lymphocyte proliferation , IL-2 and other cytokine production. • Cyclosporine is the most effective drug for prevention and treatment of graft rejection reaction. • Cyclosporine can interact with a large number of drugs. All nephrotoxic drugs like, aminoglycosides, vancomycin, amphotericin B and NSAIDs enhance its toxicity by depressing renal function. Cyclosporine
  11. 11. Mechanism of action 11/38
  12. 12. Pharmacokinetics • It is effective by both oral and IV route. • It is metabolized by microsomal enzyme CYP3A4 in the liver (On the other hand, CYP3A4 inhibitors erythromycin, ketoconazole and related drugs inhibit its metabolism to increase bioavailability and cause toxicity) • Excretion of the metabolites is through the biliary route, with only a small fraction of the parent drug appearing in the urine. • Plasma half-life is biphasic 4-6 hrs and 12-18 hrs. Adverse effects • Nephrotoxicity • Hepatotoxicity • Gum hypertrophy • Hypertension • Hyperlipidemia • Osteoporosis • Seizures Cyclosporine 12/38
  13. 13. Tarcolimus • Tacrolimus (FK506) This immunosuppressant is chemically different from cyclosporine, but has the same mechanism of action. • It is generally ~100 times more potent than cyclosporine. • Tacrolimus may be useful in patients whose rejection reaction is not suppressed by cyclosporine. • It is particularly valuable in liver transplantation because its absorption is not dependent on bile and it is also used in renal transplantation. Pharmacokinetics • Tacrolimus is administered orally as well as by i.v infusion. Oral absorption decreased by food. • It is metabolized by CYP3A4 and excreted in bile. • Plasma half-life is 12 hrs. 13/38
  14. 14. Tarcolimus Adverse effects • Neurotoxicity. • Gastrointestinal disturbances. • Tremors. • Alopecia • Diarrhoea. 14/38
  15. 15. m-TOR inhibitors 15/38
  16. 16. Sirolimus • Sirolimus is a macrolide antibiotic. • Earlier named as Rapamycin. • It binds to the same FKBP as tacrolimus, but the sirolimus-FKBP complex inhibits another kinase called ‘mammalian target of rapamycin’ (mTOR), and does not interact with calcineurin. • mTOR is an important for proliferation and differentiation of T-cells. Pharmacokinetics • Sirolimus is absorbed orally, but fatty meal reduces absorption. • It is metabolized by CYP3A4 and excreted in bile. • Plasma half-life ~60 hrs. Adverse effects • Liver damage. • Diarrhoea. • Pneumonitis • Hyperlipidemia 16/38
  17. 17. Mechanism of action 17/38
  18. 18. Everolimus • It is similar to sirolimus in mechanism, clinical efficacy, doses, toxicity and drug interactions, but is better absorbed orally and has more consistent bioavailability. • Plasma half-life ~40 hrs. 18/38
  19. 19. Antiproliferative drugs 19/38
  20. 20. Azathioprine • It is a prodrug of mercaptopurine which is a purine analog. • CMI is primarily depressed. • The most important application of azathioprine is prevention of renal and other graft rejection. • Less effective than cyclosporine and used in patients developing cyclosporine toxicity. • It is also used in lower doses (1–2 mg/kg/day) for rheumatoid arthritis and Inflammatory bowel disease. 20/38
  21. 21. Mechanism of action HPRT = Hypoxanthine phosphoribosyl transferase. TPMT = Thiopurine S-methyltransferase 21/38
  22. 22. Pharmacokinetics • Well absorbed orally. • Plasma Half-life 5 hrs. Adverse effects • Bleeding gums. • Chest pain. • Fever or chills. • Painful urination. • Sore throat. • Swollen joints. • Bone marrow suppression. • Hepatic dysfunction. 22/38
  23. 23. Methotrexate • Methotrexate (Mtx) is a folate antagonist. • It is Used as a first line drug in many autoimmune diseases like rapidly progres sing rheumatoid arthritis, severe psoriasis, pemphigus, myasthenia gravis, uveitis, chronic active hepatitis. • It is a potent immunosuppressant and depresses cytokine production. • It has antiinflammatory property. Pharmacokinetics • Absorbed orally, 50% plasma protein bound. • Little metabolized and largely excreted unchanged in urine. Adverse effects • Cardiotoxicity. • Bone marrow suppression. • Alopecia. • Stomatitis. 23/38
  24. 24. Cyclophosphamide • Cyclophosphamide has more marked effect on B cells and humoral immunity. • Utilized in bone marrow transplantation. Pharmacokinetics • I.V route is more preferred. • Cyclophosphamide is minimally protein bound but some of its metabolites are more than 60% protein bound. • Plasma half life 3-4 hrs. • Clearance of CYC is decreased in patients with reduced renal function Adverse effects • Alopecia. • High fever. • Stomatitis. • Loss of appetit. • Bleeding gum. 24/38
  25. 25. Chlorambucil • Chlorambucil has relatively weak immunosuppressant action which is sometime utilized in autoimmune diseases and transplant maintenance regimens. • It is an aromatic nitrogen mustard derivative and alkylating agent. • Chlorambucil is probably mutagenic and teratogenic in humans. • Chlorambucil produces human infertility. Pharmacokinetics • Well absorbed orally. • Plasma Half-life 1-1.5 hrs. Adverse effects • Nausea. • Vomiting. • Diarrhea. • Tremors. • Hepatotoxicity. 25/38
  26. 26. Mechanism of Action Chlorambucil interferes with DNA replication Induces cellular apoptosis via the accumulation of cytosolic p53 Subsequent activation of Bax, an apoptosis promoter. 26/38
  27. 27. Mycophenolate mofetil • It is a newer immunosuppressant. • It is a semi synthetic derivative of mycophenolic acid. • It is an inhibitor of inosine monophosphate dehydrogenase. Pharmacokinetics • Rapidly absorbed orally. • Half-life is ~16hr. Adverse effects • Vomiting • Diarrhoea. • Leucopenia. • Gastrointestinal disturbances. • Hypertension. • Bone marrow suppression. • Anorexia. 27/38
  28. 28. Mechanism of Action 28/38
  29. 29. Glucocorticoids 29/38
  30. 30. Prednisolone • Nonspecific anti-inflammatory that interrupts multiple steps in immune activation. • Highly effective for prevention of rejection. • Many adverse-effects long-term. • Used for allergic, inflammatory, autoimmune diseases and in malignancies. • Used in combination with other Immunosuppressant drugs. Pharmacokinetics • Absorbed and are effective by the oral route. • Half-life is ~1.5hrs. Adverse effects • Hyperlipidemia. • Hyperglycemia. • Poor wound healing. • Peptic ulcers. 30/38
  31. 31. Biological agents 31/38
  32. 32. Muromonab CD3 ( Anti CD-3 antibody) • It is a murine monoclonal antibody that is synthesized by hybridoma technology • It is used in treatment of acute rejection of renal allograft, etc. • It is used to deplete T-cells from donor bone marrow prior to transplantation. • Use as second-line agent when cyclosporine and glucocorticoids fail. Pharmacokinetics • The antibody is administered intravenously. • The antibody is extensively metabolized and predominantly excreted in the bile. Adverse effects • Anaphylactoid reactions. • High fever, chills. • Seizures. • Cerebral edema. • Headache. 32/38
  33. 33. Mechanism of action Muromonab-CD3 binds to CD3 antigen which obstructs the approach of MHCII-an tigen complex to the T-cell receptor. This prevents the participation of T-cell in the immune response. The T-cells get rapidly depleted from blood, partly by cytolysis and partly by their migration to non-lymphoid organs. T-cells usually return to normal within 48hrs of discontinuation of therapy. 33/38
  34. 34. IL-2 receptor antagonists • Both agents have been approved for prophylaxis of acute rejection in renal transplantation. 34/38
  35. 35. DacliIzumab • It is a highly humanized chimeric monoclonal anti CD-25 antibody. • Combined with glucocorticoids, calcineurin antagonists and/or azathioprine/MMF. • It is used to prevent renal and other transplant rejection reaction. Pharmacokinetics • DacliIzumab antibodies are given intravenously. • Serum half-life is about 20 days. • Blockade of the receptor is 120 days. Adverse effects • Gastrointestinal disorders. • Anaphylactic reactions. 35/38
  36. 36. Basilizumab • This is another anti CD-25 antibody with higher affinity for the IL-2 receptor. • Clinical use of basiliximab is similar to that of daclizumab. • It is ten-fold more potent than daclizumab. Pharmacokinetics • Basilizumab antibodies are given intravenously. • Serum half-life is about 7 days. Adverse effects • Gastrointestinal disorders. • Anaphylactic reactions. 36/38
  37. 37. Mechanism of action Both Daclizumab and Basiliximab are anti-CD25 antibodies. Both bind to the ɑ-chain of the interleukin-2 receptor on the activated T-cells and interfere with the proliferation of the T cells. Blockade of the IL-2 receptor foils the ability of any antigenic stimulus to activate the T-cell response system. 37/38
  38. 38. References • Tripathi KD. Essentials of Medical Pharmacology. Jaypee Brothers Medical Publishers. 2015:878-885. • Elion GB. The pharmacology of azathioprine. Annals of the New York Academy of Sciences. 1993 Jun;685(1):401-7. • Zhou S. Clinical pharmacogenomics of thiopurine S-methyl transferase. Current clinical pharmacology. 2006 Jan 1;1(1):119-28. • Haubitz M, Bohnenstengel F, Brunkhorst R, Schwab M, Hofmann U, Busse D. Cyclophosphamide pharmacokinetics and dose requirements in patients with renal insufficiency. Kidney international. 2002 Apr 1;61(4):1495-501. • Grochow LB, Colvin M. Clinical pharmacokinetics of cyclophosphamide. Clinical pharmacokinetics. 1979 Oct 1;4(5):380-94. 38/38

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