Immunosuppressants.pptx

Pharmacology of Immunosuppressant drugs

1. Immunosuppressant Drugs Dr KG Bandekar MD (Pharmacology)

2. Intro What are Immunosuppressant Drugs? Why are they required?

3. Autoimmunity Activation of self-reactive T and B lymphocytes that generate cell-mediated or humoral immune responses directed against self antigens. Ref Katzung

4. Mechanisms

5. 1. Molecular mimicry Rheumatic fever following Streptococcus infection Heart damage : immune response directed against streptococcal antigens shared with heart muscle. The suggested viral etiology of autoimmune diseases has been ascribed to immune responses ( both cell-mediated and humoral ) directed against virus epitopes that mimic self antigens.

6. 2. Inappropriate expression of class II MHC molecules On the membranes of cells that normally do not express class II MHC ( eg , islet beta cells) Increased expression of MHC II may increase presentation of self peptides to T helper cells

7. Classification

8. Drugs & Mechanism

9. A. Inhibitors of cytokine ( IL-2 ) production or action: 1) Calcineurin inhibitors: Cyclosporine & Tacrolimus 2) PSI ( Proliferation signal inh ) or mTOR Inhibitors: Sirolimus B) Inhibitors of cytokine gene expression: Corticosteroids

10. C. Inhibitors of purine or pyrimidine synthesis ( Antimetabolites ): Azathioprine Myclophenolate Mofetil Leflunomide

11. D. Immunosuppressive antibodies that block T cell surface molecules involved in signaling immunoglobulinsantilymphocyte globulins (ALG). Antithymocyte globulins (ATG). Rho (D) immunoglobulin. Basiliximab Daclizumab Muromonab

12. Glucocorticoids : As Immunosuppressants Most commonly used immunosuppressant First line immunosuppressive drugs for solid organ & hematological stem cell transplant recipients Treatment of graft rejection and graft versus host disease (GVHD), Rheumatoid arthritis

13. Examples Prednisolone Methyl prednisolone

14. Mechanism Modify cellular functions rather than direct cytotoxicity

15. Mechanism Inhibition of the production of prostaglandins, leukotrienes , histamine, bradykinin and PAF. Decrease chemotactic activity of neutrophils and monocytes . Sequestration of lymphocytes in lymphoid tissue resulting in lymphopenia . By inhibiting IL-1 production, these drugs cause a decrease in IL-2 and IFN γ production Continuous administration can increase the catabolism of IgG .

16. Adverse Drug Reactions ??

17. Calcineurin Inhibitors

18. T4 cell activation 2 signals req

19. Calcineurin Action

20. Co-stimulatory signal

21. When both signals are prst T cell gets activated

22. Calcineurin effect

23. Cyclosporine Peptide antibiotic Acts at an early stage in the antigen receptor-induced differentiation of T cells and blocks their activation IV or orally: slowly and incompletely absorbed (20–50%).

24. Uses Methotrexate + cyclosporine = prophylactic regimen GVH (Less potent than Tacrolimus + Methotrexate )

25. CyclosporineToxicity Nephrotoxicity Hypertension, Hyperglycemia Liver dysfunction Hyperkalemia Seizures Hirsutism Lymphoma and other cancers (Kaposi’s sarcoma, skin cancer)

26. MCQ Cyclosporin acts by inhibiting (a) IL- 8 (b) IL -1 (c) IL -2 (d) IL- 6 Via calcineurin inhibition

27. Tacrolimus Tacrolimus is a macrolide antibiotic. Produced by Streptomyces tsukubaensis 10–100 times more potent than cyclosporine orally or iv

28. Uses: Tacrolimus Standard prophylactic agent (usually in combination with methotrexate or MMF ) for GVH disease. Topical preparation : ointment - atopic dermatitis and psoriasis . Most favored calcineurin inh for Liver & Lung transpl but avoided in Renal transp

29. Tacrolimus : Toxicity Similar to cyclosporine except …. Hirsutism , gum hyperplasia, hyperuricemia and hyperlipidemia are not caused by tacrolimus Seizures

30. Calcineurin inhibitors do not affect B cell activation

31. PSI (Proliferation signal inhibitors) Sirolimus Everolimus (derivative of sirolimus )

32. Mechanism Blocks the ‘ M ammalian T arget of R apamycin ’ ( mTOR ).

33. mTOR inhitotrs

34. Sirolimus of Uses With corticosteroids/ cyclosporine/ tacrolimus , and mycophenolate mofetil : to prevent rejection of solid organ allografts . Steroid refractory acute and chronic GVH Topically (Alone/in combination with cyclosporine) : dermatological disorders & uveoretinitis .

35. Sirolimus of Uses Sirolimus -eluting coronary stents have been shown to reduce re- stenosis with severe coronary artery disease, due to antiproliferative effects.

36. ADR: Sirolimus Thrombocytopenia

37. Sirolimus also inhibits B cell activation Not nephrotoxic

38. Purine synthesis inhibitors/ Antimetabolites

39. Mycophenolate mofetil (MMF) Inhibits inosine monophosphate dehydrogenase after conversion to its active metabolite mycophenolic acid . This enzyme is necessary for de novo synthesis of purines Selectively inhibits proliferation of lymphocytes It is used as immunosuppressant in patients who are refractory to steroids . GI disturbances and myelosuppression are major adverse effects of this drug Not Nephrotoxic

40. MCQ All of the following in r/o MMF are correct except (a) Is prodrug (b) GI Toxicity Common (c) Used in transplant recipients where other drugs are not effective (d) Highly nephrotoxic (e) Selectively inhibits proliferation of lymphocytes

41. Azathioprine Only antimetabolite that is used as immunosuppressant but not as an anticancer drug Nucleotide derivative It is a prodrug and is activated in the body to 6-mercaptopurine (anticancer drug). Lacks anticancer properties Major toxic effect is bone marrow suppression . Its dose should be reduced if allopurinol is used concurrently because 6-MP is metabolized by xanthine oxidase .( allopurinol inhibits xanthine oxidase ….used in gout )

42. Anticancer drugs as immunosuppressants Cyclophosphamide , Chlorambucil Methotrexate ( Mtx ) Cyclophosphamide and chlorambucil are used in childhood nephrotic syndrome. Cyclophosphamide is also used in - SLE and Wegner’s granulomatosis .

43. MCQ 50 yr male patient underwent renal transplant for which a nucleotide derivative was prescribed … (a) Allopurinol (b) Cyclophosphamide (c) Azathioprine (d) Cytarabine (e) 5FU Also nucleotides but used in cancer treatment

44. Mtx Methotrexate has 50,000 times higher affinity for dihydrofolate reductase than the normal substrate DH FA. – folate antagonist Depresses cytokine production Anti-inflammatory Use – Rheumatoid arthritis, psoriasis

45. Solution 4.1 kdt Since Mtx binds to the same site of DHFRase as the endogenous metabolite DHFA, it will act as a competitive inhibitor. However, because the binding affinity of Mtx for the enzyme is 50,000 times greater, even excess DHFA will not be able to displace it from the enzyme and nonequilibrium type of inhibition will be produced. b. Folic acid administered as a drug will not be able to counteract Mtx toxicity because it will not be converted to the active coenzyme form THFA. On the other hand, folinic acid will supply readymade active coenzyme THFA and will be able to overcome Mtx toxicity.

46. Drugs affecting Co-stimulatory signal

47. Co-stimulatory signal

48. Co-stimulation inhibitor Certain costimulatory molecules are present on the surface of T cells as well as antigen presenting cells (APCs). Interaction of these molecules is necessary for activation of T cells. Abatacept and belatacept act by inhibiting CD 80 and CD 86 costimulatory molecules present on APC. Abatacept is used in severe rheumatoid arthritis resistant to DMARDs. Belatacept is used for prevention of kidney transplants rejection.

49. Abatacept

50. IL -2 receptor antagonists Daclizumab Basilixizumab CD25 Antibody

51. Muromonab Anti-CD3 Antibody Murine Mab Use: Steroid resistant Acute transplant

52. CD3 molecule

53. Mechanism of action:Muromonab Obstruction to..MHCII –Ag complex to TCR binding No Ag recognition Depletion of T cell

54. Anakinra IL-1 receptor antagonist Inhibitor is an inhibitor of IL-1 being investigated for use in septic shock and RA.

55. Polyclonal Ab Anti thymocyte globulin (ATG) Anti-D immune globulin

56. ATG Antibodies against many Ag on T4 cells HLA Ag T4 Cell lysis

57. All drugs mech of action

58. MCQ Which of the following immunosuppressant/s is/are Co-stimulation inhibitor/s (a) Daclizumab (b) Muromonab (c) Etanercept (d) Abatacept (e) Both a and c

59. Thank you!