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):
i. Azathioprine
ii. Myclophenolate Mofetil
iii. Leflunomide

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

13. 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

14. Examples
• Prednisolone
• Methyl prednisolone

15. Mechanism
• Modify cellular functions rather than direct
cytotoxicity

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

17. Adverse Drug Reactions
• ??

18. Calcineurin Inhibitors

19. T4 cell activation
• 2 signals req

20. Calcineurin Action

21. Co-stimulatory signal

22. • When both signals are prst T cell gets
activated

24. Calcineurin effect

25. 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%).

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

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

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

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

30. 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

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

32. Calcineurin inhibitors
do not affect B cell activation

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

34. Mechanism
• Blocks the ‘Mammalian Target of Rapamycin’
(mTOR).

35. mTOR inhitotrs

36. 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.

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

38. ADR: Sirolimus
• Thrombocytopenia

39. • Sirolimus
also inhibits B cell activation
• Not nephrotoxic

40. Purine synthesis
inhibitors/Antimetabolites

41. 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

42. 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

43. 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)

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

45. 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

46. 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

47. Drugs affecting Co-stimulatory signal

48. Co-stimulatory signal

49. 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.

50. Abatacept

51. IL -2 receptor antagonists
• Daclizumab
• Basilixizumab
• CD25 Antibody

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

53. CD3 molecule

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

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

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

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

58. All drugs mech of action

59. 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

60. Thank you!