Immunosuppressant Drugs
Dr KG Bandekar
MD (Pharmacology)
Intro
• What are Immunosuppressant Drugs?
• Why are they required?
Autoimmunity
• Activation of self-reactive T and B
lymphocytes that generate cell-mediated or
humoral immune responses directed against
self antigens.
• Ref Katzung
Mechanisms
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.
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
Classification
Drugs & Mechanism
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
C. Inhibitors of purine or pyrimidine
synthesis (Antimetabolites):
i. Azathioprine
ii. Myclophenolate Mofetil
iii. Leflunomide
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
Immunosuppressants.pptx
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
Examples
• Prednisolone
• Methyl prednisolone
Mechanism
• Modify cellular functions rather than direct
cytotoxicity
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.
Adverse Drug Reactions
• ??
Calcineurin Inhibitors
T4 cell activation
• 2 signals req
Calcineurin Action
Co-stimulatory signal
• When both signals are prst T cell gets
activated
Immunosuppressants.pptx
Calcineurin effect
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%).
Uses
• Methotrexate + cyclosporine = prophylactic
regimen GVH
(Less potent than Tacrolimus+ Methotrexate)
CyclosporineToxicity
• Nephrotoxicity
• Hypertension,
• Hyperglycemia
• Liver dysfunction
• Hyperkalemia
• Seizures
• Hirsutism
• Lymphoma and other cancers (Kaposi’s
sarcoma, skin cancer)
MCQ
• Cyclosporin acts by inhibiting
• (a) IL- 8
• (b) IL -1
• (c) IL -2
• (d) IL- 6
• Via calcineurin inhibition
Tacrolimus
• Tacrolimus is a macrolide antibiotic.
• Produced by Streptomyces tsukubaensis
• 10–100 times more potent than cyclosporine
• orally or iv
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
Tacrolimus: Toxicity
• Similar to cyclosporine except….
• Hirsutism, gum hyperplasia, hyperuricemia
and hyperlipidemia are not caused by
tacrolimus
• Seizures
Calcineurin inhibitors
do not affect B cell activation
PSI (Proliferation signal inhibitors)
• Sirolimus
• Everolimus(derivative of sirolimus)
Mechanism
• Blocks the ‘Mammalian Target of Rapamycin’
(mTOR).
mTOR inhitotrs
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.
Sirolimus of Uses
• Sirolimus-eluting coronary stents have been
shown to reduce re-stenosis with severe
coronary artery disease, due to
antiproliferative effects.
ADR: Sirolimus
• Thrombocytopenia
• Sirolimus
also inhibits B cell activation
• Not nephrotoxic
Purine synthesis
inhibitors/Antimetabolites
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
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
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)
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.
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
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
Drugs affecting Co-stimulatory signal
Co-stimulatory signal
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.
Abatacept
IL -2 receptor antagonists
• Daclizumab
• Basilixizumab
• CD25 Antibody
Muromonab
• Anti-CD3 Antibody
• Murine Mab
• Use: Steroid resistant Acute transplant
CD3 molecule
Mechanism of action:Muromonab
Obstruction to..MHCII –Ag complex to TCR
binding
No Ag recognition
Depletion of T cell
Anakinra
• IL-1 receptor antagonist
• Inhibitor is an inhibitor of IL-1 being
investigated for use in septic shock and RA.
Polyclonal Ab
• Anti thymocyte globulin (ATG)
• Anti-D immune globulin
ATG
• Antibodies against many Ag on T4 cells HLA Ag
• T4 Cell lysis
All drugs mech of action
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
Thank you!

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Immunosuppressants.pptx

  • 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
  • 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
  • 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
  • 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.
  • 19. T4 cell activation • 2 signals req
  • 22. • When both signals are prst T cell gets activated
  • 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).
  • 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.
  • 39. • Sirolimus also inhibits B cell activation • Not nephrotoxic
  • 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
  • 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.
  • 51. IL -2 receptor antagonists • Daclizumab • Basilixizumab • CD25 Antibody
  • 52. Muromonab • Anti-CD3 Antibody • Murine Mab • Use: Steroid resistant Acute transplant
  • 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

Editor's Notes

  • #44: It lacks anticancer properties because conversion to active metabolite occurs only in lymphoid cells.
  • #47: From KdT pg 47 Gen pharm competitive enz inhibibeing recycled after partial degradation….from garg pg 605 qn 6…10th edition De novo synthesis: synthesis of complex molecules from simple molecules like sugar, amino acid as opposed to their being recycled after partial degradation