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Submitted by: Pankaj Kumar Maurya
M.Pharm ( Pharmacology)
Roll No. 1888024002
Submitted to: Dr. Saurabh Sharma
Head of the...
Contents
• Syllabus
• Introduction
• Cascade of immune response
• Classification of immunosuppressant agents
• References
...
Syllabus
Module 3 :- Chemotherapy
• Drugs used in Protozoal Infections
• Drugs used in the treatment of Helminthiasis
• Ch...
Introduction
• Immunosuppressant drugs inhibit cellular/humoral or
both immune response and have their major use in
organ ...
Cascade of immune response
5/38
Cascade of immune responses
6/38
Classification of immunosuppressant agents
1. Calcineurin inhibitors
Cyclosporine , Tacrolimus.
2. m-TOR inhibitors
Siroli...
Classification of immunosuppressant agents
5. Biological agents.
(a) Anti CD-3 antibody: Muromonab CD3.
(b) IL-2 receptor ...
Calcineurin inhibitors
9/38
10/38
• Cyclosporine is a cyclic polypeptide with 11 amino acids obtained from a
fungus and introduced in 1997.
• Cyclospo...
Mechanism of action
11/38
Pharmacokinetics
• It is effective by both oral and IV route.
• It is metabolized by microsomal enzyme CYP3A4 in the liver...
Tarcolimus
• Tacrolimus (FK506) This immunosuppressant is chemically different from
cyclosporine, but has the same mechani...
Tarcolimus
Adverse effects
• Neurotoxicity.
• Gastrointestinal disturbances.
• Tremors.
• Alopecia
• Diarrhoea.
14/38
m-TOR inhibitors
15/38
Sirolimus
• Sirolimus is a macrolide antibiotic.
• Earlier named as Rapamycin.
• It binds to the same FKBP as tacrolimus, ...
Mechanism of action
17/38
Everolimus
• It is similar to sirolimus in mechanism, clinical efficacy, doses, toxicity and
drug interactions, but is bet...
Antiproliferative drugs
19/38
Azathioprine
• It is a prodrug of mercaptopurine which is a purine analog.
• CMI is primarily depressed.
• The most import...
Mechanism of action
HPRT = Hypoxanthine phosphoribosyl transferase.
TPMT = Thiopurine S-methyltransferase
21/38
Pharmacokinetics
• Well absorbed orally.
• Plasma Half-life 5 hrs.
Adverse effects
• Bleeding gums.
• Chest pain.
• Fever ...
Methotrexate
• Methotrexate (Mtx) is a folate antagonist.
• It is Used as a first line drug in many autoimmune diseases li...
Cyclophosphamide
• Cyclophosphamide has more marked effect on B cells and humoral immunity.
• Utilized in bone marrow tran...
Chlorambucil
• Chlorambucil has relatively weak immunosuppressant action which is sometime
utilized in autoimmune diseases...
Mechanism of Action
Chlorambucil interferes with DNA replication
Induces cellular apoptosis via the accumulation of cytoso...
Mycophenolate mofetil
• It is a newer immunosuppressant.
• It is a semi synthetic derivative of mycophenolic acid.
• It is...
Mechanism of Action
28/38
Glucocorticoids
29/38
Prednisolone
• Nonspecific anti-inflammatory that interrupts multiple steps in immune
activation.
• Highly effective for p...
Biological agents
31/38
Muromonab CD3 ( Anti CD-3 antibody)
• It is a murine monoclonal antibody that is synthesized by hybridoma technology
• It ...
Mechanism of action
Muromonab-CD3 binds to CD3 antigen which obstructs the approach of MHCII-an
tigen complex to the T-cel...
IL-2 receptor antagonists
• Both agents have been approved for prophylaxis of acute rejection in
renal transplantation.
34...
DacliIzumab
• It is a highly humanized chimeric monoclonal anti CD-25 antibody.
• Combined with glucocorticoids, calcineur...
Basilizumab
• This is another anti CD-25 antibody with higher affinity for the IL-2
receptor.
• Clinical use of basilixima...
Mechanism of action
Both Daclizumab and Basiliximab are anti-CD25 antibodies.
Both bind to the ɑ-chain of the interleukin-...
References
• Tripathi KD. Essentials of Medical Pharmacology. Jaypee Brothers Medical
Publishers. 2015:878-885.
• Elion GB...
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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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