definition classification cascade of immune system

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. Contents
• Syllabus
• Introduction
• Cascade of immune response
• Classification of immunosuppressant agents
• References
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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
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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.
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5. Cascade of immune response
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6. Cascade of immune responses
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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.
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8. Classification of immunosuppressant agents
5. Biological agents.
(a) Anti CD-3 antibody: Muromonab CD3.
(b) IL-2 receptor antagonists: Daclizumab, Basiliximab.
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9. Calcineurin inhibitors
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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. Mechanism of action
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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
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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.
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14. Tarcolimus
Adverse effects
• Neurotoxicity.
• Gastrointestinal disturbances.
• Tremors.
• Alopecia
• Diarrhoea.
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15. m-TOR inhibitors
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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. Mechanism of action
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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.
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19. Antiproliferative drugs
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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.
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21. Mechanism of action
HPRT = Hypoxanthine phosphoribosyl transferase.
TPMT = Thiopurine S-methyltransferase
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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.
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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.
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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. 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. Mechanism of Action
Chlorambucil interferes with DNA replication
Induces cellular apoptosis via the accumulation of cytosolic p53
Subsequent activation of Bax, an apoptosis promoter.
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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. Mechanism of Action
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29. Glucocorticoids
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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. Biological agents
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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.
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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.
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34. IL-2 receptor antagonists
• Both agents have been approved for prophylaxis of acute rejection in
renal transplantation.
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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.
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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.
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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.
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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.
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