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Immunosuppressant drugs by Pankaj Maurya
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 ā MPL 201T
SCHOOL OF PHARMACEUTICAL AND HEALTH CARE SCIENCES
3. Syllabus
Module 3 :- Chemotherapy
ā¢ Drugs used in Protozoal Infections
ā¢ Drugs used in the treatment of Helminthiasis
ā¢ Chemotherapy of cancer
ā¢ Immunopharmacology
ā¢ Cellular and biochemical mediators of inflammation and
immune response.
ā¢ Allergic or hypersensitivity reactions.
ā¢ Pharmacotherapy of asthma and COPD.
ā¢ Immunosuppressants and Immunostimulants
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4. Introduction
ā¢ Immunosuppressant drugs inhibit cellular/humoral or
both immune response and have their major use in
organ transplantation and autoimmune diseases.
ā¢ Steroids were the first immunosuppressant identified,
but side effects limited its use.
ā¢ Azathioprine was identified in 1960, but it was the
discovery of cyclosporin in 1980.
ā¢ These drugs have met high degree of success in
organ transplant and autoimmune diseases.
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10. 10/38
ā¢ Cyclosporine is a cyclic polypeptide with 11 amino acids obtained from a
fungus and introduced in 1997.
ā¢ Cyclosporine is a second line drug in autoimmune diseases, like severe
rheumatoid arthritis, uveitis, bronchial asthma, inflammatory bowel
disease, dermatomyositis, etc
ā¢ Used in organ transplantation:- Kidney, liver, bone marrow, and other
transplant.
ā¢ It selectively inhibits T lymphocyte proliferation , IL-2 and other cytokine
production.
ā¢ Cyclosporine is the most effective drug for prevention and treatment of
graft rejection reaction.
ā¢ 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
12. Pharmacokinetics
ā¢ It is effective by both oral and IV route.
ā¢ 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)
ā¢ Excretion of the metabolites is through the biliary route, with only a small
fraction of the parent drug appearing in the urine.
ā¢ Plasma half-life is biphasic 4-6 hrs and 12-18 hrs.
Adverse effects
ā¢ Nephrotoxicity
ā¢ Hepatotoxicity
ā¢ Gum hypertrophy
ā¢ Hypertension
ā¢ Hyperlipidemia
ā¢ Osteoporosis
ā¢ Seizures
Cyclosporine
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13. Tarcolimus
ā¢ Tacrolimus (FK506) This immunosuppressant is chemically different from
cyclosporine, but has the same mechanism of action.
ā¢ It is generally ~100 times more potent than cyclosporine.
ā¢ Tacrolimus may be useful in patients whose rejection reaction is not suppressed
by cyclosporine.
ā¢ It is particularly valuable in liver transplantation because its absorption is not
dependent on bile and it is also used in renal transplantation.
Pharmacokinetics
ā¢ Tacrolimus is administered orally as well as by i.v infusion. Oral absorption
decreased by food.
ā¢ It is metabolized by CYP3A4 and excreted in bile.
ā¢ Plasma half-life is 12 hrs.
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16. Sirolimus
ā¢ Sirolimus is a macrolide antibiotic.
ā¢ Earlier named as Rapamycin.
ā¢ It binds to the same FKBP as tacrolimus, but the sirolimus-FKBP complex
inhibits another kinase called āmammalian target of rapamycinā (mTOR), and
does not interact with calcineurin.
ā¢ mTOR is an important for proliferation and differentiation of T-cells.
Pharmacokinetics
ā¢ Sirolimus is absorbed orally, but fatty meal reduces absorption.
ā¢ It is metabolized by CYP3A4 and excreted in bile.
ā¢ Plasma half-life ~60 hrs.
Adverse effects
ā¢ Liver damage.
ā¢ Diarrhoea.
ā¢ Pneumonitis
ā¢ Hyperlipidemia 16/38
18. Everolimus
ā¢ It is similar to sirolimus in mechanism, clinical efficacy, doses, toxicity and
drug interactions, but is better absorbed orally and has more consistent
bioavailability.
ā¢ Plasma half-life ~40 hrs.
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20. Azathioprine
ā¢ It is a prodrug of mercaptopurine which is a purine analog.
ā¢ CMI is primarily depressed.
ā¢ The most important application of azathioprine is prevention of renal and other
graft rejection.
ā¢ Less effective than cyclosporine and used in patients developing cyclosporine
toxicity.
ā¢ It is also used in lower doses (1ā2 mg/kg/day) for rheumatoid arthritis and
Inflammatory bowel disease.
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23. Methotrexate
ā¢ Methotrexate (Mtx) is a folate antagonist.
ā¢ 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.
ā¢ It is a potent immunosuppressant and depresses cytokine production.
ā¢ It has antiinflammatory property.
Pharmacokinetics
ā¢ Absorbed orally, 50% plasma protein bound.
ā¢ Little metabolized and largely excreted unchanged in urine.
Adverse effects
ā¢ Cardiotoxicity.
ā¢ Bone marrow suppression.
ā¢ Alopecia.
ā¢ Stomatitis.
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24. Cyclophosphamide
ā¢ Cyclophosphamide has more marked effect on B cells and humoral immunity.
ā¢ Utilized in bone marrow transplantation.
Pharmacokinetics
ā¢ I.V route is more preferred.
ā¢ Cyclophosphamide is minimally protein bound but some of its metabolites are
more than 60% protein bound.
ā¢ Plasma half life 3-4 hrs.
ā¢ Clearance of CYC is decreased in patients with reduced renal function
Adverse effects
ā¢ Alopecia.
ā¢ High fever.
ā¢ Stomatitis.
ā¢ Loss of appetit.
ā¢ Bleeding gum. 24/38
25. Chlorambucil
ā¢ Chlorambucil has relatively weak immunosuppressant action which is sometime
utilized in autoimmune diseases and transplant maintenance regimens.
ā¢ It is an aromatic nitrogen mustard derivative and alkylating agent.
ā¢ Chlorambucil is probably mutagenic and teratogenic in humans.
ā¢ Chlorambucil produces human infertility.
Pharmacokinetics
ā¢ Well absorbed orally.
ā¢ Plasma Half-life 1-1.5 hrs.
Adverse effects
ā¢ Nausea.
ā¢ Vomiting.
ā¢ Diarrhea.
ā¢ Tremors.
ā¢ 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
ā¢ It is a newer immunosuppressant.
ā¢ It is a semi synthetic derivative of mycophenolic acid.
ā¢ It is an inhibitor of inosine monophosphate dehydrogenase.
Pharmacokinetics
ā¢ Rapidly absorbed orally.
ā¢ Half-life is ~16hr.
Adverse effects
ā¢ Vomiting
ā¢ Diarrhoea.
ā¢ Leucopenia.
ā¢ Gastrointestinal disturbances.
ā¢ Hypertension.
ā¢ Bone marrow suppression.
ā¢ Anorexia. 27/38
30. Prednisolone
ā¢ Nonspecific anti-inflammatory that interrupts multiple steps in immune
activation.
ā¢ Highly effective for prevention of rejection.
ā¢ Many adverse-effects long-term.
ā¢ Used for allergic, inflammatory, autoimmune diseases and in malignancies.
ā¢ Used in combination with other Immunosuppressant drugs.
Pharmacokinetics
ā¢ Absorbed and are effective by the oral route.
ā¢ Half-life is ~1.5hrs.
Adverse effects
ā¢ Hyperlipidemia.
ā¢ Hyperglycemia.
ā¢ Poor wound healing.
ā¢ Peptic ulcers. 30/38
32. Muromonab CD3 ( Anti CD-3 antibody)
ā¢ It is a murine monoclonal antibody that is synthesized by hybridoma technology
ā¢ It is used in treatment of acute rejection of renal allograft, etc.
ā¢ It is used to deplete T-cells from donor bone marrow prior to transplantation.
ā¢ Use as second-line agent when cyclosporine and glucocorticoids fail.
Pharmacokinetics
ā¢ The antibody is administered intravenously.
ā¢ The antibody is extensively metabolized and predominantly excreted in the bile.
Adverse effects
ā¢ Anaphylactoid reactions.
ā¢ High fever, chills.
ā¢ Seizures.
ā¢ Cerebral edema.
ā¢ 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
ā¢ Both agents have been approved for prophylaxis of acute rejection in
renal transplantation.
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35. DacliIzumab
ā¢ It is a highly humanized chimeric monoclonal anti CD-25 antibody.
ā¢ Combined with glucocorticoids, calcineurin antagonists and/or
azathioprine/MMF.
ā¢ It is used to prevent renal and other transplant rejection reaction.
Pharmacokinetics
ā¢ DacliIzumab antibodies are given intravenously.
ā¢ Serum half-life is about 20 days.
ā¢ Blockade of the receptor is 120 days.
Adverse effects
ā¢ Gastrointestinal disorders.
ā¢ Anaphylactic reactions.
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36. Basilizumab
ā¢ This is another anti CD-25 antibody with higher affinity for the IL-2
receptor.
ā¢ Clinical use of basiliximab is similar to that of daclizumab.
ā¢ It is ten-fold more potent than daclizumab.
Pharmacokinetics
ā¢ Basilizumab antibodies are given intravenously.
ā¢ Serum half-life is about 7 days.
Adverse effects
ā¢ Gastrointestinal disorders.
ā¢ Anaphylactic reactions.
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37. Mechanism of action
Both Daclizumab and Basiliximab are anti-CD25 antibodies.
Both bind to the É-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
ā¢ Tripathi KD. Essentials of Medical Pharmacology. Jaypee Brothers Medical
Publishers. 2015:878-885.
ā¢ Elion GB. The pharmacology of azathioprine. Annals of the New York
Academy of Sciences. 1993 Jun;685(1):401-7.
ā¢ Zhou S. Clinical pharmacogenomics of thiopurine S-methyl transferase. Current
clinical pharmacology. 2006 Jan 1;1(1):119-28.
ā¢ 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.
ā¢ Grochow LB, Colvin M. Clinical pharmacokinetics of cyclophosphamide.
Clinical pharmacokinetics. 1979 Oct 1;4(5):380-94.
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