For Pharamcology students

1. Immunosuppressive agents and their role in organ transplantation
PC-660
Subject teacher: Dr. B.V.S Lakshmi
Presented by: Aditya Ajit Singh
Department of Pharmacology and
Toxicology
Reg. no. : PC/2019/212

2. General Introduction
• These are drugs that suppress immune responses.
• These drugs are useful in case of autoimmune disorders.
• They have capability of suppressing both humoral as well as cell mediated immunity.
• Highly successful in Organ Transplantation process.

3. Drugs Classification
1. Calcineurin inhibitors
(Specific T-cell inhibitors)
Cyclosporine (Ciclosporin), Tacrolimus
2. m-TOR inhibitors
Sirolimus, Everolimus
3. Antiproliferative drugs (Cytotoxic drugs)
Azathioprine, Methotrexate,
Cyclophosphamide, Chlorambucil,
Mycophenolate mofetil (MMF)
4. Glucocorticoids
Prednisolone and others
5. Biological agents
(a) TNFα inhibitors: Etanercept,
Infliximab, Adalimumab
(b) IL-1 receptor antagonist: Anakinra
(c) IL-2 receptor antagonists: Daclizumab,
(anti CD-25 antibodies) Basiliximab
(d) Anti CD-3 antibody: Muromonab CD3
(e) Polyclonal antibodies: Antithymocyte
antibody (ATG), Rho (D) immune globulin.

4. Immunological Targets at a glance!

5. Calcineurin Inhibitors
Cyclosporine
• It is a cyclic polypeptide with 11 amino acids and obtained from the
fungus Tolypolcadium inflatum
• It profoundly and selectively inhibit T cell proliferation also
synthesis and sensitivity to Interleukins is inhibited.
• Plasma life is 27 hrs.
• Dose is 50mg
Uses:
• Severe Rheumatoid Arthritis
• Uveitis
• Graft rejection reaction (Renal, hepatic, bone marrow transplant)
Drug interactions/Pharmacokinetics:
• Absorption from GIT is only 20-30%
• Interacts with CYP3A4 inhibitors like antifungals

6. Calcineurin Inhibitors
Tacrolimus
• Tacrolimus is called FK 506
• It is a macrolide derived from soil bacterium
called Streptomyces tsukabaensis
• 50-100 times more potent than Cyclosporine
• Dose is 5mg
Uses:
• Fistulating Crohn’s disease
• Atopic Dermatitis
• Autoimmune and graft rejection reactions
(particularly liver as absorption dosen’t
depend on bile)
Drug interactions/Pharmacokinetics:
• Binds to α glycoprotein, absorption from GIT is variable
• Enzyme inhibitor of CYP450 enzyme

7. Side effects
• Hypertension
• Hirsutism
• Gum Hyperplasia
• Hyperuricaemia ( More seen in Cyclosporine)
• Diabetes ( More with Tacrolimus)
Hyperplasic gum Classic Hirsutism

8. m-TOR Inhibitors
• It is a macrolide antibiotic like Tacrolimus
• The MOA remains the same only difference being binding to a different kinase molecule
• Sirolimus arrests the immune response at a later stage than Cyclosporine
• Well absorbed orally, but Fatty meal reduces absorption
• The side effects remain similar

9. Mechanism of Action

10. Antiproliferative drugs
Azathioprine
• It is a purine antimetabolite
• Selectively being up taken by immune cells, it gets converted to active
metabolites 6-MP
• Further this metabolite is transformed and blocks DNA synthesis and cell
proliferation of T cells
• Dose is 1-2mg/kg
Uses:
• Prevention of graft rejection (Particularly renal)
• Inflammatory bowel disease
Methotrexate
• It is a folate antagonist
• Prevents cytokine production and
suppresses cellular immunity
Uses:
• Rheumatoid Arthritis
• Psoriasis
• Pemphigus
Pemphigus

11. Antiproliferative drugs
Cyclophosphamide
• Marked effect on B cells and humoral
immunity
• Particularly used for marrow transplantation
• Reserve drug for Rheumatoid arthritis
• Dose is 10mg
Mycophenolate mofetil
• Prodrug, active form is mycophenolic acid
• Inhibits ionosine monophosphate dehydrogenase, thus guanosine nucleotides for
synthesis of B and T cells are not formed
• Half life is 16 hrs
• Dose is 1 g oral
Glucocorticoids
• Anti inflammatory in nature
• Particularly inhibit MHC expression in T cells
Drug interactions/Pharmacokinetics:
• Given orally and through i.v route
• Metabolite acrolein causes bladder cancer
Drug interactions/Pharmacokinetics:
• Well absorbed orally
• Interaction with antacids retards absorption

12. Biological agents
TNF-α INHIBITORS:
Etanercept
• Fusion protein of TNF receptor and Fc portion of IgG1 antibody
• Prevents activation of macrophages and T cells
• Used for ankylosing spondylitis
Infliximab and Adalimumab
These are monoclonal antibodies
Both inhibit TNF-α activation
Used in spondilytis

13. Biological agents
(Interleukin Inhibitors)
Anakinra
• It is a IL-1 receptor antagonist
• Selectively inhibits the binding of IL-1 to its receptor
• It is used in Rheumatoid Arthritis
Daclizumab and Infliximab
• These antibodies are directed to CD-25 molecules
• Acts as an IL-2 receptor antagonist
• Half life of Daclizumab is 3 weeks and that of Infliximab is 1 week

14. Anti CD3 antibody:
Muromonab CD3
• It is a murine antibody
• Binds to CD3 antigen and subsequently obstruct MHC complex binding to helper T cells
• Oldest discovered antibody
• Used for acute transplant reactions
• Causes cytokine release syndrome associated to chills and fever
• Dose 10mg/kg i.v
Polyclonal antibodies
• Includes two drugs : Antithymocyte globulin(ATG) and Anti D immunoglobulin
• ATG is obtained from purified rabbit plasma, binds to T lymphocytes and depletes them
• Anti D immunoglobulin is human IgG antibody against Rh(D) antigen
• Both drugs are hardly used for organ transplant
Biological agents

15. Immunosuppression and Organ transplantation
Induction regimen:
1. Given pre-operative just before surgery and post
transplant for 2-12 weeks.
2. Triple therapy of cyclosporine/tacrolimus/sirolimus +
prednisolone + MMF/Azathioprine
3. Combination of sirolimus + prednisolone + MMF avoids
renal toxicity
Maintenance regimen:
1. Given for prolonged periods
2. Therapy includes cyclosporine/tacrolimus, sirolimus,
prednisolone, azathioprine/ MMF
3. Nephrotoxicity generally seen in cyclosporine and
tacrolimus, thus after a year cyclosporine is dropped
Antirejection regimen:
1. Given to suppress an acute rejection reaction
2. In case of no response, Muromonab CD3 is given as
rescue therapy
3. If maintenance therapy is not given, its addition can treat
acute rejection reactions
Adverse effects:
1. Increased risk of bacterial, viral, fungal and other
opportunistic infections
2. Leads to development of melanoma and lymphoma after
a long latency

16. Summary
• Immunosuppressive drugs are used to treat variety of autoimmune disorders and other diseases
• Recently, role of these drugs have been defined and included for management of COVID-19 Infection,
owing to their potential to alleviate ‘cytokine storm’
• These drugs are well tolerated with minimums side effects, but problems related to opportunistic are deadly
• Maintenance therapy is very important for treating graft rejection reactions
• Prolonged use can lead to cancer of blood cells

17. References
1. K. D. Tripathi, Essentials of Medical Pharmacology, 8th Edition, Page no: 885-891, Jaypee Brothers
Medical Publishers (P) LTD, New Delhi, 2015.
2. Dale, M M, H P. Rang, and Maureen M. Dale. Rang & Dale's Pharmacology, Page no: 317-329 .
Edinburgh: Churchill Livingstone, 2007.
3. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, Thirteenth Edition, Page no: 1005-
1031.
4. Satoskar, Kale, Bhandarkar's Pharmacology and pharmacotherapeutics. Chapter XV.