The document summarizes various immunosuppressant drugs used to prevent rejection of organ transplants. It discusses calcineurin inhibitors like cyclosporine and tacrolimus, mTOR inhibitors sirolimus and everolimus, antiproliferative drugs, glucocorticoids, and biological agents. Cyclosporine inhibits T-cell activation by blocking calcineurin. Tacrolimus is more potent than cyclosporine. Sirolimus inhibits T-cell proliferation by blocking mTOR. Other drugs discussed include azathioprine, mycophenolate mofetil, methotrexate, cyclophosphamide, chlorambucil, prednisone, infliximab,

1. Dr SUMITHA. A MBBS .,MD.,
ASSISTANT PROFESSOR
PHARMACOLOGY
ACS MEDICAL COLLEGE
IMMUNOSUPPRESSANTS

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3. IMMUNOSUPPRESSANT
DRUGS
CALCINEURIN INHIBITORS
• Cyclosporine, Tacrolimus
m. TOR INHIBITORS
• Sirolimus, Everolimus
ANTIPROLIFERATIVE DRUGS
• Azathioprine, Methotrexate, Cyclophosphamide, Chlorambucil,
Mycophenolate mofetil.
GLUCOCORTICOIDS
• Prednisolone
BIOLOGICAL AGENTS
• TNFɑ Inhibitors:-Infliximab,Adalimumab
• IL-1Receptor antagonist:- Anakinra
• IL-2Receptor antagonist:- Daclizumab,Basiliximab
• Antibodies:- Muromonab CD3 4

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6. CYCLOSPORI
NE
Cyclosporine is a cyclic polypeptide with 11 amino acids,
derived from fungus
Cyclosporine is a specific inhibitor of T-cell mediated
immunity which enabled whole-organ transplantation.
It is used to prevent rejection of kidney, liver, and cardiac
allogeneic transplants.
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7. MECHANISM OF ACTION-CALCINEURIN
INHIBITORS
 Cyclosporine binds to intracellular protein
cyclophilin and this complex inhibits calcineurin
(calcium calmodulin activated phosphatase)
 Calcineurin dephosphorylates a nuclear factor of
activated T cells (NFAT)
translocates to nucleus
triggers transcription of cytokine genes –
production of IL-2 and other cytokines.
IL-2 binds to IL-2 receptor to stimulate T cell
proliferation.

8. PHARMACOKINETICS
It is effective by both oral and IV route.
Dose:10-15mg/kg/day till 1-2 weeks after transplantation ,reduced to
maintenance dose 2-6 mg/kg/day
It is metabolixed by microsomal enzyme cytochrome P450in theliver.
Excretion of the metabolites is through the biliary route, with onlya
small fraction of the parent drug appearing in theurine.
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USES
In organ transplantation:- Kidney, liver, bone marrow, and
other transplants.
Autoimmune disorders:- severe psoriasis, uveitis, atopic
dermatitis, inflammatory bowel disease and nephrotic
syndrome.
In treatment of asthma.
Rheumatoid arthritis.
Prevention and treatment of graft rejection reactions.

10. ADVERSE EFFECTS:-
Nephrotoxicity
Hepatotoxicity
Anorexia
Gum hypertrophy
Hypertension
Hyperlipidemia
Hirsutism
Osteoporosis
Tremor
Seizures

11. DRUG INTERACTIONS
 All nephrotoxic drugs
aminoglycosides,amphotericin B,NSAIDS
enhance toxicity.
 PHENOBARBITONE and Phenytoin enzyme
inducers lower its blood levels so that transplant
rejection occurs.
 CYP 3A4 inhibitors –increase bioavailability and
cause toxicity.
 Potassium supplements and K+ sparing diuretics
–hyperkalemia.

12. TACROLIMU
S
Tacrolimus , originally called FK506.
It is a macrolide derived from soil fungus Streptomyces
tsukabaensis.
It is generally 50-100 times more potent than cyclosporine.
Use:-
For prevention and graft rejection in organ transplantation
similar to cyclosporine.
Fistulating crohn disease,atopic dermatitis
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13.  PHARMACOKINETICS
orally and i.v. Infusion
metabolised by CYP 3A4,excreted in bile.
half life-12 hours
 ADVERSE EFFECTS
Diabetes,neurotoxicity,alopecia and diarrhoea.
Renal toxicity
Hypertension,hirsuitism,gum
hyperplasia,hyperuricemia less marked than
cyclosporine.

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15. SIROLIMUS ,EVEROLIMUS
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16. SIROLIMUS:
-
Sirolimus is a macrolide antibiotic.
Earlier named as Rapamycin
Mechanism of action
It binds to FKBP and this complex inhibits kinase called
mammalian target of rapamycin(m TOR)
mTOR –proliferation and differentiation of T cells activated
by IL-2 and other cytokines.
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17. PHARMACOKINETICS
Available only as oral preparation.
Rapidly absorbed, high fatty meals can decrease the
drug’sabsorption.
It is extensively bound to plasma protein.
Metabolized by cytochrome P-450 enzyme.
Plasma half-life ~60hr.
Elimination –biliary route

18. USES
Prophylaxisandtherapyofgraftrejectionreaction.
Stemcelltransplants.
Sirolimuscoatedstents–reduceincidenceofcoronaryarteryrestenosis-inhibiting
endothelialproliferation
Adverseeffects
NOTNEPHROTOXIC, SUPPRESSBONEMARROW
Hyperlipidemia
Headache
Nausea
Diarrhoea
Hypertension
Leukopenia
Thrombocytopenia 16

19. ANTIPROLIFERATIVE DRUGS
 AZATHIOPRINE
 METHOTREXATE
 CYCLOPHOSPHAMIDE
 CHLORAMBUCIL
 MYOPHENOLATE MOFETIL
 GLUCOCORTICOIDS

20. AZATHIOPRINE:
-
It is a prodrug of mercaptopurine which is a purineanalog.
It was the first drug to be used for suppression of
immune system aftertransplantation.
MECHANISM OF ACTION:
Selective uptake in to immune cells and intracellular
conversion in to active metabolite 6-mercaptopurine :
undergoes further transformation to inhibit de novo purine
synthesis and damage to DNA.
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21.  Affects differentiation and function of T cells.CMI
is primarily depressed.
USES:
Prevention of renal and graft rejection.Lower
doses(1-2 mg/kg/day) – used in rheumatoid
arthritis.Maintaining remission in inflammatory
bowel disease.

22. MYCOPHENOLAT
E MOFETIL:-
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It is a newer immunosuppressant.
It is a semi synthetic derivative of mycophenolicacid.
It is an inhibitor of inosine monophosphate dehydrogenase.
IMPD – enzyme for de novo synthesis of guanosine
nucleotides in T and B cells.
Antibody formation,cell mediated immunity and lymphocyte
proliferation are inhibited.

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24. PHARMACOKINETICS
Rapidly absorbed orally-1 gram BD orally
Half-life is~16hr
USES
 MMF+GLUCOCORTICOID+SIROLIMUS-
non nephrotoxic combination :renal transplantation
In treatment of autoimmunedisease.
In rheumatoid arthritis.
In treatment of myasthenia gravis.
Psoriasis.
Autoimmune hemolyticanaemia.
Inflammatory bowel disease.
Kidney transplantation.

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ADVERSEEFFECTS
Vomiting.
Diarrhoea.
Leucopenia.
Headache.
Gastrointestinaldisturbances.
GI bleeds

26. METHOTREXATE- depress cytokine production
and cellular immunity.anti inflammatory property.
Used in Rheumatoid
arthritis,psoriasis,Pemphigus,Myasthenia gravis.
CYCLOPHOSPHAMIDE-marked effect on B CELLS
and humoral immunity. Used in bone marrow
transplantation.
CHLORAMBUCIL: immunosupressant action.Used
in autoimmune and transplant maintenance
regimens.
GLUCOCORTICOIDS: INHIBIT MHC expression
and activation of T lymphocyte.Expression of IL s
and cytokine genes is regulated by steroids.

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28. BIOLOGICAL AGENTS
 TNF alpha Inhibitors
 IL 1 receptor antagonist -Anakinra
 IL 2 receptor antagonist –Basiliximab,Daclizumab
 Anti CD 3 antibody-muromonab
 Polyclonal antibodies-Antithymocyte globulin
Anti D immune globulin

29. Anti-TNF-α Treatments
 Etanercept – human fusion protein made of TNF-
αR2 and the Fc region of IgG1
 Subcutaneous injection
 Non-selective for tmTNF or solTNF
 Doesn’t activate complement system
 Infliximab – chimeric monoclonal antibody made
up of human Ig constant region, 2 mouse variable
regions to TNF-α
 Can trigger complement system
 Non-selective for tmTNF or solTNF
http://media.pharmacologycorner.com/wp-
content/uploads/2009/05/tnfmoa7.gif
(Brightling et al. 2008)

31. MUROMONAB-
CD3(OKT3):-
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It is a murine monoclonal antibody that is
synthesized by hybridoma technology.
It is used in treatment of acute rejection of renal
allografts, etc.
It is used to deplete T-cells from donor bone
marrow prior to transplantation.
Use as second-line agent when
cyclosporine andglucocorticoids fail.

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33. MECHANISM OF ACTION
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Muromonab-CD3 binds to CD3 antigen which obstructs
the approach of MHCII-antigen 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 tonon-lymphoid
organs.
T-cells usually return to normal within 48hrs of
discontinuation of therapy.

34. Pharmacokinetics:-
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The antibody is administered intravenously.
Theantibodyisextensivelymetabolizedandpredominantlyexcretedinthe bile.
ADVERSEEFECT
s:-
CYTOKINE RELEASE SYNDROME
 Anaphylactoidreactions.
 High fever
,chills,wheezing,malaise.
Seizures.
 Encephalopathy.
 Cerebraledema.
 Asepticmeningitis.
 Headache.

35. POLYCLONAL ANTIBODIES
Antithymocyte globulin
Anti D immune globulin
 ANAKINRA:
Recombinant human IL-1receptor antagonist prevents
IL-1 binding to its receptor –use in refractory rheumatoid
arthritis.

36. INTERLEUKIN-2
RECEPTOR
antagonist:-
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Both agents have been approved for prophylaxis of
acute rejection in renal transplantation.
IL-2 antagonist
DACLIZUMAB BASILIXIMAB

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MECHANISM OF ACTION
Both Daclizumab and Basiliximab are anti-CD25
antibodies.
Both bind to the ɑ-chainof theinterleukin-2receptoronthe
activatedT-cellsandinterferewiththeproliferationof theT- cells.
Basiliximabisten-foldmorepotentthandaclizumab.
Pharmacokinetics
DACLIZUMAB:-
Serumhalf-lifeisabout20days.
BASILIXIMAB:-
Serumhalf-lifeisabout7days.

38. IMMUNOSUPRESSION IN ORGAN
TRANSPLANTATION
INDUCTION REGIMEN
Given in perioperative period:just before transplant to about
2-12 weeks after it.
Accelerated regimen develops in first week.Acute rejection -
2-12 weeks.
Triple therapy-
cyclosporine/tacrolimus/sirolimus+prednisolone+MMF/
Azathioprine: avoids risk of renal toxicity.
MAINTENANCE REGIMEN
This is given for prolonged periods.Life long.
Cyclosporine,tacrolimus,sirolimus,prednisolone,MMF :Each
component is needed in lower doses.

39.  In case of intolerance to first line drugs,second line
drugs like cyclophosphamide,chlorambucil
,Daclizumab are substituted.
Antirejection regimen:
Given to suppress an acute rejection.Steroid pulse
therapy (methylprednisolone 0.5 -1 gm i.v. Daily for
3-5 days) is effective in majority of cases.
ADVERSE EFFECTS
Increased risk of bacterial,fungal,viral as well as
opportunistic infections.
Development of lymphomas and malignancies after
long latency.

40. THANK YOU