Pharmacology of immunosuppressants..

1. IMMUNOSUPPRESSANTS
By : Mr. Shyam B. Doiphode
(B.Pharm IVth year)
Guided by : Miss. Nikita Takle
Government College of Pharmacy,
Amravati

2. INTRODUCTION
 inhibit cellular/humoral or both types of immune
responses
 major use in organ transplantation and autoimmune
diseases.
 used to control severe manifestations of allergic,
autoimmune and transplant-related diseases.
 there are now over 80 autoimmune diseases and several
common allergic conditions in which
immunosuppressants could play a role although they
may not be life-saving.

3. CLASSIFICATION
1.Calcineurin inhibitors (Specific T-cell inhibitors)
 Cyclosporine (Ciclosporin), Tacrolimus
2. m-TOR inhibitors
Sirolimus, Everolimus
3. Antiproliferative drugs (Cytotoxic drugs)
Azathioprine, Mycophenolate mofetil (MMF)
4. Glucocorticoids
Prednisolone and others
5. Biological agents
(a) TNFα inhibitors:
Etanercept, Infliximab,Adalimumab
(b) IL-1 receptor antagonist:
Anakinra
(c) antibody:
Muromonab CD3

4. GENERAL MECHANISM

5. 1.CALCINEURIN INHIBITORS
 Cyclosporin
 cyclic polypeptide with 11 amino acids,
 obtained from a fungus s
 electively inhibits T lymphocyte proliferation, IL-2 and
other cytokine production
 Mode of action:
enters target cells binds to cyclophilin
cyclosporine-cyclophilin complex complex then binds
to and inactivates calcineurin blocks the NFAT by
antigen decreased production of IL-2 and other
cytokines supress cell mediated immunity

6.  Pharmacokinetics:
 Given by oral,IV route
 Metabolized in liver by CYP3A4
 excreted in bile.
 The plasma t½ is biphasic 4–6 hr and 12–18 hr
 Dose: 10–15 mg/kg/day with milk or fruit juice
 maintenance dose of 2–6 mg/kg/day.

7.  Adverse effects:
 nephrotoxicity ,
 hepatotoxicity, Rise in BP ,
 hyperglycemia,
 increased suseptibility to infection
 bone marrow toxicity .
 Uses:
 autoimmune diseases, rheumatoid arthritis, uveitis,
bronchial asthma, inflammatory bowel disease,
dermatomyositis.
 To prevent and treat rejection episode of organ
transplantation: kidney, bone marrow, liver etc.

8. 2.M-TOR INHIBITORS:
SIROLIMUS:
 This new potent immunosuppressant
 earlier named Rapamycin.
Mode of action:
Binds immunophillin FKBP sirolimus-FKBP
complex inhibits ‘mammalian target of rapamycin’
(mTOR)
m-TOR is important for the proliferation and production of T-
cells activated by IL-2 and another cytokines and that results
into suppressed immune response.

9.  Pharmacokinetics
 absorbed orally, but fatty mealreduces absorption
 metabolized by CYP3A4
 bioavailability is only 15–20%.
 Elimination by the biliary route;
 t½ is ~60 hours.
 Dose: loading dose 1 mg/m2 daily
 Adverse effects:
 suppress bone marrow
 thrombocytopenia.
 Rise in serum lipids is common.
 diarrhoea, liver damage and pneumonitis.
 Uses
 to prevent and treat graft rejection reaction.
 in stem cell transplant.

10.  Everolimus
 similar to sirolimus in mechanism, clinical efficacy,
doses, toxicity and drug interactions.
 better absorbed orally and has more consistent
bioavailability.
 t½ is shorter (~40 hours)

11. 3.ANTIPROLIFERATIVE DRUGS
 Azathioprine
 purine antimetabolite.
 Mode of Action
taken up into the immune cell
converted to 6-mercaptopurine
inhibit the purine synthesis and damage to DNA.
selectively affects the differentiation and function of T-cell
and suppress the cell mediated immune response.

12.  Pharmacokinetics
 oral and IV route.
 Dose is 1-2 mg/kg/day
 Adverse effects:
 Bone marrow suppression,
 hepatotoxicity and GIT side effects
 Uses
 Prevention of renal and other graft rejection.
 Lower dose is used in progressive rheumatoid arthritis.

13.  Mycophenolate mofetil (MMF)
 prodrug of mycophenolic acid.
 Mode of Action
In body it converts to mycophenolic acid
selectively inhibits inosine monophosphate
dehydrogenase(essential enzyme in purine synthesis).
It suppresses proliferation both of T and B lymphocytes,
antibody production that results into suppressed cell
mediated immunity.

14.  Pharmacokinetics
 rapidly absorbed orally
 slowly inactivated by glucuronidation
 t½ of ~ 16 hours.
 glucuronide excreted in urine.
 Adverse effects:
 gastro-intestinal disturbances – diarrhoea and
haemorrhage;
 bone marrow suppression, especially leukopenia and
anaemia;
 CMV infection;
 lymphomas.
 Uses
 in solid-organ (e.g. renal,cardiac) transplantation.
 in the treatment of other autoimmune disorders;rheumatoid
arthritis and psoriasis.

15.  Adverse effects:
Hyperglycemia, infections, Cushing's habbit, osteoporosis
Uses
Used for allergic, inflammatory, autoimmune diseases and
in malignancies

16. GLUCOCORTICOIDS
 Prednisolone
Mode of action
inhibit MHC expression and production of IL-1, IL-2,IL-6
helper T-cell are not activated
inhibition of proliferation of T- lymphocytes and decrease
expression of IL.
So the cell mediated immunity mainly depressed.
Pharmacokinetics
 Dose 5–60 mg/day oral,
10–40 mg i.m., intraarticular; also topically.

17. 5. BIOLOGICALAGENTS:
 A) TNFα inhibitors
 TNFα is secreted by activated macrophages and other
immune cells to act on TNF receptors.
 TNFα amplifies immune inflammation by releasing other
cytokines and enzymes like collagenases and
metalloproteinases.
 The TNFα inhibitors are mainly used in autoimmune
diseases.

18.  Etanercept
 It is a recombinant fusion protein of TNF-receptor and
Fc portion of human IgG1.
 prevents activation of macrophages and T-cells during
immune reaction.
 administered by s.c. injection 50 mg weekly.
 Pain,redness, itching and swelling occur at injection site
and chest infections may be increased
 Dose: 25–50 mg s.c. once or twice weekly;

19.  B) IL-1 receptor antagonist
Stimulated macrophages and other mononuclear cells
produce IL-1 which activates helper T-cells and induces
production of other ILs, metalloproteinases, etc.
 Anakinra:
 clinically less effective than TNF inhibitors.
 it has been used in cases who have failed on one or more
disease modifying antirheumatic drugs.
 Dose: 100 mg s.c. daily.
 Local reaction and chest infections are the main adverse
effects.

20. C) ANTIBODY
 Muromonab CD3
 Mechanism of action
Anti-CD3 antibodies bind CD3 protein, blocking antigen
binding to the T-cell antigen–recognition complex, and
decreasing the number of circulating CD3-positive
lymphocytes.
 binding of anti-CD3 to its receptor causes cytokine
release .
 overall effect is to reduce T-cell activation in acute solid-
organ graft rejection.

21.  Adverse effects
 cytokine release syndrome, with chest pain, wheezing.
 hypersensitivity reactions ranging from anaphylaxis to an
acute influenza-like syndrome.
 CNS effects – seizures, reversible meningo-encephalitis
and cerebral oedema.
 Uses
 used as second-line immunosuppressive therapy in
patients with acute transplant rejection.

22. REFERENCES:
 A Textbook of Clinical Pharmacology and Therapeutics.
By JAMES M RITTER ,LIONEL D LEWIS ,
TIMOTHY GK MANT, ALBERT FERRO 5th edition.
published in Great Britain in 2008 by Hodder Arnold, an
imprint of Hodden Education, part of Hachette Livre
UK, 338 Euston Road, London NW1 3BH.
 Essentials of Medical Pharmacology. By KD TRIPATHI.
JAYPEE BROTHERS MEDICAL PUBLISHERS (P)
LTD New Delhi, London ,Philadelphia ,Panama. Seventh
Edition: 2013.
 Pharmacology for Medical graduates. By Tara V
Shanbhag, Smita Shenoy.ELSEVIER publication. Third
Edition;2016-17.

23. THANK YOU…!!!