This document summarizes immunosuppressive drugs. It discusses how they work to suppress the immune system and are used to prevent organ rejection after transplantation and treat autoimmune diseases. The main classes of immunosuppressive drugs covered are glucocorticoids, calcineurin inhibitors like cyclosporine and tacrolimus, antiproliferative drugs including mycophenolate mofetil and mTOR inhibitors, immunosuppressive antibodies, and others. Specific drugs within each class are described in terms of their mechanisms of action, pharmacokinetics, uses, and side effects.

1. Immunosuppressive
drugs
Prepared and Presented By :
Ayatollah Abdel-Sattar
Mohammed

2. Immunosuppressive drugs
• Agent that suppress or reduce the strength of the
body’s immune response,
1. They used in organ transplantation (anti-rejection
drugs ) to prevent organ rejection as in liver, heart
and kidney transplantation .
2. They also used to treat autoimmune diseases in
which the body attacks it’s own tissue as RA,Systemic
Lupus Erythematosus, Multiple Sclerosis ,…

3. Quick review of immune response

4. Quick review of immune response
The Immune system consist of two type :
1-Innate immune system(non specific, no memory response is the first
line of defense against invading pathogens consists of :
• Mechanical components ( skin/epidermis and mucus membrane)
• Biochemical components ( Interferons, acidic pH, and free radicals).
• Cellular components ( neutrophils, macrophages and NK,…)
2-The adaptive immune system (specific, memory response) 2nd line
of defense consist of :
• Cell-mediated immunity ( activation of T lymphocytes).
• Humoral immunity (production of antibodies).

5. Cell-mediated immunity Humoral immunity

6. Classification of
Immunosuppressant
I. Glucocorticoids .
II. Calcineurin inhibitors.
III.Antiproliferative and Antimetabolic drugs.
IV.Immunosuppressive antibodies.

7. II-Calcineurin
inhibitors(Cyclosporine&Tacrolimus)

8. Cyclosporine (peptide antibiotic) eg.Neoral
MOA : as above
PK :It can be given IV or orally .. slowly absorbed (20–50%).
• Metabolized by the P450 3A enzyme system in the liver (multiple drug
interactions)
• Requires individualization of dose based on steady-state blood levels and the
desired therapeutic ranges for the drug (TDM)
SE:nephrotoxicity, hypertension, hyperglycemia, liver dysfunction, hirsutism
and little bone marrow toxicity.
• incidence of lymphoma and other cancers ( induc. TGF-β tumor invasion and
metastasis)

9. Uses :
• Alone or in combination with glucocorticoids.
• It has been used successfully as the sole immunosuppressant for
cadaveric transplantation of the kidney, pancreas, and liver, and it has
proved extremely useful in cardiac transplantation as well.
• In combination with methotrexate in sever of autoimmune disorders
(RA, psoriasis) .
• As standard prophylactic regimen to prevent GVH disease after
allogeneic stem cell transplantation.
• Cyclosporine ophthalmic solution for ocular GVH disease.
• Inhaled cyclosporine is being investigated for use in lung
transplantation.

10. Tacrolimus FK 506 (macrolide antibiotic) eg. Prograf
MOA : as above
PK : 10–100 times more potent than cyclosporine.
• It can be administered orally or intravenously.
• Metabolized primarily by P450 enzymes in the liver ( drug interactions).
• The dosage is determined by trough blood level at steady state (TDM)
SE : like CAS nephrotoxicity, neurotoxicity, hypertension, hyperkalemia, and
gastrointestinal complaints but no hirsutism and more hyperglucmia effect.
Uses :
• considered a standard prophylactic agent (usually in combination
with methotrexate or mycophenolate mofetil) for GVH disease.
• Topically dermatitis and psoriasis.

11. III-Antiproliferative and
Antimetabolic drugs:
1. Mammalin targtet of rapamycin (mTOR)
inhibitor .
2. Mycophenolate mofetil.
3. Azathioprine .
4. Leflunomide .
5. Hydroxychloroquine
6. MTX

12. 1-Mammalin targtet of rapamycin
(mTOR) inhibitor sirolimus

13. Sirolimus
MOA : as above
PK : Available only as oral preparation.
• Rapidly absorbed , with high fatty meals it’s absorption decreased .
• Metabolized by cytochrome P-450 enzyme (Drug interaction)
• Target dose-ranges of these drugs vary depending on clinical use (TDM).
SE: thrombocytopenia, hepatotoxicity, diarrhea, hypertriglyceridemia,
pneumonitis, and headache.

14. Uses :
• In combination with (corticosteroids, cyclosporine, tacrolimus, and
mycophenolate mofetil) to prevent rejection of solid organ allografts.
• As prophylaxis when combined with tacrolimus in stem cell transplantation
regimens as GVH disease.
• Topical sirolimus is also used in some dermatologic disorders .
• Recently, sirolimus-eluting coronary stents have been shown to reduce
restenosis and additional adverse cardiac events in patients with severe
coronary artery disease, due to the drug’s antiproliferative effects.

15. 2-MYCOPHENOLATE MOFETIL
Mycophenolate mofetil (MMF) is a semisynthetic derivative of mycophenolic acid
(to enhance bioavailability)
MOA :it inhibits T- and B-lymphocyte responses, by inhibition synthesis of
purines.
PK : available in both oral and intravenous forms.
• Mycophenolate mofetil is hydrolyzed to mycophenolic acid(active moiety)
• The oral form is rapidly metabolized to mycophenolic acid.
• Although the cytochrome P450 3A system is not involved, some drug interactions
still occur.
• Plasma drug levels are frequently monitored.
SE :
• Toxicities include gastrointestinal disturbances (N,V,D and abdominal pain)
• Headache, hypertension, and reversible myelosuppression (primarily
neutropenia)

16. Uses :
• used in solid organ transplant patients for refractory rejection .
• In combination with prednisone, as an alternative to cyclosporine or
tacrolimus in patients who do not tolerate those drugs.
• Its antiproliferative properties make it the first-line drug for preventing or
reducing chronic allograft vasculopathy in cardiac transplant recipients.
• Mycophenolate mofetil is used as prophylaxis for and treatment of both
acute and chronic GVH disease in hematopoietic stem cell transplant
patients.
• Newer applications for MMF include lupus nephritis, RA,IBS and some
dermatologic disorders.

17. 3- Azathioprine
It is antimetabolite group of cytotoxic immunosuppressive drugs, and
many other agents that kill proliferative cells appear to work at a similar
level in the immune response.
Pk:
• it is a prodrug of mercaptopurine .
• Metabolized primarily to mercaptopurine and further metabolites ,
• As Xanthine oxidase converts much of the active material to 6-thiouric
acid prior to excretion in the urine. (Drug interaction with Allopurinol
dose reduction )
SE:
• BM suppression (manifested as leukopenia, thrombocytopenia and
anemia and may occur)
• Skin rashes, fever, GIT symptoms seen mainly at higher dosages. (N,V
&D)
• Hepatic dysfunction (manifested by very high serum alkaline
phosphatase levels and mild jaundice Spe. with preexisting hepatic
dysfunction.

18. 4-Leflunomideis a prodrug of an inhibitor of
pyrimidine synthesis rather than purine like azathioprine and
mycophenolate.
Orally active used only for RA
uses:
• It is approved only for rheumatoid arthritis at present
SE:
• Elevate liver enzymes with some risk of liver damage .
• Nephrotoxicity.
• Teratogenic .
• A low frequency of cardiovascular effects (angina, tachycardia) has
been reported.

19. 5-Hydroxychloroquine
• It is an antimalarial agent with immunosuppressant properties.
MOA : It is thought to suppress intracellular antigen processing and
loading of peptides onto MHC class II molecules by increasing the pH of
lysosomal and endosomal compartments, thereby decreasing T-cell activation
Uses:
• Treat some autoimmune disorders ( eg, RA and SLE)
• Treat and prevent GVH disease after allogeneic stem cell transplantation.

20. 6-MTX
MOA: It inhibts (AICAR-transformylase) amino-imidazolecarboxamide
ribonucleotide transformylase. which accumulates intracellularly,
competitively inhibits AMP deaminase, leading to an accumulation of AMP
which converted extracellularly to adenosine, which is a potent inhibitor of
inflammation.
As a result, the inflammatory functions of neutrophils, macrophages,
dendritic cells, and lymphocytes are suppressed.

21. IV- Immunosuppressive antibodies:
1. Polyclonal anti bodies : (ALG,ATG)
they are a heterologous polyclonal antibodies are obtained from the
serum of animals (e.g., horse, rabbit,) and injected with the patient's
Thymocytes or Lymphocytes.
The antilymphocyte (ALG]) and antithymocyte antigens (ATG) are
being used.
MOA: They inhibit T lymphocytes and cause their lysis >> inhibit cell-
mediated immune reactions, including graft rejection, and the graft-versus-
host disease (GVHD) .
SE : Due to their high immunogenicit almost all patients have an acute reaction to
the treatment. As (fever, and even anaphylaxis).
• Later during the treatment, fever, joint pain, and erythema ( steroids and analgesics) .
• It is possible to diminish their toxicity by taking intravenous administration in the
combination with other immunosuppressants, for example, calcineurin inhibitors,
cytostatics and cortisteroids.
• Need hospitilization (3Weaks) as it cause general immunosuppression & may lead to
post-transplant lymphoproliferative disorders (PTLD) or serious infection.

22. 2- Monoclonal antibodies
They are more specific (defined antigens), less SE.
They are used to prevent the rejection of transplanted
organs.
There are several MABs mechanism of action .
1. Anti-CD3 MABs.(eg, Muromonab-CD3)
2. Anti-IL-2 receptor (Anti-CD25) antibodies.(eg,
Daclizumab, Basiliximab)
3. Anti-TNF reagents.(eg, Adalimumab,Etanercept,
Infliximab)
4. IL-1 Inhibition. ( eg, Anakinra)

23. 1-Anti-CD3 MABs:
Muromonab-CD3 (OKT3) :
By Blocking the Cytotoxic human T-cell (CTL)action and other
T-cell function
MOA:
It acts bind to T-cell surface protein CD3 thes complex
prevents antigen recognition, cell signaling(deplation of T-
cell).
USES:
• Autoimmun dieseas and transplantation setting .
• Ttt Acute renal allograft rejection , steroid resistant acute
cardiac & renal rejection .

24. 2-Anti-IL-2 receptor antibodies.
• Daclizumab (humanized AB) & Basiliximab (chimeric AB) :
MOA: It bind to the IL-2 receptor (CD25) on the surface of T-
cells prevent binding to activated lymphocytes .
Uses :
• As prophylaxis of acute organ rejection pt.
• It can be combined with others (CSA & glucocorticoids )

25. 3-Anti-TNF reagents:
• TNF-T is a proinflammatory cytokine that is important im RA and similar
disease .
By binding to TNF receptors it suppress inflammatory cytokines (IL-1,IL-6)
and decrease leucocyte activation and migration .
Infliximab It binds with high affinity to TNF-α and prevents the cytokine
from binding to its receptors.
Uses treating the symptoms of RA .
In combination with methotrexate in patients who do not respond to methotrexate
alone.
Infliximab also is approved for treatment of symptoms of Crohn disease, ankylosing
spondylitis, plaque psoriasis, psoriatic arthritis, and ulcerative colitis .
SE :
fever, urticaria,hypotension, and dyspnea within 1-2 h after adminstration

26. Etanercept : It binds to TNF-α, and prevents it from interacting with its
receptors.
Uses :
It is approved for treatment of the symptoms of RA, ankylosing spondylitis..
In combination with methotrexate in patients who have not responded
adequately to methotrexate alone.
SE: Ireactions (i.e., erythema, itching, pain, or swelling) have occurred.
All anti-TNF agents (i.e., infliximab, etanercept, adalimumab) increase
the risk for serious infections, lymphomas, and other malignancies.

27. 4-IL-1 Inhibition:
Plasma IL-1 levels are increased in patients with active inflammation .
Anakinra is an FDA-approved for the management of joint disease in
rheumatoid arthritis.
It can be used alone or in combination with anti-TNF agents such as
etanercept,infliximab, or adalimumab.

28. Thank you