Immunosuppressants

Pharmacology Team
Naim Kittana, Suhaib Hattab, Ansam Sawalha, Adham Abu Taha,
Waleed Sweileh, Ramzi Shawahneh

Faculty of Medicine & Health Sciences

An-Najah National University 1
 Introduction

• in the case of organ transplantation, the immune system can elicit a

damaging immune response

• This causes rejection of the transplanted tissue.

• Transplantation of organs and tissues (for example, kidney, heart, or bone

marrow) has become routine due to improved surgical techniques and
better tissue typing.

• Drugs are now available that more selectively inhibit rejection of

transplanted tissues while preventing the patient from becoming
immunologically compromised

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 Introduction

• Earlier drugs were nonselective

• Patients frequently succumbed to infection due to suppression of both the

antibody-mediated (humoral) and cell-mediated arms of the immune
system

• Today, the principal approach to immunosuppressive therapy is to alter

lymphocyte function using drugs or antibodies against immune proteins

• A combination of immunosuppressive agents, usually at lower doses are

used to minimize toxicity

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 Introduction

• Immunosuppressive drug regimens usually consist of anywhere from two

to four agents with different mechanisms of action that disrupt various
levels of T-cell activation

• Immunosuppressive agents may be generally used for:

 Prevention of organ transplantation rejection
 Psoriasis
 Rheumatoid arthritis
 Multiple sclerosis
 Crohn disease and ulcerative colitis

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Immunosuppressant Agents

SELECTIVE INHIBITORS OF CYTOKINE

PRODUCTION AND FUNCTION

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 Cytokines

• Cytokines are soluble, antigen-nonspecific signaling proteins that bind to

cell surface receptors on a variety of cells.

• The term cytokine includes:

 interleukins (ILs)
 interferons (IFNs),
 tumor necrosis factors (TNFs),
 transforming growth factors (TGF)
 colony-stimulating factors

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 Cytokines

• IL-2 is a growth factor that stimulates the proliferation of antigen-primed

(helper) T cells, which subsequently produce more IL-2, IFN-γ, and TNF-α

• These cytokines collectively activate natural killer cells, macrophages, and

cytotoxic T lymphocytes

• Drugs that interfere with the production or activity of IL-2 significantly

dampen the immune response and, thereby, decrease graft rejection

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 Cytokines

• These drugs can be further divided into three main classes:

1) calcineurin inhibitors (cyclosporine and tacrolimus)

2) costimulation blockers (belatacept),

3) mTOR inhibitors (sirolimus and everolimus).

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 Cyclosporine

• Mechanism of action:
 Suppresses cell-mediated immune reactions

 A calcineurin inhibitor

 Calcineurin is responsible for dephosphorylating NFATc (cytosolic

Nuclear Factor of Activated T cells)

 NFATc cannot enter the nucleus to promote reactions that are required
for the synthesis of cytokines, including IL-2.

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 Therapeutic uses of Cyclosporine

• Used to prevent rejection of kidney, liver, and cardiac allogeneic

transplants

• It is typically combined in a double-drug or triple-drug regimen

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 Adverse effects of Cyclosporine

• Dose dependent

• Nephrotoxicity:

 The most common and important, it is critical to monitor kidney

function

 Reduction of the cyclosporine dosage can result in reversal of

nephrotoxicity in most cases

 Coadministration of drugs that also can cause kidney dysfunction, such

as aminoglycosides and NSAIDs, can potentiate the nephrotoxicity of
cyclosporine

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 Adverse effects of Cyclosporine

• Hepatotoxicity: liver function should be periodically assessed

• Life-threatening infections: Viral infections due to the herpes group and

cytomegalovirus (CMV)

• Other toxicities
– Lymphoma
– hypertension
– hyperlipidemia
– Hyperkalemia (K+-sparing diuretics should be avoided in these patients),
– Tremor
– Hirsutism
– Glucose intolerance
– Gum hyperplasia

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 Tacrolimus

• Mechanism of action: Calcineurin inhibitor

• Preferred over cyclosporine because of

 Its increased potency
 Decreased episodes of rejection
 Steroid-sparing effects: reducing the
likelihood of steroid-associated adverse
effects.

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 Therapeutic uses of Tacrolimus

• Prevention of liver, kidney, heart and pancreas rejections (along with

glucocorticoids).

• Rescue therapy in patients after failure of standard rejection therapy.

• An ointment preparation is approved for moderate to severe atopic

dermatitis unresponsive to conventional therapies

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 Adverse effects of Tacrolimus

• Nephrotoxicity and neurotoxicity (tremor, seizures, and hallucinations)

• More severe with tacrolimus than with cyclosporine, but careful dose
adjustment can minimize this problem.

• Development of post-transplant insulin-dependent diabetes, especially in

black and Hispanic patients.

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 Adverse effects of Tacrolimus

• Other toxicities are similar to cyclosporine, except that tacrolimus does

not cause hirsutism or gingival hyperplasia, but it can cause alopecia.

• Compared with cyclosporine, tacrolimus has a lower incidence of

cardiovascular toxicities, such as hypertension and hyperlipidemia

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 Sirolimus

• Mechanism of action: Unlike cyclosporine and tacrolimus, sirolimus does

not lower IL-2 production but, rather, inhibits the cellular response to IL-2.

• Therapeutic uses:
 Approved for use in renal transplantation, in combination with
cyclosporine (synergistic) and corticosteroids
 Allow lower doses of those medications to be used thus lower their
toxic potential.

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 Adverse effects of Sirolimus

• Hyperlipidemia, common, (elevated cholesterol and triglycerides), which

may require treatment.

• The combination of cyclosporine and sirolimus is more nephrotoxic than

cyclosporine alone due to the drug interaction between the two,
necessitating lower doses.

• Headache, nausea and diarrhea

• Leukopenia, and thrombocytopenia.

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Immunosuppressant Agents

IMMUNOSUPPRESSIVE
ANTIMETABOLITES

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 Azathioprine

• It is a prodrug that is converted first to 6-mercaptopurine (6-MP)

• Lymphocytes are predominantly affected by the cytotoxic effects of

azathioprine.

• This is because of their rapid proliferation in the immune response and

their dependence on the de novo synthesis of purines required for cell
division

• major nonimmune toxicity: bone marrow suppression

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Immunosuppressant Agents

ANTIBODIES

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 Basiliximab

• It is approved for prophylaxis of acute rejection in renal transplantation in

combination with cyclosporine and corticosteroids.

• It is not used for the treatment of ongoing rejection.

• Basiliximab is an anti-CD25 antibody that binds to the α chain of the IL-2

receptor on activated T cells and, thus, interferes with the proliferation of
these cells

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 Basiliximab

• Usually, two doses of this drug are administered—the first at 2 hours prior
to transplantation and the second at 4 days after the surgery.

• The drug is generally well tolerated, with GI toxicity as the main adverse
effect

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Immunosuppressant Agents

CORTICOSTEROIDS
Discussed in details before 
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