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CHAPTER # 16 IMMUNOSUPPRESSIVE DRUGS

IMMUNOSUPPRESSIVE DRUGS

INTRODUCTION:

DEFINITION:

Immunosuppressive drugs or immunosuppressive agents are drugs that inhibit or prevent activity
of the immune system.

EXPLANATION:

They are used in immunosuppressive therapy to prevent the rejection of transplanted organs and
tissues (e.g., bone marrow, heart, kidney, liver). They are used to treat autoimmune diseases or
diseases that are most likely of autoimmune origin (e.g., rheumatoid arthritis).They are also used
to treat some other non-autoimmune inflammatory diseases (e.g., long term allergic asthma
control).
A common side-effect of many immunosuppressive drugs is immunodeficiency, because the
majority of them act non-selectively, resulting in increased susceptibility to infections and
decreased cancer immunosurveillance. There are also other side-effects, such as hypertension,
dyslipidemia, hyperglycemia, peptic ulcers, lipodystrophy, moon face, liver and kidney injury.
The immunosuppressive drugs also interact with other medicines and affect their metabolism and
action. Actual or suspected immunosuppressive agents can be evaluated in terms of their effects
on lymphocyte subpopulations in tissues using immunohistochemistry.

CLASSIFICATION OF IMMUNOSUPPRESSIVE DRUGS:

Immunosuppressive drugs can be classified into five groups:

1. Glucocorticoids: In pharmacologic doses, glucocorticoids are used to suppress various

allergic, inflammatory, and autoimmune disorders. They are also administered as post-
transplantory immunosuppressants to prevent the acute transplant rejection.

2. Cytostatics: It inhibit cell division. In immunotherapy, they are used in smaller doses
than in the treatment of malignant diseases. They affect the proliferation of both T cells
and B cells. Due to their highest effectiveness, purine analogs are most frequently
administered. It includes alkylating agents and antimetabolites.

3. Antibodies: These are sometimes used as a quick and potent immunosuppressive therapy
to prevent the acute rejection reactions as well as a targeted treatment of
lymphoproliferative or autoimmune disorders (e.g. anti-CD20 monoclonals).

4. Drugs acting on immunophilins: Like tacrolimus, ciclosporin is a calcineurin inhibitor

(CNI). It has been in use since 1983 and is one of the most widely used
immunosuppressive drugs. It is a cyclic fungal peptide, composed of 11 amino acids.

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5. Other Drugs: It includes, interferons, opioids etc.

AZATHIOPRINE

INTRODUCTION:
Azathioprine is a purine analogue immunosuppressive drug used to prevent rejection following
organ transplantation, and to treat autoimmune diseases. It inhibits an enzyme that is required for
the synthesis of DNA, thus most strongly affects proliferating cells, such as the T cells and B
cells of the immune system. It is produced by a number of manufacturers under different brand
names (Azasan by Salix in the U.S., Imuran by GlaxoSmithKline in Canada, the U.S, Australia,
Ireland and Great Britain, Azamun in Finland and Imurel in Scandinavia and France).

STRUCTURE:

DESCRIPTION:

Azathioprine is a thiopurine and a pale yellow solid with a slightly bitter taste and a melting
point of about 238–245 °C. It is practically unsoluble in water and only slightly soluble in
lipophilic solvents such as chloroform, ehanol and diethylether. It dissolves in alkaline aqueous
solutions, where it hydrolyzes to 6-mercaptopurine.

PHARMACODYNAMICS:
Mechanism of Action:

Antimetabolites are structural analogs of ordinary cellular metabolites such as folic acid,
pyrimidines and pyrines, which after being introduced in the body, begin to imitate the structure
of ordinary metabolites. They compete with metabolites to block important reactions leading to
formation of DNA/RNA. So, by competing with natural pyrines and pyrimidines in metabolic
schemes, they interfere with the synthesis of nucleic acids, thus being included in place of
ordinary metabolites. This leads to the formation of cellular products, which cannot function
normally. Thus, cellular processes of division and multiplication are disrupted.

SYNTHESIS OF AZATHIOPRINE:

Azathioprine is synthesized by heteroarylation of the sulfhydrile group of 6-mercaptopurine with

5-chloro-1-methyl-4-nitroimidazol in the presence of sodium acetate as a weak base. As a matter
of fact, azathioprine is a prodrug since it turns into mercaptopurine in the body. This is a possibly
reason why it is advantageous over mercaptopurine as an immunosuppressant.

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CLINICAL USES:

1. Azathioprine is the primary drug used for transplants, especially for kidney transplants.
2. Azathioprine is useful in combination with cyclosporine, and it is even preferred in
certain cases.

DOSE:
 Usual, adult, and children: 1 to 25 mg per kg body weight daily by mouth.

CICLOSPORINE

INTRODUCTION:
Ciclosporin is an immunosuppressant drug widely used in organ transplantation to prevent
rejection. It reduces the activity of the immune system by interfering with the activity and growth
of T cells. It was initially isolated from the fungus Tolypocladium inflatum, found in a soil
sample obtained by Sandoz scientists at Hardangervidda, Norway, in 1969. Most peptides are
synthesized by ribosomes, but ciclosporin is a cyclic nonribosomal peptide of 11 amino acids
and contains a single D-amino acid, which are rarely encountered in nature.

STRUCTURE:

DESCRIPTION:
It is white or category of white crystalline powder, odorless and tasteless. It do not dissolve in
water.

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PHARMACODYNAMICS:
Ciclosporin binds to the cytosolic protein cyclophilin (immunophilin) of lymphocytes, especially
T cells. This complex of ciclosporin and cyclophilin inhibits calcineurin, which, under normal
circumstances, is responsible for activating the transcription of interleukin 2. In T-cells,
activation of the T-cell receptor normally increases intracellular calcium, which acts via
calmodulin to activate calcineurin. Calcineurin then dephosphorylates the transcription factor
nuclear factor of activated T-cells (NFATc), which moves to the nucleus of the T-cell and
increases the activity of genes coding for IL-2 and related cytokines. Ciclosporin prevents the
dephosphorlyation of NF-AT by binding to cyclophilin. It also inhibits lymphokine production
and interleukin release and, therefore, leads to a reduced function of effector T-cells. It does not
affect cytostatic activity.

Ciclosporin affects mitochondria by preventing the mitochondrial permeability transition pore

from opening, thus inhibiting cytochrome c release, a potent apoptotic stimulation factor. This is
not the primary mechanism of action for clinical use, but is an important effect for research on
apoptosis.

SYNTHESIS OF CICLOSPORINE:
Cyclosporine A is extracted from a cultural liquid of products of the vital activity of the
mushroom Tolypocladium inflatum Tricoderma polysporum, and Cylindrocarpon lucidum,
which are found in the ground. It is also proposed to obtain synthetically.

CLINICAL USES:
1. Cyclosporine A is a powerful immunosuppressive drug intended for preventing rejection
of kidney, heart, and lung transplants.
2. It is used for treating a number of autoimmune diseases, including diabetes, multiple
sclerosis, myasthenia, rheumatoid arthritis, and psoriasis.
3. It also has had a great effect in treating schistosomiasis, malaria, and filariasis.

DOSE:
 Cyclosporin …………………………….. 2 to 4 mg/kg/day IV infusion once a day over 4 to
6 hours.

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