CONTENT

1. Introduction
2. History
3. Terms
4. Some definition
5. Classification & Mechanism
6. Drugs
7. Interaction
8. Side effect
9. Uses
10. Precaution
11. Special condition
12. Conclusion
13. References

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IMMUNOSUPPRESENT DRUGS
Introduction:-
Immunosuppressant drugs are medicines that reduce the body's natural defensesagainst foreign
invaders or materials. Used in transplant patients, these drugs help prevent their bodies from
rejecting transplanted organs.
When an organ, such as a liver, a heart or a kidney, is transplanted from oneperson (the donor)
into another (the recipient), the recipient's immune system has the same response it has to any
foreign material: It attacks and tries to destroy the organ. Immunosuppressant drugs help prevent
this fromhappening by subduing the natural immune response. However, the drugs' actionalso
makes the body more vulnerable to infection. For that reason, people who take these kinds of
medicine need to be especially careful to avoid infections.
In addition to being used to prevent organ rejection, immunosuppressant drugssometimes are
used to treat severe skin disorders such as psoriasis and other diseases such as rheumatoid
arthritis, Crohn's disease (chronic inflammation of the digestive tract) and patchy hair loss
(alopecia areata).
Immunosuppressant drugs are available only with a physician's prescription and come in tablet,
capsule, liquid, and injectable forms. Commonly used immunosuppressant drugs include
azathioprine (Imuran), cyclosporine (Sandimmune) and tacrolimus (Prograf).
The physician will decide exactly how much of the medicine each patient needs. It is vital that
the patient take this medicine exactly as directed. Nevertake smaller, larger or more frequent
doses, and do not take the drug for longer than directed. Taking too much may increase the risk

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of side effects, while taking too little may not do any good. Nor should a patient stop taking the
drug without checking with the physician who prescribed it.
Seeing a physician regularly while taking immunosuppressant drugs is important. These regular
check-ups will allow the physician to make sure the medicineis working as it should and to
watch for unwanted effects. These medicines are very powerful and can cause serious side
effects, such as high blood pressure, kidney problems and liver problems. Some side effects may
not show up until years after the medicine is used. However, the good these drugs can do may
outweigh the possible harm. Anyone who has been advised to take immunosuppressant drugs
should thoroughly discuss the risks and benefits with his or herphysician
Immunosuppressant drugs lower a person's resistance to infection and can makeinfections harder
to treat. The drugs can also increase the chance of uncontrolled bleeding. Anyone who has a
serious infection or injury while taking immunosuppressant drugs should get prompt medical
attention and should make sure that the physician in charge knows about the medicine.
Immunosuppressant drugs may cause the gums to become tender and swollen or tobleed. If this
happens, check with a physician or dentist right away. Regular brushing, flossing, cleaning and
gum massage may help prevent this problem. Ask the dentist for advice on how to clean the teeth
and mouth without causing injury.
People who have certain medical conditions or who are taking certain other medicines may have
problems if they take immunosuppressant drugs. Before takingthese drugs, be sure to let the
physician know about allergies, whether you are pregnant or on oral birth control pills, or who
have shingles or chicken poxx
People who take immunosuppressant drugs may be at higher than normal risk of developing
certain kinds of cancer later in life. However, the drugs may be necessary to prevent the failure
of a life-saving transplant. The possible harm must be carefully weighed against the drugs'
benefits. Discussing the medicine's good and bad points with a physician will help a patient
decideabout whether to take immunosuppressant drugs.
The risk of cancer or infection may be greater when immunosuppressant drugs are combined
with certain other drugs which also lower the body's ability to fight disease and infection.
Anyone who takes immunosuppressant drugs should let the physician know all other medicines
he or she is taking and should ask whether the possible interactions can interfere with treatment.

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History:-
A firestorm has erupted with the revelation on March 29, 2005 that a 3rd patient dosed with
Tysabri had been discovered to have Progressive multifocal leukoencephalopathy (PML). PML is
a demyelinating disease of the brain caused by the JC virus. This patient had 8 doses of Tysabri
over the course of 18 months during a clinical trial for Crohn's disease, an autoimmune disorder
that strikes the bowels. The doses were spaced out as follows: 3 months Tysabri, 9 months
placebo, then 5 months Tysabri. The patient passed away in December of 2003, with his death
originally attributed to a fatal brain tumor.
The recent revelation of 2 cases of PML found in extended combination therapy of Avonex and
Tysabri prompted a reinvestigation of this death. The new conclusion was that the patient had
actually died of PML, not a brain tumor. This has been viewed by many as devastating the
chances of Tysabri ever returning to market, given that it seems on the surface that Tysabri can
cause PML even when used alone (monotherapy).
However, This is MS became suspicious of the link between Tysabri and PML in this case,
particularly given the low number of Tysabri doses that the patient had been exposed to, the
spacing of those doses, and the mysterious mention of a past history of severe
immunosuppresion. If PML were so "easy" to contract when exposed to Tysabri, why would we
not see higher numbers of incidents in the multiple sclerosis Tysabri groups, who are more
frequently dosed (monthly) over longer periods of time (over three years for the extended trial
participants) with higher Tysabri circulation (when combined with Avonex, Tysabri clearance is
reduced by ~30%).
The investigation is enlightening, and we believe, shows that Tysabri cannot easily be considered
the critical factor for this case of PML. As you will see, it is not a foregone conclusion that this
patient could be considered to have been on Tysabri monotherapy, given the long-term effects of
his previous therapies. To preface this article, note that this is an opinion piece based upon
information in the public domain and written by non-medical personnel, so all conclusions are
meant to serve as discussion points and not definitive answers.
That being said, Elan disclosed the list of medications Patient 3 was treated with:

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• Steroids no surprise here, and this relatively weak immunosuppressant is used commonly with
most MSers.
• Remicade, which is a powerful drug used to treat Crohn's disease. Now things get more
interesting. A *partial* list of warnings for Remicade: "Many people with heart failure should
not take REMICADE...There are reports of serious infections, including tuberculosis (TB),
sepsis and pneumonia. Some of these infections have been fatal. ...REMICADE can lower your
ability to fight infections, so if you are prone to or have a history of infections, or develop any
signs of an infection such as fever, fatigue, cough, or the flu while taking REMICADE, tell your
doctor right away...There have been rare cases of serious liver injury in people taking
REMICADE, some fatal...Blood disorders have been reported, some fatal...Nervous system
disorders have also been reported. Tell your doctor if you have or have had a disease that affects
the nervous system, or if you experience any numbness, weakness, tingling, or visual
disturbances while taking REMICADE. Reports of lymphoma (a type of cancer) in patients on
REMICADE and other TNF blockers are rare but occur more often than in the general
population. Tell your doctor if you have or have had cancer.
Clearly, Remicade is not a treatment to be undertaken lightly and has a number of ways of
causing fatalities.
• Azathioprine (aka Imuran) - This is where things get extremely interesting. The patient was
treated for approximately five years with this powerful drug commonly used for preventing the
rejection of organ transplants and in lower doses, rheumatoid arthritis and other inflammatory
diseases such as Crohn's. Quoting Medline: [Azathioprine] works by weakening the body's
immune system so it will not attack the transplanted organ or the joints." It is not clear for what
indication this patient took this drug, but it was likely taken off-label for what would obviously
have to be a severe case of Crohn's disease. Let us examine this drug's mode of action and safety
profile:
"Imuran [is] used as an immunosuppressant antimetabolite either alone or, more commonly, in
combination with other agents (usually corticosteroids) and procedures which influence the
immune response. Therapeutic effect may be evident only after weeks or months..." Note that
Imuran is commonly prescribed in combination with another immunosuppressant AND the effect
of the drug-- severe immunosuppression is often delayed.
Continuing on with the litany of grave warnings: -

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"Severe leukopenia [an abnormal decrease of white blood cells] and/or thrombocytopenia
[abnormal decrease of blood platelets] may occur in patients on azathioprine. Macrocytic anemia
and severe bone marrow depression may also occur...Delayed hematologic suppression may
occur. Prompt reduction in dosage or temporary withdrawal of the drug may be necessary if there
is a rapid fall in, or persistently low leukocyte count or other evidence of bone marrow
depression [Tysabri works by preventing leukocytes from crossing the Blood-Brain-Barrier, so if
they are already severely reduced...]...Serious infections are a constant hazard for patients on
chronic immunosuppression...Fungal, viral, bacterial and protozoal infections may be fatal and
should be treated vigorously...Azathioprine is mutagenic in animals and humans, carcinogenic in
animals, and may increase the patient's risk of neoplasia [pre-cancerous cell growth]...acute
myelogenous leukemia as well as solid tumors have been reported in patients...who have
received azathioprine.
Let us recap: Azathrioprine can be incredibly toxic, can decimate the immune system long after
its dosing, and leaves the patient susceptible to potentially fatal infection. Could Imuran still
have been exerting its effects during the Tysabri infusions? We don't have an answer to that, but
if so, let us explore "the smoking gun":
While looking at the reported adverse reactions for Azathioprine, we found this:
"A case of progressive leukencephalopathy (PML) after a four year azathioprine therapy...was
reported (Schnider,1991). That's right-- a case of PML linked directly with long-term
administration of azathioprine. Patient #3 was actually on azathioprine for one year longer than
this PML-azathioprine case. This is not the only case, here's another:
"A 71-year-old woman receiving azathioprine and glucocorticoid therapy experienced onset of
right-sided hemiplegia within a few days, became comatose, and died within a few
days...postmortem examination showed PML.
Simply put, we are aghast that this ravaged individual, exposed to years of dosing with a cocktail
of potentially lethal drugs-- that among other things, can cause delayed immunosuppression,
cancer, and even PML itself, was participating in a clinical trial with another experimental
immunosuppresant. Maybe his case was so bad, he had no other hope, but in such an extreme
situation, the fault of his death cannot be placed squarely on Tysabri. That he died is of course
tragic, but quite frankly, a serious adverse event is not entirely surprising given his cumulative
medical history.

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 To conclude that Tysabri is the key factor for his contraction of PML and ultimate death, based
on the post-mortem analysis of a patient that clearly was severely ill is to us, simply
preposterous. While we are not doctors and so our opinion is purely non-medical, this situation
cannot reasonably be viewed as akin to an otherwise healthy individual contracting PML after
exposure to Tysabri monotherapy. In fact, given the latent effects of the Imuran treatment,
without further information as to treatment start and stop dates, it cannot even be said
definitively that this patient was on Tysabri monotherapy, as after five years of treatment, Imuran
could still have been exerting its effects without being actively dosed.
The contraindications for prescribing Tysabri are becoming clear, and coupled with the increased
vigilance for PML that would be sure to accompany any Tysabri prescription, the risk factor
would seem to be acceptable for many MSers anxious for a new treatment option. The fact that
toxic drugs like Remicade and Imuran are tolerated but Tysabri would not be is at the very least
extremely puzzling. Tysabri is extremely effective at what it does, and because of that potency,
cannot be coupled with drugs that cause, or people who have, a history of immunosuppression,
cancer and serious infections.

DEFINITIONS:-
 Immunosuppression:-
Suppression of immunity with drugs, usually to prevent rejection of an organ transplant. Its aim
is to allow the recipient to accept the organ permanently with no unpleasant side effects. In some
cases the dosage can be reduced or even stopped without causing rejection. Other uses are in the
treatment of certain autoimmune diseases and for prevention of erythroblastosis fetalis. Its main
drawback is the increased risk of infection for the duration of treatment and of lymphoma in the
case of long-term immunosuppression.
The natural or induced active suppression of the immune response, as contrasted with deficiency
or absence of components of the immune system. Like many other complex biological processes,
the immune response is controlled by a series of regulatory factors. A variety of suppressor cells
play a role in essentially all of the known immunoregulatory mechanisms, such as maintenance
of immunological tolerance; limitation of antibody response to antigens of both thymic-

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 dependent and thymic-independent types, as well as to antigens that stimulate reaginic antibody
(antibodies involved in allergic reactions); genetic control of the immune response; idiotype
suppression; control of contact and delayed hypersensitivity; and antigenic competition. All of
the major cell types involved in the positive side of cellular interactions required for an immune
response have also been found capable of functioning as suppressors in different regulatory
systems.

 Suppressor cells:-
Some suppressor functions are antigen or carrier-specific. (A carrier is a molecule that can be
chemically bound to another small molecule, called a hapten, in such a way that the combination
induces an immune response that the hapten alone would not induce.) Others may not be carrier-
specific, but may be specific for the type of response, such as immunoglobulin production but
not delayed hypersensitivity. In the case of immunoglobulin production, the suppressor T cell
may regulate the production of all immunoglobulin classes, a single class of immunoglobulins,
or molecules that bind only a given antigen. Other suppressors may affect only cellular immunity
and not humoral immunity.
Suppressor cells are critical in the regulation of the normal immune response. Immunological
tolerance refers to the ability of an individual's immune system to distinguish between its own
and foreign antigens and to mount a response only to foreign antigens. A major role has been
established for suppressor T lymphocytes in this phenomenon. Suppressor cells also play a role
in regulating the magnitude and duration of the specific antibody response to an antigenic
challenge.
Reagin or IgE is the class of immunoglobulin that mediates allergic reactions such as asthma and
urticaria. The reaginic antibody response depends heavily on nonspecific cooperator T cells and
specific helper T cells as well as the B cells that produce the antibody. In a negative direction,
IgG-blocking antibodies regulate the response, but antigen-specific and antigen-nonspecific
suppressor T cells also play a critical role in regulating this response. See Allergy
T cells are the major cells involved in immunosuppression, although activated phagocytic
mononuclear cells are also significant as nonspecific suppressors in many systems. Helper T
cells and suppressor T cells are different cell populations that are distinguished to a considerable

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 extent by surface antigens that react with monoclonal antibodies or receptors for specific
substances such as histamine.
No single model explains the entire array of cellular suppressor phenomena. In different systems,
other T cells, macrophages, or even B cells may be the immediate targets of the suppressor cells
and their secretions. Some suppression requires direct cell-cell interaction, whereas other
suppression may be mediated by suppressor lymphokines. Both antigen-specific and antigen-
nonspecific factors are known, and they may be secreted to act upon other cells, or especially in
the case of antigen-specific factors, they may be integral parts of the cell membrane. The soluble
immune-response suppressor factor, produced by activated T cells and then activated by
monocytes, inhibits B-cell proliferation and immunoglobulin production in response to antigens.
Macrophages also secrete suppressor factors, including prostaglandins that act on T cells and
other soluble factors that are B-cell-specific.
There are a variety of disorders of immunoglobulin production in humans. In many cases these
involve intrinsic defects in the bone marrow stem cells that normally mature into
immunoglobulin-producing plasma cells. Defects in cell-mediated immunity occur in individuals
who are infected with various fungal organisms. Suppressor T cells have been implicated;
although it is not clear whether the appearance of suppressor cells is the initial event allowing
development of the fungal infection or whether they develop secondarily after infection. Those
individuals found to have suppressor T cells are at high risk for dissemination of the fungal
infection and relapse following therapy. Although probably only one of many mechanisms,
suppressor cells interfere with the host tumor-growth-inhibiting immune response to the foreign
tumor-specific transplantation antigens that occur on malignant cells, thus allowing the tumors to
progress. Both animal and human studies indicate a major role for both an activation of
immunoglobulin-producing B cells as well as the absence or reduced numbers or function of
suppressor T cells in autoimmune disorders such as Coombs-positive hemolytic anemia,
systemic lupus erythematosus, rheumatoid disorders, and thyroid disorders in which antithyroid
antibodies appear in the serum.

 Immunosuppressors:-
Suppression of the immune response may be specific to a particular antigen or may be a response
to a wide range of antigens encountered. The whole immune response may be depressed, or a

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particular population of immunologically active lymphocytes may be selectively affected. In
some cases, the effect may be preferentially on T cells rather than B cells. If B cells are affected,
it may be on a specific subclass of antibody-producing cells. Antigen-specific
immunosuppression may be the result of deletion or suppression of a particular clone of antigen-
specific cells, or the result of enhanced regulation of the immune response by antigen-specific
suppressor cells. It can also be the result of increased production of antiidiotypic antibody.
Nonspecific suppression of the immune response occurs in a number of rare immunological
deficiency diseases of childhood. Acquired deficiency states affecting mainly T-cell function
occur in states of malnutrition and in the presence of tumors, particularly those of the
lymphoreticular system. Acquired deficiencies may also occur secondary to a number of
infectious diseases. The acquired immune deficiency syndrome (AIDS) is probably of similar
origin; its manifestations are similar although more severe and more dramatic.
There are a number of compounds capable of suppressing the immune response. The main
stimulus for studies designed to identify these substances has been to devise means for
controlling organ graft rejection. However, there has also been considerable activity in looking
for compounds that will suppress the immune response and reduce the inflammatory process in
experimental models of rheumatoid arthritis. The ideal immunosuppressive drug should fulfill
five main requirements: (1) There should be a wide margin of safety between a toxic and a
therapeutic dose. (2) The drug should have a selective effect on lymphoid cells and not cause
damage to the rest of the body. (3) If possible, this effect should be only on those cells, which are
involved, in the specific immune process to be suppressed. (4) The drug should need to be
administered for only a limited period until the immunological processes become familiar with
the foreign antigen and begin to recognize it as part of “self.’’ (5) The drug should be effective
against immune processes once they have developed.
The result of any immune response is a balance between the action of effector cells mediating the
phenomenon and suppressor cells regulating the response. Anything that reduces the regulatory
function of suppressor cells will functionally increase the immune response. As suppressor cells
are derived from rapidly turning-over precursor cells, and effector cells of T-cell-mediated
immunity are derived from slowly dividing precursors, it is possible preferentially to depress the
action of suppressor cells without affecting effector cells. This may be done by the use of
alkylating agents such as cyclophosphamide given before immunization. Cyclophosphamide

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 used in this way can increase a normal cell-mediated immune response, reverse immunological
tolerance caused by increased regulatory activity of suppressor cells, and even reverse antigenic
competition. It is likely that the chemotherapeutic effect of alkylating agents which are used
extensively in the treatment of cancer in humans is partially due to these agents modifying the
biological response to the tumor, producing an immunopotentiating action.

Classification & Mechanism:-

Immunosuppressive drugs can be classified into four groups:

• Glucocorticoids
• Cytostatics
• Antibodies
• Drugs acting on immunophilins
• Other remedies

1 Glucocorticoids

1.1The mode of action

1.2Immunosuppressive effect
1.3 Antiinflammatory action
1.4 Glucocorticoid remedies

2 Cytostatics
2.1 Cytostatics and the immune system
2.2 Classification of cytostatics and major representatives
2.2.1 Alkylating agents
2.2.2 Antimetabolites
3.1 Polyclonal antibodies
3.2 Monoclonal antibodies

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3.2.1 Antibodies directed towards T-cell receptor
3.2.2 Antibodies directed towards IL-2 receptor
4 Drugs acting on immunophilins
4.1 Cyclosporine A
4.2 Tacrolimus (Prograf(TM), FK506)
4.3 Sirolimus (Rapamune (Tm), Rapamicin)
5 Other remedies
5.1 Interferons
5.1.1 The effect of interferons
5.2 Opioids
5.3 TNF-α binding drugs
5.4 Mycophenolic acid
5.5 Small biological agents
5.5.1 FTY120

Glucocorticoids
Endogenous glucocorticoids are essential hormones the lack of which is not compatible with life.
Their main effects are the maintenance of the appropriate level of glucose in the blood, the
maintenance of blood pressure and the prevention of excessive immune response.
Pharmacological or supraphysiological dosages are used in treatment of inflammatory and
allergic disorders. They are also used as immunosuppressants after transplantations to prevent the
acute transplant rejection by the receiver and also the immune response of the receiver to the
receiver's antigens. However, they have many side effects: the gain of body mass, development
or aggravation of diabetes, arterial hypertension and/or steroid induced osteoporosis. Therefore,
the production of new glucocorticoid remedies is directed to the discovery of selective
immunosuppressive drugs.

The mode of action

Glucocorticoids bind to the cytosolic glucocorticoid receptor that is one of the receptors
activated after ligand binding. After the hormone binds to the receptor, the receptor-ligand
complex is translocated into the cell nucleus, where it binds to many glucocorticoid response
elements (GRE) in the promoter region of target genes. The DNA bound receptor then interacts

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with basic transcription factors, which causes the increase in expression of specific target genes.
This process is called transactivation. The transactivation mediates most of the main metabolic
and cardiovascular side effects.
The mechanism contrary to transactivation is transrepression. Here, the activated hormone
receptor interacts with transcription factors that cooperate in the transcription of a specific gene
and prevents it. Glucocorticoids are able to prevent the transcription of the IL-2 gene and all
other immune genes .
The ordinary glucocorticoids do not differentiate between transactivation and transrepression,
therefore they influence the "wanted" genes and also "unwanted" ones. Currently, intensive
research is focused on searching selective glucocorticoids. These will be able to transrepress the
immune genes without affecting the metabolic and cardiovascular ones.

Immunosuppressive effect
Glucocorticoids diminish the cell immunity: they act by inhibiting genes that code the following
cytokines: IL-1, IL-2, IL-3 , IL-4 , IL-5 , IL-6, IL-8 and TNF-γ. Smaller production of cytokines
causes reduced proliferation of T lymphocytes. This diminishes their effect and clone expansion
of CD4+ cells (T-helper lymphocytes). Hereby, especially the IL-2 is important.
Glucocorticoids also diminish the humoral immunity. Like T lymphocytes, B lymphocytes
express smaller amounts of IL-2 genes and of genes coding for IL-2 receptors . This means
reduced B lymphocyte clone expansion and consequentially, the diminished synthesis of
immunoglobulins.
Antiinflammatory action
Glucocorticoids influence all types of inflammatory reactions independently of their cause. They
induct the synthesis of lipocortin-1 (annexin-1) that binds to phospholipid membranes and
prevents the activity of phospholipase A2, as the enzyme is not able to come into contact with its
substrate. Phospholipase A2 is involved in the first step of the production of some eicosanoids.
The expression of genes coding for cyclooxygenase (COX-1 and COX-2), which catalyzes
further steps, also diminishes.
Glucocorticoids also cause the release of lipocortin-1 in the extracellular space, where it binds to
leukocyte membrane receptors and inhibits epithelial adhesion, emmigration, chemo taxis,
phagocytosis, respiratory burst, release of lysosome enzymes, release of chemotactic substances,

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release of the activator plasminogen and of other inflammatory mediators from neutrophils and
macrophages. By the action of lypocortin-1 it is also possible to explain the inhibitory effect of
glucocorticoids on the release of histamine from tissue basophils. Glucocorticoids successfully
soothe all signs of inflammation, however they do not prevent infection. They also inhibit later
reparative processes .
Glucocorticoid remedies
There are many different glucocorticoids in use: cortisol, dexamethasone, hydrocortisone,
methylprednisolone Medrol prednisone, prednisolone and others. They differ in
pharmacokinetics absorption factor, their half-life, the volume of distribution, clearance and in
pharmacodynamics (for example the capacity of mineralocorticoid activity: retention of sodium
(Na+) and water; They are primarily administered per os (by mouth), as they are well absorbed
in the intestines, and topically on skin, but also by other ways. The majority (more than 90 per
cent) of glucocorticoids bind different plasma proteins, however, they differ in their binding
specificity. Endogenous glucocorticoids and some synthetic corticoids bind with high affinity the
protein transcortin (also CBG, corticosteroid binding protein), while all of glucocorticoids are
able to bind albumin. They are metabolised quickly in the liver, where they conjugate with a
sulfate or glucuronic acid, and are secreted in urine.

Cytostatics
Main article: Cytostatics.
Cytostatics are drugs that inhibit the cell division and therefore damage or destroy cells. They are
especially used in cancer therapy. However, because they are not only specific for cancer cells,
they also affect all other quickly dividing cells. This can most often be observed as the
chemotherapy side effects. It is nonetheless reasonable to use them, as the cancer cells divide
faster than normal ones and are therefore more sensitive.

Cytostatics and the immune system

Quickly dividing cells are also T-lymphocytes and B-lymphocytes. As they recognize the specific
antigen, they quickly proliferate to secure the adequate number of clones for the immune
response. However, this makes them a suitable target of cytostatics. Therefore, we can use
cytostatics whenever the immune response is not wanted. As immunosuppressants, cytostatics

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 are used in smaller dosages as in the treatment of malign diseases. Their antiproliferative effect is
in general not limited and it includes both T-lymphocytes and B-lymphocytes.

Classification of cytostatics and major representatives

On the basis of the site of action, cytostatics can be divided into four groups:
• Alkylating agents (e.g. cyclophosphamide)

• Antimetabolites (e.g. methotrexate, azathioprine)

• Cytotoxic antibiotics
• Inhibitors of the mitotic spindle
Mainly purine analogs are administered, as they are the most effective, while the others are less
frequently used.
Alkylating agents
Their main representative are nitrogen mustards (cyclophosphamide), nitrosoureas, platinum
compounds etc. They act cytostatically by effecting the DNA.
Cyclophosphamide is an alkylating agent and probably the most potent immunosuppressive
substance. It inhibits the DNA replication by making covalent bonds with it. In small doses, it is
very efficient in the treatment of systemic lupus erytematosus, autoimmune hemolytic anemia’s,
Wegener's granulomatosis and other immune diseases. High doses of cyclophosphamide can
cause pancytopenia and hemorrhagic cystitis.
Antimetabolites
Their main representatives are folic acid analogues (methotrexate), purine analogues
(azathioprine, mercaptopurine), pyrimidine analogues, and protein synthesis inhibitors. They
affect all nucleic acids.
Methotrexate
Methotrexate is a folic acid analogue. It binds dihydrofolate reductase and prevents the synthesis
of tetrahydrofolate. This way, it inhibits the synthesis of DNA, RNA and proteins (as
tetrahydrofolate is involved in the synthesis of serine and methionine). It is used in the treatment
of autoimmune diseases, as rheumatoid arthritis, and in some transplantation.
Azathioprine
Azathioprine is the main cytotoxic substance, used in immunosuppression. It is widely used in
transplantations to control rejection reactions. It is nonezymathically cleaved to 6-

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mercaptopurine, which act as a purine analogue and the inhibitor of DNA synthesis. By
preventing the clone expansion of lymphocytes in the induction phase of the immune response, it
affects both the cell and humoral immunity. It is also successful in the treatment of autoimmune
diseases.
Cytotoxic antibiotics
Among these, dactinomycin is the most important. It is used in kidney transplantations. Other
cytotoxic antibiotics are anthracyclines, mitomycin C, bleomycin, and mitramycin. All these
substances act on DNA to mediate their effects.
Mitotic spindle inhibitors
(Vinca alkaloids, e.g. vincristine, vinblastine; podophyllins) are used in the therapy of some
autoimmune diseases. They repress the M phase of the cell cycle. Vincristine depolimerizes
mitotic spindle.
Antibodies.
Antibodies are used in the induction therapy that by a quick and potent immunosuppression tries
to prevent the acute rejection reaction.
Polyclonal antibodies
Heterologous polyclonal antibodies are obtained from the serum of different animals (e.g. rabbit,
horse) that the pacient's thymocytes or lymphocytes have been injected to. The antilymphocyte
(ALG) and antithymocyte antigens (ATG) are used. They are a part of the treatment of steroid-
resistant acute rejection reaction and of the treatment of grave aplastic anemia. However, they are
mostly used as additives to other immunosuppressives, which allows for the diminishment of the
latter's dosage and their toxicity. The antibodies also allow the later transition to cyclosporine
therapy. They are usually administered for five days intravenously in the appropriate quantity.
Patient stays in the hospital for three weeks so the immune system recovers and there is no risk
of serum sickness anymore.
Polyclonal antibodies inhibit T lymphocytes and cause their lysis through the interaction with
different cell surface markers (e.g. CD2, CD3, CD4, CD8, CD11a, CD18, CD45, CD3, CD4).
The lysis is both complement mediated cytolysis and cell-mediated opsonization followed by
removal of reticuloendothelial cells from the circulation in the spleen and liver. This way,
polyclonal antibodies inhibit cell-mediated immmune reactions, including the graft rejection, the

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delayed hypersensitivity (i.e. tuberculin skin reaction), and the graft-versus-host disease
(GVHD), however their effect on the thymus-dependent antibody production is smaller.
Currently (March 2005) there are two preparations available, Atgam (R), obtained from horse
serum, and Thymoglobuline (R), obtained from rabbit serum.
Polyclonal antibodies act non-specifically on all the lymphocytes and cause general
immunosuppression that can lead to post-transplant lymphoproliferative disorders (PTLD) or
serious infections, especially with cytomegalovirus .Therefore, the therapy must necessarily be
performed in a hospital, where adequate isolation from infection is available.
As polyclonal antibodies are also highly immunogen, by almost all the patients an acute reaction
develops in the first few days of the treatment. It is characterized by fever, sometimes rigor
episodes and in some cases, even anaphylaxis develops. Later during the treatment, the serum
sickness or by the immune complexes induced glomerulonephritis can develop. The serum
sickness appears seven to fourteen days after the beginning of therapy. The patient suffers from
fever, joint pain and erythema that can be soothed with the use of steroids and analgesics.
Urticaria (hives) can also be present. Because of their immunogenicity, patients gradually
develop a strong immune response against them, so these drugs cease to be effective. Their
toxicity can be diminished by the use of highly purified serum fractions, intravenous application
and their administration in the combination with other immunosuppressants, for example
calcineurin inhibitors, cytostatics and cortisteroids. The most common combination is the
simultaneous use of antibodies and cyclosporine.
Monoclonal antibodies
Monoclonal antibodies are much more specific, as they are directed towards exactly defined
antigens and therefore, they cause fewer side effects. Especially important are antibodies against
the IL-2 receptor (CD25) and against CD3, and probably new will appear. They are used to
prevent rejection of transplanted organs, but also in the tracking of changes in lymphocyte
subpopulations in immunosuppressive therapy.
Antibodies directed towards T-cell receptor
Till now, OKT3 is the only approved anti-CD3 antibody. It is a mous anti-CD3 monoclonal
antibody of the IgG2a type that acts by binding the T-cell receptor complex, which is present on
all differentiated T cells. In this way, it prevents T-cell activation and proliferation. It is one of
the most potent immunosuppressive substances and is clinically used to control episodes of acute

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rejection, where steroids and/or polyclonal antibodies are not effective. As it is more specific
than polyclonal antibodies, it is also used preventively in transplantations. The exact mechanism
of OKT3 (R) is not adequatly explained yet. It is known that it binds the T-cell receptor complex
of antigen (TCR/CD3). In the first few administrations, this binding causes non-specific
activation of T cells; therefore a serious syndrome develops 30 to 60 minutes after its
application. It is characterized by the fever, myalgia, headache, and artralgia and can progress till
the life-threatening reaction, that seriously affects cardiovascular system and the CNS and that a
lengthy therapy is needed for. Later CD3 (R) blocks binding of TCR on antigen and causes
change of conformation or the removal of the entire TCR3/CD3 from the T-cell surface. In this
way, the CD3 antibodies lower the number of T cells, perhaps by sensitising them for the uptake
by the reticular epithelial cells. The cross binding of CD3 molecules also provokes an
intracellular signal, which causes the anergy or the apoptosis of T cells, if they do not receive
another signal by one of more costimulatory molecules. CD3 antibodies also cause the shift in
the balance of T cells from Th1 cells to Th2 cells. When making a decision about the use of
OKT3(R) in the treatment, it is necessary to consider not only its great effectiveness, bu also its
toxic side effects. These are the risk of excessive immunosuppression and the risk that the patient
develops neutralizing antibodies against it, which would mean that the drug would not be
effective anymore. Although CD3(R) antibodies are more specific than polyclonal antibodies,
they significantly lower the cell-mediated immunity and predispose patient to opportunistic
infections and malignancies.
Antibodies directed towards IL-2 receptor
Interleukin-2 is an important immune system regulator that is necessary for the clone expansion
and survival of activated lymphocytes T. Its effects are mediated by the trimer cell surface
receptor IL-2a, composed of α, β and γ chains. IL-2a (CD25, T-cell activation antigen, TAC) is
expressed only on those T lymphocytes, that were previously activated in the interaction with a
foreign antigen or with IL-2 and is the only IL-2 specific molecule. Therefore, it has a special
significance in the selective immunosuppressive treatment. On the basis of these findings,
research focused on the development of effective and safe anti-IL-2 antibodies. The modification
of mouse anti-Tac antibodies with the recombinant gene technology enabled the presentation of
two himeric mouse/human anti-Tac antibodies in the year 1998. One of these is basiliximab
(Simulect (R)) and the other is daclizumab (Zenapax (R)). They work by binding the α chain of

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the IL-2a receptor on the activated T lymphocytes. This prevents the IL-2 induced clonal
expansion of activated lymphocytes and shortens their survival. These two remedies are used as a
profilaxis of the acute organ rejection in the patients, who have both kidneys transplanted. They
cause few side effects and are similarly effective, as both of them decrease the frequency of the
acute rejection for approximately a third.

Drugs acting on immunophilins:-

Cyclosporine A:-
Together with tacrolimus, cyclosporin is a calcineurin inhibitor. It has been in use since 1984 and
is one of the most widely used immunosuppressive drugs. It is a fungal peptide, composed of 11
amino acids.
When T-helper cell's receptor interacts with an antigen, the intracellular concentration of calcium
in the cell rises. This increase activates the cytoplasmic phosphatase calcineurin. Calcineurin
activates different transcription factors that are important in the transcription of IL-2 genes. IL-2
activates T-helper lymphocytes and induces the production of other cytokines. This way, it
directs the action of cytotoxic lymphocytes and NK cells. The amount of IL-2 being produced by
the T-helper cells is believed to influence the extent of the immune response significantly.
Cyclosporin is administered per intravenously. It reaches its highest concentration three to four
hours later. Its tissue concentrations are to four times higher than in the plasma. In the tissue, it
binds to the cytosolic immunophilin, named cyclofilin. The complex then binds to calcineurin
and inhibits it. Cyclosporin is metabolized in the liver and secreted to the bile; its half time is
about 24 hours.
Cyclosporin is used in the treatment of acute rejection reactions, however because of its
nephrotoxicity, it is substituted with newer immunosuppressants more and more. The
nephrotoxicity affects 40 — 70% of patients. Especially the proximal tubules are destroyed.

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Other less frequent side effects are hypertension, venous thrombosis, tremor, headache,
parestesias and hyperkalemia.
Tacrolimus (Prograf(TM), FK506)
Tacrolimus is a fungal product (Streptomyces tsukubaensis). It is a macrolide lactone and acts by
inhibiting calcineurin.
Tacrolimus is used particularly in the transplantation of kidney and liver. It can be administered
per os or intravenously, and 99% of it degrades in the liver. Its half-life is approximately 12
hours. Tacrolimus binds an immunophilin, after which the complex binds to calcineurin and
inhibits its phosphatase activity. In this way, it prevents the first phase of the T lymphocyte
activation .
Tacrolimus is more potent than cyclosporine and has less pronounced side effects. Among these,
the most frequent are nephropathies, convulsions, tremor, hypertension, diabetes, hyperkalemia,
insomnia, neuropathies and gout.
Sirolimus (Rapamune (Tm), Rapamicin)
Actinomycetes Streptomyces hygroscopicus produce it. Chemically it is a macrolide lactone.
Sirolimus is used as an immunosuppresant in the transplantation. Although it is a structural
analogue of tacrolimus, it acts somewhat differently and has different side effects. It is
administered solely per os in the form of tablets or a solution. It is metabolized in the liver by the
CYP34A4 cytochrome, with the half time of about 62 hours. It is excreted particularly in feces,
only 2% in urine.
Contrary to cyclosporine and tacrolimus that affect the first phase of the T lymphocyte
activation, it affects the second one, namely the signal transduction and their clonal proliferation.
It binds to the same receptor (immunophilin) as tacrolimus, however the produced complex does
not inhibit calcineurin, but a special protein. Therefore, sirolimus acts synergistically with
cyclosporine and, in combination with other immunosuppressants, has few side effects.
Indirectly it inhibits several kinases and phosphates of T lymphocytes and prevents the
transmission of signal into their activity and the continuation of the cell cycle from G1 phase to S
phase. Similarly, it prevents B cell differentiation in the plasma cells, which means a lower
quantity of IgM, IgG and IgA antibodies is produced. It acts immunoregulatory.

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 Sirolimus' side effects are hyperlipidemia, leuko- and thrombocytopenia, anemia and
hypokalemia. Its toxicity to the transplanted organ has not been proved, therefore it substitutes
cyclosporin in kidney transplantations.

Other remedies:-
Interferons
Interferons (IFNs) are cell proteins of the cytokine class and important antiviral factors, but they
are synthesized also in response to other stimuli. Three major groups of interferons are known:
IFN-α (leukocytic), IFN-β (fibroblastic) and IFN-γ (immune). These differ in their physical,
chemical and biological properties.
In a majority of cases, the production of interferons is induced by other cytokines, e.g. IL-1, IL-
2, TNF and CSF. IFN-α and IFN-β are synthesized in many cell types - macrophages, fibroblasts,
endothelial cells, osteoblasts and others. Their synthesis is mainly caused by the appearance of
viruses in the body. IFN-γ is produced in antigen-activated cells T in inflammatory and
autoimmune conditions and has a central role in the immune response control.
The effect of interferons
All interferons have antiviral and antitumour effect and they cause fever. Beside this, IFN-β and
IFN-γ have anti-inflammatory and immunosuppressive effects:
• IFN-γ is an inflammatory cytokine that by as yet unknown mechanism triggers apoptosis in
lymphocytes
• IFN-β inhibits the progression of multiple sclerosis. By an as yet unknown mechanism, it inhibits
the production of Th1 cytokines and the monocyte activation.
The production of IFN-γ during the infection is highly important to destroy foreign antigens and
overcome the disease, however at the same time it can lead to autoimmune activity. Namely,
IFN-γ has an exceptionally important immunoregulatory function.
When used in the systemic therapy, IFN-α and IFN-γ are mostly administered by an
intramuscular injection. Interferons hardly traverse the placenta and the blood-brain barrier. Their
metabolism and excretion take place mainly in the liver and kidneys.
The injection of interferons in the muscle, vein or under skin is generally well tolerated. The
most frequent side effects are flu-like symptoms: raised body temperature, feeling ill, fatigue,
headache, muscle pain, and convulsion. Erythema, pain and hardness on the spot of injection are

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also frequently observed. Rarely, patients experience their hair falling out, dizziness and
depression. All known effects are reversible and disappear a few days after the therapy is
finished.
Opioids
A prolonged taking of opioids (analgesics, illegal drugs) can cause immunosuppression, which
means the risk of infection is increased. Their effects are not yet fully researched, however they
cause diminished migration of leukocytes.

TNF-α binding drugs

TNF-α binding drugs are proteins or antibodies, that bind to TNF (tumor necrotising factor) and
prevent its action, that is the production of IL-1 and IL-6 and the adhesion of molecules that
activate lymphocytes. They are intravenously administered and are used in the treatment or
inhibition of progression of rheumatoid arthritis, ankylosing spondylitis, Chron's disease etc.
Besides respiratory and other infections, their side effects also include the edema on the spot of
administration, pancytopenia and sometimes vasculitis develops. In prolonged therapy, the risk
of lymphoma is increased. The representatives of this class of drugs are Etanercept (Enbrel (Tm))
and Infliximab (Remicade(TM)).

Mycophenolic acid
Mycophenolic acid (MPA) is an active component produced from Mycophenolate mofetil
(MMF) and a new substance Mycophenolate sodium (Myfortic(R)). It acts as a non-competitive,
selective and reversible inhibitor of inosin monophosphate dehydrogenase (IMPDH), which is a
key enzyme in de novo gvanosin nucleotide synthesis. In contrast to other human body cells,
lymphocytes B and T are much more dependent of the de novo synthesized gvanosin.

Small biological agents

FTY120
FTY120 is a new synthetic immunosuppressor, a chemical modification of the ISP-1 metabolite
of the fungus Iscaria sincaliri. It is a structural analogue of sphyngosine and gets phosphorylated
with the sphyngosine kinase in the cell. It increases the expression or changes the function of

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 certain adhesion molecules (α4/β7 integrine) in lymphocytes, so they accumulate in the
lymphatic tissue (lymphatic nodes) and their number in the circulation is diminished. In this
respect, it differs from all other known immunosuppressants.

Drugs: -
Many of the currently available immunosuppressants were developed for use in oncology or
transplantation. As this treatment is potentially life saving desperate measures can be justified.
However, 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.
Some immunosuppressants act through immunodepletion of effector cells, while others are
predominantly immunomodulatory, affecting the activity of cells, usually through cytokine
inhibition. Immunosuppressants can be categorised as glucocorticoids, small molecules or
proteins.
 Glucocorticoids
Corticosteroids are the mainstay of most immunosuppressive regimens in both the induction and
maintenance phases. In high intravenous pulse doses .
(methylprednisolone 250-1000 mg daily for 1-3 days) they are directly lymphocytotoxic. In
smaller doses, they are immunosuppressive and anti-inflammatory by limiting cytokine
production. The required dose and duration of treatment therefore tends to be disease specific.
Some diseases, for example asthma, respond to a short course, which can be abruptly stopped,
but most rheumatic diseases require the dose to be very slowly tapered over months, especially
when single figure milligram doses of prednisone are reached. Abrupt cessation runs the risk not
only of relapse of disease, but also hypoadrenocorticism. (Adrenal suppression can be confirmed
by a one-hour synthetic ACTH stimulation test if there is clinical concern.) In the withdrawal
phase, non-specific polyarthralgias and myalgias are common, but generally respond to a small
dose.

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 Second-line drugs, usually antiproliferative drugs such as azathioprine, mycophenolate or
methotrexate, may have a steroid-sparing effect in the maintenance phase of treatment. However,
they also have their own toxicities. Patients prescribed corticosteroids should be told to expect
the common early adverse effects, such as sweatiness, hoarse voice, loss of diurnal sleep
patterns, and appetite stimulation. Rarely, more serious acute psychiatric disturbances are seen
such as agitation, aggression or psychosis. Long-term, and less reversible, adverse effects include

Cushingoid appearance, proximal myopathy, hypertension, hyperlipidaemia, diabetes, cataract

formation, peptic ulceration, osteopenia and aseptic necrosis of bone.
(Table1) The small molecule immunosuppressants include calcineurin inhibitors, such as
cyclosporin, and antiproliferative drugs, such as sirolimus.

 Calcineurin inhibitors :-

Since the 1980s, calcineurin inhibitors have been the main contributors to the success of solid
organ transplantation, especially kidneys. By blocking interleukin-2 synthesis, they prevent
activation of T-lymphocytes and are therefore useful in disorders of cell-mediated immunity.
Calcineurin inhibitors have a proven role in the prevention of acute cellular rejection of
transplanted organs, in psoriasis and in nephrotic syndrome.

They have been used in many other autoimmune conditions but have a diminishing role in
rheumatoid arthritis. While they are good at maintaining autoimmune diseases in remission,
withdrawal often leads to relapse.
In solid organ transplantation, combinations of calcineurin inhibitors, mycophenolate mofetil and
prednisone give better results than monotherapy. Ironically, calcineurin inhibitors are
nephrotoxic and may contribute to long-term renal failure, both in transplanted organs and
normal kidneys. They also aggravate hypertension and hyperlipidaemia thereby inducing an
unfavourable cardiovascular profile. There is also an increased risk of diabetes.
Mycophenolate mofetil.
Since it was introduced into Australia in 1996 mycophenolate mofetil has largely replaced
azathioprine in organ transplantation. One advantage over azathioprine is that allopurinol can be

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used for gout prophylaxis without the need to reduce the dose of mycophenolate. Possibly
because of its anti-B cell properties2 mycophenolate seems particularly effective in severe forms
of systemic lupus erythematosus. It is also gaining favour as a steroid-sparing drug in the
maintenance phase of a number of immune disorders, particularly the vasculitides.3
The main adverse effects are haematological and gastrointestinal. On higher doses a third of
patients will develop diarrhoea. An enteric-coated formulation of mycophenolate has been
developed to try and reduce gastrointestinal adverse effects. Therapeutic drug monitoring is
available but not widely used.
Sirolimus and everolimus
These potent antiproliferative drugs have gained acceptance in renal transplantation as a strategy
to minimise the use of calcineurin inhibitors in low immunological risk patients.4 They have a
decreased likelihood of causing hypertension and glucose intolerance. Although these drugs are
associated with less nephrotoxicity than calcineurin antagonists, they potentiate the renal toxicity
of cyclosporin and regular monitoring of renal function is recommended. Sirolimus and
everolimus are generally avoided perioperatively because they can severely delay wound
healing. They are potent inhibitors of intimal hyperplasia in arteries, and sirolimus-eluting intra-
arterial stents are now used to reduce re-stenosis rates. However, they can increase serum
cholesterol and lipids. The balance of the harm and benefit of continued treatment should be re-
evaluated in patients who develop severe refractory hyperlipidaemia. Therapeutic drug
monitoring is essential because of the risk of toxicity such as anaemia, leucopenia and
thrombocytopenia.
Cyclophosphamide
Cyclophosphamide is a cytotoxic drug. It is the drug of choice for Wegener's granulomatosis, but
is also used in other vasculitides such as microscopic polyangiitis and systemic lupus
erythematosus.5 Monthly intravenous pulses are as effective as daily oral use in systemic lupus
erythematosus, but allow a reduced total dosage. Cyclophosphamide is also used to induce
sustained remission in relapsing nephrotic syndrome. Marrow suppression with neutropenia is
common after six weeks of treatment and continuing more than six months runs the risk of
gonadal suppression and infertility in both sexes.
Methotrexate

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This antimetabolite is used in some autoimmune diseases including psoriasis, psoriatic arthritis,
rheumatoid arthritis and Crohn's disease. As a disease-modifying antirheumatic drug, its use in
combination with tumour necrosis factor inhibitors (such as infliximab or etanercept) or
leflunomide has been shown to markedly improve symptoms in rheumatoid arthritis.6
Proteins (Table 2)
Polyclonal antilymphocyte (antithymocyte) antibodies have been used in Australia since the
1960s. More recently, hybridoma technology has produced a plethora of monoclonal antibodies
against molecules expressed by human immune effector cells.
T-lymphocyte depleting antibodies such as muromonab-CD3 have been widely used to prevent
or treat acute rejection of organ transplants. The main drawback is a 'cytokine storm' reaction to
the first dose, which can cause life-threatening pulmonary oedema.
Basiliximab and daclizumab are monoclonal antibodies against the interleukin-2 receptor
(CD25). They are used as induction drugs in transplantation as they significantly reduce the acute
rejection rate, with little or no increase in morbidity. They are not yet significantly used in
autoimmune diseases.
The anti-B cell antibody (anti-CD20), rituximab, is licensed for use against B-cell lymphomata,
but there are now published anecdotal reports of its effectiveness in 29 different autoimmune
diseases.7 Randomised controlled trials are proceeding in systemic lupus erythematosus,
rheumatoid arthritis, dermatomyositis, antineutrophil cytoplasmic antibody (ANCA)-positive
vasculitis and in renal transplantation of highly sensitised recipients.
A new monoclonal antibody, alemtuzumab, is directed against a surface molecule (CD54), which
is widely distributed on lymphocytes, macrophages and dendritic cells, thereby causing severe
and long-lasting depletion of these cell lines. As a result, the risk of serious infection is
increased. The use of this antibody is cautiously making the transition from immunoprophylaxis
in transplant recipients to a wider use in immune diseases.
Two monoclonal antibodies against tumour necrosis factor, infliximab and adalimumab, and
etanercept, which prevents tumour necrosis factor binding to its receptor, are licensed for use in
rheumatoid arthritis. They are also being used in ankylosing spondylitis, psoriatic arthritis and
inflammatory bowel disease. Infusion reactions are common.
Pooled intravenous immunoglobulin was introduced to restore immunocompetence to patients
with congenital acquired immune deficiency syndrome. Paradoxically, the discovery of its ability

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to inhibit the production and binding of auto-and allo-antibodies means that it is now more
widely used as an immunomodulatory drug in the treatment of debilitating autoimmune diseases
and antibody-mediated allograft rejection.10 The fact that immunoglobulin also provides passive
immunity means that it is regarded as having a low risk of infectious complications compared to
other immunosuppressants. Consequently, it has been used in many conditions without good
supportive evidence of efficacy, so the Australian National Blood Authority guidelines now
restrict its use.11 Nevertheless, it is likely that immunoglobulin use will continue to rise as
knowledge about its mechanisms of action accumulates.

Using immunosuppressants - strategies and protocols

Treatment protocols are designed to:
(a) Remove suppress the predominant immune effectors
(b) Resolve acute inflammation
(c) Prevent relapse.
To achieve (a) and (b), high doses are often used initially ('induction phase'). To achieve (c),
lower doses of safer drugs are often chosen for the longer term ('maintenance phase').
Withdrawal of therapy is usually only considered after achieving clinical and laboratory evidence
of sustained remission. Drugs are withdrawn gradually, one at a time and in the case of
corticosteroids only after a long taper.
Empiricism vs. controlled trials
Many protocols have evolved empirically from an understanding of the putative immune
mechanisms operating in a particular disease. Sometimes the protocols were derived from what
had been seen to work in conditions with apparently similar immunopathology. Randomised
controlled trials of immunosuppressive protocols are available in the more common conditions
such as rheumatoid arthritis or organ transplantation, but as new drugs emerge, the combinations
for comparison become bewildering. Today's 'gold standard' treatment can be very quickly
outdated, perhaps even before it has been optimised. Tailoring of immunotherapy to the
individual is desirable, but this approach makes protocol comparisons difficult.
Similarly, the disease being treated may be so pleomorphic that finding like populations to
compare in trials becomes very difficult. For example, lupus nephritis has five distinct
histological subtypes, each with their own prognosis.
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Choosing immunosuppressive regimens
In order to make sound judgements when choosing a treatment protocol the clinician has to
consider the clinical trial evidence and then decide:
• Is the aim to pre-empt an anticipated immune response (for example, after organ
transplantation) or to suppress an established immune-mediated inflammation (for example,
acute glomerulonephritis)?
• In the case of an immune disease, how much immunosuppression will be required and for
how long (that is, an assessment of disease activity)? Consider:
• The natural history of the untreated disease

• Is the disease multiphase (for example, polyarteritis nodosa) or 'single shot'

• (for example, microscopic polyangiitis)

• The extent and severity of the disease in this particular patient

• Is the affected organ beyond recovery

• The likelihood of relapse

• The ability to monitor disease parameters long term

• Is this patient likely to withstand the treatment I will recommend (host fitness parameters)?
Consider:
• Age (older patients are easier to immunosuppress but have a greater risk of infection)

• Sepsis risk

• Cancer risk

• Cardiovascular/diabetes risk

• Presence of comorbidities

• Patient compliance and availability for follow-up.

• In choosing the dose and duration of immunosuppressive treatments, one must always weigh
disease activity versus host fitness. For example, an elderly patient with perinuclear-ANCA
positive microscopic polyangiitis, confined to the kidneys, with crescents in 10% of
glomeruli, will not need as aggressive an approach as the same disease in a young patient,
with 80% crescents, lung haemorrhage and mononeuritis multiplex.

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 Managing and monitoring patients taking immunosuppressants
Patients need to be under constant surveillance, usually by a partnership between the specialist
and the general practitioner. Frequency of visits depends on perceived level of risk, but typical
parameters to monitor are summarised in Table 3. Patients may need prophylaxis against the
adverse effects of their treatment (Table 4).
Therapeutic drug monitoring is available now for a number of drugs, for example cyclosporin,
tacrolimus, sirolimus and mycophenolate. This allows for 'concentration-controlled' regimens.
Some common drugs, for example corticosteroids, still have no good measure of individual
bioavailability.
 Infection risk
Immunosuppression increases susceptibility to infections which can become life-threatening in a
matter of hours. At first, common bacterial infections of wounds, chest or urine predominate, but
after 1-2 months of therapy opportunistic infections emerge, particularly herpes viruses,
pneumocystis pneumonia, fungi and atypical mycobacteria.
Vaccinations against influenza (injected) and pneumococcus are recommended in chronically
immunosuppressed patients.12 They are safe and reasonably effective when given in the stable
maintenance phase. In general, live attenuated virus vaccines, such as varicella or measles,
should not be given to immunosuppressed patients (or to close family contacts).

Interaction:-

Immunosuppressant drugs may interact with other medicines. When this happens, the effects of
one or both drugs may change or the risk of side effects may be greater. Other drugs may also
have an adverse effect on immunosuppressant therapy. This is particularly important for patients
taking cyclosporin or tacrolimus. For example, some drugs can cause the blood levels to rise,
while others can cause the blood levels to fall and it is important to avoid such contraindicated
combinations. Other examples are:

• The effects of azathioprine may be greater in people who take allopurinol, a medicine used to
treat gout.

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• A number of drugs, including female hormones (estrogens), male hormones (androgens), the
antifungal drug ketoconazole (Nizoral), the ulcer drug cimetidine (Tagamet) and the
erythromycins (used to treat infections), may increase the effects of cyclosporine.
• When sirolimus is taken at the same time as cyclosporin, the blood levels of sirolimus may be
increased to a level where there are severe side effects. Although these two drugs are usually
used together, the sirolimus should be taken four hours after the dose of cyclosporin.
• Tacrolimus is eliminated through the kidneys. When the drug is used with other drugs that may
harm the kidneys, such as cyclosporin, the antibiotics gentamicin and amikacin, or the antifungal
drug amphotericin B, blood levels of tacrolimus may be increased. Careful kidney monitoring is
essential when tacrolimus is given with any drug that might cause kidney damage.
• The risk of cancer or infection may be greater when immunosuppressant drugs are combined
with certain other drugs which also lower the body's ability to fight disease and infection. These
drugs include corticosteroids such as prednisone; the anticancer drugs chlorambucil (Leukeran),
cyclophosphamide (Cytoxan) and mercaptopurine (Purinethol); and the monoclonal antibody
muromonab-CD3 (Orthoclone), which also is used to prevent transplanted organ rejection.

Not every drug that may interact with immunosuppressant drugs is listed here. Anyone who takes
immunosuppressant drugs should let the physician know all other medicines he or she is taking
and should ask whether the possible interactions can interfere with treatment.

Side effects:-
Increased risk of infection is a common side effect of all the immunosuppressant drugs. The
immune system protects the body from infections and when the immune system is suppressed,
infections are more likely. Taking antibiotics such as co-trimoxazole prevents some of these
infections. Immunosuppressant drugs are also associated with a slightly increased risk of cancer
because the immune system also plays a role in protecting the body against some forms of
cancer. For example, long-term use of immunosuppressant drugs carries an increased risk of
developing skin cancer as a result of the combination of the drugs and exposure to sunlight.
Other side effects of immunosuppressant drugs are minor and usually go away as the body
adjusts to the medicine. These include loss of appetite, nausea or vomiting, increased hair

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 growth, and trembling or shaking of the hands. Medical attention is not necessary unless these
side effects continue or cause problems.

The treating physician should be notified immediately if any of the following side effects occur:

• unusual tiredness or weakness

• fever or chills
• frequent need to urinate

Uses:-
• Used in conjunction with steroids

• Used in autoimmune disorders

• Used to reduce the immune response when foreign tissue is transplanted into the body

• Older drugs depressed immune system; had unfortunate SE. Infections, cancer, hypertension and
metabolic bone disease.

Precautions:-

Seeing a physician regularly while taking immunosuppressant drugs is important. These regular
check-ups will allow the physician to make sure the drug is working as it should and to watch for
unwanted side effects. These drugs are very powerful and can cause serious side effects, such as
high blood pressure, kidney problems and liver problems. Some side effects may not show up

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until years after the medicine is used. Anyone who has been advised to take immunosuppressant
drugs should thoroughly discuss the risks and benefits with the prescribing physician

Immunosuppressant drugs lower a person's resistance to infection and can make infections
harder to treat. The drugs can also increase the chance of uncontrolled bleeding. Anyone who has
a serious infection or injury while taking immunosuppressant drugs should get prompt medical
attention and should make sure that the treating physician knows about the immunosuppressant
prescription. The prescribing physician should be immediately informed if signs of infection,
such as fever or chills, cough or hoarseness, pain in the lower back or side, or painful or difficult
urination, bruising or bleeding, blood in the urine, bloody or black, tarry stools occur. Other ways
of preventing infection and injury include washing the hands frequently, avoiding sports in which
injuries may occur, and being careful when using knives, razors, fingernail clippers or other
sharp objects. Avoiding contact with people who have infections is also important. In addition,
people who are taking or have been taking immunosuppressant drugs should not have
immunizations, such as smallpox vaccinations, without checking with their physicians. Because
of their low resistance to infection, people taking these drugs might get the disease that the
vaccine is designed to prevent. People taking immunosuppressant drugs also should avoid
contact with anyone who has taken the oral polio vaccine, as there is a chance the virus could be
passed on to them. Other people living in their home should not take the oral polio vaccine.

Immunosuppressant drugs may cause the gums to become tender and swollen or to bleed. If this
happens, a physician or dentist should be notified. Regular brushing, flossing, cleaning and gum
massage may help prevent this problem. A dentist can provide advice on how to clean the teeth
and mouth without causing injury.

Special conditions:-

People who have certain medical conditions or who are taking certain other medicines may have
problems if they take immunosuppressant drugs. Before taking these drugs, the prescribing
physician should be informed about any of these conditions:

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  ALLERGIES
 Anyone who has had unusual reactions to immunosuppressant drugs in the past should let
his or her physician know before taking the drugs again. The physician should also be
told about any allergies to foods, dyes, preservatives, or other substances.
 PREGNANCY

Azathioprine may cause birth defects if used during pregnancy, or if either the male or female is
using it at time of conception. Anyone taking this medicine should use a barrier method of birth
control, such as a diaphragm or condoms. Birth control pills should not be used without a
physician's approval. Women who become pregnant while taking this medicine should check
with their physicians immediately.

The medicine's effects have not been studied in humans during pregnancy. Women who are
pregnant or who may become pregnant and who need to take this medicine should check with
their physicians.

 BREASTFEEDING

Immunosuppressant drugs pass into breast milk and may cause problems in nursing babies
whose mothers take it. Breastfeeding is not recommended for women taking this medicine.

 OTHER MEDICAL CONDITIONS

People who have certain medical conditions may have problems if they take immunosuppressant
drugs. For example:

• People who have shingles (herpes zoster) or chickenpox, or who have recently been exposed to
chickenpox, may develop severe disease in other parts of their bodies when they take these
medicines.
• The medicine's effects may be greater in people with kidney disease or liver disease, because
their bodies are slow to get rid of the medicine.
• The effects of oral forms of this medicine may be weakened in people with intestinal problems,
because the medicine cannot be absorbed into the body.

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Before using immunosuppressant drugs, people with these or other medical problems should
make sure their physicians are aware of their conditions.

Conclusion:-

In addition to being used to prevent organ rejection, immunosuppressant drugssometimes are

used to treat severe skin disorders such as psoriasis and other diseases such as rheumatoid
arthritis, Crohn's disease (chronic inflammation of the digestive tract) and patchy hair loss
(alopecia areata).
Immunosuppressant drugs lower a person's resistance to infection and can makeinfections harder
to treat. The drugs can also increase the chance of uncontrolled bleeding. Anyone who has a
serious infection or injury while taking immunosuppressant drugs should get prompt medical
attention and should make sure that the physician in charge knows about the medicine.
People who have certain medical conditions or who are taking certain other medicines may have
problems if they take immunosuppressant drugs. Before takingthese drugs, be sure to let the
physician know about allergies, whether you are pregnant or on oral birth control pills, or who
have shingles or chicken pox.
Although corticosteroids and drugs such as azathioprine still have a role, there is increasing use
of newer potent immunosuppressants. Many of these drugs act on T-lymphocytes. Tacrolimus is
a calcineurin inhibitor which has a similar mechanism of action to cyclosporin, reducing T-cell
differentiation. Sirolimus and everolimus bind to the same protein as tacrolimus, but have a
different mechanism of action. As some of these drugs have a narrow therapeutic range, drug
concentrations must be monitored. Mycophenolate is an inhibitor of purine synthesis.
Another approach is to block the receptors on T-cells with immunosuppressant antibodies such
as basiliximab, daclizumab and muromonab-CD3.

References:-
 Abbas, A. K., and A. H. Lichtman. Basic Immunology: Functions and Disorders of
theImmune System. Philadelphia: W. B. Saunders Co., 2001.
 Sompayrac, L. M. How the Immune System Works. Boston: Blackwell Science, 1999.

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  Travers, P. Immunobiology: The Immune System in Health and Disease, 5th ed. New
York: Garland Publishers, 2001.
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Immunosuppressant pharmacodynamics on lymphocytes from healthy
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 responsiveness in focal segmental glomerulosclerosis. J Clin Pharmacol
40, p115-123, 2000
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