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IMMUNOSUPPRESSANT
DRUGS
31st March, 2017
Revision:
• READ ON:
• Cellular mechanisms:host defence (Pharmacology
by Rang & Dale-7th Edition, chapter 6)
• Mediators of inflammation and immune reactions
(Pharmacology by Rang & Dale-7th Edition, chapter
17)
• Understanding the cellular responses and their functions
provides an essential basis for understanding the actions
of anti-inflammatory and immunosuppressant drugsa major class of therapeutic agents.
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Immunosuppressants
• Most immunosuppressants act in the induction
phase of immunological response,
• Reducing lymphocyte proliferation; some also
inhibit aspects of the effector phase.
• The drugs used for immunosuppression can
roughly be divided into agents that-:
 Inhibit interleukin-2 (IL-2) production or action,
e.g. Ciclosporin, Tacrolimus; Rapamycin ( also
known as Sirolimus ).
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Immunosuppressants…
Inhibit cytokine gene expression e.g. the
Corticosteroids.
• Act by cytotoxic mechanism; e.g.
Cyclophosphamide; Chlorambucil
Inhibit purine or pyrimidine synthesis, e.g.
Azathioprine; Myclophenolate mofetil
Block the T cell surface molecules
involved in signaling, e.g. Polyclonal and
monoclonal antibodies.
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Immunosuppressants…
• Immunosuppressants are used in the
therapy of auto-immune disease and to
prevent and/or treat transplant rejection.
• Because they impair immune responses,
they carry the hazard of a decrease
response to infections and may facilitate
the emergence of malignant cells.
• However; the relationship between these
adverse effects and potency in preventing
graft rejection varies with different drugs.
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Summary: Clinical Use of
Immunosuppressants
• Are used for three main purposes:
To suppress rejection of transplanted
organs and tissues ( kidneys, bone
marrow, heart, liver, etc)
To suppress graft-versus-host disease
(i.e. the response of lymphocytes in the
graft to host antigens) in bone marrow
transplants
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Summary: Clinical Use of
Immunosuppressants…
 To treat a variety of conditions that, while not
completely understood, are believed to have an
important autoimmune component in their
pathogenesis:
-idiopathic thrombocytopenic purpura,
-some forms of haemolytic anaemia,
-some forms of glomerulonephritis,
-myasthenia gravis,
-systemic lupus erythematosus,
-rheumatoid arthritis,
-psoriasis and ulcerative colitis
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Summary: Clinical Use of
Immunosuppressants…
• The therapy for this third category often
involves a combination of glucocorticoid
and cytotoxic agents
• For transplantation of organs or bone
marrow, ciclosporin is usually combined
with glucocorticoid, a cytotoxic drug or
an antilymphocyte immunoglobin
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1. CYCLOSPORIN
• Is a fungal peptide with potent
immunosuppressive activity but no effect
on the acute inflammatory reaction per se.
• It was discovered by Borel and his coworkers in 1976 in the course of screening
fungal products for anti-fungal activity and
soon revolutionized the field of organ
transplantation; significantly reducing the
morbidity and the incidence of rejection.
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Mechanism of Action
• Cyclosporin has numerous actions on
various cell types; including-:
Decreased clonal proliferation of T cells,
primarily by inhibiting interleukin-2 release
and possibly also by decreasing
expression of interleukin-2 receptors.
Reduced induction of and clonal
proliferation of cytotoxic T cells from CD8+
precursor T cells.
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Mechanism of Action…
Reduced function of the effector T cells
that mediate cell-mediated responses
( e.g. decreased delayed-type
hypersensitivity ).
Some reduction of T-cell-dependent B cell
responses
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Pharmacokinetic Aspects
• Cyclosporin can be given orally or by
intravenous infusion.
• After oral administration, absorption from
G.I.T. is rather poor and varies in different
individuals but peak plasma
concentrations are usually attained in
about 3 to 4 hours.
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Pharmacokinetic Aspects…
• Alternative formulations with improved oral
absorption are now available.
• Plasma half-life is approx. 24 hours.
• Metabolism occurs in the liver and most of
metabolite ( of which 14 have been
identified ) are excreted in the bile.
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Pharmacokinetic Aspects…
• It accumulates in most tissues at
concentrations 3 to 4 times that seen in
the plasma.
• Some of the drug remains in
lymphomyeloid tissue and later in fat
depots for some time after administration
has been stopped.
• Other drugs (e.g. Ketoconazole ) may
increase the plasma concentration of
cyclosporin.
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Unwanted Effects
• The commonest and most serious is
nephrotoxicity. Hepatotoxicity and
hypertension can also occur.
• Less important unwanted effects are
anorexia; lethargy; hirsutism; tremor
paraesthesia ( tingling sensation ) gum
hypertrophy and G.I.T. disturbances.
• Cyclosporin has no depressant effects on
the bone marrow.
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2. TACROLIMUS
• Originally termed FK506; is a macrolide
antibiotic with a very similar mechanism of
action to cyclosporin, the main difference
being that the internal receptor for this
drug is not cyclophilin but FK-binding
protein ( FKBP ).
• The tacrolimus-FKBP complex inhibits
calcineurin with the effects described
above.
• Tacrolimus is active at lower
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concentrations than Cyclosporin.
Pharmacokinetic aspects
• Tacrolimus can be given orally or by
intravenous injection.
• It is 99 % metabolized by the liver and has
a half-life of approximately 7 hours.
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Unwanted Effects
• The unwanted effects of Tacrolimus are
similar to those of Cyclosporin but are
more severe.
• Nephrotoxicity and hypertension have so
far not been a serious problem.
• Neurotoxicity; G.I.T. upsets and metabolic
disturbances (hyperglycaemia) can occur.
• Thrombocytopenia and hyperlipidaemia
have been reported but are reversible by
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reducing the dosage.
3. GLUCOCORTICOIDS
• Immunosuppression by
glucocorticoids involves both their
effects on the immune response and
their inflammatory actions.
• Glucocorticoids are immunosuppressant
mainly because, like Cyclosporin, they
restrain the clonal proliferation of the
Th cells, through decreasing
transcription of the gene for IL-2;
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GLUCOCORTICOIDS…
• However, they also decrease the transcription of
many other cytokine genes ( including those for
tumour necrosis factor-TNF-, interferon-, IL-1
and many other interleukins ) in both the
induction and effector phases of the immune
response.
• These effects on transcription are mediated
through inhibition of the action of transcription
factors, such as AP-1 and NF-KappaB
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4. AZATHIOPRINE
• It interferes with purine synthesis and is
cytotoxic.
• It is widely used for immunosuppression
particularly for control of tissue rejection in
transplant surgery.
• This drug is metabolized to give
Mercaptopurine, a purine analogue that
inhibits DNA synthesis.
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AZATHIOPRINE…
• Both cell-mediated and antibody-mediated
immune reactions are depressed by this
drug since it inhibits clonal proliferation in
the induction phase of the immune
response by a cytotoxic action on dividing
cells.
• The unwanted effect in this drug is
depression of bone-marrow.
• Other toxic effects are nausea and
vomiting, skin eruptions and a mild
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hepatotoxicity.
5. CYCLOPHOSPHAMIDE
• Is a cytotoxic agent with powerful
immunosuppressive effects.
• It is an alkylating agent with particular
action on lymphocytes.
• As an immunosuppressant it affects the
clonal proliferative phase of immune
response and reduces both antibodymediated and cell-mediated immune
reactions.
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6. CHLORAMBUCIL
• Another alkylating cytotoxic agent; is also
used for immunosuppression and has
effects similar to those of
Cyclophosphamide.
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7. MYCOPHENOLATE MOFETIL
• Is a semi-synthetic derivative of fungal antibiotic.
• In the body it is converted to Mycophenolic acid
which restrains proliferation of both T and B
lymphocytes and reduces production of
cytotoxic T cells by inhibiting inosine
monophosphate dehydrogenase; an enzyme
crucial for de novo purine biosynthesis.
• T and B cells are particularly dependent on this
pathway so the drug has a fairly selective action
on these cells.
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Pharmacokinetic Aspects &
Unwanted Effects
• It is given orally and well absorbed.
• Magnesium and Aluminium hydroxides
impair absorption and Cholestyramine
reduces plasma concentrations.
• The metabolite Mycophenolic acid,
undergoes enterohepatic cycling and is
eliminated by the kidney as the inactive
glucuronide.
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• Unwanted G.I.T. effects are common.
• Used with Cyclosporin and Steroids; it has
proved to have effective
immunosuppressant action in several
clinical trials of kidney transplant rejection.
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8. IMMUNOGLOBULINS
• Antibodies against human lymphocytes
have significant immunosuppressant
action.
• These antibodies are raised by
immunizing horses or rabbits, or from mice
using hybridoma technology.
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8. IMMUNOGLOBULINS…
• Their disadvantage is that the foreign
antibodies themselves elicit an immune
response.
• To avoid this, animal immunoglobulin can
now be ‘ humanized ‘ by genetic
engineering to combine the antigenbinding ( Fab ) site of a mouse monoclonal
antibody with human immunoglobulin.
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9. POLYCLONAL ANTIBODIES
• Anti-lymphocyte immunoglobulin (ALG )
and anti-thymocyte immunoglobulin ( ATG
) are obtained by immunizing horses
with human lymphocytes or with fetal
thymic tissue respectively.
• These antibodies interact with multiple
surface proteins implicated in T cell signal
transduction and have indiscriminate
action against both useful T cells and
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those that produce unwanted effects.
POLYCLONAL ANTIBODIES…
• The immunoglobulin ‘ recognizes ‘ and
binds to protein on the lymphocyte surface
causing exposure of the complementbinding site on the Fc portion of the
immunoglobulin; this activates the
complement system leading to the lysis of
the lymphocyte.
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POLYCLONAL ANTIBODIES…
• The unwanted effects are mainly
those to be expected with injection of
foreign protein.
• Antibodies against the foreign
immunoglobulin can be produced;
anaphylactic reaction can occur.
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10. MONOCLONAL ANTIBODIES
• Monoclonal antibodies directed against surface
component of T cells include immunoglobulin
targeting the complex CD3 protein with antigen
receptor ( muromonab-CD3; OKT3 ), the CD4
co-receptor and IL-2 receptor.
• Some are currently being used, some are being
assessed.
• Initial doses of OKT3 can cause fever,
hypotension, pulmonary oedema, nephropathy
and encephalopathy, which is thought to be due
to cytokine release; pretreatment with steroids
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diminishes these effects.
11. RAPAMYCIN ( SIROLIMUS )
• This is a macrolide antibiotic that, like
Tacrolimus, binds to the intracellular
immunophilin FKBP.
• However, the complex does not bind calcineurin
nor does it affect IL-2 gene transcription; it
interferes with the IL-2 signal transduction
pathway, blocking the cell cycle of activated
T cell in G1 phase .
• Rapamycin competes with Tacrolimus for FKBP
in vitro but their effects are additive in vivo.
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RAPAMYCIN ( SIROLIMUS )
• This drug also reduces smooth muscle
proliferation.
• Phase I and II clinical trials of Rapamycin
supplementation of Cyclosporin regimes
are under way.
• Nephrotoxicity and hypertension have not
been serious problems and
hyperlipidaemia and thrombocytopenia,
have responded to reduction in drug
dosage.
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