INTRODUCTION:

Immunosuppression involves an act that reduces the activation or efficacy of the immune
system. Some portions of the immune system itself have immunosuppressive effects on other
parts of the immune system, and immunosuppression may occur as an adverse reaction to
treatment of other conditions. Immunosuppressants are used to control severe manifestations
of allergic, autoimmune and transplant-related diseases. Some drugs have a diffuse effect on
the immune system while others have specific targets. Drugs with diffuse effects are more
likely to cause damaging adverse effects, but the effectiveness of the more specific drugs may
be reduced if their action can be bypassed by alternative metabolic pathways. Treatment
protocols therefore frequently use drug combinations to minimize adverse effects and to
prevent resistance to treatment. Although protocols are essential to allow scientific
evaluation, the clinician must be prepared to tailor treatment based on the ongoing assessment
of drug effects, disease activity and the robustness of the individual patient.

Clinically they are used to:

 Prevent the rejection of transplanted organs and tissues (e.g. bone marrow, heart, kidney,
liver)

 Treatment of autoimmune diseases or diseases that are most likely of autoimmune origin
(e.g. rheumatoid arthritis, myasthenia gravis, systemic lupus erythematosus, Crohn's disease,
and ulcerative colitis).

 Treatment of some other non-autoimmune inflammatory diseases (eg. long term Allergic
Asthma control).

Cortisone was the first immunosuppressant identified, but its wide range of side effects
limited its use. The more specific azathioprine was identified in 1959, but it was the
discovery of cyclosporine in 1970 that allowed for significant expansion of kidney
transplantation to less wellmatched donor-recipient pairs as well as broad application of liver
transplantation, lung transplantation, pancreas transplantation, and heart transplantation.
Some immunosuppressants act through immunodepletion of effector cells, while others are
predominantly immunomodulatory, affecting the activity of cells, usually through cytokine
inhibition

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Classification:

There are several different types of immunosuppressant drugs. The drug or drugs you’ll be
prescribed depend on whether you have an organ transplant, an autoimmune disorder, or
another condition.

Corticosteroids

 prednisone (Deltasone, Orasone)

 budesonide (Entocort EC)

 prednisolone (Millipred)

Janus kinase inhibitors

 tofacitinib (Xeljanz)

Calcineurin inhibitors

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  cyclosporine (Neoral, Sandimmune, SangCya)

 tacrolimus (Astagraf XL, Envarsus XR, Prograf)

mTOR inhibitors

 sirolimus (Rapamune)

 everolimus (Afinitor, Zortress)

Biologics

 abatacept (Orencia)

 adalimumab (Humira)

 anakinra (Kineret)

 certolizumab (Cimzia)

 etanercept (Enbrel)

 golimumab (Simponi)

 infliximab (Remicade)

 ixekizumab (Taltz)

 natalizumab (Tysabri)

 rituximab (Rituxan)

 secukinumab (Cosentyx)

 tocilizumab (Actemra)

Monoclonal antibodies

 basiliximab (Simulect)

 daclizumab (Zinbryta)

Treatment regimen:

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All immunosuppressant drugs are available only by a prescription from your doctor.

Immunosuppressant drugs come as tablets, capsules, liquids, and injections. Your doctor will
decide the best drug forms and treatment regimen for you.

They may prescribe a combination of drugs. The goal of immunosuppressant therapy is to

find the treatment plan that will suppress your immune system while having the fewest, least
harmful side effects.

If you take immunosuppressant drugs, you must take them exactly as prescribed. if you have
an autoimmune disorder, a regimen change can cause a flare-up of your condition. If you’re
an organ recipient, even the slightest change from the medication regimen can trigger an
organ rejection. No matter why you’re being treated, if you miss a dose, be sure to call your
doctor right away.

Indications:

Tofacitinib:

It is a nonbiologic small molecule that works inside the cell to inhibit inflammation by
blocking JAK-dependent signaling pathways and production of many inflammatory cytokines
tofacitinib is indicated for the treatment of adult patients with moderately to severely
active ulcerative colitis (UC), who have had an inadequate response or who are intolerant to
TNF blockers.

Azathioprine:

It is a purine antimetabolites. Its immunosuppressive action is more marked. It may be due

to selective uptake by the immune cellsand conversion intra-cellular to active metabolite 6-
mercaptopurine.
It is useful in kidney transplantation, glomerulonephritis, rheumatoid arthritis
It is less effective than cyclosporine and used in patients developing cyclosporine
toxicity. It has been used safely in pregnancy. Azathioprine has been used in animals for the
treatmentof immune-mediated anemia, immune-mediated skin disease, acquired myasthenia
gravis and colitis.

Sirolimus

It is a macro-cyclic lactone, a microbial product produced by Streptomyces hygroscopicus.

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It is a structural analogue of tacrolimus but its action and side effects are somewhat
differentIt is used as prophylactic agent in organ transplant rejection. It is used in
combinationwith cyclosporine, tacrolimus and glucocorticoids. It is used in combination with
glucocorticoids andmycophenolate mofetil in place of calcineurin inhibitor to avoid the
nephrotoxicity in patients

Tacrolimus (FK506)

Tacrolimus is a macrolide antibiotic which is a metabolite of an actinomyces Streptomyces

tsukubaensis. It is originally termed as FK 506, having action similar to cyclosporine.
Tacrolimus is used for the immunosuppression during the transplantation of kidney
and liver, idiopathic facial dermatitis .

Glucocorticoids

These are steroids which are released as needed and not stored preformed. Prednisone,
prednisolone and other glucocorticoids are used alone or in combination with other
immunosuppressive agents for the treatment of autoimmune diseases and transplant
rejection. These drugs have both immunosuppressive as well as anti-inflammatory action.
When these drugs are used to prevent graft rejection, they suppress the initiation and
generation of new immune response more efficiently than a response that is already
established and in which clonal proliferation has already occurred

Cyclosporine (Cyclosporine A)
It is a fungal cyclic polypeptide having eleven amino acids. It was discovered by Borel and
coworkers during the screening of fungal products, for antifungal activity. Cyclosporine is a
metabolic product of the fungus Beauveria nivea. It is highly lipophilic and hydrophobic in
nature. It was introduced in 1977 as highly selective immunosuppressant. It is most
widely used immunosuppressive drug in organ transplant patients now a days to prevent the
acute rejection and sometimes used in renal diseases (especially in nephrotic syndrome)

Side effects:

All immunosuppressant drugs carry the serious risk of infection. When an

immunosuppressant drug weakens your immune system, your body becomes less resistant to
infection. That means they make you more likely to get infections. It also means that any
infections get will be harder to treat.

If you have any of these symptoms of infection, call your doctor right away:

 fever or chills

 pain in the side of your lower back

 trouble urinating

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  pain while urinating

 frequent urination

 unusual tiredness or weakness

 loss of appetite
 nausea
 vomiting
 increased hair growth
 hand trembling.

Drug interactions

Before you start taking an immunosuppressant drug, be sure to tell your doctor about all
medications you take. This includes prescription and over-the-counter medications, as well as
vitamins and supplements. Your doctor can tell you about the possible drug interactions that
your immunosuppressant medication might cause. Like side effects, the risk of drug
interactions depends on the specific drug you take.

Warnings

Immunosuppressant drugs can cause problems for people with certain health conditions. Tell
your doctor if you have any of these conditions before you start to take immunosuppressants:

 allergy to the specific drug

 history of shingles or chickenpox

 kidney or liver disease

AZATHIOPRINE
Azathioprine (Imuran) belongs to a class of drugs called DMARDs, Immunomodulators;
Immunosuppressants. Azathioprine inhibits purine synthesis. Purines are needed to
produce DNA and RNA. By inhibiting purine synthesis, less DNA and RNA are produced for
the synthesis of white blood cells, thus causing immunosuppression.

THERAPEUTIC APPLICATIONS

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  It is used to prevent organ rejection in people who have received a kidney transplant. It is
usually taken along with other medications to allow your new kidney to function
normally.
 Azathioprine is indicated as an adjunct for the prevention of rejection in renal
homotransplantations. Experience with over 16,000 transplants shows a 5-year
patient survival of 35% to 55%.
 Azathioprine is also used to treat rheumatoid arthritis. IMURAN is usually given on a
daily basis. The initial dose should be approximately 1.0 mg/kg (50 to 100 mg) given
as a single dose or on a twice-daily schedule. The dose may be increased, beginning at
6 to 8 weeks and thereafter by steps at 4-week intervals, if there are no serious
toxicities.
 It was widely used for the treatment of multiple sclerosis until the first half of the
1990s. Concerns about increased risk of malignancy has led to a decreased use, yet it
is still used in maintenance treatment for people who frequently relapse.
 Azathioprine is sometimes used in systemic lupus erythematous, requiring a
maintenance dose of 15 mg or higher of prednisolone in those who experience
recurrent flares
 It is used as an add-on therapy when steroid therapy is given by mouth for
pemphigus and myasthenia gravis, as a "steroid-sparing" agent
 Azathioprine has been used in the management of moderate to severe chronically
active Crohn's disease.

STRUCTURE ACTIVITY RELATIONSHIP (SAR)

 The activity of the drug increases with increase in the carbon chain upto 15-16
carbons, after that, it again decreases.
 Substituent at position 6 which can lead to the increase in the resonance at 6th position
will lead to increase in the activity of the drug.
 Introduction of the hydrophobic substituent at 6th position will increase the activity of
the drug.
 Substitutions at 2nd position may not change the activity of the drug, or it may
decrease the activity of the drug depending upon the type of substituent.

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CYCLOSPORINE

Cyclosporine (Neoral) belongs to a class of drugs known as immunosuppressant. Its major

mode of action is inhibition of the production of cytokines involved in the regulation of T-
cell activation. In particular, cyclosporine inhibits the transcription of interleukin 2.

THERAPEUTIC APPLICATIONS OF CYCLOSPORINE:

 It works by slowing down body's defense system (immune system) to prevent the
body from rejecting a transplanted organ that’s why it is administered to patients
who have received a liver, kidney, or heart transplant.
 It is usually used along with other medications to allow your new organ to function
normally.
 It may also be used to treat other conditions that may be helped by affecting
the immune system (e.g., Crohn's disease, ulcerative colitis).
 Prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants in
combination with corticosteroids.
 Children as young as 6 months have received cyclosporine to prevent solid organ
transplant rejection
 Used for severe active, rheumatoid arthritis where the disease has not adequately
responded to methotrexate; may be used in combination with methotrexate.
Discontinue if no improvement observed by 16 weeks.
 Indicated for treatment of adult, non-immunocompromised patients with
severe, recalcitrant, plaque psoriasis who have failed to respond to at least 1 systemic
therapy (e.g., PUVA, retinoids, or methotrexate) or in patients for whom
other systemic therapies are contraindicated, or cannot be tolerated. It is highly
effective in clearing psoriasis and can prevent relapse
 Used as an ophthalmic emulsion for the treatment of dry eyes (Restasis)
 Also used in severe atopic dermatitis ,Kimura's disease, pyoderma gangrenosum,
chronic autoimmune urticarial.

STRUCTURE ACTIVITY RELATIONSHIP (SAR)

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  Cyclosporine A is an 11 residue macrocyclic peptide.
 It is synthesized by a non- ribosomal peptide synthetase, cyclosporine synthetase.

 Seven peptide bonds are N- methylated (highlighted in blue). Two residues possess
non-proteinogenic side chains (highlighted in pink) and a single D –alanine.

 Pgp inhibition is favored by larger hydrophobic side chains on cyclosporine residues

1, 4, 6, and 8 and a smaller one on residue 7 with no effect on the residue 5 side chain.

 A large portion of the cyclosporine molecule is involved in interactions with its

lymphocyte receptor and that this includes amino acids 1, 2, 3 and 11.
 Essential for the immunosuppression are the amino acids methylated butenyl-methyl-
L4 threonine (MeBmt), Abu, Sar, and MeVal in the positions 1, 2, 3 and 11.

DIFFERENCE BETWEEN CYCLOSPORINE AND AZATHIOPRINE

CYCLOSPORINE
Its major mode of action is inhibition of the
production of cytokines involved in the
regulation of T-cell activation. In particular,
cyclosporine inhibits the transcription of
interleukin 2.
AZATHIOPRINE
Azathioprine inhibits purine synthesis. Purines
are needed to produce DNA and RNA. By
inhibiting purine synthesis, less DNA and
RNA are produced for the synthesis of white
blood cells, thus causing immunosuppression.

It does not affect blood sugar levels as much. Effects blood sugar levels

Used for prevention of heart, kidney, liver and Used for kidney and pancreas transplant
lung transplant rejection. rejection.
Used in psoriasis. Used in dermatitis.

Possible side effects include abnormal kidney
function, tremors, gum swelling, blood cell
tumor, liver damage, acne etc.
Risk factors include cancer, serious infections,
high blood pressure and kidney damage.
Possible side effects include infections ,
leukopenia in which leucocytes count is
<2500 cells/mm3, Increased stomach
irritation, abdominal pain, Changes in hair
color and texture, along with hair loss, Blood
in the urine or stool, unusual bruising.
Risk factors include harm to fetus, increased
risk for infection, decreased blood cells etc.

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Despite mild nephrotoxicity, cyclosporine is It is less effective primary immunosuppressant
superior to azathioprine as primary than cyclosporine.
immunosuppressant in cadaver kidney
transplantation according to research studies.
It increases blood pressure and serum creatinine It doesn’t increase blood pressure and serum
level in patients with Rheumatoid Arthritis. creatinine level in patients with Rheumatoid
Arthritis.

It is safe to use in pregnancy. Not safe to use in pregnancy.

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