Immunosuppressant Drugs

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Chapter: Essential pharmacology : Immunosuppressant Drugs, Gene Therapy

These are drugs which inhibit cellular/humoral or both immune response and have their major use in organ transplantation and autoimmune diseases.



These are drugs which inhibit cellular/humoral or both immune response and have their major use in organ transplantation and autoimmune diseases. The drugs are:


1. Calcineurin Inhibitors (Specific Tcell inhibitors)

Cyclosporine (Ciclosporin), Tacrolimus


2. Antiproliferative Drugs (Cytotoxic drugs)

Azathioprine, Cyclophosphamide, Methotrexate, Chlorambucil, Mycophenolate mofetil (MMF)


3. Glucocorticoids

Prednisolone and others


4. Antibodies

Muromonab CD3, Antithymocyte globulin (ATG), Rho (D) immuneglobulin


The development of immune response and the sites of action of different immunosuppressants is summarized in Fig. 63.1.




(Specific Tcell inhibitors)




It is a cyclic polypeptide with 11 amino acids, obtained from a fungus and introduced in 1977 as a highly selective immuno-suppressant which has markedly increased the success of organ transplantations. It profoundly and selectively inhibits T lymphocyte proliferation, IL2 and other cytokine production and response of inducer T cells to IL1, without any effect on suppressor Tcells. Lymphocytes are arrested in G0 or G1 phase.


The CD4 molecule associated with T cell receptor on helper T cells anchors the major histocompatibility complex class II (MHC II) carrying the antigen peptide so that it is able to activate the T cell receptor (Fig. 63.2). Stimulation of T cell receptor produces a cascade of Ca2+ dependent events and protein kinase C (PKC) activation. The Ca2+ ions after binding to calmodulin activate a membrane associated serine/ threonine phosphatase called calcineurin which dephosphorylates regulatory protein ‘nuclear factor of activated Tcell’ (NFAT), permitting its intranuclear migration and transcription of cytokine genes leading to production of IL2 along with other interleukins, GMCSF, TNFα, interferon, etc. Cyclosporine enters target cells and binds to cyclophilin, an immunophilin class of protein. The complex then binds to and inactivates calcineurin response of the helper T cell to antigenic stimulation fails. Cyclosporine also enhances expression of an inhibitor of IL2 which attenuates IL2 stimulated Tcell proliferation and production of killer lymphocytes. Cyclosporine is most active when administered before antigen exposure, but can, in addition, suppress the responses of primed helper T cells; hence useful in autoimmune diseases as well.



Cyclosporine selectively suppresses cell-mediated immunity, prevents graft rejection and yet leaves the recipient with enough immune activity to combat bacterial infection. Unlike cytotoxic immunosuppressants, it is free of toxic effects on bone marrow and RE system. Humoral immunity remains intact. However, it is nephrotoxic—the major limitation, and impairs liver function. Other adverse effects are sustained rise in BP, precipitation of diabetes, anorexia, lethargy, hyperkalaemia, opportunistic infections, hirsutism, gum hyperplasia, tremor and seizures.


Cyclosporine is the most effective drug for prevention and treatment of graft rejection reaction. It is routinely used in renal, hepatic, cardiac, bone marrow and other transplantations. For induction it is started orally 12 hours before the transplant and continued for as long as needed. When graft rejection has started, it can be given i.v., because oral bioavailability is low, dependent on presence of bile and is highly variable. It is concentrated in WBCs and RBCs, metabolized in liver by CYP3A4 and excreted in bile. The plasma t½ is biphasic 4–6 hr and 12–18 hr.


Dose: 10–15 mg/kg/day with milk or fruit juice till 1–2 weeks after transplantation, gradually reduced to maintenance dose of 2–6 mg/kg/day. Therapy may be started with 3–5 mg/kg i.v. infusion.


IMUSPORIN 25, 50, 100 mg soft gelatin cap. Absorption from this preparation is slower and more variable. A newer microemulsion formulation SANDIMMUN NEORAL, PANIMUN BIORAL 25, 50, 100 mg caps, has more consistent bioavailability. For i.v. use cyclosporine is dispersed in cremaphor emulsion: SANDIMMUN, PANIMUN 100 mg/ml inj in 1 ml, 5 ml, 50 ml vial, which is diluted and infused over 4–6 hours. An acute reaction consisting of chills, fever, bodyache and dyspnoea often occurs because of the solvent; i.v. cyclosporine is used only in emergency, and is substituted by oral medication as soon as possible.


Cyclosporine is a second line drug in autoimmune diseases, like severe rheumatoid arthritis, uveitis, bronchial asthma, inflammatory bowel disease, dermatomyositis, etc. and in psoriasis, especially to suppress acute exacerbations. It is often used along with corticosteroids or Mtx. Good results have been obtained in some cases of aplastic anaemia. For these conditions, lower doses (2–5 mg/kg/day) are needed and adverse effects are mild. However, it is not curative and relapses occur when the drug is withdrawn.


Drug interactions with a large number of drugs occur. All nephrotoxic drugs like aminoglycosides, vancomycin, amphotericin B and NSAIDs enhance its toxicity. By depressing renal function, it can reduce excretion of many drugs. Phenytoin, phenobarbitone, rifampin and other enzyme inducers lower its blood levels so that transplant rejection may result. On the other hand, CYP3A4 inhibitors erythromycin, ketoconazole and related drugs inhibit its metabolism to increase bioavailability and cause toxicity. Pot. supplements and K+ sparing diuretics can produce marked hyperkalaemia in patients on cyclosporine.


Tacrolimus (FK506)


It is a newer immunosuppressant chemically different from cyclosporine, but having the same mechanism of action, and is ~100 times more potent. It binds to a different cytoplasmic immunophilin protein labelled ‘FKBP’, but the subsequent steps are the same, i.e. inhibition of helper T cells via calcineurin.


Tacrolimus is administered orally as well as by i.v. infusion. Oral absorption is variable and decreased by food. It is metabolized by CYP3A4 and excreted in bile with a longer t½ of 12 hour. Therapeutic application, clinical efficacy as well as toxicity profile are similar to cyclosporine. It is particularly valuable in liver transplantation because its absorption is not dependent on bile. Because of more potent action, it is also suitable for suppressing acute rejection that has set in. Hypertension, hirsutism and gum hyperplasia are less marked than cyclosporine, but tacrolimus is more likely to precipitate diabetes, cause neurotoxicity, alopecia and diarrhoea. Dose limiting toxicity is renal.


Dose: 0.050.1 mg/kg BD oral (for renal transplant), 0.1–0.2 mg/kg BD (for liver transplant).


TACROMUS, PANGRAF 1, 5 mg cap.



(Cytotoxic Immunosuppressants)


Certain cytotoxic drugs used in cancer chemotherapy exhibit prominent immunosuppressant action, mainly by preventing clonal expansion of T and B lymphocytes (see Fig. 63.1).




It is a purine antimetabolite which has more marked immunosuppressant than anti-tumour action. The basis for this difference is not clear, but may be due to its selective uptake into immune cells and intracellular conversion to the active metabolite 6mercaptopurine, which then undergoes further transformations to inhibit de novo purine synthesis and damage to DNA. It selectively affects differentiation and function of T cells and inhibits cytolylic lymphocytes; cell-mediated immunity is primarily depressed.


The most important application of azathioprine is prevention of renal and other graft rejection, but it is less effective than cyclosporine; generally combined with it or used in patients developing cyclosporine toxicity. It has also been used in progressive rheumatoid arthritis and some other autoimmune diseases.




This cytotoxic drug has more marked effect on B cells and humoral immunity compared to that on T cells and cell-mediated immunity. It has been particularly utilized in bone marrow transplantation in which a short course with high dose is generally given. In other organ transplants it is employed only as a reserve drug. In rheumatoid arthritis, it is rarely used, only when systemic manifestations are marked. Low doses are occasionally employed for maintenance therapy in pemphigus, systemic lupus erythematosus and idiopathic thrombocytopenic purpura.


Methotrexate (Mtx.)


This folate antagonist is a potent immunosuppressant which markedly depresses cytokine production and cellular immunity, and has anti-inflammatory property. It has been used as a first line drug in many autoimmune diseases like rapidly progressing rheumatoid arthritis, severe psoriasis, pemphigus, myasthenia gravis, uveitis, chronic active hepatitis. Low dose Mtx maintenance therapy is relatively well tolerated.




It has relatively weak immunosuppressant action which is sometimes utilized in autoimmune diseases and transplant maintenance regimens.


Mycophenolate mofetil (MMF)


It is a new immunosuppressant; prodrug of mycophenolic acid which selectively inhibits inosine monophosphate dehydrogenase an enzyme essential for de novo synthesis of guanosine nucleotides in the T and B cells (these cells, unlike others, do not have the purine salvage pathway). Lymphocyte proliferation, antibody production and cellmediated immunity are inhibited. As ‘add on’ drug to cyclosporine + glucocorticoid in renal transplantation, it has been found as good or even superior to azathioprine, but should not be combined with azathioprine. It can help to reduce the dose of cyclosporine and thus its toxicity. Vomiting, diarrhoea, leucopenia and predisposition to CMV infection, g.i. bleeds are the prominent adverse effects.


Dose: 1.0 g BD oral; CELLMUNE, MYCEPT, MYCOFIT 250, 500 mg tab/cap.




Glucocorticoids have potent immunosuppressant and anti-inflammatory action, inhibit several components of the immune response. They particularly inhibit MHC expression (Fig. 63.1) and proliferation of T lymphocytes. Expression of several IL and other cytokine genes is regulated by corticosteroids and production of adhesion molecules is depressed. The short-lived rapid lymphopenic effect of steroids is due to sequestration of lymphocytes in tissues. Accordingly, they have a more marked effect on CMI.


The corticosteroids are widely employed as companion drug to cyclosporine in various organ transplants. In case graft rejection sets in—large doses of corticoids i.v. are employed for short periods. They are used in practically all cases of severe autoimmune diseases, especially during exacerbation. Long-term complications are the greatest limitations of steroid use.




Muromonab CD3


It is a murine monoclonal antibody against the CD3 glycoprotein located near to the T cell receptor on helper T cells (see Fig. 63.2). Binding of muromonab CD3 to the CD3 antigen obstructs the binding of MHC IIantigen complex to the T cell receptor: antigen recognition is interfered, so that participation of T cells in the immune response is prevented and T cells rapidly disappear from circulation leading to an immune blocked state. The response to this monoclonal antibody is less variable than to the polyclonal anti-thymocyte globulin. It is also less likely to produce allergic reactions.


Muromonab CD3 has been used as induction therapy together with corticosteroids and azathioprine with delayed use of cyclosporine in ‘sequential regimen’ for organ transplantation. This serves to postpone potential nephro and hepatotoxicity of cyclosporine. This sequential regimen has been found to be more effective than the standard triple therapy in renal and hepatic, but not in cardiac transplant recipients. It is also valuable for steroid-resistant rejection reactions and has been used to deplete T cells from the donor bone marrow before transplantation.


The initial doses of muromonab CD3 are associated with ‘cytokine release’ syndrome with flu like symptoms: chills, rigor and wheezing. Occasionally aseptic meningitis, intragraft thrombosis, pulmonary edema, seizures and a shock like state are produced. High dose corticosteroid pretreatment reduces the reaction.


Antithymocyte Globulin (ATG)


It is a polyclonal antibody purified from horse or rabbit immunized with human thymic lymphocytes which binds to T lymphocytes and depletes them. It is a potent immunosuppressant and has been used primarily to suppress acute allograft rejection episodes, especially in steroid-resistant cases or is combined with them. It can also be used in induction regimens, but responses are less consistent than with muromonab CD3, and it has the potential to produce serum sickness or anaphylaxis, but is less expensive than muromonab CD3.


LYMPHOGLOBULIN (equine) 100 mg/vial inj.; 10 mg/ kg/day i.v.; THYMOGLOBULIN (rabbit) 25 mg/vial inj.; 1.52.5 mg/ kg/day.


ATG 100 mg inj; 200 mg i.v./day.


Anti-D Immuneglobulin


It is human IgG having a high titer of antibodies against Rh (D) antigen. It binds the Rho antigens and does not allow them to induce antibody formation in Rh negative individuals. It is used for prevention of postpartum/postabortion formation of antibodies in RhoD negative, DU negative women who have delivered or aborted an RhoD positive, DU positive baby/foetus. Administered within 72 hours of delivery/ abortion, such treatment prevents Rh haemolytic disease in future offspring. It has also been given at 28th week of pregnancy.


Dose: 250–350 μg i.m. of freez dried preparation. RHIGGAL 100, 350 μg vial, RHESUMAN, RHOGAM 300 μg/vial inj.


Higher doses (1000–2000 μg) are needed for Rh negative recipients of inadvertantly administered Rh positive blood. It should never be given to the infant or to RhoD positive, DU positive individuals.


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