Drugs which are used to suppress the immunity are called immunosuppressant. The ability of the body to recognize self from non-self is the basis of immunity. It is liable to cause disorders due to failure to recognize and tolerate antigen produced by its own tissues. This may cause exacerbation of an existing disease process called autoimmune diseases. Immunosuppressive drugs are useful in:

1. Treating autoimmune diseases and

2. Preventing immune-rejection of organ transplants.

Immunosuppressive drugs can be classified into four groups:

Glucocorticoids Prednisone and prednisolone

Cytostatics Alkylating agents

Antimetabolites

Cytotoxic antibiotics

Antibodies Polyclonal antibodies

Monoclonal antibodies

T-cell receptor directed antibodies

IL-2 receptor directed antibodies

Selective inhibitor of cytokine production and function Cyclosporin

Tacrolimus

Sirolimus

Cyclosporine

Cyclosporine, a Calcineurin Inhibitor is a lipophilic cyclic polypeptide of 11 amino acids.

Cyclosporine isolated from Tolypocladium inflatum (soil fungus). (Harvey et al.,2012.)

MECHANISM OF ACTION

When T-cells activated they increase IL-2 production.

When T-cells activated intracellular Ca2+ increased which activate calcineurin, a Ca2+ dependent phosphatase. Calcineurin dephosphorylated NFAT(nuclear factor of activated T-cells), a cytoplasmic transcription factor.

Then NFAT moves to the nucleus and transcription of IL-2 gene occurs which eventually produce IL-2.

Cyclosporine complex with cyclophilin(immunophilin, which is a cytoplasmic receptor protein present in target cells). This complex can bind to calcineurin which prevent dephosphorylation of NFAT. As a result, NFAT does not enter the nucleus and gene transcription does not occur. Thus T lymphocyte fails to respond to specific antigenic stimulation.(Goodman et al., 2011)

Fig: Mechanism of Cyclosporine

PHARMACOKINETICS

Cyclosporine may be given either IV infusion or orally.

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The oral dosage forms can be soft gelatin capsules and oral solutions.

Oral absorption is variable. P-glycoprotein (P-gp), a drug efflux pump can limit cyclosporine absorption (as Cyclosporine is a substrate for P-gp) by transporting the drug into the gut lumen.

Distribution of cyclosporin depends on its physicochemical characteristics and biological carriers such as lipoproteins and RBC in blood. Cyclophilin influences distribution of cyclosporin in the body. Though Cyclosporine is lipophilic it does not appear in the brain. About 50% of the drug is associated with the blood fraction. Half associated with erythrocytes, and less than one tenth associated with lymphocytes.

Cyclosporine is extensively metabolized, primarily by hepatic CYP3A4. Interpatient variability may be due to metabolism by cytochrome P450 (CYP3A4). It is unclear whether any of the 25 or more metabolites have any activity.

Drug elimination occurs via the bile as metabolites. (Fahr, 1993)

Sirolimus

Sirolimus (SRL) is a macrolide obtained from fermentations of a soil mold. SRL is approved for use in renal transplantation, to be used together with CsA (cyclosporine) and corticosteroids, thereby allowing lower doses of those medications to be employed and thus, lowering their toxic potential. The combination of SRL and CsA is apparently synergistic because SRL works later in the immune activation cascade.

MECHANISM OF ACTION

Sirolimus (SRL) bind to the cytoplasmic FK-binding protein, but instead of forming a complex with calcineurin, SRL binds to the mTOR (mammalian target of Rapamycin). Binding of SEL to mTOR blocks the progression of activated T-cells (from the G1 to the S phase of the cell cycle) and consequently the proliferation of these cells.

SRL does not own its effect to lowering IL-2 production but rather inhibiting the cellular responses to IL-2.

Fig: Mechanism of Sirolimus

PHARMACOKINETICS

1. The drug is available only as oral preparation. Although it is readily absorbed, high fat meals can decrease the drug’s absorption.

2. SRL is extensively bound to plasma proteins and its immunosuppressive action persist for six months after suspension of therapy.

3. It is metabolized by CYP-450 (CYP-3A4 isozyme)

4. The parent drug and its metabolites are predominantly eliminated in the feces.

Prednisone and Prednisolone

Prednisone and prednisolone are inter-convertible to each other through metabolism. Prednisolone is the one that is the pharmacologically active species. These are used as the most prescribed corticosteroids, to treat conditions like allograft rejection, systemic lupus erythematosus, asthma, and many inflammatory conditions(“Prednisone – DrugBank”, 2019). Among these two prednisone has little bit of mineralocorticoid activity and might affect ion exchange within the kidney.

MECHANISM OF ACTION

Prednisone is a GR (glucocorticoid receptor) agonist. Within the liver, it is coverted to prednisolone by the enzyme11-beta-hydroxysteroid dehydrogenase (“prednisone [TUSOM | Pharmwiki]”, 2019), which then crosses the cell membrane and bind to specific cytoplasmic receptors with high affinity. As a result, normal protein synthesis mechanism is affected as these agents inhibit the NF-?B (a protein complex that controls transcription of DNA, cytokine production and cell survival), leukocyte infiltration at the site of inflammation is inhibited, functions of inflammatory mediators are interfered, humoral immune responses are suppressed, and edemas or scar tissues are reduced (“Prednisone – DrugBank”, 2019). Phospholipase A2 inhibitory proteins produce the anti-inflammatory actions, lipocortins, which are responsible for the control of biosynthesis of potent inflammatory mediators, like PG (prostaglandins) and LT (leukotrienes). Prednisone stimulates secretion of many components of gastric juice. Reduction of the production of corticotropin may result inthe suppression of endogenous corticosteroids. As it has slight mineralocorticoid activity, sodium ions enter into cells and intracellular potassium loss is stimulated. This is especially evident in the kidney, whereby quick ion exchange produce sodium retention and hypertension in patients.

Fig: Mechanism of Prednisolone

PHARMACOKINETICS

Rapidly absorbed through oral administration, peakconcentrations in plasma is reached after 1-3 hours. Generally, plasma half-lifeof prednisone is slightly longer (3.4-3.8 hours) than prednisolone (2.1-3.5h). Any of the two drugs can be prescribed by the physician in most conditions(Pickup, 1979).

On average, the bioavailability of prednisolone after oral prednisone is approximately 80% of that after prednisolone.

An inter-subject variation in concentration of prednisolone has been found after both drugs, which suggest impaired absorption of drug might occur in some persons.

Prednisolone show dose-dependent pharmacokinetics; that is, an increased dose leads to an increased VD (volume of distribution) and plasma clearance.

Pharmacokinetics of prednisolone also depend on age; half-life is shorter in children. Prednisolone half-life is increased if liver disease is there, and, due to associated hypoalbuminaemia, also percentage of unbound drug is increased.Some recommend prednisone over prednisolone in case of liver disease.

These are excreted through the urine in the form of sulfate and glucuronide conjugates(“Prednisone – DrugBank”, 2019).

Mycophenolate mofetil

Azathioprine has for the most part been replaced by mycophenolate mofetil (MMF) because of the safety and efficacy in prolonging graft survival. It has been successfully used in heart, kidney, and liver transplants. As an ester, it is rapidly hydrolyzed in the gastrointestinal tract to mycophenolic acid (MPA), which is a potent, reversible, uncompetitive inhibitor of inosine monophosphate dehydrogenase, blocking the de novo formation of guanosine phosphate.

MECHANISM OF ACTION

Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), an inhibitor of inosine-5′-monophosphate dehydrogenase, has several immunosuppressant actions. MPA depletes guanosine and deoxyguanosine nucleotides preferentially in T and B lymphocytes, inhibiting proliferation and suppressing cell-mediated immune responses and antibody formation, major factors in acute and chronic rejection. MPA also can induce T-lymphocyte apoptosis. MPA suppresses dendritic cell maturation and can induce human monocyte-macrophage cell line differentiation, decreasing the expression of interleukin (IL)-1 and enhancing expression of the IL-1 receptor antagonist. In addition, MPA inhibits adhesion molecule glycosylation and expression and lymphocyte and monocyte recruitment. Activated macrophages produce nitric oxide (NO) and superoxide, which combine to generate tissue-damaging peroxynitrite. MPA depletes tetrahydrobiopterin and decreases NO production by inducible NO synthase without affecting constitutive NO synthase activity. By these mechanisms, MMF exerts anti-inflammatory activity, which could attenuate both acute and chronic rejection.

Fig: Mechanism of Mycophenolate mofetil

PHARMACOKINETICS

It has been given orally and it is well absorbed.

Magnesium and aluminium hydroxide impair its absorption and cholestyramine reduces its plasma concentration .

Mycophenolic acid and Glucuronidated metabolites are highly bound (>90%) to plasma albumin but no displacement type of interaction is reported.

Glucuronide is excreted in kidney predominantly.

Orally administered MMF is absorbed into the circulation , where plasma esterase rapidly cleave the ester bond to yield Mycophenolic acid .

Cyclosporine + Glucucorticoid + Mycophenolate mofetil is good in renal transplantation .

MMF help to reduce the dose of Cyclosporine and thus reduce toxicity.

Rituximab

Rituximab is monoclonal immunoglobulin antibody. It is an immunosuppressive agents. It targets CD20 antigen. It acts as cell surface marker found on B lymphocytes. It is indicated in Non-Hodgkin`s lymphoma. First therapeutic antibody rituximab has been approved for oncology patients and in 2016. (Pierpont, Limper and Richards, 2018)

MECHANISM OF ACTION

There are 4 types of mechanism.

Firstly, CD20 antigen is targeted by rituximab antibody and directly triggers apoptosis through both caspase dependent and independent mechanisms.

Secondly, bound rituximab can recruit C1 complex,triggers cascade reactions. They insert membrane attack complex (MAC) and cell lysis occurs. This is known as complement dependent cytotoxicity (CDC).

Fig: Mechanism of Rituximab

Thirdly, bound rituximab can be recognized by FcyRIII and recruit natural killer cells. This causes antibody dependent cell mediated cytotoxicity (ADCC). This release perforin that assembles into membrane compromising pores in the target cell and granzyme B enters the target cell, triggers apoptosis by cleaving caspases.

The last one is that macrophages recognize CD20 bound rituximab through Fcy receptors. This causes antibody dependent phagocytosis (ADP) of the target cell. (Pierpont, Limper and Richards, 2018)

Fig: Mechanism of Rituximab

PHARMACOKINETICS

When patients receiving rituximab once weekly or once every three weeks, the estimated terminal elimination half-life is 22 days. Pharmacokinetics of rituximab is not dependent on age and gender. The estimated clearance of rituximab is 0.335 L/day and volume of distribution is 3.1 litre.ADDIN CSL_CITATION {“citationItems”:[{“id”:”ITEM-1″,”itemData”:{“URL”:” Ministry of Health”,”type”:”webpage”},”uris”:[” Ministry of Health</i>, no date)”,”plainTextFormattedCitation”:”(Italian Ministry of Health, no date)”,”previouslyFormattedCitation”:”(<i>Italian Ministry of Health</i>, no date)”},”properties”:{“noteIndex”:0},”schema”:” Ministry of Health, no date)

CONCLUSION

The immunosuppressive drugs are a blessing to us and have been in use for not too long. These drugs are required to treat at the times when we need them the most like in case of an organ transplant, where immune system has to be suppressed for a brief period of time. Therefore, these agents are very much useful for such treatments. Moreover, inflammation due to the over production of inflammatory mediators can also be reduced though the use of these agents. However, use of such agents has to be strictly supervised by the physician. Thus, we can enjoy the full capacity of these agents in curing or preventing such diseases.

REFERENCES

 Allison, A. (2005). Mechanisms of action of mycophenolate mofetil. Lupus, 14(1_suppl), pp.2-8.

Fahr, Alfred. (1993). Cyclosporin Clinical Pharmacokinetics. Clinical pharmacokinetics. 24. 472-95. 10.2165/00003088-199324060-00004.

Goodman, L., Gilman, A., Brunton, L. and Knollmann, B. (2011). Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. McGraw Hill Education, pp.1009-1010.

Harvey, R., Clark, M., Finkel, R., Rey, J. and Whalen, K. (2012). Lippincott Illustrated Reviews: Pharmacology. pp.514-515.

Howland, R., Mycek, M., Harvey, R., Champe, P. and Mycek, M. (2006). Pharmacology. 3rd ed. Philadelphia: Lippincott Williams & Wilkins, pp.488,489,490.

Italian Ministry of Health (no date). Available at: (Accessed: 10 May 2019).

Pickup, M.E. Clin-Pharmacokinet (1979) 4: 111. T. M., Limper, C. B. and Richards, K. L. (2018) ‘Past, Present, and Future of Rituximab—The World’s First Oncology Monoclonal Antibody Therapy’, Frontiers in Oncology. Frontiers, 8, p. 163. doi: 10.3389/fonc.2018.00163.

Prednisone – DrugBank. (2019). Retrieved from [TUSOM | Pharmwiki]. (2019). Retrieved from

Rituximab (Rituxim) – Beacon Pharmaceuticals Limited (no date). Available at: (Accessed: 10 May 2019).

Satoskar, R., Bhandarkar, S., Rege, N., Satoskar, R. and Joshi, C. (2005). Pharmacology and pharmacotherapeutics. Mumbai: Popular Prakashan, p.1094.

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Immunosuppressant. (2019, Dec 12). Retrieved from http://paperap.com/413-final-2-best-essay/

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