A Review of the Immunosuppressant Drug Cyclosporin A

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Table of Contents

Introduction
An Overview of Cyclosporin
Pharmacokinetics
Drug Uses
Mechanisms of Actions
Adverse Effects of the Agent
Contraindications
Conclusion
Works Cited

Introduction

Drugs play a crucial role in the health care provision industry. One class of drugs that play a significant role in organ transplantation and the treatment of immune mediated diseases are immunosuppressant drugs. These groups of drugs result in favorable medical results for patients by interfering with the natural immune process of the body. One powerful immunosuppressive drug is cyclosporin A (CsA) and since its discovery in the 1980s, transplant patients have used the drug extensively. This paper will set out to provide a concise yet informative research into the drug cyclosporin A. It will highlight the significance of this drug in health care, its pharmacokinetics, uses, mechanisms of actions, contraindications, and adverse effects.

An Overview of Cyclosporin

Cyclosporin A is a “neutral lipophilic cyclic undecapeptide isolated from the fungus Hypocladium inflatum gams” (Matsuda and Koyasu 119). The drug was introduced into the market in the 1980s following the discovery of its immunosuppressant properties by a Norwegian biologist. The introduction of CsA had significant consequences for organ transplantation. Murphy declares that since its discovery, CsA has been a cornerstone of transplant immunosuppression (160). This drug greatly improved the outcomes for solid organ transplantation by preventing organ rejection.

Martin et al. document that CsA has gained widespread use in clinical organ transplantation and treatment of autoimmune diseases (318). CsA reduces the amount of time that organ transplant patients need to remain in hospital after the transplantation has taken place. Studies indicate that CsA administration significantly reduces the length of hospitalization by decreasing the complications that arise due to organ rejection (Martin et al. 318).

Pharmacokinetics

CsA is primarily administered to a patient orally but it can be taken intravenously if the patient is unable to take medication orally. However, intravenous CsA use is discouraged since it leads to additional side effects. CsA metabolism occurs almost entirely through the “hepatic and intestinal cytochrome P450 microsomal enzyme system” (Martin 319).

The pharmacokinetics of CsA vary depending on the form in which the drug is administered. When administered as an oil-based solution or gelatin capsule formulation, the peak blood concentrations occur after 2.5 hours. When administered as a microemulsion formulation, the drug is absorbed more rapidly with peak blood concentration occurring at 1.2 hours (Coukell and Plosker 693).

The use of CsA is complicated by the high inter-patient pharmacokinetic variability experienced. The variability makes it hard to accurately predict the correct dosage for all patients and places patients at risk of graft or organ rejection. Coukell and Plosker document that while there is a long history of CsA use in immunosuppressive therapy in transplant patients, this drug’s use is complicated by its poor and unpredictable gastrointestinal absorption leading to pharmacokinetic variability (704).

Due to the considerable inter-individual variation in CsA metabolism and distribution in the body, most patients are given an individually designed immunosuppressive regime with careful control of CsA (Tourchard and Bridoux 92). The variability of CsA absorption makes therapeutic drug monitoring for the patient essential especially for the first 2 weeks after the organ transplantation procedure.

Cyclosporin A is heavily present in blood with a concentration of between 41 and 58 percent in erythrocytes, 4 to 8 percent in lymphocytes and 33 to 47 percent in plasma (Murphy 161). The principle means of CsA elimination are through the bile, which accounts for up to 90% of the elimination. Only 1% of the orally administered doze remains unchanged and renal elimination accounts for 6% of the dose with as low as 0.1% of unchanged CsA found in urine.

Drug Uses

Due to its clinical efficacy as an immunosuppressant, CsA is employed in long-term maintenance therapy to decrease the probability of organ and graft rejection therefore saving lives and substantial health care costs. New liver transplant recipients experience fewer rejection episodes when they are treated with CsA. Research indicates that about 85% of transplant recipient were alive one year after their operation with CsA being used as an immunosuppressant (Coukell and Plosker 697). Rejection episodes might still be experienced with CsA use. However, the severity of the acute rejection episodes is significantly reduced therefore increasing the survival rates for the transplant patient.

Renal transplant patients also benefit from the use of CsA. Orme et al. state that the introduction of CsA increase the choice of immunosuppressant therapies that kidney transplant patients could use to prevent organ rejection (1264). The efficacy of this drug improved the chances of survival for renal transplant patients.

Cyclosporin A can be used to treat idiopathic nephrotic syndrome, a condition that occurs mainly in children and is generally characterized by high urinary protein levels. Patients suffering from this condition might become steroid resistant or steroid dependent making it impossible for INS to be treated using steroid based drugs (Henriques, Fabiola and Vaisbich 1197). Immunosuppressive drugs such as cyclosporin can be used to treat the disease with favorable outcomes.

Cyclosporin A is used to manage the immune mediated disease Psoriasis, which affects the skin. In this immune disease, the body’s immune system wrongly identified healthy skin cells as pathogens and reacts by causing an overproduction of skin cells to replace the presumed pathogens. Patients are treated with CsA to suppress the immune system and therefore mitigate the overproduction of new skin cells.

Mechanisms of Actions

The primary mechanism of action for CsA is as an immune modulator that prevents T-cell medicated immunoreactivity. CsA works by inhibiting the function of the T-cell, which are part of the white blood cells. The T-cells play a crucial role in the cell controlled immunity function of the white blood cells (Matsuda and Koyasu 122). The drug enters through the cell membrane and binds itself with high affinity to the cyclophilins, which are ubiquitous proteins processing enzymes found in the cytoplasm. The cyclophilins are a family of small proteins that have a high distribution in lymphoid cells and also exist in most human tissues. When CsA binds itself to cyclophilin, it forms a complex.

The cyclosporin-cyclophilin complex inhibits T-cell function by disrupting the calcineurin signaling function typically activates the T-cell receptors (Murphy 159). As such, there is reduced activation of the T-cell receptor during an immune response. By blocking T-cell activation, the proliferation of activated T-cells in the blood is inhibited therefore leading to immune suppression.

Adverse Effects of the Agent

All immunosuppressive medications expose the patients to varied side effects. One of the most serious side effects of CsA is the increased risk of development of cancer. Thoms states that patients who use CsA are predisposed to developing skin cancer and premalignant and malignant skin tumors can develop in areas of the skin that are exposed to sunlight (232). The association between skin cancer and CsA use is because of the mechanism of action of CsA (Thoms 232). This drug achieves its immunosuppressive effects by blocking calcineurin therefore preventing nuclear localization of NFAT. The drug also enhances the production of tumor promoting cytokines that can contribute to the development of cancer. CsA use impairs the person’s immune system therefore degrading the ability of the body to effectively eliminate tumor cells. In addition to this, CsA has a negative effect on the ability of DNA to repair itself.

CsA use may result in a number of significant adverse drug reactions in the patient. These reactions include the development of peptic ulcers due to the erosive effect of the drug on the mucosa of the stomach. CsA also predisposes the patient to opportunistic infections. Since the drug interferes with the immunity of the body, the patient is vulnerable to a number of fungal and viral infections.

The drug can lead to liver damage due to hepatotoxicity, which is the damaging of the liver by chemicals. This chemical-driven liver damage by CsA occurs since the liver is responsible for clearing chemicals from the body. While hepatotoxicity mostly occurs due to drug overdose, it can occur even when CsA is used within therapeutic ranges due to the requirement for higher concentration of the drug in the blood for better response. CsA use can also cause nephrotoxicity, which is the negative effect of medication on the kidneys. The nephrotoxicity caused by CsA is well tolerated expect in patients who suffer from some form of renal impairment.

CsA also results in neurotoxicity, which is the condition where the normal function of the nervous system is altered by exposure to chemicals. CsA might lead to nervous tissue damage, which can impede on the normal functioning or even kill neutrons. This will have significant negative effects since the neurons are responsible for transmitting and processing signals to and from the brain. The severe side effects of CsA are responsible for the lack of universal use of this drug in spite of its high efficacy in preventing organ rejection (Matsuda and Koyasu 122). To control some of the side effects of CsA, the patient should have regular liver, kidney, and blood tests to check for toxicity.

Contraindications

Since CsA affects the kidneys though nephrotoxicity, patients using the drug should have good renal function. Patients taking drugs that are likely to reduce kidney activity, such as nonsteroidal anti-inflammatory agents, should avoid taking CsA. As an immunosuppressant, CsA reduces natural immunity and should therefore not be taken by patients who have active infections or a history of lymphoma. Patients who are currently taking immune stimulating drugs or products should not use CsA since the two drug groups will counteract each other (Murphy 166). Patients using CsA should avoid using other immunosuppressive agents since any immune suppression beyond that caused by the CsA therapy would be harmful to the person.

Patients with high blood pressure and other vascular related medical problems risk having their conditions exacerbated by CsA since the drug causes vasoconstriction. A person with high blood pressure will therefore be susceptible to adverse effects such as a stroke if he/she makes use of the drug. Pregnant women should not use CsA unless it is absolutely necessary since the drug is likely to lead to premature births and low birth weight (Murphy 166).

Conclusion

This paper set out to discuss the immunosuppressive drug, cyclosporin. The paper began by nothing that the introduction of CsA in the early 1980s improved the health outcomes of transplant patients. The paper has documented that CsA is mostly administered orally and it has a half-life of up to 24hrs. The drug has a high clinical efficacy as an immunosuppressant and it is used to prevent organ rejection and treat autoimmune conditions. However, CsA has significant adverse effects including increased risk of skin cancer, peptic ulcers, liver damage, and kidney damage. In spite of these significant adverse effects, CsA continues to be a preferred immunosuppressive drug due to its positive outcomes for patients.

Works Cited

Coukell, Allan and Plosker Greg. “Cyclosporin Microemulsion: A Pharmacoeconomic Review of its Use Compared with Standard Cyclosporin in Renal and Hepatic Transplantation.” Pharmacoeconomics 14.6 (2000): 691-708. Web.

Henriques, Luciana, Fabiola Marcos and Vaisbich, Maria. “Pharmacokinetics of Cyclosporin – a Microemulsion in Children with Idiopathic Nephrotic Syndrome.” Clinics 67.10 (2012): 1197–1202. Web.

Martin, Jill, Daoud Jamal, Schroeder Timothy and First Roy. “The Clinical and Economic Potential of Cyclosporin Drug Interactions.” PharmacoEconomics 15.4 (2009): 317-337. Web.

Matsuda, Satoshi and Koyasu Shigeo. “Mechanisms of Action of Cyclosporine.” Immunopharmacology 47.1 (2000): 119–125. Web.

Murphy, John. Clinical Pharmacokinetics. NY: ASHP, 2011. Print.

Orme, Michelle, Wieslaw Jurewicz, Kumar Nagappan and McKechnie Tracy. “The Cost Effectiveness of Tacrolimus versus Microemulsified Cyclosporin: A 10-Year Model of Renal Transplantation Outcomes.” Pharmacoeconomics 21.17 (2003): 1263-1276. Print.

Thoms, Martin. “Cyclosporin A, but not Everolimus, Inhibits DNA Repair Mediated by Calcineurin: Implications for Tumorigenesis under Immunosuppression.” Experimental Dermatology 20.1(2010): 232–236. Web.

Tourchard, Verove and Bridoux Bauwens. “Cyclosporin Maintenance Monotherapy After Renal Transplantation: What Factors Predict Success?” BioDrugs 12.2 (2002): 91-113. Web.

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