Immunosuppression

Adverse reactions. Ciclosporin constricts the pre-glomerular afferent arteriole and reduces glomerular filtration; acute or chronic renal impairment may develop if the trough plasma concentration consistently exceeds 250 mg/1. In the main, renal changes resolve if the drug is withdrawn. Hypertension develops in about 50% of patients, more commonly when a corticosteroid is co-administered but possibly due in part to mineralocorticosteroid action of Ciclosporin. The blood pressure can be controlled by standard antihypertensive therapy without need to discontinue Ciclosporin. Other adverse effects include gastrointestinal reactions, hepatotoxicity, hyperkalemia, hypertichosis, gingival hypertrophy and convulsions. The clinical syndrome of thrombotic thrombocytopenic purpura may rarely follow cyclosporin therapy.

Interactions. Careful attention to co-administered drugs is essential as many may interact. The plasma concentration of Ciclosporin, and risk of toxicity, is increased by drugs that include ketoconazole, erythromycin, chloroquine, Cimetidine, oral contraceptives, anabolic steroids and calcium channel antagonists. Grapefruit juice also elevates plasma Ciclosporin concentrations; flavonoids in the juice inhibit the cytochrome that metabolises Ciclosporin. Drugs that reduce the plasma concentration of Ciclosporin, risking loss of effect, include enzyme-inducing antiepileptics (e.g. phenytoin, carba-mazepine, phénobarbital) and rifampicin. Inherently nephrotoxic drugs add to the risk of renal damage with Ciclosporin, e.g. aminoglycoside antibiotics, amphotericin, NSAIDs (diclofenac). Potassium-sparing diuretics add to the risk of hyperkalaemia.

Tacrolimus is a macrolide immunosuppressant agent that is isolated from a bacterium. It acts like Ciclosporin and is used to protect and treat liver and kidney grafts when conventional immunosuppressants fail. Such rescue treatment may be graftor life-saving. Tacrolimus may cause nephrotoxicity, neurotoxicity, disturbance of glucose metabolism, hyperkalaemia and hypertrophic cardiomyopathy.

Antilymphocyte immunoglobin is used in organ graft rejection, a process in which lymphocytes are involved; it is made by preparing antisera to human lymphocytes in animals (horses or rabbits); allergic reactions are common. It largely spares the patient's response to infection. It is also used in the treatment of severe aplastic anaemia and frequently produces a good partial response either as a single agent or in combination with ciclosporin. It is the treatment of choice for patients with severe aplastic anaemia for whom no bone marrow donor can be found or who are too old or unfit for bone marrow transplant.

Mycophenolate selectively blocks the proliferation of T and B lymphocytes and acts like azathioprine; it is being evaluated in combination immunosuppressive regimens for organ transplantation.

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