Cyclosporine belongs to a family of cyclic polypeptides derived from the fungus Tolypocladium inflatum Gams. It is lipophilic and hydrophobic, and therefore must be solubilised for clinical use.
· To prevent transplant rejection in the transplantation of kidney, heart, and liver. Cyclosporine is usually combined with corti-costeroids. It is also being increasingly used in transplantation of other organs such as lung, pancreas, and bone marrow.
· Cyclosporine is also beneficial in the treatment of psoriasis, rheumatoid arthritis, Crohn’s disease, nephrotic syndrome, endogenous uveitis, atopic dermatitis, and acute ocular Behcet’s syndrome.
· There are also indications that cyclosporine may be useful in the treatment of primary biliary cirrhosis, pyoderma gangrenosum, polymyositis, aplastic anaemia, myasthenia gravis and severe asthma.
Cyclosporine can be administered orally, intravenously, or by injection. When given orally, it is metabolised on first pass through the liver, its absolute bioavailability being about 35%. Peak plasma concentration occurs at about 2.5 hours. About 50% of the drug in whole blood is bound to erythrocytes. The apparent volume of distribution in adults is 4.7 L/kg. Elimination occurs predominantly by metabolism in the liver by cytochrome P450 III A oxidase, and only about 0.1% of a dose is excreted unchanged.
therapeutic purposes, cyclosporine levels in plasma should not exceed 150 ng/ml
(600 ng/ml in whole blood).
· Inhibition of T-lymphocyte proliferation.
· Inhibition (reversible) of activation of primary helper T cell.
· Decreases production and secretion of interleukin-2.
· Inhibition of production of interferon gamma by lymphocytes.
· CNS: Tremor, palmar and plantar paraesthesia, headache, flushing, depression, visual disorders, convulsions.
· GIT: Anorexia, nausea, vomiting, acute pancreatitis (rare).
· Hepatic: Cholestasis with hyperbilirubinaemia.
· Renal: Nephropathy can occur in up to 75% of patients, and is the most consistent and serious of the adverse effects.
· CVS: Hypertension.
· Other effects: Hypertrichosis, gingival hyperplasia, hyper- glycaemia, hyperkalaemia, gynaecomastia, myopathies, increased susceptibility to infections.
Nephrotoxicity is greatly enhanced by concomitant admin-istration of aminoglycosides, ciprofloxacin, cotrimoxazole, NSAIDs, colchicine and amphotericin B.
Blood levels of cyclosporine are increased by diltiazem, doxycycline, erythromycin, cephalosporines, ketoconazole, H2 antagonists, verapamil, and oral contraceptives, while they are decreased by carbamazepine, isoniazid, phenobarbitone, phenytoin and rifampicin.
The following have been reported in cyclosporine overdose (accidental and deliberate):
Headache, nausea, vomiting, vertigo, hyperaesthesia of hands, burning sensation of feet, abdominal pain, diarrhoea, sinus tachycardia and hypertension.
Premature infants and neonates have developed hypoten-sion, wheezing, tachycardia, cyanosis, metabolic acidosis, respiratory depression and renal failure.
· Decontamination: Gastric lavage or emesis, activatedcharcoal, etc., may be beneficial. Multiple dose activated charcoal produced good results in one reported case.
· Admission to intensive care unit followed by monitoring of vital signs and parameters.
· Patients with stable renal function can be treated sympto-matically and supportively. Most cases recover within 24 hours.
· Tacrolimus is a macrolide compound produced by Streptomycestsukubaensis.
· Immunosuppressive agent to prevent organ transplant rejec-tion. Tacrolimus is said to be 100 times more potent than cyclosporine.
· Treatment of cyclosporine-induced haemolytic uraemic syndrome, severe psoriasis, Behcet’s disease, and Type I diabetes mellitus.
Tacrolimus is poorly absorbed orally, and intravenous adminis-tration is preferred, especially at the time of starting the course. The mean bioavailability is 25%, and the mean apparent volume of distribution is about 19 L/kg. RBCs concentrate tacrolimus so that whole blood values are higher than plasma values. The drug is completely metabolised before elimination, and less than 1% of an oral or IV dose of tacrolimus is excreted in the urine. Tacrolimus is eliminated mainly by hepatic cytochrome P450 III A metabolism.
suppresses cell-mediated and humoral responses, and is a more potent inhibitor
of lymphoproliferation than cyclosporine. It prevents the activation of T
lymphocytes in response to antigenic or mitogenic stimulation.
· These are more pronounced with intravenous use than with oral therapy. Common adverse effects include insomnia, tremor,
· headache, paraesthesia, myalgia, visual sensitivity to light, and GI distress. Serious adverse effects include nephrotoxicity, convulsions, movement disorders, encephalopathy, psychosis, infectious complications, hyperkalaemia and hyperglycaemia.
Overdose leads to profound immunosuppression and severe infection. Neurological complications such as those listed in Table 32.6 are frequently seen, and generally correlate wellwith blood levels.
Supportive and symptomatic measures. Hyperkalaemia responds to fludrocortisone acetate.
Most of the cytotoxic drugs have been discussed in a subsequent section ( vide infra). Only azathioprine and mycophenolate mofetil will be discussed here.
Azathioprine is a purine antagonist and is mainly used as an adjunct for the prevention of kidney allografts. It is also useful in the treatment of rheumatoid arthritis. It is invariably admin-istered orally. Azathioprine inhibits DNA synthesis, and as a purine antagonist, exerts its effect on activated lymphocytes, which require purines during their proliferative phase. The immunosuppressive effect of azathioprine is believed to be due to mercaptopurine (a metabolite).
Adverse effects include bone marrow depression, hepatic dysfunction, infection, drug fever, nausea, vomiting, and diar-rhoea. Rash, urticaria, and vasculitis (allergic) have also been reported. In overdose, it causes vomiting, diarrhoea, leucopenia, hepatotoxicity.
Treatment consists of supportive and symptomatic meas-ures. Early GI decontamination may minimise the likelihood of bone marrow depression and hepatotoxicity. Haemodialysis may be beneficial.
Mycophenolate mofetil is a recently introduced oral prepara-tion for use as an immunosuppressant in renal transplantation.
After absorption it is hydrolysed to mycophenolic acid (MPA), which is an active metabolite, and is a potent inhibitor of inosine monophosphate dehydrogenase which is necessary for the synthesis of purines. Mycophenolate mofetil suppresses lymphocyte proliferation and antibody formation by B cells.
Toxicity results in bone marrow suppression and hepatic dysfunction.
Antibody reagents represent a promising therapeutic strategy, as they cause rapid lowering of lymphocytes, as well as suppres-sion of function of specific lymphocyte populations.
It is a purified immunoglobulin prepared commercially from hyperimmune serum of horse, rabbit, sheep, or goat, following immunisation with human thymic lymphocytes. It is used primarily to treat allograft rejection in kidney and heart trans-plantation. Toxic effects include anaphylaxis, serum sickness, nephritis, leukopenia, thrombocytopenia and fever.
This is a mouse monoclonal antibody which causes a more consistent immune suppressive response than Atgam. It has been used to prevent acute rejection of kidney, liver, and heart transplants. Adverse effects include anaphylactoid reactions, cytokine release syndrome,* and CNS toxicity.
This antibody is prepared by alcohol fraction of plasma from donors, and is used in Rh-negative mothers to prevent sensitisa-tion to Rh(D) antigen (to prevent erythroblastosis foetalis). It is given intramuscularly. Adverse effects include local pain, fever and anaphylaxis.
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