Dr Lake said that there were few more rewarding areas for pharmacy practice than organ transplantation and that it was a wonderful area to work in.
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Kathleen Lake: generally not possible to use a single drug alone for effective imunosuppresssion |
In the early days, patients had been over-immunosuppressed with steroids, radiation and azathioprine, but the arrival of ciclosporin had revolutionised treatment. In the mid-1980s, OKT3, the first monoclonal antibody, was introduced and had been very useful in the treatment of acute rejection. Another advance was the inclusion of monoclonal antibodies in induction regimens, to spare the use of the more toxic drugs. The past decade had seen the introduction of a large number of new drugs, including polyclonal antibodies and monoclonal antibodies such as interleukin-2 receptor antibodies. Some drugs, such as mycophenolate mofetil (MMF) and rapamycin had been tested for other indications and abandoned due to perceived toxicity, but had re-emerged in the light of new knowledge.
In Dr Lake's experience, it was generally not possible to use a single drug alone for effective immunosuppression. Two, three or even four drugs had to be used together to optimise efficacy and minimise toxicity. Generally, ciclosporin or tacrolimus were used as the primary treatment, together with two or three others selected from prednisone, azathioprine, mycophenolate mofetil, sirolimus, polyclonal antibody, or monoclonal antibody. If prednisone was used, the dose was always rapidly reduced, to minimise side effects. The aim was to exploit the multiple pathways of the immune system in such a way as to block graft rejection activity while preserving the ability to fight off infections.
Dr Lake suggested that, in the future, MMF and possibly sirolimus might become primary treatments, as many people were concerned about giving ciclosporin - a drug with known nephrotoxicity - to patients who had received kidney transplants. Similarly in heart transplant patients, for many of whom severe coronary artery disease was a critical factor, it would be better to avoid drugs that raised plasma lipid levels. Unfortunately, the drugs in use at present had moderate to high toxicity and had to be given continuously, whereas the ideal drug would be one that could be given in a single dose at the time of transplantation.
As better immunosuppressive protocols were designed, there was the opportunity to focus on issues such as quality of life, said Dr Lake. It was important to tailor the treatment regimen to the patient's desires because it was hard to be compliant with medications that made one sick. Pharmacists should reinforce patient education about immunosuppressive treatment whenever the opportunity arose. Sometimes patients altered their own medication and decreased the degree of immunosuppression. "Have discussions with them and reinforce the messages as much and as often as possible," Dr Lake said.
Acute rejection could be reduced to 45-50 per cent using two drugs and to less than 40 per cent with the addition of a third drug. One study using four drugs had reported a rejection rate below 5 per cent. There was no single, magical combination. In fact, it was almost possible to "dial down" the rate of rejection simply by designing the study appropriately. Trials which contained a large proportion of patients with living, related donors and few African Americans tended to produce low rejection rates. However, to be useful in practice, a trial should include the types of patient most likely to receive the drugs in real life.
Pharmacy always got the blame for drug costs and immunosuppressants were a case in point, Dr Lake said. Annual expenditure on the top five immunosuppressants (ciclosporin, tacrolimus, MMF, azathioprine and atgam [antithymocyte immunoglobulin]) in the US had reached $865m by 1997 (although they were used for other conditions in addition to organ transplantation). One year's treatment with ciclosporin or tacrolimus typically cost $8-10,000. The addition of azathioprine or MMF would account for a further $1,200 or $6,000, respectively. It was tempting to see MMF as being too expensive; however, if it reduced rejection episodes by 50 per cent compared with azathioprine, the picture looked different. An episode of rejection, which required treatment with multiple doses of mono- or poly-clonal antibody, could cost up to $14,500 for the drugs alone, which wiped out the benefits of using a cheap drug. If the graft failed and the patient required dialysis, the costs increased considerably as haemodialysis currently cost $50,000 per annum. It might be better to spend more at the early stage and avoid problems. After all, the cheapest drug treatment for long-term maintenance therapy would be high-dose prednisolone, but this would no longer be considered appropriate treatment, because of the side effects.
Transplant patients typically had about 10 prescription items. Cost was a significant issue in the US where the prescriptions were issued on a monthly basis and the patient would be required to make a co-payment on each item. Most of the products currently in use would soon become generic items, said Dr Lake. She felt it was wrong to scare patients about generic drugs by suggesting that they were less effective than branded products. She said that it was "better to use a generic old drug and use the savings to buy a new drug that offered a real advance".
The complications of transplant treatment could be divided into problems related to immunosuppression, such as acute rejection, infection, chronic rejection and malignancy, and problems related to immunosuppressant drug side effects, such as nephrotoxicity, hypertension, hyperlipidaemia, osteoporosis, obesity and diabetes. For transplant patients, immunosuppression was essential and so the only option was to prescribe other drugs to treat the side effects of the immunosuppressants. However, the newer immunosuppressants provided some opportunities to individualise drug therapy and minimise side effects.
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Case exampleA healthy, stable, heart transplant patient, already receiving azathioprine 200mg daily was prescribed allopurinol, the prescriber apparently being unaware of the interaction. The pharmacist did not notice the combination and the patient did not follow the recommended procedure of calling the transplant centre to report a new treatment. The patient experienced progressive weakness, headache, dysphagia and a sore tongue and finally suffered a syncopal episode. When examined, his haemoglobin had fallen from 14.3g/dl to 3.7g/dl, platelets had fallen to 11,000 and white cells to 1,400. The patient required protective isolation and was treated with red cell and platelet transfusions and GCSF. This small oversight resulted in a hospital admission costing $13,000 and significant impairment of the patient's quality of life. |
Several immunosuppressants, including steroids, ciclosporin and rapamycin, caused hyperlipidaemia. Some patients might have a family history of hyperlipidaemia and coronary artery disease and this should influence the choice of drugs. Pharmacists should try to ensure that transplant patients were not prescribed other drugs which worsened lipid profiles. Patients treated with a combination of ciclosporin, sirolimus and prednisone, all of which affected lipids levels, commonly required large amounts of lipid lowering agents. Sirolimus and tacrolimus together might turn out to be more effective because the combination caused less hyperlipidemia than others. This might be because tacrolimus had a lesser effect on lipids or because less prednisone was needed with that combination, or both.
Bone and muscle disorders could also be a problem for transplant patients. A number of factors could contribute, including steroid treatment, sedentary lifestyle, cigarette smoking, renal osteodystrophy, old age or being a postmenopausal woman. Prevention was better than cure in this situation and steroid-sparing protocols should be used, advised Dr Lake.
Obesity was a common problem for transplant patients. Contributory factors included diet, lack of exercise, prednisone treatment and psychosocial factors. As with any other type of obesity, the treatment involved a combination of exercise and diet. Many patients blamed their weight gain on prednisone, said Dr Lake. However, when prednisone had been discontinued in heart transplant patients none of them had lost weight. Medication-induced diabetes was to be avoided if at all possible. In particular, tacrolimus and steroids could exacerbate diabetes, she noted. However, newer regimens, such as tacrolimus and MMF, which resulted in less rejection and less steroid use, actually had similar rates of diabetes to ciclosporin, MMF and prednisone.
Neurotoxicity was a feature of ciclosporin and tacrolimus treatment. Patients commonly complained of tremors and it was noticeable that if drug levels rose, the tremor got worse. This had been dramatically illustrated when patients changed from Sandimmune to Neoral (the micro-emulsion form of ciclosporin). Some patients had started to develop headaches and tremors again.
Hyperuricaemia was a problem associated with a number of drugs, including ciclosporin and diuretics. Provided that the patient had good renal function, with a glomerular filtration rate (GFR) of more than 50ml/min, probenecid treatment could be given. However, it was important to remember that probenecid could reduce the tubular excretion of methotrexate and MMF. One patient who had been stable on tacrolimus and MMF had been prescribed probenecid. She reported having 12 loose stools within 48 hours. Plasma levels of MMF later turned out to be three times the normal value. Allopurinol could also cause problems, as the inhibition of xanthine oxidase also blocked the metabolism of azathioprine. A 75 per cent reduction of the dose was required to avoid azathioprine toxicity, said Dr Lake.
Gingival hyperplasia occurred with ciclosporin, calcium channel blockers and phenytoin. It was an uncomfortable condition, because the gums were sore and tender, and something that community pharmacists might notice before others. Other common and distressing side effects included GI upsets, caused by tacrolimus (a macrolide) or MMF, and CMV infections causing gastritis. Hypertrichosis or hirsutism arising from treatment with ciclosporin, steroids or minoxidil was particularly distressing. Minoxidil should never be given to women or children, said Dr Lake. In her experience, some patients preferred dialysis to the cosmetic changes that occurred during treatment with a minoxidil, ciclosporin and steroid combination.
Compliance was extremely important among transplant patients. Because they had such large numbers of medicines, they needed to be continuously educated about side effects, in particular, so that they did not attribute new side effects to the wrong drug and stop taking it.
Another problem of the large numbers of medicines was the potential for interactions, and pharmacists played a crucial role in identifying these. The primary immunosuppressants, ciclosporin, tacrolimus and sirolimus, were metabolised through CYP3A (the 3A subfraction of cytochrome p450). This meant that there was a potential for interactions with any other compound that required the same metabolic pathway. This embraced a wide range of drugs, including selective serotonin re-uptake inhibitors (SSRIs), 50 per cent of calcium channel blockers, synthetic oestrogens, protease inhibitors, antihistamines, sedatives and antineoplastic agents. When dealing with known interactions, early intervention was called for because the effects could be rapid and dramatic. For example, ketoconazole inhibited the metabolism of ciclosporin to such an extent that a 10-fold ciclosporin dosage reduction was needed (from 10mg/kg to 1mg/kg), whereas one or two doses of rifampicin could accelerate the metabolism of ciclosporin and "make drug levels plummet". In the case of a new drug with no documented interactions, a good starting point was to check the metabolic route. If the new drug was metabolised through CYP3A then an interaction was possible and monitoring was necessary to document it accurately.
Asked about strategies to improve compliance, Dr Lake said that three measures were helpful: A chart which illustrated the medicines and provided a brief explanation; adjusting the regimen to the best medicines and schedules for the patient; and education and explanations. In addition, practitioners should always try to reduce the number of medications, if possible. Dr Lake emphasised the part that pharmacists could play in working out practical regimens and educating patients.