De Soyza AG, Corris PA. 2001. Immunosuppression [online]. Freeman Hospital, Newcastle Upon Tyne, UK. Available from http://www.cysticfibrosismedicine.com
Immunosuppression post-lung transplant almost always includes a combination of drugs. Triple therapy with cyclosporin, azathioprine and prednisolone is the most common regime used although as the newer agents emerge this is likely to change.
Cyclosporin remains first line immunosuppression in many centres. It is usually given twice daily and trough levels are monitored regularly.
Absorption
Absorption is variable. Various formulations are available, each having very different bioavailabilities. It is therefore important that the brand is specified when prescribing. Micro-emulsion forms are the most commonly prescribed type of cyclosporin. As the emulsion formula is fat based it is recommended that pancreatic supplements are taken at the same time. Diet (most notoriously grapefruit juice) can cause increased cyclosporin levels. Any alteration in medication must be discussed with the transplant centre.
Side effects
Diabetogenic, hyperlipidaemia, abnormal liver enzyme, hypertension, hirsutism, neuropathy, nephrotoxicity, tremor, and hyperkalaemia.
Drug interactions
Macrolides such as clarithromycin as well as antifungals e.g. itraconazole can greatly increase cyclosporin levels. This can result in acute renal failure and these drugs are bets avoided unless advised by a transplant centre. Non-steroidal anti-inflammatory drugs also increase the nephrotoxicity of cyclosporin.
Although Tacrolimus is not currently licensed in the UK for immunosuppression in pulmonary transplant recipients, it is widely used and appears to have important benefits in patients with recurrent acute rejection and obliterative bronchiolitis. It is given twice daily and regular therapeutic drug monitoring is essential. Tacrolimus has a similar side effect profile to cyclosporin although certain side-effects are less common e.g. hirsutism. Tacrolimus may however be associated with reduced rates of infection and chronic rejection. Antibiotics especially the macrolides and anti-fungal agents may increase levels resulting in hyperkalaemia and renal failure.
Azathioprine alters white cell metabolism via purine metabolic pathways reducing the total white cell count. It can however affect all bone marrow cell lines causing bone marrow failure. Patients should therefore report any infection, unexpected bruising or bleeding. Azathioprine is given once daily and white cell count must be monitored.
Drug interactions
The metabolism of azathioprine can be altered by allopurinol. The combination of these two agents has resulted in serious and fatal bone marrow failure.
MMF is given orally and metabolised into active MPA. The mechanism of action broadly parallels that of azathioprine with inhibition of nucleoside and therefore DNA metabolism. The drug effects are in general relatively specific but bone marrow suppression has been described. Other mechanisms of action appear to include inhibition of leukocyte migration and antibody mediated rejection. A recent large multicentre study showed that MMF did not reduce rates of rejection but did reduce the rates of serious infections.
Side effects
Gastrointestinal especially diarrhoea and nausea along with leukopenia. The absence of obvious nephrotoxicity or neurotoxicity is noteworthy. Therapeutic drug monitoring is possible but the role of this is unclear, currently many centres simply monitor white cell counts and tolerability when deciding on dose adjustment.
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