Drug Therapy in the Heart Transplant Recipient

Abstract

With improving survival, the heart transplant recipient faces an increasing number of medical problems caused by both aging and the cumulative complications of immunosuppressive drugs. 1 The availability of new drugs to treat infection, obesity, hypertension, hyperlipidemia, renal insufficiency, diabetes, osteoporosis, gout, and malignancies has resulted in the heart transplant recipient and their physicians facing an almost overwhelming number of important drug-drug interactions. In parts 1 through 3 of this series, we reviewed commonly used immunosuppressive drugs and their pharmacology, as well as the common medical problems faced by the heart transplant recipient. In this article, we provide an overview of the mechanisms of common and important potential drug-drug interactions and guidelines for avoiding these interactions. Principles of Drug-Drug InteractionsThe risk for drug-drug interactions is increased by advanced age, polypharmacy, medications with a narrow therapeutic index, or medications requiring intensive monitoring. All of these factors except advanced age are present in the heart transplant recipient. A 10-fold interpatient variability may exist in the magnitude of a drug interaction resulting from patient-related and drug-related factors. 2 Patient-related factors predisposing to drug interactions include concomitant diseases, genetics, diet, and environmental exposures. For example, commonly used immunosuppressants, antifungal agents, and lipid-lowering medications are metabolized through the cytochrome P450 (CYP450) enzyme system and effluxed from cells by the multiple drug resistance transporter protein p-glycoprotein (P-gp). Both systems are found in the liver and gastrointestinal tract and exhibit genetic polymorphism. 2 The CYP450 enzymes belong to a superfamily of oxygenases; the primary purpose of these oxygenases is to add a functional group to a drug to increase its polarity and to promote its excretion from the body. If enzymes possess Ͼ40% homology, they are grouped together into families designated by an Arabic numeral (eg, the CYP1 family). Families are further divided into subfamilies, which are designated by a letter after the number (eg, CYP2C and CYP2D subfamilies); members of each subfamily have Ͼ55% homology with each another. Individual members are given an additional number (eg, CYP3A4) to identify a specific enzyme pathway. 2 CYP3A4 is particularly important because 60% of oxidized drugs, including the calcineurin inhibitors (CIs) cyclosporine (CSA) and tacrolimus (TAC), sirolimus (SIR), and everolimus (EVER), undergo biotransformation through this particular enzyme system. 3 P-gp is a membrane-bound glycoprotein belonging to the superfamily of ATP-binding cassette transporters. Like the CYP450 enzyme system, P-gp acts in a protective capacity by "effluxing" drug from the cell membrane or cytoplasm. P-gp density is highest within the small intestine, proximal tubules of the kidney, and biliary canalicular membranes. Some medications such as CIs and SIR use both the CYP450...

Recommendations for Management of Clinically Significant Drug-Drug Interactions With Statins and Select Agents Used in Patients With Cardiovascular Disease: A Scientific Statement From the American Heart Association

“…156,157 Although the majority of data in this population have been with simvastatin (5-20 mg daily) and pravastatin (20-40 mg daily), considerable controversy exists on which statin and what doses to use because of potential DDIs with the calcineurin inhibitors (eg, cyclosporine and tacrolimus) that could lead to myopathy or rhabdomyolysis. [153][154][155][156]158 CALCIneURIn InHIbItORS…”

“…Because of the metabolism of tacrolimus, the patterns of statin DDIs would be expected to be similar to those of cyclosporine. 158 Unfortunately, limited data exist on tacrolimus and statin interactions. One open-label evaluation of 13 healthy volunteers suggested that after 4 days of therapy with atorvastatin 40 mg daily, 2 doses of tacrolimus had no impact on the atorvastatin pharmacokinetics.…”

“…158 As with tacrolimus, extremely limited data exist on the interactions between target of rapamycin inhibitors and statins. Because of their metabolism, it is feasible that interactions with statins could occur and result in tissue injury.…”

ESC/EAS Guidelines for the management of dyslipidaemias

“…Fluvastatin, pravastatin, pitavastatin and rosuvastatin have less potential for interaction. 402 Tacrolimus is also metabolized by CYP3A4, but appears to have less potential for harmful interaction with statins than ciclosporin. Other drugs that influence CYP3A4 activity should be avoided if possible and used with extreme caution in patients receiving both calcineurin inhibitors and statins.…”

Prevalence and predictors of hypertension in cardiac recipients

“…Это означает, что полученные результаты могут расцениваться как репрезентативные для всей российской популя-ции реципиентов сердца. Полученные в настоящем исследовании результаты близки к опубликованным данным, согласно которым распространенность АГ спустя 5 лет после трансплантации сердца состав-ляет от 50 до 95% [6,7].…”