Drug Therapy in the Heart Transplant Recipient

Lindenfeld, Jo Ann; Page, Robert L.; Zolty, Ronald; Shakar, Simon F.; Levi, Marilyn E.; Lowes, Brian D.; Wolfel, Eugene E.; Miller, Geraldine G.

doi:10.1161/01.cir.0000151609.60618.3c

Cited by 114 publications

(47 citation statements)

References 78 publications

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“…[152][153][154][155] Additionally, between 60% and 81% of heart transplant recipients exhibit lipid abnormalities. 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…”

Section: Immunosuppressive Agentsmentioning

confidence: 99%

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

Wiggins¹,

Saseen²,

Page³

et al. 2016

Circulation

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249

194

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A drug-drug interaction (DDI) is a pharmacokinetic or pharmacological influence of 1 medication on another that differs from the known or anticipated effects of each agent alone.1 A DDI may result in a change in either drug efficacy or drug toxicity for 1 or both of the interacting medications.2 Pharmacokinetic DDIs result in altered absorption, distribution, metabolism, or excretion of a medication. A pharmacodynamic DDI occurs when 1 medication modifies the pharmacological effect of another in an additive, a synergistic, or an antagonistic fashion.It is estimated that ≈2.8% of hospital admissions occur as a direct result of DDIs. 3 However, the actual incidence of hospitalization secondary to clinically significant DDIs is likely to be highly underestimated because medication-related issues are more commonly reported as adverse drug reactions. Complex underlying disease states also may make recognizing a DDI more challenging, further contributing to a lower reported incidence. The overall clinical impact of a DDI can range from mild to life-threatening. Therefore, not all DDIs require a modification in therapy. The variability in the clinical significance of a DDI depends on both medication-specific and patient-specific factors. Medication-specific factors include the individual pharmacokinetic characteristics of each medication implicated in the DDI (eg, binding affinity, half-life [t 1/2 ]), dose of the medications, serum concentrations, timing and sequence of administration, and duration of therapy. Patient-specific factors include age, sex, lifestyle, genetic polymorphisms causing differences in enzyme expression or activity, and disease impairment affecting drug metabolism (eg, hepatic or renal impairment, cardiac failure) or predisposition to differences in efficacy or safety (eg, statin intolerance in patients with a history of myopathy). Clinically significant DDIs are usually preventable. To optimize patient safety, healthcare providers must have an understanding of the mechanisms, magnitude, and potential consequences of any given DDI. Interpreting this information will assist clinicians in the safe prescribing of medications and permits careful consideration of the benefits and risks of concomitant medications.Statins reduce morbidity and mortality in patients with known atherosclerotic cardiovascular disease (ASCVD) and in many primary prevention patients.4-9 Current guidelines recommend high-intensity statin therapy in all patients with ASCVD age ≤75 years and moderate-to high-intensity statin therapy in patients with ASCVD and age >75 years, diabetes mellitus, and familial hypercholesterolemia and in primary prevention patients with 10-year ASCVD risk ≥7.5%.10 Given the important role of statins in patients with ASCVD and those at high ASCVD risk, combination therapy with statins and other cardiovascular medications is highly likely, and potentially significant DDIs must be considered in patients treated with statins.Another important aspect of prescribing medications in combination is evalu...

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Section: Immunosuppressive Agentsmentioning

confidence: 99%

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

Wiggins¹,

Saseen²,

Page³

et al. 2016

Circulation

Self Cite

249

194

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“…Rapamycin and FK506 are known to cause endothelial dysfunction and hypertension in organ transplant recipients, 13,14 however the mechanisms remain unknown. Also, it was unknown whether rapamycin and FK506 increase blood pressure by direct or indirect vascular effects and whether the displacement of FKBP12/12.6 from RyRs plays a role.…”

Section: Long Et Al Fkbp12/126 and Endothelial Dysfunctionmentioning

confidence: 99%

“…Although rapamycin and FK506 markedly increase the success of organ transplantation, they both can cause endothelial dysfunction and hypertension. 13,14 Furthermore, treatment of rats with FK506 decreases production of the potent endotheliumderived vasodilator nitric oxide (NO), and genetic deletion of FKBP12.6 in mice causes hypertension. 15,16 These findings suggest the possibility that depletion of vascular FKBP12/ 12.6, and thus an endothelial intracellular Ca 2ϩ leak, may alter endothelial function and blood pressure regulation, however this has not been studied previously.…”

mentioning

confidence: 99%

Removal of Fkbp12/12.6 From Endothelial Ryanodine Receptors Leads to an Intracellular Calcium Leak and Endothelial Dysfunction

Long

Cook

et al. 2007

ATVB

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Objectives-FK506Binding Protein 12 and its related isoform 12.6 (FKBP12/12.6) stabilize a closed state of intracellular Ca 2ϩ release channels (ryanodine receptors [RyRs]), and in myocytes removal of FKBP12/12.6 from RyRs alters intracellular Ca 2ϩ levels. The immunosuppressive drugs rapamycin and FK506 bind and displace FKBP12/12.6 from RyRs, and can also cause endothelial dysfunction and hypertension. We tested whether rapamycin and FK506 cause an intracellular Ca 2ϩ leak in endothelial cells and whether this affects endothelial function and blood pressure regulation. Methods and Results-Rapamycin or FK506 concentration-dependently caused a Ca 2ϩ leak in isolated endothelial cells, decreased aortic NO production and endothelium-dependent dilation, and increased systolic blood pressure in control mice. Rapamycin or FK506 at 10 mol/L abolished aortic NO production and endothelium-dependent dilation. Similar results were obtained in isolated endothelial cells and aortas from FKBP12.6 Ϫ/Ϫ mice after displacement of FKBP12 with 1 mol/L rapamycin or FK506. In hypertensive FKBP12.6 Ϫ/Ϫ mice, systolic blood pressures were further elevated after treatment with either rapamycin or FK506. Blockade of the Ca 2ϩ leak with ryanodine normalized NO production and endothelium-dependent dilation. Conclusions-Complete removal of FKBP12 and 12.6 from endothelial RyRs induces an intracellular Ca 2ϩ leak which may contribute to the pathogenesis of endothelial dysfunction and hypertension caused by rapamycin or FK506.

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“…В литературе встречается мнение, что преиму-щество в выборе гипотензивных средств следует отдавать дилтиазему, в связи с тем что на фоне его приема происходит снижение активности изофер-мента цитохрома P450 CYP3A4, что «позволяет снизить дозу ингибиторов кальциневрина благода-ря их замедленному выведению» [67,68]. Однако такая точка зрения представляется спорной, в связи с тем что терапия АГ требует подбора доз и заме-ны гипотензивных средств, что может привести к непредсказуемым изменениям концентрации имму-носупрессантов в крови.…”

Section: ингибиторы ангиотензинпревращающего фермента и блокаторы рецunclassified

Hypertension in cardiac transplant recipients

Шевченко

Никитина

Тюняева

2017

RJTAO

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1 ФГБУ «Федеральный научный центр трансплантологии и искусственных органов имени академика В.И. Шумакова» Минздрава России, Москва, Российская Федерация 2 ФГАОУ ВО «Первый Московский государственный медицинский университет имени И.М. Сеченова» Минздрава России (Сеченовский университет), Москва, Российская ФедерацияАртериальная гипертония -один из наиболее распространенных патологических синдромов среди реци-пиентов трансплантированноого сердца, как взрослых, так и детей. Хроническое повышение артериаль-ного давления является важным модифицируемым фактором риска дисфункции сердечного трансплан-тата, васкулопатии, жизнеопасных нарушений ритма, мозгового инсульта, почечной недостаточности и смерти. Данная статья построена на обзоре литературы и посвящена особенностям патогенеза, профи-лактики, немедикаментозной и лекарственной терапии посттрансплантационной артериальной гиперто-нии у реципиентов сердца.Ключевые слова: трансплантация сердца, реципиент сердца, артериальная гипертония, профилактика, лечение.

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Drug Therapy in the Heart Transplant Recipient

Cited by 114 publications

References 78 publications

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

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

Removal of Fkbp12/12.6 From Endothelial Ryanodine Receptors Leads to an Intracellular Calcium Leak and Endothelial Dysfunction

Hypertension in cardiac transplant recipients

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