Abstract
The syndromes of mineralocorticoid excess describe a heterogeneous group of clinical manifestations leading to endocrine hypertension, typically either through direct activation of mineralocorticoid receptors or indirectly by impaired pre-receptor enzymatic regulation or through disturbed renal sodium homeostasis. The phenotypes of these disorders can be caused by inherited gene variants and somatic mutations or may be acquired upon exposures to exogenous substances. Regarding the latter, the symptoms of an acquired mineralocorticoid excess have been reported during treatment with azole antifungal drugs. The current review describes the occurrence of mineralocorticoid excess particularly during the therapy with posaconazole and itraconazole, addresses the underlying mechanisms as well as inter- and intra-individual differences, and proposes a therapeutic drug monitoring strategy for these two azole antifungals. Moreover, other therapeutically used azole antifungals and ongoing efforts to avoid adverse mineralocorticoid effects of azole compounds are shortly discussed.
Highlights
The management and prevention of hypertension represents an important global health challenge
In view of the mineralocorticoid excess symptoms associated with serum posaconazole and itraconazole concentrations ≥2.5–3 μg/mL, we propose the intro duction of upper plasma target levels in combination with a therapeutic drug monitoring (TDM) strategy in order to prevent the occurrence of syndromes of mineralocorticoid excess (SME)
Inhibition of CYP11B1 and 11β-HSD2 by posaconazole and itraco nazole has been found to cause a phenotype of mineralocorticoid excess
Summary
The management and prevention of hypertension represents an important global health challenge. The causes of secondary hypertension include in particular renal and endocrine disorders (Whelton et al, 2018; Young et al, 2017). The syndromes of mineralocorticoid excess (SME) describe a heterogeneous group of clinical manifestations that lead to endocrine hypertension, typically either directly through activation of mineralocorticoid receptors (MR) and indirectly by disruption of pre-receptor regulation or through disturbed renal sodium homeostasis (Beck et al, 2020b; Carvajal et al, 2020). SME can be genetically determined or due to exposures to environmental factors such as certain nutrients or drugs, and the phe notypes can vary from severe to mild. Whilst genetic causes to SME have been extensively studied, less is known on the contribution of environ mental factors that are expected to lead to milder phenotypes, which may often be unrecognized. The following sections cover the targets and mechanisms involved in SME, followed by a discussion of recent findings on azole antifungals causing acquired SME
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