Unravelling drug-induced hypertension: molecular mechanisms of aldosterone-independent mineralocorticoid receptor activation by posaconazole

Abstract

Drug-induced hypertension offers the opportunity to further understand pathways involved in the regulation of blood pressure. Posaconazole is an antifungal agent known to induce hypertension and hypokalaemia. In recent months, a flurry of reports has unravelled the metabolic processes involved. In this issue of CKJ, Barton K, Davis TK, Marshall B et al. Posaconazole-induced hypertension and hypokalemia due to inhibition of the 11β-hydroxylase enzyme. Clin Kidney J 2018; 11: 691–693 present convincing evidence of 11β-hydroxylase inhibition resulting in a biochemical syndrome resembling genetic congenital adrenal hyperplasia and characterized by high 11-deoxycorticosterone and 11-deoxycortisol levels as well as androgen levels. This adds to prior evidence supporting inhibition of 11β-hydroxysteroid dehydrogenase 2, the enzyme that inactivates cortisol in aldosterone-sensitive tissues such as the kidneys, yielding a syndrome resembling genetic apparent mineralocorticoid excess or licorice toxicity, characterized by a high cortisol/cortisone ratio.

Posaconazole Serum Drug Levels Associated With Pseudohyperaldosteronism

“…Inhibition of 11β-hydroxylase results in the accumulation of 11-deoxycorticosterone and 11-deoxycortisol, with mineralocorticoid effects (hypertension, hypokalemia, and alkalosis). Blocking 11β-HSD2 abolishes inactivation of cortisol in the kidney with subsequent glucocorticoid-mediated activation of mineralocorticoid receptors [12,13,16].…”

Revisiting resistant hypertension: a comprehensive review

“…Rifampin can reduce the efficacy of most BP‐lowering drugs by cytochrome p450 enzyme induction 22 . Posaconazole can cause aldosterone‐independent mineralocorticoid receptor activation 23 …”