Posaconazole‐induced Pseudohyperaldosteronism

An 87-year-old man presented with a gastric ulcer; its pathology revealed aseptate fungal hyphae consistent with mucormycosis. The patient's past medical history was remarkable for bilateral adrenal histoplasmosis complicated by primary adrenal insufficiency which had been diagnosed one-year prior to this presentation; he has well responded well to voriconazole (VCZ) and prednisolone replacement. Intravenous lipophilic amphotericin B was given for a one-week duration, and was then switched to oral daily posaconazole (PCZ) 300 mg. Two weeks later, the patient's blood pressure rose to 180-200/100-110 mmHg and hypokalemia with metabolic alkalosis (K 2.2 mEq/L, bicarbonate 34 mEq/L) occurred. Posaconazoleinduced pseudohyperaldosteronism (PIPH) was proposed due to his suppressed plasma renin activity (0.17 ng/mL/hr, reference 0.2-2.85) and low aldosterone levels (3.24 ng/dL, reference 4-31) while the PCZ levels were 3.99 μg/mL and 2.43 μg/mL, respectively (therapeutic levels for treatment >1 μg/mL). One week later, his hypertension and electrolyte abnormalities resolved with 100 mg of spironolactone daily. Subsequently, PCZ was switched back to VCZ after repeated gastroscopy showing an improving ulcer and no further bleeding. PCZ is a new, potent, broad-spectrum triazole antifungal agent, inhibiting lanosterol 14α-demethylase, a key enzyme in ergosterol synthesis of the fungal cell membranes. It is approved as a prophylaxis and first-line treatment of invasive fungal infections including aspergillosis and mucormycosis. Its current preparation, a delayed-release tablet taken in a once-daily dose, is well-tolerated and offers better bioavailability compared to the previous soluble formulation. However, about 20% to 30% of the patients developed hypertension and hypokalemia from PIPH. Two possible mechanisms have been proposed. Firstly, PCZ inhibits the peripheral enzyme 11βhydroxysteroid dehydrogenase type 2 (11β-HSD2) resulting in an excessive cortisol-dependent mineralocorticoid receptor activation. Alternatively, PCZ could inhibit the adrenal enzyme 11β-hydroxylase (11β-OH), leading to an accumulation of the precursor hormones, 11-deoxycorticosterone, and 11-deoxycortisol, which can activate the mineralocorticoid receptor and may cause hypocortisolism. Recently, it has been hypothesized that PIPH may be associated with serum drug concentrations, while other adverse events including headache, dizziness, fatigue, and dry mouth do not show in a dose-dependent manner. PIPH mainly occurs in patients with PCZ levels above 4 μg/ mL, and is less likely to occur when levels are below 2 μg/mL. Other risk factors are old age and pre-existing hypertension. Treatment with mineralocorticoid antagonists-spironolactone and a dose reduction or discontinuation of PCZ should be considered as management strategies. This report substantiates that PIPH should be associated with the serum drug concentrations. The patients have to be regularly monitored for hypokalemia, hypertension, and symptoms of adrenal insufficiency during the use of this medication. In addition, therapeutic drug monitoring is recommended in those with identified adverse events in order to optimize dosage.