Pharmacological Research 154 (2020) 104311 Contents lists available at ScienceDirect Pharmacological Research journal homepage: www.elsevier.com/locate/yphrs Review Drug-induced endocrine blood pressure elevation T Katharina R. Becka, George R. Thompson IIIb, Alex Odermatta,* a Swiss Centre for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland b Department of Internal Medicine, Division of Infectious Diseases and the Department of Medical Microbiology and Immunology, University of California Davis Medical Center, Davis, California, USA ARTICLE INFO ABSTRACT Chemical compounds studied in this article: Patients with uncontrolled hypertension are at risk for cardiovascular complications. The majority of them Abiraterone suffers from unidentified forms of hypertension and a fraction has so-called secondary hypertension withan Carbenoxolone identifiable cause. The patient’s medications, its use of certain herbal supplements and over-the-counter agents Danazol represent potential causal factors for secondary hypertension that are often overlooked. The current review Etomidate focuses on drugs that are likely to elevate blood pressure by affecting the human endocrine system at the level of Itraconazole steroid synthesis or metabolism, mineralocorticoid receptor activity, or by affecting the catecholaminergic Ketoconazole Lisdexamphetamine system. Drugs with known adverse effects but where benefits outweigh their risks, drug candidates andmarket Metyrapone withdrawals are reviewed. Finally, potential therapeutic strategies are discussed. Mifepristone Posaconazole Keywords: Hypertension Mineralocorticoid excess Steroidogenesis 11beta-hydroxysteroid dehydrogenase Catecholamine Adverse drug reaction 1. Introduction syndrome (CS) (< 0.1%), hyper-/hypothyroidism (< 1%), pheochro- mocytoma (0.2-0.6%), and coarctation of the aorta (0.1%) [1,4,6]. The majority of diagnosed hypertensive patients suffer from idio- Concomitant medications promoting hypertension or blunting the ef- pathic hypertension. Secondary forms of hypertension due to an iden- fects of anti-hypertensive therapy are frequently underrecognized by tifiable cause are less prevalent and found in approximately 10%of health care providers as contributors to secondary hypertension [7,8]. adult hypertensive patients and in up to 30% of patients with treat- The patient’s personal use of certain herbal supplements, over-the- ment-resistant hypertension [1–4]. However, a recent review described counter agents or psychostimulants associated with blood pressure primary aldosteronism (PA) as a major public health problem, with elevation renders individual assessments even more demanding. Im- inappropriate aldosterone secretion detected in up to 50% of patients portantly, a direct relationship between the degree of vascular disease with essential hypertension [5]. Other causes of secondary hyperten- and mortality risk over the normal range of blood pressure has been sion include obstructive sleep apnea (prevalence > 15%), renal par- demonstrated [9]. Moreover, even a reduction of as little as 2 mm Hg of enchymal disease (1–8%), renal artery stenosis (1–8%), Cushing’s systolic blood pressure has been shown to lower mortality due to stroke Abbreviations: 11β-HSD2, 11β-hydroxysteroid dehydrogenase type 2; 11-DOC, 11-deoxycorticosterone; AAS, androgenic anabolic steroids; ACE, angiotensin converting enzyme; ACTH, adrenocorticotropic hormone; ADHD, attention deficit/hyperactivity disorder; AR, androgen receptor; COX, cyclooxygenase; CS, Cushing’s syndrome; CYP, cytochrome P450; DHEA, dehydroepiandrosterone; MAO, monoamine oxidase; MR, mineralocorticoid receptor; NSAIDs, non-steroidal anti-inflammatory drugs; PA, primary aldosteronism; P-gp, P-glycoprotein; RAAS, renin-angiotensin-aldosterone system; SNRI, serotonin-noradrenaline reuptake inhibitors; SSRI, selective serotonin reuptake inhibitors; TCA, tricyclic antidepressants ⁎ Corresponding author at: Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. E-mail address: [email protected] (A. Odermatt). https://doi.org/10.1016/j.phrs.2019.104311 Received 7 March 2019; Received in revised form 8 June 2019; Accepted 10 June 2019 Available online 15 June 2019 1043-6618/ © 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/). K.R. Beck, et al. Pharmacological Research 154 (2020) 104311 by 10% and due to ischemic heart disease by 7% [9]. This raises the for inhibition of CYP11B1 by posaconazole. Besides, both studies re- question whether a slight increase of blood pressure, although still in ported increased androstenedione and 17-hydroxyprogesterone levels, the “normal” range, represents an unappreciated clinical issue. There- indicating that CYP17A1 was not compromised. The reported high fore, it is crucial to consider the patient’s medications as potential serum 11-DOC and androgen concentrations differ from those found in contributors to blood pressure elevation and to know the underlying a patient receiving posaconazole that showed normal 11-DOC and an- pathways in order to apply an appropriate therapy. Three major me- drogen levels, along with an increased cortisol/cortisone ratio [22]. chanisms leading to blood pressure elevation can be distinguished: However, the moderately elevated 11-deoxycortisol as well as 17-hy- plasma volume expansion, increased sympathetic activity and direct droxyprogesterone concentrations seemed to account at least for partial vasoconstriction [10]. This review outlines mechanisms of drug-in- CYP11B1 inhibition. In addition, Wassermann et al. described a case duced blood pressure elevation due to direct interference with the en- with clearly elevated 11-deoxycortisol levels and an increased serum docrine system, including the mimicking of endogenous hormones or cortisol/cortisone ratio during posaconazole treatment [24], further disturbance of hormone synthesis, transport and metabolism. supporting inhibition of both CYP11B1 and CYP11B2 by this azole. These reports did not or only partially assess the patient’s plasma and 2. Mineralocorticoid effects urinary steroid profile, allowing only a limited insight into theme- chanism of azole-induced hypertension and hypokalemia. However, a 2.1. Interference with adrenal steroidogenesis recent report on two cases of posaconazole-induced hypertension and hypokalemia that included detailed steroid metabolite analyses in The central role of the adrenal glands in stress responses makes blood and urine samples emphasized inter-individual differences in the them a particularly sensitive organ as seen in toxicological studies [11]. mechanism underlying mineralocorticoid-dependent hypertension and Despite this, the assessment of off-target effects on the adrenals inen- hypokalemia, with predominant inhibition of CYP11B1 and CYP11B2 docrine-related drug toxicity studies represents a neglected topic of in one patient and predominant inhibition of 11β-HSD2 in the other investigation, although administration of drugs such as etomidate and [26]. aminoglutethimide caused the death of patients due to unrecognized Importantly, all cited case studies have reported serum drug con- interference with adrenocortical steroidogenesis [12]. The importance centrations that exceeded the therapeutic range. In three cases, a low- of evaluating drug candidates for their potential to interfere with ering of the dose resolved the mineralocorticoid symptoms [22–24]. steroidogenic enzymes has recently been addressed by the United States Substitution of posaconazole or itraconazole with voriconazole or flu- Food and Drug Administration guidance on non-clinical evaluation of conazole also resolved the mineralocorticoid phenotype [21,22,25,26]. endocrine-related drug toxicity [13]. It recommends the use of cyto- It is accepted knowledge that most azole antifungals are potent chrome P450 (CYP) isoenzyme assays during early drug development, CYP3A4 inhibitors [27,28]. Therefore, care has to be taken when co- including those for CYP11A1, CYP11B1, CYP11B2, CYP17A1 and administering drugs that are metabolized by CYP3A4 (e.g. corticoster- CYP21A1 that are involved in adrenal androgen, mineralo- and gluco- oids). For the same reason, a combined use of calcium channel blockers corticoid synthesis. and itraconazole should be avoided as this can cause negative inotropic CYP11B1 (also known as 11β-hydroxylase) catalyzes the conversion effects [29]. Moreover, ketoconazole and itraconazole are potent in- of 11-deoxycortisol to the potent glucocorticoid cortisol, whereas hibitors of the efflux pump P-glycoprotein (P-gp) [30]. Therefore, doses CYP11B2 (also known as aldosterone synthase) converts 11-deox- of substrates of P-gp, such as corticosteroids or cyclosporin A, should be ycorticosterone (11-DOC) via corticosterone and 18-hydro- lowered when they are co-administered with these azoles. xycorticosterone to the potent mineralocorticoid aldosterone [14]. In- In addition to CYP11B inhibition, certain azole fungicides have been hibition of CYP11B1 results in decreased cortisol production along with shown to interfere with the cortisol-metabolizing enzyme 11β-hydro- increased levels of 11-deoxycortisol and 11-DOC that possess miner- xysteroid dehydrogenase type 2 (11β-HSD2) (discussed in section alocorticoid activity