ABC | Volume 115, Nº2, August 2020

Viewpoint Feitosa et al. Pharmacological treatment of hypertension Arq Bras Cardiol. 2020; 115(2):270-272 side effects, resulting in gynecomastia or breast tenderness, impotence in men, and menstrual irregularities in women. In this regard, the results of the PATHWAY-2 trial suggested that 10-20 mg/day of amiloride, a potassium-sparing diuretic, is as effective as spironolactone in reducing BP in resistant hypertensive patients, thus constituting an alternative to spironolactone in the treatment of resistant hypertension. 15 However, it should be noted that amiloride, as an isolated formulation and at the aforementioned dosage, is not currently available in Brazil. The ReHOT study compared the effects of spironolactone versus a central alpha-2 agonist (clonidine) in resistant hypertensive patients. Although there were no differences in the primary endpoint (BP control during office and ambulatory BP monitoring) achieved by spironolactone or clonidine, results of the secondary analysis showed greater 24-hour BP reduction with spironolactone, reinforcing the use of spironolactone as the fourth preferential drug for the treatment of resistant hypertension. 6 However, BP reductions achieved by clonidine were also substantial, which may establish this drug as a good option to be added to spironolactone when BP control has not been attained. The PATHWAY-2 trial also investigated the BP effects of a β B (bisoprolol) or an alpha-1 adrenergic blocker (doxazosin) as alternative medications to spironolactone. These drugs were not as effective as spironolactone, but significantly reduced BP versus placebo when added to baseline antihypertensive medications in resistant hypertensive patients. 5 Therefore, a β B or an alpha-1 adrenergic blocker should be added subsequently to spironolactone in patients with uncontrolled BP. However, because the ALLHAT study showed that doxazosin was markedly inferior to chlortalidone in preventing cardiovascular events, particularly heart failure, 18 we suggest that an alpha-1 adrenergic blocker should be one of the last antihypertensive classes to be added to the treatment of patients with resistant hypertension. Few studies have evaluated the impact of direct vasodilators, such as hydralazine or minoxidil, in the treatment of resistant hypertension. In addition, this antihypertensive class may cause marked fluid retention and tachycardia, and therefore should be considered as one of last choices in the treatment of resistant hypertension. 11 In summary, based on the abovementioned data, we propose a structured octet for the pharmacological treatment of hypertension (Figure 1). Lifestyle changes and components of the golden trio (RASI, CCB and THIAZ) comprise the bottom of the treatment algorithm. Spironolactone should be preferentially used as the fourth antihypertensive class when there is no adequate BP control with the latter medications. Then, central alpha-2 agonists and β B may be added, while direct vasodilators and alpha-1 adrenergic blockers should be considered as the last options to be instituted for hypertension treatment. Author Contributions Conception and design of the research: Feitosa ADM, Mota-Gomes M, Passarelli Júnior O, Barroso WKS, Miranda RD, Barbosa ECD, Brandão AA, Nadruz W; Writing of the manuscript: Feitosa ADM, Nadruz W; Critical revision of the manuscript for intellectual content: Mota-Gomes M, Passarelli Júnior O, Barroso WKS, Miranda RD, Barbosa ECD, Brandão AA. Figure 1 – Structured octet for the treatment of hypertension. THIAZ: thiazide-type/thiazide-like diuretic; RASI: renin angiotensin system inhibitor; CCB: calcium-channel blocker; βB: Beta-blocker; α2A: central alpha-2 agonist; α1B: alpha-1 adrenergic blocker; VD: direct vasodilator. *When BP control is not achieved with THIAZ, RASI and CCB, and the THIAZ is hydrochlorothiazide, substitute this latter drug by a long-acting THIAZ (chlortalidone or indapamide). If glomerular filtration rate <30 mL/min, substitute THIAZ by a loop diuretic, such as furosemide. †If spironolactone is not tolerated, particularly due to anti-androgenic side effects, consider substituting this drug by amiloride. ‡βB is indicated as the first choice for the initial treatment when there are specific indications, such as angina, post-myocardial infarction, heart failure, arrhythmia or heart rate control. 271