Journal of Human Hypertension (2002) 16 (Suppl 1), S78–S83 2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh Diuretics in the therapy of hypertension AJ Reyes Institute of Cardiovascular Theory, Montevideo, Uruguay Antihypertensive monopharmacotherapy with diuretics elicit or cause only mild unfavourable neuroendocrine renders blood pressure (BP) values under control in a and metabolic changes. When a low dose of an antihy- large percentage of patients suffering from essential pertensive diuretic substance is used as monophar- hypertension, and it reduces cardiovascular morbidity macotherapy, it may take 12–14 weeks after the and mortality. Diuretics are effective in adult and elderly initiation of treatment for BP to attain final stable values. hypertensive subjects, independently of their race. The following low-dose oral formulations of diuretics Treatments with classic (high) doses of antihyperten- constitute effective once-daily monopharmacotherapies sive diuretics, such as 25 mg hydrochlorothiazide once for mild-to-moderate uncomplicated essential hyperten- daily, raise the activity of the RAA system, decrease sion: bendrofluazide 1.25 mg, chlorthalidone 12.5 and plasma potassium and magnesium concentrations, and 15 mg, cicletanine 50 mg, cyclopenthiazide 0.125 mg, cause untoward changes in carbohydrate metabolism HCTZ 12.5 mg, and torasemide 2.5 and 5 mg. These for- and in the plasma lipid profile. These changes appear mulations are safer than classically used high-dose for- to limit the positive response of cardiovascular prog- mulations such as hydrochlorothiazide 25 and 50 mg. nosis to antihypertensive therapy with classic doses of Journal of Human Hypertension (2002) 16 (Suppl 1), S78– diuretics. Lower doses of diuretics reduce high BP to S83. DOI: 10.1038/sj/jhh/1001349 the sought extent in many patients, and they do not Keywords: diuretics; hydrochlorothiazide; hypertension; hypokalaemia; torasemide; uric acid Introduction and magnesium, untoward changes in carbohydrate metabolism (reduction in glucose tolerance) and in Diuretics are in the forefront of the antihypertensive the plasma lipid profile (increases in plasma choles- armamentarium and constitute the reference anti- terol and in plasma triglyceride concentrations), an hypertensive drugs. This is so because monopharm- increase in the serum concentration of uric acid, an acotherapy with these substances lowers high blood increase in the activity of the renin-angiotensin- pressure (BP) to acceptable levels in many patients aldosterone (RAA) System, a decrease in the pro- who suffer from mild-to-moderate uncomplicated duction of natriuretic peptides and, in certain cases, essential hypertension, and because the decrease in an increase in the plasma concentration of vasopres- BP induced by diuretics entails an important sin.5 reduction in cardiovascular risk.1 The beneficial effects of diuretics on high BP and on cardiovascular risk hold in adult and in elderly patients,2 irrespec- Importance of the dose tive of the race. Effective once-daily treatment with The antihypertensive and unfavourable effects of a diuretic controls high BP over 24 h. diuretics increase as functions of the dose. However, the maximal antihypertensive action of diuretics The range of effectively antihypertensive occurs at a dose that is lower than the doses that cause maximal unwanted effects. Thus, doses above doses of diuretics the dose that is maximally effective in terms of BP The beneficial actions of effective antihypertensive reduction provoke more intense unwanted neuroen- therapy with diuretics on cardiovascular prognosis docrine and metabolic changes and thereby reduce notwithstanding, these substances elicit dose- the beneficial effect that the decrease in BP has on dependent neuroendocrine, biochemical and meta- hypertension-associated cardiovascular risk. bolic responses that oppose the beneficial effect that The unwanted pharmacological actions of com- the diminution in BP has on cardiovascular risk.3,4 mon thiazide-type and loop diuretics are increasing These untoward effects of diuretics include functions of the natriuretic response to these sub- decreases in the serum concentrations of potassium stances, ie appreciable variations in the unfavour- able neuroendocrine and metabolic responses to common diuretics and in the renal excretory effects Correspondence: AJ Reyes, Institute of Cardiovascular Theory, of these drugs share their dose-dependence range. Sotelo 3908, 11700 Montevideo, Uruguay This holds for the unwanted actions of diuretics that E-mail: ajreyesȰinternet.com.uy bear a well-known functional relationship with Diuretics in the therapy of hypertension AJ Reyes S79 forced natriuresis (eg, the rise in the activity of the high-dose antihypertensive formulations of RAA System) and for the undesired effects whose diuretics includes clopamide 5 mg, indapamide functional link with increased renal sodium 2.5 mg, xipamide 10 and 20 mg, and hydrochloro- excretion, if any, has not been established (eg, the thiazide 50 mg.5 reduction in glucose tolerance). For this reason, the magnitude of the natriuretic response to the oral for- Low-dose formulations of diuretics mulations of diuretics used to treat hypertension is taken as a broad overall indicator of the magnitude The expression ‘low-dose’, as usually applied to of the unwanted effects of these medications. amounts or formulations of diuretics that constitute efficacious once-daily antihypertensive monophar- macotherapies, encompasses very-low, low and High-dose formulations of diuretics lower doses. Hydrochlorothiazide 25 mg is considered a high- A single dose or the first once-daily dose of low- dose formulation of a diuretic, since mean 24-h dose formulations of diuretics, such as torasemide natriuresis increases by more than 40% in response 5 mg (Figure 2) or cicletanine 50 mg,5 increase 24-h to a single dose or to the first once-daily dose of this natriuresis by less than 40%. On average, low-dose antihypertensive preparation in certain reference formulations of diuretics do not raise the activity of clinicoexperimental circumstances (Figure 1).5–8 the RAA System to a considerable extent, and they This increase in natriuresis wanes in a few days do not increase 24-h kaliuresis (Figure 2) upon pro- (established ‘braking phenomenon’)5 in healthy sub- longed treatment.5 jects (Figure 1), due to the action of reactive func- Very-low-dose formulations of diuretics do not tional changes that tend to preserve bodily sodium. elevate 24-h natriuresis in healthy subjects.5 Torase- Some of the processes that conserve sodium, includ- mide 2.5 mg, which is a very-low-dose formulation ing an elevation in the activity of the RAA System, (Figure 2), has practically no effect on the activity of also augment renal potassium excretion and there- the RAA System, and it does not change the magni- fore keep 24-h kaliuresis elevated after 24-h natriur- tude of the 24-h renal excretions of chloride, potass- esis is no longer increased in the course of once- ium, calcium, magnesium, and zinc.10–12 daily treatment with hydrochlorothiazide 25 mg Several oral formulations of classic diuretics, (Figure 1). Thus, high-dose diuretics reduce serum such as bendrofluazide 1.25 mg,13–15 chlorthalidone potassium concentration. Hypokalaemia offsets the cardiovascular benefit conferred by the reduction in high BP caused by diuretics.9 In addition to hy- drochlorothiazide 25 mg, the set of formally defined Figure 1 Eleven healthy subjects staying in a metabolic unit took Figure 2 Partial results of a study in which 16 healthy subjects once-daily oral doses of placebo and of hydrochlorothiazide staying in a metabolic unit took once-daily oral doses of placebo 25 mg, at 08.00 hours, during two conveniently separated single- and of torasemide 2.5, 5 and 10 mg, at 08.00 hours, during four treatment periods of 4 days each. An individually randomised, conveniently separated single-treatment periods of 7 days each. crossover and double-blind design was followed. Adapted from An individually randomised, crossover and double-blind design numerical results published in Leary et al6; figure reproduced was followed. From AJ Reyes, WP Leary and K van der Byl: from Reyes,7 by courtesy of Monduzzi Editore. unpublished study. Journal of Human Hypertension Diuretics in the therapy of hypertension AJ Reyes S80 12.5 mg16 and 15 mg,17 cyclopenthiazide 0.125 mg,18,19 hydrochlorothiazide 12.5 mg20–25 and indapamide 1.25 mg26,27 and 1.5 mg, that contain a lower amount of active substance than the formulation(s) of the same drugs used to treat high BP in the past, may be termed lower-dose formu- lations, given that their natriuretic potency has not been formally evaluated. The unwanted neuroen- docrine and metabolic responses to antihyperten- sive treatments with lower-dose formulations are definitely less intense than those that occur in response to treatments with higher-dose formu- lations of the same substances.13,17,18,25,28–32 Antihypertensive action of low-dose formulations of diuretics The decrease in BP caused by monopharmacother- apy with low-dose formulations of diuretics taken once daily progresses slower over the first weeks of treatment than the reductions caused by high-dose formulations (Figure 3). The response of BP to mon- opharmacotherapy with a low dose of a diuretic should not be considered complete until 12–14 weeks have elapsed after the initiation of treatment. Smooth decreases in BP over the first weeks of treat- ment