Diuretics in the Therapy of Hypertension

Home , Cicletanine, Clopamide, Cyclopenthiazide, Indapamide, Loop diuretic, Torasemide

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 unfavourable 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 monopharmacotherapies, 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 hydrochlorothiazide 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 formulations, given that their natriuretic potency has not been formally evaluated. The unwanted neuroendocrine and metabolic responses to antihypertensive treatments with lower-dose formulations are deﬁnitely less intense than those that occur in response to treatments with higher-dose formulations of the same substances.13,17,18,25,28–32

Antihypertensive action of low-dose formulations of diuretics The decrease in BP caused by monopharmacotherapy 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 monopharmacotherapy 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 treatment could be better tolerated than quick reductions by patients with impaired circulation in certain vas- cular circuits. The circadian rhythm of BP is not affected by efficacious antihypertensive monopharmacotherapy with a low dose of a diuretic.15,35

Safety of diuretics at low doses Figure 3 Elderly patients suffering from essential hypertension Antihypertensive treatment with a low dose of a were randomly assigned to double-blind once-daily monopharmacotherapy with hydrochlorothiazide (HCTZ) 25 mg or with tor- diuretic has little effect on serum potassium and asemide 2.5 mg, at the end of a 4-week placebo run-in (time 0).33 magnesium concentrations, on fasting glucose and The Montevideo Mathematical Model34 was fitted to mean values on plasma cholesterol fractions.13–32,36–42 The only of BP (dots) as functions of time (upper panel). The curves biochemical variable that is affected by most antihy- depicted in the lower panel are the first derivatives34 of the func- pertensive diuretics irrespective of the dose is serum tions evinced in the upper panel. Evaluated from numerical results published in reference 33, by courtesy of Progress in Phar- uric acid concentration, which undergoes a small macology and Clinical Pharmacology; reproduced from Reyes,7 increase, on average, even when low doses are by courtesy of Monduzzi Editore. used.13,21,43 Cicletanine 50 mg does not modify the renal handling of urate,44 and it does not elevate 37,44 serum uric acid concentration. as non-steroidal inflammatory drugs and corticos- teroids, may attenuate or blunt the antihypertensive Prescribing diuretics for hypertension effect of diuretics. When BP has not decreased to the sought extent in Antihypertensive pharmacotherapy may be started response to 12–14 weeks of monopharmacotherapy with a diuretic in patients who present mild-to- with a diuretic at the doses quoted in Table 1, moderate uncomplicated essential hypertension, despite good compliance with dietary and pharma- provided that no contraindication exists and that cological prescriptions and in the absence of fac- there is no compelling indication for a drug of a dif- tors—such as certain co-medications—that might ferent pharmacological class. Some antihyperten- have attenuated the response of BP, the dose of the sive diuretic substances and the initial doses at diuretic may be augmented if the substance used has which they should be used to treat hypertension are been well tolerated. However, the alternative of listed in Table 1. adding a drug of a different pharmacological class High sodium intakes and certain medicines that instead of increasing the dose of the diuretic should tend to make external sodium balance positive, such be considered in these circumstances, in-so-far as

Journal of Human Hypertension Diuretics in the therapy of hypertension AJ Reyes S81 Table 1 Selected antihypertensive diuretics for the oral treatment constitutes an example of an adequate fixed-dose of mild-to-moderate uncomplicated essential hypertension combination of antihypertensive drugs for the first- line treatment of mild-to-moderate uncomplicated Type of diuretic Substance Initial once- References daily dose essential hypertension. This is so because once- daily antihypertensive therapy with this combi- 51–53 Early distal Bendrofluazide 1.25 mg 13–15 nation lowers high BP effectively, whereas the tubule diuretics (bendroflumethiazide) diuretic indapamide at 0.625 mg once daily may be (thiazides and Chlorthalidone 12.5–15 mg 16, 17 assumed not to be efficacious54,55 and the 2 mg prep- thiazide-type Cicletanine 50 mg 36, 37 aration of perindopril does not meet the criteria that substances) Cyclopenthiazide 0.125 mg 18, 19 Hydrochlorothiazide 12.5 mg 20–25 would permit to qualify it as an effective once-daily 56 Indapamide 1.25 mg 26, 27 antihypertensive formulation. Indapamide SR* 1.5 45, 46 Loop diuretic Torasemide 2.5–5mg 38–42 Future research

*Slow-release formulation. The responses of cardiovascular prognosis to effective control of high BP with the low doses of diuretics quoted in Table 1 and with slightly higher escalating the dose elevates the intensity of the doses of the same substances should be subjected to unfavourable neuroendocrine and metabolic actions comprehensive investigative scrutiny. of diuretics. The responses of cardiovascular prognosis to Diuretics should be prescribed to patients in attainment of target BP values by increasing the whom antihypertensive therapy with a drug of a dif- initial doses of diuretics quoted in Table 1 and by ferent class has not reduced BP satisfactorily, when adding a drug of a different pharmacological class, it is decided to add a second drug and provided no when the response of BP to the initial doses of contraindication exists. Diuretics should substitute diuretics is insufficient, should be contrasted in for- for ineffectual antihypertensive drugs of a different mal research endeavours. class. Diuretics may be used in patients with type 2 diabetes, since they reduce cardiovascular risk in these References patients when they lower high BP effectively.47–49 1 Psaty BM et al. Health outcomes associated with anti- However, diuretics affect carbohydrate metabolism hypertensive therapies used as first-line agents: a sys- untowardly5 in dose-dependent fashion and there- tematic review and meta-analysis. JAMA 1997; 277: fore the doses quoted in Table 1 should not be sur- 739–745. ␤ passed in patients with mild-to-moderate hyperten- 2 Messerli FH, Grossman E, Goldbourt U. Are -blockers sion and type 2 diabetes. efficacious as first-line therapy for hypertension in the In patients with advanced renal insufficiency, elderly? A systematic review. JAMA 1998; 279: 1903–1907. high BP usually has the expansion of extracellular 3 Siscovic DS et al. Diuretic therapy for hypertension volume as its main determinant. These cases should and the risk of primary cardiac arrest. N Engl J Med be treated with a loop diuretic at a dose that 1994; 330: 1852–1857. increases natriuresis. 4 Grobbee DE, Hoes AW. Non-potassium-sparing diuretics and risk of sudden cardiac death. J Hypertens 1995; 13: 1539–1545. Combinations of diuretics 5 Reyes AJ, Taylor SH. Diuretics in cardiovascular medi- When low doses of diuretics are used, there is usu- cine: the new clinicopharmacological bases that mat- ally no need to add a potassium-retaining diuretic, ter. Cardiovasc Drugs Ther 1999; 13: 371–398. such as amiloride, to the therapeutic regimen to pre- 6 Leary WP, Reyes AJ, van der Byl K. Urinary excretory responses to the alpha-2 sympathetic agonist rilmeni- vent hypokalaemia. Available fixed-dose combi- dine, to hydrochlorothiazide and to their combination nations of a thiazide and a potassium-retaining in healthy subjects. In: Puschett JB, Greenberg A (eds). diuretic should not be used to treat uncomplicated Diuretics IV: Chemistry, Pharmacology and Clinical essential hypertension since they may cause hypo- Applications. Excerpta Medica: Amsterdam, 1993, natraemia, particularly in elderly women.50 pp 387–390. Fixed-dose combinations of a diuretic and an anti- 7 Reyes AJ. Antihypertensive monopharmacotherapy hypertensive substance of another class are justified with very-low-dose, low-dose, and high-dose formu- when the amount of each active moiety is not an lations of diuretics: efficacy and safety. In: Reyes AJ, efficacious once-daily antihypertensive per se but Maranho MFC (eds). Cardiovascular Pharmaco- contributes to the effective action of the combi- therapy. Proceedings of the 9th International Congress on Cardiovascular Pharmacotherapy. Monduzzi: nation, and provided the combined drugs do not Bologna, 2000, pp 229–234. concur to the production of undesired effects. Thus, 8 Reyes AJ, Leary WP. Clinicopharmacological reap- pharmacological unwanted actions are minimised. praisal of the potency of diuretics. Cardiovasc Drugs The combination of 0.625 mg of the diuretic indapa- Ther 1993; 7:23–28. mide and of 2 mg of the ACE inhibitor perindopril 9 Franse LV et al. Hypokalemia associated with diuretic

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