Diuretics in the Treatment of Patients Who Present Congestive Heart Failure and Hypertension

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

Journal of Human Hypertension (2002) 16 (Suppl 1), S104–S113  2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh Diuretics in the treatment of patients who present congestive heart failure and hypertension

AJ Reyes Institute of Cardiovascular Theory, Montevideo, Uruguay

The main operational objective of diuretic therapy in ment natriuresis in patients with congestive heart failure patients who present congestive heart failure and hyper- and hypertension. The state of renal function, the exis- tension is to reduce or to suppress excess bodily ﬂuid. tence of certain co-morbid conditions, potential Effective diuretic therapy decreases cardiac size when untoward drug actions, and possible interactions of the heart is dilated, and it reduces lung congestion and diuretics with nutrients and with other drugs are some excess water. Consequently, external respiratory work of the factors that must be considered at the time of diminishes and cardiac output would be redistributed in deciding on the diuretic drug(s) and dose(s) to be pre- favour of systemic vascular beds other than that of the scribed. Spironolactone has been found to increase life respiratory muscles; dyspnoea decreases markedly and expectancy and to reduce hospitalisation frequency there is a slight reduction in fatigue. This clinical when added to the conventional therapeutic regimen of improvement and the fall in body weight caused by patients with advanced congestive heart failure and sys- diuretics entail an increase in effort capacity. Sub- tolic dysfunction. Therefore, spironolactone should be sequent exercise training ameliorates the abnormal ven- the drug of choice to oppose the kaliuretic effect of a tilatory response to physical effort and the skeletal mus- loop or of a thiazide-type diuretic. cle myopathy that occur in heart failure, and thereby it Journal of Human Hypertension (2002) 16 (Suppl 1), S104– attenuates dyspnoea and decreases fatigue further. S113. DOI: 10.1038/sj/jhh/1001354 Loop and/or thiazide-type diuretics may be used to aug-

Keywords: congestive heart failure; diuretics; hypertension; hypokalaemia; hyponatraemia; spironolactone

Introduction pulmonary circulation wedge pressure, and stroke volume and cardiac output decrease initially. Upon Congestive heart failure (CHF) and hypertension prolonged administration, the cardiac index may coexist in many patients. Coronary artery disease, stay below, equal or surpass its pre-treatment value, diabetes mellitus and/or renal insufficiency fre- but the magnitude of these changes is generally quently accompany the CHF-hypertension associ- low.7,8 There is a lack of correlation between vari- ation. Few investigative endeavours have addressed ables indicating effort capacity and cardiac output the effect of diuretic therapy in patients with CHF in patients suffering from chronic CHF, but we have and hypertension specifically, despite the fact that found that the NYHA functional class9 correlates diuretics are indicated for both conditions. Effective positively and that the 6-min mean walking velo- diuretic therapy is mandatory in patients with CHF, city10 correlates negatively with clinical (Figure 1) since no drug class other than diuretics can achieve and radiological11 increasing ordinal indicators of what diuretics can in terms of control of excess bod- the magnitude of lung congestion and pulmonary 1 ily fluid and its attendant symptom mitigation. water and with the cardiothoracic ratio.12 These findings strongly suggest that the beneficial effects The clinical and functional effects of of diuretics on the main symptoms of CHF are diuretics mainly due to the decrease in thoracic fluid that results from their diuretic action. Thus, lung conges- Effective diuretic therapy provides impressive tion and water and cardiac size should be con- symptomatic relief in patients with CHF.2–5 Haemo- sidered operational objectives of diuretic therapy dynamically, forced diuresis results in a decrease in in CHF. The substantial symptomatic relief produced by diuretics in patients with CHF is independent of Correspondence: AJ Reyes, Institute of Cardiovascular Theory, whether patients also present hypertension. How- Sotelo 3908, 11700 Montevideo, Uruguay ever, the blood pressure (BP) lowering effect of E-mail: [email protected] diuretics may result in improved cardiac pump Diuretics in heart failure and hypertension AJ Reyes S105

Figure 1 The 6-min walking test was carried out and the pulmonary congestion-and-water clinical score was evaluated in 59 ambulatory patients who presented NYHA functional class I-IV congestive heart failure after 1 month of stable pharmacotherapy. Thirty-nine patients also suffered from essential hypertension. The pulmonary congestion-and-water clinical score, which has a possible range of 0–24, equals the sum of the scores assigned to eight symptoms and four signs that denote pulmonary congestion and excess water in congestive heart failure. Some dots comprise more than one patient each. From AJ Reyes, G Crippa, MG Meny, E Sverzellati, RD Espinas and M Giorgi-Pierfranceschi: unpublished study. function and thus contribute to the clinical improve- upon exercise. Patients perceive these intense ment when hypertension coexists. Reductions in and/or rapid increases in respiratory work per dyspnoea, in systemic oedema and in BP have been minute as dyspnoea.26 found to progress in parallel over the first weeks of Elevations in respiratory work per minute imply monopharmacotherapy with a diuretic in patients that a high fraction of cardiac output should be with CHF and hypertension.13 addressed to the muscles of the external respiration, The processes giving place to the two cardinal to the detriment of the fraction that perfuses other symptoms that limit physical activity in heart fail- systemic vascular beds. This added underperfusion ure, namely dyspnoea and fatigue,14,15 have not been that affects the muscles of the limbs during physical fully unveiled.16 This paucity of information pre- effort is an immediate determinant of fatigue.27 cludes that the mechanism(s) of the symptom Resting and exercise local underperfusion and the attenuation brought about by forced diuresis in systemic functional shifts that occur in CHF would patients with CHF should be fully understood, account for the muscle waste and for the microana- mainly in view that diuretic therapy does not tomical, biochemical and functional unfavourable increase cardiac output to a great extent in most changes undergone by skeletal muscle in CHF. cases. We designed an hypothesis that focuses on These changes would constitute the basis of the the possible key role played by pulmonary conges- development of fatigue when physical activity aug- tion and water and by the respiratory muscles in this ments relative underperfusion. apparent paradox,17,18 and have been updating19–21 When treatment of chronic CHF with a diuretic is our construct while considering progress in research effective, ie when it increases diuresis to the sought and opinion.22 extent, pulmonary wedge pressure and lung water Pulmonary circulation wedge pressure is decrease,28 and therefore respiratory work per increased in CHF. In consequence, there is a net minute decreases. Cardiac output would undergo a passage of fluid from the pulmonary circulation to redistribution whereby a lower fraction is addressed the lung interstitium and to the small airway.23 to the respiratory muscles, which might be better Excess lung water and pulmonary circulation en- perfused than before the institution of diuretic ther- gorgement entail a decrease in pulmonary com- apy despite this reduction, and more blood would pliance and an increase in the airway resistance to reach other systemic regions, including the muscles air flow.24 These two changes determine an increase of the limbs. Additionally, cardiomegaly subsides, in the work done by the respiratory muscles per and body weight decreases. These favourable respiratory cycle. The rise in volumes and pressures changes result in an important reduction in in the heart, in the pulmonary circulation and per- dyspnoea and in a small decrease in fatigue, and haps in intrathoracic lymphatics, the decrease in therefore in an increase in the capacity to perform pulmonary compliance, and the underperfusion and physical activity.27 In the medium range, increased structural, biochemical and functional deterioration physical activity, particularly if it includes exercise that affects certain organs such as skeletal muscles,25 training, would improve the structure and function including the respiratory muscles, originate stimuli of skeletal muscle29–33 and would reduce excess ven- that increase (effort) ventilation inordinately in tilation,33–36 thereby mitigating dyspnoea and patients with CHF. Therefore, respiratory work per fatigue further. cycle and respiratory rate rise strikingly and quickly Diuretics provide the prime relief of the symp-

Journal of Human Hypertension Diuretics in heart failure and hypertension AJ Reyes S106 toms that limit physical activity. In practice, excretory response to loop diuretics is quicker than patients with CHF should be treated with diuretics the responses to the diuretics of any other class. and with other drugs. Certain co-therapies may Furosemide, bumetanide and piretanide have an amplify the beneficial effects of diuretics. ancillary site of renal action in the proximal tubule of the nephron, where they inhibit carbonic anhyd- Modern diuretics rase. Ethacrynic acid and torasemide do not exert a significant action on the proximal tubule. Torase- Modern diuretics augment natriuresis by blocking mide reduces high BP effectively when it is used as the reabsorption of sodium from the microtubular oral monopharmacotherapy in patients with essen- structures of the kidney. In normal circumstances, tial hypertension. about 65, 25, 8 and 2% of filtered sodium is reabsorbed in the proximal convoluted tubule, in the Potassium-retaining diuretics thick ascending limb of the loop of Henle, in the early distal tubule, and in the connecting tubule and Potassium-retaining diuretics have their site of renal the cortical collecting duct, respectively. The clini- action in the connecting tubule and in the adjacent cal pharmacology of modern diuretics has been cortical collecting duct,40 ie at the level where reviewed recently.37 sodium is reabsorbed from the tubular lumen and potassium and hydrogen are excreted in exchange. This physiological process is stimulated by aldos- Early distal tubular (thiazide-type) diuretics terone. The potassium-retaining diuretics amiloride Early distal tubular diuretics comprehend the thia- and triamterene increase natriuresis by blocking a zides, which are benzothiadiazine derivatives, and sodium channel involved in the exchange of this a set of other compounds that includes chlorthali- cation for potassium and hydrogen.9 Spironolactone done, chlorexolone, cicletanine, clopamide, indapa- and potassium canrenoate compete with aldosterone mide, metolazone, and xipamide. Cicletanine is the for the intracellular receptor of this hormone in the only thiazide-type diuretic in use that is not a sul- tubular cells. fonamide drug. Potassium-retaining diuretics increase natriuresis Early distal tubular diuretics reach the nephronal and cause renal retention of potassium and of hydro- tubular lumen through the cells of the proximal gen ions through the decrease in sodium reabsorp- tubule, and act on the cells of the early distal tubule tion that they provoke. Antikaliuretics increase from the tubular fluid. There, these diuretics inter- natriuresis modestly and they may provoke hyperka- fere with the reabsorption of sodium chloride and laemia. For this reason, potassium-retaining thus increase natriuresis.38 The elevations in tubular diuretics are generally co-prescribed with a thiazide- fluid flow and sodium concentration that result from type or with a loop diuretic. the blockade of sodium reabsorption in the early distal tubule give place to an increase in the reabsorp- New use of spironolactone in congestive heart tion of sodium in the connecting tubule and the col- failure lecting duct. At this level, reabsorbed sodium is exchanged for potassium and hydrogen, and kaliu- The anti-aldosterone substance spironolactone is resis rises in consequence. currently classified as a facultative diuretic and anti- Early distal tubular diuretics are efficacious antikaliuretic,41,42 since it increases natriuresis and hypertensives. Indapamide and cicletanine lower decreases kaliuresis only when plasma aldosterone high BP effectively, but the actions of these diuretics concentration is high, as occurs when sodium intake in patients with CHF remain largely unexplored. is low or when loop or thiazide-type diuretics are used at diuretic doses.43 Spironolactone has been classically used in patients with CHF treated with Loop diuretics loop or with early distal tubular diuretics mainly to Loop diuretics (furosemide, bumetanide, ethacrynic prevent or to co-treat hypokalaemia. Recently, it was acid, piretanide and torasemide) reach the lumen of found that the addition of a relatively small dose of the nephron at the proximal tubule, and they spironolactone to the classic treatment of CHF with increase natriuresis by interfering with the reabsorp- a loop or a thiazide-type diuretic, digitalis and an tion of filtered sodium in the thick ascending limb angiotensin-converting enzyme (ACE) inhibitor pro- of the loop of Henle.39 Part of the sodium whose longs life and reduces hospitalisation frequency in reabsorption is impeded in the loop of Henle is reab- patients with advanced cardiac failure and systolic sorbed in the early distal tubule and in later tubular dysfunction.44 It is not known whether this salutary structures. The natriuretic response to loop diuretics action of spironolactone is due to a decrease in the is accompanied by an elevation in kaliuresis. rate at which cardiac interstitial fibrosis pro- The effect of loop diuretics on renal sodium gresses,45,46 to an improvement in bodily potassium excretion increases as a function of the dose over a turnover, to added natriuresis, or to a combination wider dose range than the natriuresis that occurs in of factors. The addition of a low amount of spirono- response to the other diuretic classes, and the renal lactone to antihypertensive treatment with conven-

Journal of Human Hypertension Diuretics in heart failure and hypertension AJ Reyes S107 tional doses of diuretics may result in a supplemen- ever, the doses of diuretics should be kept below tary fall in high BP.47 those that produce very quick and/or intense The fact that spironolactone could oppose aldos- diuresis, to avoid symptomatic and asymptomatic terone-induced processes that could favour cardiac pathophysiologically detrimental falls in cardiac fibrosis in patients with CHF makes this drug the output. If BP is not controlled, co-treatment with second diuretic of choice in three circumstances that other drug classes that are established antihyperten- may apply to patients with CHF and hypertension, sives and are used in CHF in addition to diuretics, provided it is not contraindicated: first, when it is such as ACE inhibitors, must be adjusted. Other decided to increase the natriuretic response to ongo- antihypertensive agents should be added if neces- ing therapy with a thiazide-type or a loop substance sary. by adding a diuretic of a different class to the thera- The amount of sodium in the diet should be peutic regimen; second, when it is decided to pre- optimised. A diet containing 70–90 mmol of sodium vent the development of hypokalaemia by using an daily should be prescribed to patients with mild or antikaliuretic; third, when a slight increase in the moderate cardiac failure who do not present renal antihypertensive action of existing diuretic therapy insufficiency and are not co-treated with spironolac- is sought. tone. Lower intakes activate the renin-angiotensin- Spironolactone should be used with caution, aldosterone (RAA) System and thereby increase kali- since its additive natriuretic effect in cases who also uresis and result in added cardiovascular damage; receive a loop or a thiazide-type diuretic may facili- higher intakes increase the amount of filtered tate the development of hyponatraemia. Further- sodium that reaches the sodium-potassium more, hyperkalaemia may develop when renal func- exchange site in the kidney and thus increase kaliur- tion is impaired or when spironolactone is co- esis, and they require that higher doses of diuretics administered with potassium supplements, and also should be used. Water intake should be decreased when it is co-administered with an ACE inhibitor or when thiazide-type diuretics are used, to decrease an angiotensin II receptor blocker.48 Spironolactone the risk of hyponatraemia. provokes renal retention of hydrogen ions; therefore, it should not be used in patients with metabolic acidosis and it should be used with great care in Initial treatment and maintenance therapy patients who are prone to develop this syndrome (eg patients who also present insulin-dependent dia- Treatment may be initiated with a thiazide-type betes mellitus). diuretic in patients who present CHF and hypertension and normal renal function. Once-daily oral Use of diuretics in the clinical setting doses of 5 mg bendrofluazide, 50 mg chlorthalidone, 5 mg clopamide, 0.5 mg cyclopenthiazide, 25– The principal operational objective of diuretic ther- 50 mg hydrochlorothiazide, 5–10 mg metolazone apy in patients with CHF and hypertension is to rid and 20 mg xipamide are appropriate starting doses the lungs of excess fluid to the maximal extent com- in most cases. In patients with mild CHF, these patible with a safe general haemodynamic response. amounts of early distal tubular diuretics may be In patients who also present serious renal insuf- effective when taken every other day. ficiency, the increase in BP is usually determined by The usefulness of thiazide-type agents notwith- excess fluid; consequently, lowering high BP consti- standing, loop diuretics are generally preferred as tutes an important additional operational objective first-line agents given that they have an ampler dose- of diuretic therapy in these cases. response range than early distal tubular drugs. Additionally, loop diuretics are safer than thiazide- type substances with respect to the reductions in the General principles serum concentrations of sodium (particularly when All the subtleties of good clinical handling should patients are also treated with spironolactone) and be brought about to individualise treatment with potassium that may accompany any given natriu- diuretics in patients who present CHF and hyperten- retic effect. When renal function is seriously sion. The existence of other syndromes or diseases impaired, thiazide-type drugs per se are ineffectual that may be relevant to diuretic therapy either per se whereas loop diuretics preserve their capacity for (eg renal insufficiency) or because of the medication increasing natriuresis. Treatment with loop necessary to treat them (eg chronic rheumatic diuretics may be started with daily oral doses of diseases) should be taken into account. Due atten- 40 mg furosemide, 1 mg bumetanide, 6 mg pireta- tion should be paid to the interactions between nide or 10 mg torasemide. diuretics and the other drugs used for heart failure Spironolactone should be co-prescribed in and eventually for hypertension. Some general prin- patients with advanced heart failure and systolic ciples should be observed with respect to the han- dysfunction in whom it is not contraindicated. The dling of diuretics. These drugs must be used at starting dose should be 12.5 mg once daily. Eventu- diuretic doses, ie at doses higher than those used to ally this amount may be doubled in patients who treat uncomplicated essential hypertension. How- present normal renal function, no hyperkalaemia

Journal of Human Hypertension Diuretics in heart failure and hypertension AJ Reyes S108 and no hyponatraemia and who tolerate spironolac- in patients without important renal function impair- tone clinically. ment. Most frequently this is due to low compliance The dose of the diuretic and the amount of excess with treatment, to excess sodium intake, or to the bodily fluid are two important determinants of the effect of co-medications that cause renal retention of response of diuresis. When treatment is effective, sodium. The latter include agents for heart failure, 24-h diuresis increases markedly over the first 1–4 such as vasodilators, or for other conditions (eg non- days, it declines over the following 7–20 days, and steroidal anti-inflammatory drugs, corticosteroids). it stabilises thereafter. The new external sodium bal- In other instances, the prevailing mechanism con- ance is sensitive to various factors, including ducing to failure of loop diuretic therapy to control sodium intake, the intensity of diuretic therapy, car- excess bodily fluid is significant true resistance of diac function and renal function.49 The dose of the the nephron to the action of loop diuretics.51 diuretic(s) should be adjusted as necessary in the True resistance to a loop diuretic may be solved course of treatment, according to changes in the by augmenting the dose in some circumstances. external sodium balance that might be necessary to However, very high doses many times fail to pro- maintain ’dry lungs’, and to control hypertension in duce an adequate therapeutic response,51 and they patients with advanced renal insufficiency. convey an increased risk of loop diuretic ototoxicity. We do not usually surpass total oral daily doses of 160 mg furosemide, 4 mg bumetanide or 60 mg tora- Monitoring efficacy and safety semide when renal function is not seriously The response to diuretic therapy should be moni- impaired. In case these doses are not effective, we tored adequately. Efficacy evaluation should focus implement the time-honoured manoeuvre of block- on the presentations of congestion and excess water ing sodium reabsorption in different sites of the in the lungs and in the rest of the thorax.1 Other tubular structure of the kidney. Sequential blockade efficacy variables to be considered include urinary of sodium reabsorption, by co-administration of a output, body weight, the possible systemic clinical loop diuretic and a thiazide-type drug and/or a po- presentations of excess bodily fluid and the tassium-retaining substance, generally results in the response of BP. desired increase in natriuresis. In cases with sig- The state of the lungs should always be evaluated nificant renal insufficiency, the doses of loop through careful anamnesis on effort dyspnoea, diuretics may be higher, and the sequential blockade orthopnoea and paroxysmal nocturnal dyspnoea, of sodium reabsorption should usually be limited to and on effort and supine coughing and wheezing. these drugs and thiazide-type substances. If natriu- Auscultation of the lungs, preferably done immedi- resis does not increase to the sought extent, it is ately after nocturnal bed rest, is also important. necessary to recur to dialysis. Good quality chest X-rays are very useful since they show pleural effusion when it exists, and they may Unwanted actions of diuretics reveal pulmonary congestion and/or imbibition by showing upper vein distention, peribronchial Possible untoward actions of diuretics stem from cuffing, poor vessel margination, Kerley’s lines, their dose-dependent pharmacological actions or thickened interlobar fissures and/or perihiliar constitute idiosyncratic reactions. The most fre- haze.50 Chest X-rays also permit to evaluate the car- quent and important pharmacologically originated diothoracic ratio. undesirable effects of diuretics in patients with CHF The clinical evaluation of systemic peripheral and hypertension consist in neuroendocrine acti- oedema should focus on the lumbosacral region in vation, in unfavourable changes in sodium, potass- patients who keep bed rest, and on the existence of ium, calcium and magnesium turnovers, in an hand oedema immediately after wakening and of untoward shift in carbohydrate metabolism and in ankle-pedal-region oedema in the evening in ambu- hyperuricaemia. Potassium-retaining diuretics may latory patients. Neck vein distention, the presence of affect acid-base balance untowardly in acidosis- excess fluid in the abdominal region (hepatomegaly, prone patients. ascites) and the hepato-jugular reflex should always be searched for. Neuroendocrine activation Instrumental and laboratory safety evaluations should include, at least, frequent ECG recordings Diuretics increase the activity of the RAA System, and assessments of blood sugar and of the serum mainly through their action on the kidney, in concentrations of creatinine, sodium, potassium, patients with heart failure.52,53 This activation has calcium, magnesium and uric acid. various functional and structural negative implications for patients with CHF and hypertension; therefore it should be prophylactically minimised Diuretic pseudoresistance and resistance by prescribing a diet containing an optimal amount Diuretic therapy with a relatively high dose of a loop of sodium and by using the minimal dose of diuretic diuretic, eg 160 mg furosemide daily, may fail to that is effective. The raised activity of the RAA Sys- produce the desired reduction in excess bodily fluid tem may be attenuated or countered by the use of

Journal of Human Hypertension Diuretics in heart failure and hypertension AJ Reyes S109 drugs such as ACE inhibitors, angiotensin II antag- kalaemia. Spironolactone and amiloride may con- onists and spironolactone. Intravenous furosemide tribute to the correction of low serum potassium, but has been found to augment plasma arginine vaso- the added natriuretic effect of these potassium- pressin, apparently by a non-osmotic mechanism.54 retaining diuretics favours the development of This shift may have deleterious effects on vascular hyponatraemia and co-dministration of potassium function and may contribute to the development supplements and a potassium-retaining drug may of hyponatraemia. result in hyperkalaemia.

Hyponatraemia Hyperkalaemia The capacity of the kidney to dilute urine, ie to Hyperkalaemia elevates aldosterone production, excrete water, is impaired in CHF. The processes and it may cause cardiac death. Renal insufficiency underlying this functional change are poorly under- predisposes to the development of and may cause stood. The increased sympathetic activity that hyperkalaemia. occurs in CHF, and perhaps the rises in angiotensin Potassium supplements may increase serum po- II, natriuretic peptides and some endothelins and tassium concentration to undesirable levels. Potass- prostaglandins that also take place in this syndrome, ium-retaining diuretics, ACE inhibitors, angioten- augment the osmotic-independent production and sin-II receptor blockers, non-steroidal anti- release of arginine vasopressin and thus result in inflammatory drugs and many other agents59,60 may elevated reabsorption of water from the renal tubu- cause or facilitate the development of hyperkalae- lar system and favour the development of hypo- mia, mainly when they are co-prescribed with po- natraemia.55 Exaggerate restrictions of sodium intake tassium supplements. and water or hypotonic fluid intake in response to thirst caused by increased sodium and water losses, Hypocalcaemia and hypercalcaemia eg when sweating is intense, may conduce to hyponatraemia in patients with CHF treated with Loop diuretics increase renal calcium excretion and diuretics. thereby tend to lower the serum concentration of The natriuretic action of diuretics may eventuate calcium.61 These agents should not be used, unless in the development of hyponatraemia in patients they are indispensable, in CHF patients who present with CHF.56 Hyponatraemia is most usually caused hypocalcaemia or who are predisposed to the forma- by thiazide-type diuretics and by their fixed-dose tion of renal calcium stones. combinations with a potassium-retaining agent.48 Early distal tubular diuretics cause renal retention Women, the elderly and patients with advanced of calcium;61 therefore these substances should not CHF are at higher risk of developing diuretic- be used in patients who present hypercalcaemia. induced hyponatraemia. Thiazide-type diuretics are the agents of choice in The simplest measure aimed at lowering the risk patients with CHF who are prone to renal calcium- of hyponatraemia consists in reducing water intake. stone formation, since they appear to prevent calcium urolithiasis through their action on the renal handling of calcium.62 Hypokalaemia Amiloride decreases calciuresis,63 attenuates the Loop and thiazide-type diuretics increase kaliuresis calciuretic effect of loop diuretics64 and augments in dose-dependent fashion and thus tend to lower the calcium-retaining effect of the thiazides.65 serum potassium concentration.57 The sodium-chan- When dealing with hypocalcaemia in patients nel blockers amiloride and triamterene and the aldo- treated with diuretics, it must be taken into account sterone antagonist spironolactone, when co-pre- that it may be due to magnesium deficiency.66,67 scribed at adequate doses, significantly attenuate or blunt the increase in kaliuresis produced by loop Magnesium depletion and early distal tubular diuretics.57 ACE inhibitors and angiotensin II receptor antagonists tend to ele- Loop and early distal tubular diuretics increase mag- vate serum potassium concentration. nesiuresis.67–69 Amiloride and spironolactone tend Hypokalaemia provokes skeletal muscle weak- to cause mild renal retention of magnesium, and ness, which may express itself as an increase in they attenuate or counter the excess magnesiuresis fatigue, and it favours the occurrence of cardiac caused by loop and by thiazide-type diuretics.67,68 arrhythmias. The magnesiuretic action of common diuretics The correction of hypokalaemia conveys the may result in bodily magnesium depletion in reversal of nearly all the derangements it causes. patients who present CHF.70,71 Magnesium depletion However, reversing the increase in cardiac is more likely to develop in certain patients, includ- arrhythmogenicity requires that body magnesium ing those who also suffer from diabetes, alcoholics, depletion, which accompanies hypokalaemia in heart transplant recipients treated with the immuno- many instances, should also be corrected. Potassium suppressant cyclosporin, and individuals whose replacement58 is the most effective therapy for hypo- magnesium intake is poor.66,70–72 Magnesium

Journal of Human Hypertension Diuretics in heart failure and hypertension AJ Reyes S110 depletion frequently accompanies hypokalaemia in tries, increases the renal excretion of uric acid.86 The patients treated with diuretics, and it gives place to early distal tubular diuretic cicletanine does not hypocalcaemia.66,67 The likelihood of occurrence of affect the renal output of urate87 and does not ele- cardiac arrhythmias in patients who present hypo- vate serum uric acid concentration88 at the doses kalaemia or who are treated with digitalis is used to treat hypertension; the possible use of ciclet- enhanced by magnesium depletion.73 Magnesium anine in patients with CHF remains to be investi- depletion in patients with CHF who receive a loop gated. or a thiazide-type diuretic should be treated with Diuretic-induced increases in serum uric acid may magnesium supplements.70,71 be attenuated or countered by ACE inhibitors,89,90 since these substances increase the renal excretion of urate.64,91–94 Serum uric acid concentration usu- Changes in carbohydrate metabolism ally decreases after an ACE inhibitor is added to the Treatments with loop or with early distal tubular therapeutic regimen in patients with CHF who diuretics reduce glucose tolerance and may provoke present diuretic-induced hyperuricaemia; this hyperglycaemia.74 In patients who present diabetes makes it possible to reduce the dose or to discon- mellitus, diuretics usually increase blood sugar and tinue the use of allopurinol in many patients who glycosylated haemoglobin. The mechanism of this receive this drug to lower the production of uric seemingly unavoidable effect of diuretics on carbo- acid. The angiotensin II receptor antagonist losartan hydrate metabolism, which appears to be facilitated has been found to increase the renal excretion of by hypokalaemia and perhaps by magnesium urate in healthy subjects,95 and both losartan and depletion, is not well understood. Diuretics have irbesartan have been found to attenuate hydro- been found to decrease insulin secretion and to chlorothiazide-induced increases in serum uric acid cause resistance to insulin, but none of these in hypertensive patients.96,97 changes is a constant feature of diuretic-induced glucose intolerance.75 Diuretics may also contribute to the development of the hyperosmolar non-ketotic Changes in acid-base balance syndrome in diabetic patients.76 Potassium-retaining diuretics should be used with Potassium-retaining diuretics cause renal retention great care in cases who present insulin-dependent of hydrogen ions and thereby tend to provoke aci- diabetes mellitus, given that these patients are prone dosis,48 particularly in patients at risk such as indi- to develop metabolic acidosis and that these drugs viduals who present renal insufficiency, subjects reduce the renal excretion of hydrogen ions and who also suffer from insulin-dependent diabetes thereby tend to lower plasma pH. and elderly persons. Loop and thiazide-type diuretics generally cause sustained hypokalaemic-hopochloraemic alkalosis, Hyperuricaemia which is usually mild and does not require treat- The prevalence of hyperuricaemia is high in ment.98 However, these substances do not lower patients suffering from hypertension and in patients urine pH to an appreciable extent. This is so because who present CHF. Hyperuricaemia, which appears common diuretics exert pharmacological actions to be an independent cardiovascular risk factor77 that result in opposite changes with respect to the and is a marker of poor prognosis in patients with renal excretion of hydrogen ions. Common diuretics heart failure,78,79 may have deleterious effects on the block the reabsorption of filtered sodium in their kidney and on the urinary tract.80,81 main site of renal action, and part of the non-reab- Progressive degrees of renal insufficiency give sorbed sodium is reabsorbed in exchange for potas- place to progressively higher values of serum uric sium and for hydrogen ions, which are excreted, in acid concentration. When renal function is unim- the collecting duct. Thus, hydrogen ions excretion paired, a decrease in the renal excretion of urate tends to increase and urine pH tends to decrease. originating in the tubular nephron is an important However, the renal excretion of hydrogen ions tends determinant of hyperuricaemia in patients with CHF to decrease as a result of the inhibition of carbonic and/or hypertension.82,83 Sodium intake curtailment anhydrase that most loop and thiazide-type sub- reduces the renal excretion of urate and favours the stances cause in the proximal tubule. development of diuretic-induced hyperuricaemia. The loop diuretic torasemide, at variance with Diuretics constitute the main causative factor of furosemide, bumetanide and piretanide and with hyperuricaemia in patients with CHF.80 Diuretics in thiazide-type diuretics, does not act on the proximal use reduce the renal excretion of urate and increase tubule of the nephron;99,100 in consequence, torase- the serum concentration of uric acid in dose-depen- mide decreases urine pH significantly at the doses dent fashion,84,85 apparently by shifting the balance used to treat CHF (AJ Reyes and WP Leary, unpub- of the secretion-reabsorption process undergone by lished results). Hence torasemide should be the loop uric acid in the nephronal proximal tubule towards diuretic of choice in patients who are at natural risk reabsorption. The thiazide-type diuretic tienilic acid of developing acidosis or who are co-treated with a (ticrynafen), which is not available in most coun- potassium-retaining diuretic.

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