Drugs 30: 469-474 ( 1985) 00 I `-6667/85/0012-0469/$03,00/O 0 ADIS Press Llmiled 411 rights reserved. How Dangerous Are Diuretics? Edward D. Freis and Vasilios Papademetriou Veterans Administration and Georgetown University Medical Center, Washington Two major concerns that have been raised against the use of diuretics are: (a) diuretic-induced hypokalaemia may predispose to dangerous ar- rhythmias including sudden death (Kolata, 1982); and (b) long term diuretic use may cause an in- crease in serum cholesterol and thus an increased risk of arteriosclerosis, including coronary artery disease (Grimm et al., 1981). Diuretics have provided the basic regimen for treating hypertension for many years and have served as the primary treatment in most of the controlled trials demonstrating the effectiveness of treatment. Although most physicians still believe that treatment for hypertension usually should be- gin with a thiazide diuretic, others are apt to try alternative regimens, This is due primarily to an increased concern with the potential risks of di- uretic-induced hypokalaemia. These concerns re- sulted initially in a dramatic increase in the admin- istration of potassium supplements or potassium- sparing diuretics, the cost of which in the USA to- talled $250 million in 1981 alone (Harrington et al.. 1982). Recently, because of fear of toxicity some physicians. especially in Scandinavia, have re- duced the doses of hydrochlorothiazide to as low as 6.25 or 12.5 mg/day (e.g. Andrew et al., 1983; Berglund and Anderson, 1976). Diuretics are the only known antihypertensive agents which lower blood pressure by reducing salt, water and extracellular fluid volume (Freis, 1976). Recent controlled trials indicate that when given as the sole treatment thiazide diuretics control blood pressure in approximately half of the pa- tients treated (Veterans Administration Coopera- tive Study Group, 1982a,b,c, 1983), and in 85% of those given a diuretic plus a step-two drug (Edi- torial, 1977; Freis, 1976). Because they are effec- tive, and certainly the least expensive of the anti- hypertensive agents, the validity of the charges against them needs to be carefully examined. 1. Diuretics and Hypokalaemia 1.1 Relationship Between Dose, Volume Depletion and the Antihypertensive Effects of Diuretics There is a close association between volume re- duction and the antihypertensive response to the diuretics. It has been known for many years that diuretics cause a moderate reduction in extracel- lular fluid volume and plasma volume, approxi- mating 10 to 15% (Dustan et al., 1959; Wilson and Freis, 1959). This effect, although moderate, ap- pears to play a major role in the reduction of blood pressure (Dustan et al., 1959; Freis, 1976). Volume loss occurs during the first 3 or 4 days of contin- uous treatment with diuretics after which no fur- ther volume depletion occurs (Freis, 1976; Papa- demetriou et al., 1984a). The net reductions in fluid volume are reflected in loss of bodyweight which approximates 1 to 2kg (Papademetriou et al., 1984a; Wilson and Freis, 1959). With respect to hydroch- lorothiazide, doses of 50 mgJday were required to produce weight loss in most patients whereas lower How Dangerous are Diuretics? 470 doses of 25 or 12Smg did not result in significant weight loss (McGregor et al., 1983). Thus, in many patients, doses smaller than 50 mg/day would not be sufficient to lower volume effectively and prob- ably blood pressure as well. The antihypertensive effectiveness of long term drug therapy is often difficult to assess. Because of spontaneous decreases in blood pressure such stud- ies need to be carefully controlled. Following re- peated visits to the clinic, blood pressure often re- verts back to normal levels without any drug treatment (Carey et al., 1976; Management Com- mittee Australian Therapeutic Trial in M'ild Hy- pertension, 1982), and without proper controls it may be impossible to differentiate spontaneous and drug-induced reductions in blood pressure. A few studies have suggested that when low doses of hydrochlorothiazide are given with a @- blocker the dose-response curve becomes flat after 6.25 or 12.5 mgfday of hydrochlorothiazide (An- drew et al., 1983; Berglund and Anderson, 1976). However, it is difficult to judge the effectiveness of one drug when it is combined with another, es- pecially when there is no control evaluation of either drug used alone (Andrew et al., 1983). On the other hand there is considerable evi- dence to indicate that the antihypertensive re- sponse to hydrochlorothiazide alone does not be- come flat at low levels but rather continues to increase to quite high doses of the diuretic. For ex- ample, in the Veterans Administration Coopera- tive Study, propranolol alone was compared with hydrochlorothiazide alone in patients with mild hypertension. Doses of hydrochlorothiazide were titrated as needed from 25mg twice daily to 50mg twice daily and finally to IOOmg twice daily until the diastolic blood pressure was controlled to <90mm Hg (Veterans Administration Cooperative Study Group, 1982a,b). Of the patients controlled on hydrochlorothiazide alone, 50% attained the goal diastolic pressure with the 25mg twice daily dose. However, 30% required the 50mg twice daily dose and 20% needed 1OOmg of the diuretic twice daily before their diastolic blood pressure fell to <90mm Hg. These doses are far in excess of the 6.25 or 25mg recommended by others. Studies other than the Veterans Administration trial have found that the dose-response curve of hydrochlorothiazide also does not remain flat after small doses, and that doses as high as 100 mg/day are required in many patients (Anderson et al., 1984; Henning et al., 1980). It would appear from these results that different patients vary in their responsiveness to the diuretics and that while small doses are satisfactory in some patients they are in- adequate in others. As with most antihypertensive agents, the optimal dose of a diuretic is probably best found by individual titration. 1.2 Diuretic-Induced Hypokalaemia and Ventricular Arrhythmias Reluctance to employ standard doses of diuret- ics in treating patients with uncomplicated essen- tial hypertension derives primarily from the pos- sibility that diuretic-induced hypokalaemia may predispose to the development of life-threatening or even fatal ventricular arrhythmias (Kolata, 1982; Multiple Risk Factor Intervention Group, 1982). Contrary to popular opinion, diuretic-induced hypokalaemia is not associated with a major loss of total body potassium. The hypokalaemia is lim- ited almost exclusively to the extracellular com- partment. Review of various studies indicates that during continuous thiazide treatment, losses of body potassium approximate only a biologically unim- portant 5 to 7% of the total body content (Kassirer and Harrington, 1977). These small losses are in contrast to changes in extracellular potassium. which is reduced by about 20%. Because potassium concentrations within the cells are much greater than in extracellular fluid, large changes in extra- cellular potassium may exert only a small influence on total body potassium. The large difference be- tween extra- and intracellular potassium levels is maintained by sodium-potassium metabolic pump activity (Haddy and Pamnami, 1984). Whether selective extracellular hypokalaemia without significant change in intracellular potas- sium, such as occurs with diuretic-induced hypo- kalaemia, predisposes to increased risk of ventric- ular arrhythmias is not known. Although adequate How Dangerous are Diuretics? 471 studies in experimental animals have not been per- formed (Harrington et al., 1982) the electrophys- lological changes associated with selective extra- cellular hypokalaemia point towards a decreased rather than increased incidence of cardiac arrhyth- mias. According to the Nemst equation (Dyckner and Wester. 1979: Papademetriou, 1983) an in- crease in the intracellular/extracellular ratio which occurs in diuretic-induced hypokalaemia causes hyperpolarisation of the cell membrane. This raises rhe depoiarisation threshold of the myocardium re- sulting in decreased rather than increased suscep- tibility of the heart to the development of arrhyth- mias. Hyperpolarisation of the cell membrane, however, may also raise conduction velocity which under special circumstances such as ischaemia, heart blocks or myocardial scars may either pro- mote or retard re-entry phenomena. Regardless of these theoretical considerations. an increase in the ratio of intracellular/extracellular potassium of the type associated with thiazide diuretics has not been reported to produce life-threatening arrhythmias. Diuretic-induced hypokalaemia may have dif- fering physiological or pathological effects depend- ing on the presence or absence of heart disease. For example. in the presence of congestive heart failure there may be a reduction in the intracellular con- centration of potassium (Editorial, 1977). Local- lsed changes in potassium may occur such as in acute myocardial infarction where high concentra- tions of potassium have been measured in the is- chaemic zone (Hydegger et al., 1984). The elevated concentrations of potassium are thought to be the result of leakage of potassium from the injured cells. The role of whether diuretic-induced hypokalae- mia in these special situations has not yet been clarified. This article, however, is not concerned with these forms of heart disease, but rather with the great majority of hypertensive patients who do not have overt heart disease and whose intracell- ular potassium content is apparently normal. 1.3 Hypokalaemia and Frequency of Ventricular Arrhythmias The most practical and direct way of determin- ing whether diuretic-induced hypokalaemia pro- duces disturbances in cardiac rhythm is to carry out electrocardiographic monitoring. Using 48-hour continuous ambulatory monitoring, no association between hypokalaemia and the incidence of ven- tricular arrhythmias was found by Papademetriou et al. (1984b). Continuous electrocardiographic monitoring was carried out in patients with mild hypertension prior to any therapy and following hydrochlorothiazide treatment for 4 weeks. Pa- tients were separated into those who developed hy- pokalaemia with thiazide therapy and those in whom serum potassium concentrations remained within the normal range. Following thiazide ther- apy no change was noted in either the frequency or severity of the arrhythmias in the patients who became hypokalaemic or those who remained nor- mokalaemic. Other investigators using continuous electrocardiographic monitoring have confirmed the above findings (Leif et al., 1984; Madias et al., 1984). Further, in patients with overt hypokalae- mia on long term diuretic therapy, administration of potassium supplements and potassium-sparing diuretics in amounts sufficient to raise serum po- tassium levels to normal had no effect on ventric- ular arrhythmias (Papademetriou et al., 1983). A previous study by Holland et al. (I 98 1) using electrocardiographic monitoring indicated that hy- pokalaemia secondary to the thiazides did increase the frequency and severity of ventricular arrhyth- mias. The difference between Holland's results and the more recent studies probably can be explained by differences in methodology. Holland excluded all patients who exhibited 6 or more ventricular premature beats/hour during the control period prior to thiazide administration. However, because of the great day-to-day spontaneous fluctuation in ectopic activity (Michelson and Morgenroth, 1980) the chances of these selected patients showing greater ectopic activity on the second (hypoka- laemic) monitoring would be greatly enhanced simply by chance alone. Other investigators who did not select their patients on this basis found no increase in arrhythmias associated with the devel- opment of hypokalaemia (Leif et al., 1984, Madias et al., 1984; Papademetriou et aL, 1984b). How Dangerous are Diuretics? 472 Another previous study found an association cause for an increase in cardiac deaths in a subgroup between hypokalaemia and exercise-induced pre- of patients with minor electrocardiographic abnor- mature ventricular beats (Hollilield and Staton, malities. However, there are several problems with 1981). The results are diflicult to interpret, how- the interpretation of these data. The study was not ever, for a number of reasons: (a) the correlations designed to determine the relationship of cardiac were based on only 2- to 5-minute monito~ng of deaths with respect to treatment with thiazide di- arrhythmias which may be insufficient to distin- uretics. The relationship between thiazide diuretics guish chance occurrence of ectopic beats from those and sudden death was found after a retrospective due to hypokaiaemia; (b) the clinical significance search for correlations between many variables, of exercise-induced premature beats and their This kind of retrospective procedure often leads to prognostic value is essentially unknown; and (c) the positive correlations by chance alone. Therefore, reproducibility of this method of assessing arrhyth- evidence so derived must be confirmed by inde- mias is very poor. This work has not been repeated pendent studies. The results of other studies, how- and remains unconfirmed. ever, have not been confirmatory. Additional concern with respect to diuretic- induced hypokalaemia has been generated by the recent observation that catecholamines which in- crease entry of potassium into cells may further aggravate the hypokalaemia resulting from treat- ment with thiazides (Struthers et al., 1983). How- ever, these studies have not demonstrated that the hypokalaemia resulting from the combined effects of the diuretic and ~t~holamines has any effect on ventricular ectopic activity or that it increases either the frequency or severity of ventricular ar- rhythmias. As a result of catecholamine excess, po- tassium moves mostly into skeletal muscle cells with only minimal changes in potassium content of myocardial cells. The catecholamine-induced changes increase the ratio of intra- to extracellular potassium and theoretically at least should make the ventricle less rather than more susceptible to development of arrhythmias. Although catechol- amines are known to increase ventricular arrhyth- mias they probably do so by other mechanisms than reduction in extracellular potassium. Available data from similar trials such as The Hypertension Detection and Follow-up Program (HDFP) failed to confirm the findings of MRFIT. Thus, in HDFP no subgroup correlations were found between thiazide treatment and cardiovas- cular deaths (The Hypertension Detection and Fol- low-up Program, 1984). The HDFP investigators concluded that their results offered no support for the hy~thesis raised in MRFIT that diuretics in- crease the mortality rates of patients with resting ECG abnormalities. The recently published mor- bidity-mortality results of the Medical Research Council Working Party (MRC Trial, 198.5) indi- cated no significant differences between the effects of bendrofluazide in the prevention of all-cause mortality compared with propranolol (p = 0.24 and 0.71, respectively; cigarette smokers and non- smokers combined). Furthermore, in none of the studies (including MRFIT) has there been any cor- relation between diuretic dosage, serum potassium Ievels and deaths due to heart disease (Medical Re- search Council Working Party on Mild to Mod- erate Hy~~ension, 1983; MRFIT Trial, 1985). 1.4 Evidence from Clinical Trials Most of the concern regarding the possible re- lationship between thiazide-induced hypokalaemia and sudden death has been generated by the results of the Multiple Risk Factor Intervention Trial (MRFIT) [Kolata, 1982; Multiple Risk Factor In- tervention Trial, 19821. It was suggested that data from MRFIT implicated thiazide diuretics as the The Medical Research Council Working Party on Mild to Moderate Hypertension (1983) re- ported 2 substudies with electrocardiographic monitoring. In one study without pretreatment baseline monitoring an increased incidence of ven- tricular ectopy occurred in hypertensive patients during long term treatment with thiazides com- pared to a group receiving only placebos. In this subgroup, however, there was no correlation be- How Dangerous are Diuretics? 473 tween arrhythmias and serum potassium level, al- other studies which made only long term obser- though there was a weak correlation with serum vations on changes in plasma cholesterol. When uric acid concentration. A second trial, better con- serum cholesterol levels were measured 1 or 2 years trolled, failed to confirm the first in that there was after beginning treatment they were not elevated no increase in arrhythmias during treatment with in 2 studies (Amery et al., 1982; Kannel et al., 19771, thiazide diuretics for a period of 8 to 10 weeks. but were elevated in 1 (Goldman et al., 1980). The available evidence, therefore, fails to sup- port the view that in patients without heart disease diuretic-induced hypokalaemia causes increased ventricular arrhythmias. But, because of the undue concern that has been generated, potassium re- placement therapy has become widespread (Har- rington et al., 1982), which if overdone could be- come potentially dangerous (Lawson, 1974). Thus, elevated serum cholesterol concentration is not a risk during long term treatment with di- uretics because the almost unanimous experience has been that elevation is not persistent aRer 6 months or 1 year of treatment. 3. Summary and Conclusions 2. Diuretics and Serum Cholesterol Serum cholesterol usually increases slightly when thiazide diuretics are administered (Grimm et al., I98 1). Some investigators have expressed concern that the elevation, even though slight, would over a period of many years aggravate and accelerate the development of coronary heart disease (Grimm et al., 1981). This fear would have some justifi- cation if it could be shown that the elevation of serum cholesterol is indeed persistent. The avail- able evidence, however, indicates that it is not. Three studies have shown that expected initial Increases in serum cholesterol levels were followed later by reduction to or below the pretreatment lev- els. One of these trials was carried out in a Vet- erans Administration cooperative study in which 343 patients with mild hypertension received hy- drochlorothiazide and no other drugs or dietary treatment (Veterans Administration Cooperative Study, 1982b). Plasma cholesterol rose during the first 3 months of treatment but at 12 months the cholesterol level fell to below baseline. Similarly, Ucazar et al. (1982) also found that plasma cho- fester01 only rose initialiy, and after 3 months re- turned toward the pretreatment baseline, remain- ing there for the next several years of observation. Data taken from the HDFP also indicated that the short term rise in plasma cholesterol was followed by a long term return to baseline (Williams et al., 1983). These observations are further supported by The proposal that thiazide diuretics may in- crease cardiovascular risk receives no support from recent data. Current evidence does not indicate that diuretic-induced hypokalaemia is associated with increased ventricular ~hythmias. This evidence includes continuous electrocardiographic monitor- ing - which is the most sensitive technique for quantitating cardiac arrhythmias. In contrast to earlier reports, more recent studies found no evi- dence for increased arrhythmias during the period of hypokalaemia, or for decreased arrhythmic ac- tivity after correction of hypokalaemia. Similarly, studies claiming increased sudden death in pa- tients on diuretic treatment have not been sub- stantiated by the results of other large-scale trials. Elevation of serum cholesterol concentrations with thiazide appears to be a short term phenom- enon since most studies indicate the elevation re- verts to baseline during long term treatment. Thiazide diuretics remain as one of our most effective antihypertensive agents. 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