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PubMed1983

Effects of indapamide and various diuretics alone or combined with beta-blockers on serum lipoproteins.

A prospective evaluation was started in 1976 to study the influence of diuretics alone or combined with beta-blockers on serum lipoproteins in normal or hypertensive subjects. Compared to placebo conditions, 4 or 6-weeks' monotherapy with various diuretics significantly (p less than 0.05) increased the beta-lipoprotein fraction (furosemide, 80 mg/day or chlorthalidone, 100 mg/day; n = 16) or low-density lipoprotein-cholesterol (LDL-C) (chlorthalidone, 100 mg/day, n = 27 men; tienilic acid, 250 mg/day, n = 16 men, clopamide, 5 mg/day, n = 17 men; or muzolimine, 20 to 40 mg/day, n = 13 men or post-menopausal women). No increase in LDL-C was noted in 43 men (32 normal, 11 with mild hypertension) treated with indapamide, 2.5 mg/day. Serum high-density lipoprotein-cholesterol and apoproteins A1, A2 and B were not consistently changed by any of these agents. In women, chlorthalidone (100 mg/day) significantly increased LDL-C in the (100 mg/day) significantly increased LDL-C in the post-menopausal (n = 18) but not in the pre-menopausal (n = 22) state. Increases in LDL-C caused by chlorthalidone monotherapy were prevented or reversed by the addition of a beta-blocker, usually propranolol or atenolol (n = 18); increases in LDL-C during clopamide monotherapy were reversed after the addition of the beta-blocker pindolol (10 mg/day, n = 17). In all studies, variations in beta-lipoprotein or LDL-C levels could not be explained by changes in blood volume, serum glucose or insulin and did not correlate with alterations in blood pressure, plasma potassium, renin, aldosterone, adrenaline or noradrenaline. These observations indicate that various diuretics may increase serum LDL-C in men or post-menopausal women. Pre-menopausal women may often be protected from this side-effect. Long-term studies are now needed to clarify the pathogenic and prognostic relevance of lipoprotein changes induced by diuretics. In the meantime, it is of clinical interest that indapamide had no significant effect on serum lipoproteins and that certain beta-blockers appear to prevent or reverse increases in LDL-C during diuretic treatment in men and post-menopausal women.

Adrenergic beta-Antagonists↗
PubMed1981

Further investigations on the binding of loop diuretics to serum proteins from patients with liver disease.

The binding of three loop diuretics, piretanide, bumetanide and furosemide, to serum proteins from patients with liver cirrhosis or fulminant hepatitis was investigated using equilibrium dialysis. A good correlation was found between serum albumin concentration and the percentage of each unbound (free) loop diuretic in patients with liver disease. The binding data obtained from patients with liver cirrhosis was compared with that of patients with chronic renal failure. Calculations made according to the Sandberg-Rosenthal's formula revealed that the maximum binding concentration (nP) varied in some cases. These findings necessitated a detailed investigation into whether the increased percentage of each unbound loop diuretic in patients with liver disease is attributable not only to lowered serum albumin concentration but also to inhibition of the protein binding by some endogenous substances. Thus, similar experiments were performed using rats with experimental liver cirrhosis. The binding of the loop diuretics to serum proteins in cirrhotic rats differed greatly from the findings obtained from cirrhotic patients. The percentage of unbound loop diuretic was well correlated with serum albumin concentration but not with the concentration of serum bilirubin (an endogenous substance) in cirrhotic rats.

Adult↗
PubMed1990

Biological assessment of the enhancement of tritium excretion by administration of diuretics and excessive water in mice.

This study was undertaken to determine whether or not the administration of diuretics and excess water after tritium exposure would have any positive reducing effect not only on the retention of tritium but also on the radiation damage of hematopoietic tissue in mice. When mice were treated with diuretics and excess water for a few days after injection of tritiated water (HTO), radioactivity within the body fluid and tissues was reduced, and the number of CFU-s, clonability of splenic T cells and proliferative activity assayed by Con-A blastogenesis were increased in comparison with those in the controls. When the mice were injected with a large dose of HTO (811 MBq/mouse) to assay survival, no mice treated with diuretic and excess water died 80 days after injection, while 80% of the controls died during the first month. The final committed dose in the mice treated early with diuretics was calculated to be 60% of that in the controls. These results suggest that treatment with diuretics and excess water is useful for practical purposes when a human is accidentally exposed to tritium.

Animals↗
PubMed2003

Pharmacogenomics of diuretic drugs: data on rare monogenic disorders and on polymorphisms and requirements for further research.

This review summarizes the current status of our knowledge about the role of pharmacogenetic variation in response to diuretics and suggests future research topics for the field. Genes with a role in the pharmacokinetics of most diuretics are renal drug transporters, especially OAT1, OAT3 and OCT2 (genes SLC22A6, SLC22A8 and SLC22A2) whereas variants in carbonic anhydrase (CA), cytochrome P450 enzymes and sulfotransferases are relevant only for specific substances. Genes on the pharmacodynamic side include the primary targets of thiazide, loop, K(+)-sparing and aldosterone antagonistic diuretics: NCC, NKCC2, ENaC and the mineralocorticoid receptor (genes SLC12A3, SLC12A1, SCNN1A, B, G and NR3C2). Rare variants of these proteins cause Gitelman's syndrome, Bartter's syndrome, Liddle's syndrome or pregnancy-induced hypertension. Polymorphisms in these and in associated proteins such as GNB3, alpha-adducin and angiotensin-converting enzyme (ACE) seem to be clinically relevant. In conclusion, first knowledge has evolved that efficacy of diuretic drugs may be determined by genetic polymorphisms in genes determining pharmacokinetics and pharmacodynamics of this drug class. In the future, the selection of a diuretic drug or the dosing schedules may be individually chosen based on pharmacogenetic parameters, however, many questions remain to be answered before this fantasy becomes reality.

Animals↗
PubMed2006

Effect of various diuretic treatments on rosiglitazone-induced fluid retention.

The efficacy of diuretics in the management of rosiglitazone (RSG)-induced fluid retention was evaluated in a multicenter, randomized, open-label, parallel-group, proof-of-concept study. Of 381 patients who had type 2 diabetes and were on treatment with sulfonylurea or sulfonylurea plus metformin, 260 (63% male, 37% female) showed evidence of volume expansion as defined by an absolute reduction in hematocrit (Hct) of > or =0.5% after 12 wk of rosiglitazone 4 mg twice daily. They were randomly assigned to five treatments for 7 d: (1) Continuation of RSG (RSG-C), (2) RSG + furosemide (RSG+FRUS), (3) RSG + hydrochlorothiazide (RSG+HCTZ), (4) RSG + spironolactone (RSG+SPIRO), and (5) discontinuation of RSG. The primary end point was change in Hct at day 7 of diuretic treatment phase, powered to compare each diuretic group and the RSG discontinuation with the control group of RSG-C, with adjustments for multiple testing. After 12 wk on RSG, Hct fell by mean of 2.92% (95% confidence interval [CI] -3.10 to -2.63%; P < 0.001) and extracellular fluid volume increased by 0.62 L/1.73 m(2) (95% CI 0.26 to 0.90 L/1.73 m(2); P < 0.001). After treatment, the RSG+SPIRO group only showed a mean increase in Hct of 0.24%. The estimated mean difference in Hct reduction was significant: 1.14% (95% CI 0.29 to 1.98%) for RSG+SPIRO (P = 0.004) and 0.87% (95% CI 0.03 to 1.71%) for RSG+HCTZ (P = 0.041) only. In additional analyses of between-diuretic treatment effects SPIRO induced a greater Hct rescue at 0.88% (95% CI -0.12 to 1.87%; P = 0.095) and extracellular fluid volume reduction of -0.75 L/1.73 m(2) (95% CI -1.52 to 0.03 L/1.73 m(2); P = 0.06) compared with FRUS, suggesting superiority in the management of RSG-associated fluid retention. There were no significant differences between SPIRO and HCTZ. These findings are consistent with peroxisome proliferator-activated receptor-gamma agonist activation of the epithelial sodium channel in the distal collecting duct, a site of action of SPIRO and a potential target for thiazide diuretics.

Adult↗
PubMed1995

Metabolic adverse reactions to diuretics. Clinical relevance to elderly patients.

There is a wide variety of diuretic-induced metabolic abnormalities of unequal severity. Renal failure can be caused by excessive sodium loss, or by certain drug combinations comprising, for instance, a nonsteroidal anti-inflammatory drug (NSAID) or an ACE inhibitor. Hyponatraemia is uncommon. It is encountered with thiazides, especially among women. A sodium level less than 120 mmol/L may result in neurological complications. Hypokalaemia is frequent and might increase the risk of cardiac arrhythmia. Hyperkalaemia induced by potassium-sparing diuretics is often combined with another contributive cause. Glucidic, lipidic and uric acid abnormalities are common, but their clinical effects are slight. They do not seem to worsen cardiovascular risks among elderly patients. Nevertheless, prescribing diuretics for elderly patients requires special precautions. Reducing the diuretic dose, as is now recommended for treating hypertension, seems to lessen adverse effects, and despite all the adverse reactions just mentioned, it has been proven that diuretics are beneficial in many diseases.

Aged↗
PubMed1987

Clinical pharmacokinetics of some newer diuretics.

Several new diuretics have recently been developed. This review summarises the published knowledge about some of them. Azosemide is a loop diuretic. The bioavailability is about 15% and it has a half-life of 2 to 3 hours. Renal and non-renal clearance are 1.32 and 5.4 L/h, respectively. Etozolin is also a loop diuretic. It is rapidly metabolised to the active metabolite, ozolinone. The gastrointestinal uptake of etozolin is almost complete. The plasma half-life of etozolin and ozolinone are 2 and 10 hours, respectively. The compounds are mainly eliminated as metabolites. Renal and liver impairment do not seem to change the pharmacokinetics. Fenquizone has properties similar to the thiazides. The plasma half-life is approximately 17 hours. Apparent volume of distribution averaged 686 L and renal clearance is 7.2 L/h. Indapamide acts predominantly on the proximal segment of the distal tubule and also has direct vasodilatory effects. Gastrointestinal uptake is at least 80%. The drug binds highly to carbonic anhydrases of red blood cells. Protein binding is about 80%, while terminal plasma half-life is 15 hours and the apparent volume of distribution 25 L. Renal clearance is 0.3 L/h and non-renal clearance 0.9 L/h. Several metabolites have been described, of which one major metabolite is pharmacologically active. Muzolimine is a loop diuretic. Its uptake is almost complete, but decreased substantially by food. The protein binding is about 65%, the apparent volume of distribution is about 1 L/kg and average terminal half-life 10 to 20 hours. Elimination is mainly non-renal, and non-renal clearance ranges between 0.5 and 1.32 L/h. The pharmacokinetics of the drug do not seem to be changed in cardiac failure. Terminal plasma half-life is essentially unchanged in patients with renal failure, except in those with very severe reduction of glomerular filtration rate. Piretanide is a loop diuretic which is about 6 times as potent as frusemide (furosemide). Its bioavailability is most likely complete in healthy subjects and in renal patients. Protein binding in healthy subjects is about 95%. The plasma half-life of the drug is about 1 hour and apparent volume of distribution averages about 17 L. Renal and non-renal clearance are about 6 L/h, although renal clearance is decreased in renal failure: this decrease is correlated with glomerular filtration rate. Non-renal clearance is unchanged in renal failure, as is the apparent volume of distribution.(ABSTRACT TRUNCATED AT 400 WORDS)

Diuretics↗
PubMed1981

The risks of asymptomatic hyperuricaemia and the use of uricosuric diuretics.

Introduction of new uricosuric diuretics will be accompanied by the unknown risk factors associated with the use of any new drug, as demonstrated by reports of hepatic toxicity associated with ticrynafen. In addition to unexpected reactions, there are potential risks related to induction of uricosuria, which are serious and have been reported to occur. More importantly, the risk of developing clinical gout or coronary heart disease due to mild asymptomatic hyperuricaemia appears minimal, so indications for the use of uricosuric diuretics are limited. If a uricosuric diuretic is thought necessary (and is available), it would seem prudent to measure the daily excretion rate of uric acid to identify those patients with hyperuricaemia related to overproduction of uric acid. A uricosuric diuretic should be avoided in those patients, as well as in patients with uric acid stones, and possibly in those with calcium stones. A uricosuric diuretic might be useful for patients with hypertension who also have hyperuricaemia due to a low excretion of uric acid.

Coronary Disease↗
PubMed1984

Diuretic-induced hypokalaemia and ventricular arrhythmias.

In the past, adverse cardiac effects of potassium depletion in non-digitalised patients and in patients without cardiac disease were considered to be minimal. However, several studies have now demonstrated a significant incidence of ventricular ectopic activity in diuretic-treated patients, particularly in those who become hypokalaemic. Potassium repletion with potassium-sparing diuretics or with potassium chloride supplementation has generally demonstrated a beneficial therapeutic effect in reducing ventricular ectopic activity. However, occasional patients may have persistent ventricular ectopic activity after diuretic therapy which may result from focal myocardial lesions associated with potassium depletion. In addition, factors other than potassium depletion appear to initiate or magnify diuretic-induced ventricular ectopic activity. Thus, to avoid these adverse cardiac effects, normokalaemia should be maintained during long term diuretic therapy.

Arrhythmias, Cardiac↗
PubMed1991

How do loop diuretics act?

In the thick ascending limb of the loop of Henle, NaCl reabsorption is mediated by a Na+/2Cl-/K+ cotransport system, present in the luminal membrane of this nephron segment. Loop diuretics such as furosemide (frusemide), piretanide, bumetanide and torasemide bind reversibly to this carrier protein, thus reducing or abolishing NaCl reabsorption. This leads to a decrease in interstitial hypertonicity and thus to a reduced water reabsorption. In nephron segments other than the thick ascending limb, loop diuretics have no quantitative importance with respect to their saluretic and diuretic activities. Loop diuretics also reduce Ca++ and Mg++ reabsorption in the thick ascending limb in a way which is still not clear. Furthermore, these drugs increase the urinary K+ excretion by enhancing distal tubular K+ secretion and reducing K+ reabsorption in the loop of Henle. Finally, by reduction of active NaCl transport, loop diuretics drastically reduce the substrate requirement and oxygen dependence of the thick ascending limb cells. This renders these cells, which are characterised by high transport rates and only limited substrate reserves, less vulnerable in acute renal failure.

Animals↗
PubMed1991

The efficacy of diuretics in acute and chronic renal failure. Focus on torasemide.

Loop diuretics in high doses are the drugs of choice in the treatment of both acute renal failure (ARF) and chronic renal failure (CRF). Their pharmacokinetic and pharmacodynamic properties give them a high efficacy, even in severely compromised renal function. The serum elimination half-life and duration of action of most loop diuretics are dependent on the glomerular filtration rate and are therefore prolonged in renal failure. Torasemide, a new high ceiling and long acting loop diuretic, is as potent as furosemide (frusemide) in patients with advanced renal failure. Unlike other loop diuretics, the half-life and duration of action of torasemide are not dependent on renal function and the parent drug does not accumulate in renal failure. The extent of metabolism is clinically negligible. A number of studies have demonstrated the efficacy of furosemide, bumetanide, piretanide and torasemide in patients with ARF and CRF. When compared with the other loop diuretics, torasemide has the following advantages: a longer half-life independent of renal function, no indications of toxic side effects and apparently less influence on calciuresis.

Acute Kidney Injury↗
PubMed2000

Diuretics as a basis of antihypertensive therapy. An overview.

Diuretics have been, except for during a few recent years, the most commonly used therapy for hypertension. Although use of these agents fell significantly in the early 1990s, since then it has begun to increase again. Their recent return to popularity reflects 3 major factors: (i) recognition of the effectiveness of much lower dosages than previously used, thereby providing good antihypertensive activity with fewer adverse effects; (ii) the excellent reductions in morbidity and mortality achieved by low dosage diuretic-based therapy in multiple randomised controlled trials in elderly patients with hypertension; and (iii) the increasing recognition that some diuretic-induced shrinkage of effective blood volume is essential for the adequate treatment of many, if not most, patients with hypertension. Therefore, diuretics will probably continue to be the basis for antihypertensive therapy, and the indapamide sustained release 1.5 mg formulation provides all the essential characteristics of diuretic therapy.

Antihypertensive Agents↗
PubMedDate not supplied

Diuretic therapy and exercise performance.

Drugs that induce an increased urine flow are used both legitimately (treatment of hypertension and oedema) and otherwise (rapid weight loss) in sports and exercise. There are 5 major categories of diuretic drugs based on their mechanisms and loci of action. Common to all classes is hypohydration, which has been shown to have an array of adverse effects on performance, including impaired strength, power and endurance. Postural hypotension can be particularly troublesome in the elderly. Also common to all diuretics, except those interfering with the aldosterone mechanism in the distal nephron, is hypokalaemia. Severe symptomatic hypokalaemia (serum K+ concentration less than 3.0 mmol/L) is rare except in clinical situations in which additional hypokalaemic factors are present. Moderate levels of hypokalaemia (serum K+ concentration 3.0 to 3.5 mmol/L) can increase the risk of adverse reactions as has been shown in a variety of prospective clinical studies. Hypokalaemia has effects on cardiac rhythm, muscle function and integrity, local blood flow, carbohydrate metabolism, and the blood lipid profile. Performance studies generally show diminished exercise tolerance in direct proportion to the degree of hypohydration induced. This is not the case, however, in a clinical setting of compromised cardiopulmonary function, in which diuresis has direct and indirect inotropic effects which augment exercise tolerance and decrease symptoms. The ability of the carbonic anhydrase inhibitor, acetazolamide, to induce a hyperventilatory response to the obligatory metabolic acidosis is taken advantage of in mountaineering to prevent or ameliorate the symptoms of acute mountain sickness, thereby improving exercise performance at high altitude. It is suggested that in clinical situations in which the use of a diuretic is considered appropriate, every effort be made to maintain or restore the serum concentration and the total body store of potassium to normal. To some degree this can be accomplished through diet, although potassium chloride supplements or potassium-sparing diuretics or diuretic combinations may be necessary.

Diuretics↗
PubMed2006

Diuretics in pediatrics : current knowledge and future prospects.

This review summarizes current knowledge on the pharmacology, pharmacokinetics, pharmacodynamics, and clinical application of the most commonly used diuretics in children. Diuretics are frequently prescribed drugs in children. Their main indication is to reduce fluid overload in acute and chronic disease states such as congestive heart failure and renal failure. As with most drugs used in children, optimal dosing schedules are largely unknown and empirical. This is undesirable as it can potentially result in either under- or over-treatment with the possibility of unwanted effects. The pharmacokinetics of diuretics vary in the different pediatric age groups as well as in different disease states. To exert their action, all diuretics, except spironolactone, have to reach the tubular lumen by glomerular filtration and/or proximal tubular secretion. Therefore, renal maturation and function influence drug delivery and consequently pharmacodynamics. Currently advised doses for diuretics are largely based on adult pharmacokinetic and pharmacodynamic studies. Therefore, additional pharmacokinetic and pharmacodynamic studies for the different pediatric age groups are necessary to develop dosing regimens based on pharmacokinetic and pharmacodynamic models for all routes of administration.

Aging↗
PubMed1999

Renal diuretic duplex Doppler sonography in childhood hydronephrosis.

OBJECTIVE: The purpose of this study was to determine the diagnostic value of diuretic duplex Doppler sonography in distinguishing between obstructive and nonobstructive hydronephrosis in children by calculating the resistive indices (RI) before and after administration of furosemide. MATERIAL AND METHODS: We prospectively evaluated 28 kidneys (2 solitary) in 15 patients with unilateral or bilateral neonatal hydronephrosis. All patients underwent diuretic renography and duplex Doppler sonography before and after administration of furosemide. RESULTS: According to the half-time drainage patterns at diuretic renography, 13 kidneys were classified as nonobstructed and 15 as obstructed. At baseline, the mean RI values of nonobstructed and obstructed kidneys were not significantly different (0.66 and 0.64, respectively). Ten minutes after the injection of furosemide, the mean RI values of the nonobstructed and obstructed kidneys were 0.68 and 0.70, respectively. The increase in RI over the baseline 10 min after the diuretic injection was statistically significant (p<0.00001) in the obstructed kidneys. CONCLUSION: The baseline RI value of 0.70 is not a definite value for distinguishing obstructed from nonobstructed systems. An increase in RI of at least 10% over the baseline seems to be a more reliable criterion, especially when it is used in conjunction with diuretic renography.

Child, Preschool↗
PubMed1996

Adverse effects on risk of ischaemic heart disease of adding sugar to hot beverages in hypertensives using diuretics. A six year follow-up in the Copenhagen Male Study.

Non insulin dependent diabetes mellitus (NIDDM) and essential hypertension (EH) are two of several manifestations of the insulin resistance syndrome. Although subjects with NIDDM and subjects with EH share a common defect in carbohydrate metabolism, only diabetics are advised to avoid sugar. We tested the theory that an adverse effect of diuretics treatment in men with EH with respect to risk of ischaemic heart disease (IHD) would depend on the intake of dietary sugar using sugar in hot beverages as a marker. The cohort consisted of 2,899 men from the Copenhagen Male Study aged 53-74 years (mean 63) who were without overt cardiovascular disease. Potential confounders were: age, alcohol,smoking, physical activity, body mass index, blood pressure, fasting lipids, cotinine, NIDDM,and social class. A total of 340 men took antihypertensives; 211 took diuretics (95% thiazides and related agents), and 129 used other antihypertensives. During 6 years, 179 men (6.2%) had a first IHD event. Among the 340 men taking antihypertensives, the incidence rate was 11%. Diuretics use was associated with a high risk of IHD in hypertensive men with a relatively high intake of dietary sugar; the cumulative incidence rate was 22%; in diuretics treated men with a low intake of sugar, the rate was 7%. After controlling for potential confounders, relative risk (95% ci.) was 3.1(1.3-7.6), p = 001. Among the 129 men who took other forms of antihypertensive drugs, the IHD incidence rate was 8%, and independent of the intake of sugar. The results indicate that the risk of IHD in hypertensives using diuretics is associated with intake of dietary sugar, which may explain at least some of the discouraging effects of antihypertensive agents on the reduction of risk of IHD.

Adult↗
PubMed1983

Diuretic agents: actions on a molecular level.

The criteria upon which diuretics are classified are based upon their site of action within the nephron. Carbonic anhydrase inhibitors act in the proximal tubule, high-ceiling diuretics in the ascending loop of Henle, the thiazides in the early distal tubule and the potassium-sparing diuretics in the late distal tubule and in the collecting duct. According to the localization of carbonic anhydrase acetazolamide acts on three different sites in the proximal tubule cells. The loop diuretics inhibit the secondary active chloride reabsorption. Experiments on the isolated stripped rabbit colon under the condition of stimulated chloride secretion reveal striking similarities between the receptors for chloride reabsorption in the luminal cell membranes of the ascending loop of Henle and in the serosal cell membranes of the colon. The potassium-sparing diuretics act by blocking sodium channels in the distal parts of the nephron. The lumen negative potential difference decreases and potassium secretion is diminished.

Absorption↗
PubMed1983

The therapeutic use of a new potassium-sparing diuretic, amiloride, and a converting enzyme inhibitor, MK-421, in preventing hypokalemia associated with primary and secondary hyperaldosteronism.

This presentation is a summary of our recent clinical studies on the therapeutic use of a new potassium-sparing diuretic, amiloride, and a converting enzyme inhibitor, MK-421, in preventing hypokalemia associated with primary and secondary hyperaldosteronism. These drugs are quite different in their physiologic action but they both may be effective in preventing the potassium depletion associated with increased aldosterone production. Amiloride, which blocks the sodium channels in distal renal tubular cells, was administered to 10 patients with primary hyperaldosteronism and five patients with Bartter's syndrome (secondary hyperaldosteronism). Amiloride, at doses of 10-40 mg/day, increased mean plasma potassium levels in both primary hyperaldosteronism (3.2-4.5 mEq/L) and, to a lesser extent, in Bartter's syndrome (2.5-3.6 mEq/L). The blood pressure fell slightly but significantly in primary hyperaldosteronism (171/112 vs 150/97 mm Hg) and remained unchanged in Bartter's syndrome (116/80 vs 117/71 mm Hg). The plasma renin activity and plasma aldosterone rose in primary aldosteronism (PRA 0.39-2.21 ng A1/m1/h and PA 28.4-54.3 ng/d1); but in Bartter's syndrome, the PRA declined (25.3-11.9 ng A1/m1/h) and the PA rose (19.5-38.0 ng/d1). The discrepancy in the PRA between primary aldosteronism and Bartter's syndrome may be due to the effects of potassium repletion on suppressing renin and stimulating aldosterone; while in primary aldosteronism, a mild diuretic effect could explain the rise in PRA. In both of these disorders, despite the rise in plasma potassium levels, amiloride produced a counter-therapeutic rise in PA which could potentiate further potassium losses. Therefore, we undertook a study to evaluate the prevention of diuretic-induced hypokalemia and secondary hyperaldosteronism using a new converting enzyme inhibitor, MK-421. Eighteen normal subjects were randomized into three groups receiving either (1) hydrochlorothiazide alone (50 mg/day), (2) MK-421 alone (10 mg/day), or (3) hydrochlorothiazide (50 mg/day) plus MK-421 (10 mg/day). Although MK-421 did not prevent diuretic-induced hypokalemia or hyperaldosteronism in the first week, after that time hypokalemia was reversed and ASR returned to normal. In these studies, it therefore appears that while potassium-sparing diuretics may remain the medical mainstay in treating primary aldosteronism, new converting enzyme inhibitors such as MK-421 may be more effective in treating secondary hyperaldosteronism, since potassium levels can be normalized without increasing aldosterone secretion.

Adult↗