The use of diuretics in modern antihypertensive therapy

Abstract: A review is made to sum up the indications when diuretics may be the drug of choice in the treatment of hypertension. Advantages from the combined treatment of thiazide diuretics and other antihypertensive agents are also emphasized. Adverse effects from diuretic treatment, i. e. hypokalemia, hyperuricemia, impaired glucose tolerance and risks associated with unfavourable serum lipoprotein patterns are discussed. It is concluded that from a hemodynamic point of view thiazide diuretics can be a good therapeutic alternative for most patients, excepting those with hyperkinetic circulation. It is recommended to use lower doses of thiazide diuretics than previously and the monitoring of S-potassium is necessary in all patients.     

Hydrochlorothiazide efficacy and polymorphisms in ACE, ADD1 and GNB3 in healthy, male volunteers

Objective The antihypertensive effect of thiazide diuretics has recently been associated with genetic variation in the angiotensin I-converting enzyme (ACE), alpha-adducin (ADD1) and the G protein subunit β3 (GNB3). Analysis of short-term diuretic effects may provide insight into the mechanisms behind these findings. Methods A total of 103 male volunteers took 25 and 100 mg hydrochlorothiazide (HCT) after a placebo day, each. We measured volume, sodium, chloride, potassium, calcium excretion, blood pressure and heart rate. Results Excretion and cardiovascular parameters were highly constant between the 2 placebo days. The resting heart rate was 2–3 beats/minute (bpm) higher per ACE insertion allele on all 4 study days. The HCT-induced excretion of sodium, chloride and volume was independent of the genotypes. The additional potassium excretion induced by 100 mg HCT was 44±21, 33±27 and 16±26 mmol (mean±SD, p<0.001) in ACE II, ID and DD carriers and the same trend was observed after 25 mg HCT. As a second finding, the 100 mg HCT-induced calcium retention was 0.2±1.2, 0.7±0.8 and 1.7±2.1 mmol in ADD1 Gly/Gly, Gly/Trp and Trp/Trp carriers (p=0.002) and the same trend existed after 25 mg HCT. Conclusion The effects of genetic polymorphisms were stronger with the higher diuretic dose. ACE insertion allele carriers appeared to be more prone to hypokalaemia than deletion allele carriers. ADD1 Trp460 carriers may especially benefit from the calcium-sparing effect of thiazides. Both associations should be further studied in long-term treatment with thiazide diuretics.     

Hypokalaemia in alcoholic patients

Hypokalaemia is commonly found among the electrolyte abnormalities observed in chronic alcoholics. However, the underlying mechanisms of the decreased potassium levels are not well known. We undertook the present study to analyse the possible pathogenetic mechanisms of hypokalaemia in a large group of alcoholic patients ( n = 127) admitted to our hospital for causes related to alcohol abuse. Serum potassium levels were significantly lower in alcoholic patients compared to the control population (3.8 ±1.1 mmol/l vs. 4.6 ±0.9 mmol/l). In 12 of these patients inappropriate kaliuresis was observed due mainly to the coexistent hypomagnesaemia. Two of the remaining four patients had a history of diarrhoea, while the other two had alcohol withdrawal syndrome with considerable respiratory alkalosis. Patients with hypokalaemia had hypomagnesaemia and respiratory alkalosis more commonly compared to the normokalaemic ones. We conclude that hypokalaemia is a relatively common electrolyte abnormality observed in alcoholic patients owing to various pathophysiological mechanisms. Among them, inappropriate kaliuresis due to the co-existent hypomagnesaemia predominates.     

A comparative study of the action of frusemide and methyclothiazide on renin release by rat kidney slices and the interaction with indomethacin.

1 The effects of frusemide (a diuretic acting on the loop of Henle) and methyclothiazide (a thiazide diuretic) on renin release were studied on rat kidney slices. 2 Frusemide at concentrations of 1.5 and 7.5 mmol/l produced significant increases in renin release but had no effect at 0.15 mmol/l. 3 Methyclothiazide in a similar concentration range did not increase renin release; instead, at the highest concentration used, methyclothiazide (3.5 mmol/l) inhibited renin release. 4 Indomethacin (25 mumol/l) did not inhibit the increase of renin induced by frusemide. 5 Our limited study in vitro is consistent with the findings of other workers who have shown in vivo, in the absence of systemic electrolyte depletion, that only "loop diuretics" increase renin secretion. Under our experimental conditions, it is suggested that frusemide exerts a direct action either upon the epithelioid cells or upon the macula densa since the renal prostaglandin system does not intervene.     

Hypokalemia in cardiac decompensation

Abstract: The problem of hypokalemia in cardiac decompensation is reviewed. Some methodological sources of error in connection with blood sampling is discussed, as is the definition of hypokalemia. “Hypokalemia” may be present with a serum potassium value within the reference range of 3.5–5.0 mmol/l. Although diuretics are the most common cause of hypokalemia in patients with cardiac decompensation, there are other factors at work. One is an increase of the plasma aldosterone concentration and another the increased sympathetic nervous activity–adrenaline administration reduces the plasma potassium concentration. The clinical importance of hypokalemia, especially for cardiac arrhythmias, is discussed.     

Duloxetine-induced hyponatremia in an elderly patient treated with thiazide diuretics

Hyponatremia is a known adverse effect of duloxetine, and it can lead to potentially life-threatening complications. Administration of thiazide diuretics also has been the cause of hyponatremia. We report a case of duloxetine-induced hyponatremia in an elderly patient treated with thiazide diuretics. An 86-year-old woman treated with the trichlormethiazide was admitted for vertebral compression fracture with disorientation and nausea on the 6^th day of treatment with duloxetine. Laboratory findings revealed hyponatremia, hypo-osmolality, concentrated urine, and increased urine sodium. Syndrome of inappropriate antidiuretic hormone was considered, therefore, duloxetine, and trichlormethiazide was discontinued and treated with fluid restriction, furosemide and sodium chloride administered orally. Disorientation and nausea were improved after correction of hyponatremia. Health care practitioners should be aware of the possibility of duloxetine-induced hyponatremia, particularly in patients treated with thiazide diuretics.KEY WORDS: Drug interaction, duloxetine, syndrome of inappropriate secretion of antidiuretic hormone syndrome, trichlormethiazide     

Significance of the calcium to creatinine concentration ratio of a single-voided urine specimen in patients with hypercalciuric urolithiasis

Thirty-six patients with recurrent calcium oxalate nephrolithiasis were selected from the stone clinic. Fourteen were normocalcemic and had normal daily urinary calcium excretion. Among 22 patients with idiopathic hypercalciuria, 10 received thiazide diuretics for the prevention of new stone formation. Single-voided urine samples were collected at the outpatient clinic and 24-hour urine at the patients' homes. In hypercalciuric patients, irrespective of thiazide diuretic therapy, the mean value of the calcium/creatinine concentration ratios of postprandial single-voided urine specimens had a meaningful correlation with the man value of 24-hour urinary calcium excretion rates. Also in hypercalciuric patients with thiazide diuretics, a negative correlation was observed between the calcium/creatinine concentration ratio and the index for urinary saturation with calcium oxalate of a postprandial single-voided urine sample. Thus, in the hypercalciuric stone formers, 24-hour urinary calcium excretion rates and the degree of urinary saturation with calcium oxalate can be estimated from the calcium/creatinine concentration ratios of single-voided urinary samples.     

Continuous magnesium infusions in the management of systemic anti-cancer therapy-related hypomagnesaemia

Background Hypomagnesaemia is a relatively-common side effect of some systemic anti-cancer therapies (SACT). Oral and intravenous magnesium (given as injections or short infusions) have problems arising from their poor tolerability, and need for frequent administrations, respectively. Objective Assessing the effectiveness and safety of weekly continuous magnesium infusions (CMI) in the management of SACT-related hypomagnesaemia. Methods CMIs (initiated at 10 mmol/day and up-titrated subject to response) were prescribed to patients with ≥3 magnesium readings <0.5 mmol/L despite intravenous replacement with bolus-or-short-infusions (BSI). Efficacy (compared to BSI): (a) reduction in the number of moderate/severe hypomagnesaemia episodes, and (b) increase in mean magnesium serum levels. Safety: non-occurrence of grade ≥3 toxicities (according to the common terminology criteria for adverse events v4). Results Three patients were treated (mean age: 62-years), pre-SACT levels were 0.629 ± 0.121 mmol/L. Efficacy: (a) 1 versus 18 episodes; (b) 0.639 ± 0.093 mmol/L versus 0.533 ± 0.191 mmol/L. All comparisons were statistically significant in favour of CMI (p < 0.001). No magnesium-related grade ≥2 side effects were observed. Conclusion CMIs resulted in a marked reduction in the number of episodes of hypomagnesaemia and higher magnesium levels, with no significant side effects. CMIs represent a potential option for the management of SACT-related hypomagnesaemia, although further research in an expanded cohort is required.     

Drug-induced life-threatening potassium disturbances detected by a pharmacovigilance program from laboratory signals

Purpose

Detection and reporting of drug-induced life-threatening potassium disturbances and the study of associated factors under a Pharmacovigilance Program using Laboratory Signals at a Hospital (PPLSH) during a 2-year period.

Methods

All serum potassium levels <2 mmol/l or >7 mmol/l detected at admission to the hospital, including those of patients who died in the emergency ward or during hospitalization, were monitored prospectively from January 2009 through to December 2010. The incidence rate of each etiology of potassium disturbances was calculated. Factors associated with drug-induced potassium disturbances were detected using a multiple logistic regression model.

Results

The incidence of true life-threatening drug-induced hyper- and hypokalemia events was 3 and 4.32 (Poisson 95 % confidence interval 1.62–10.24), respectively, per 10,000 admissions. Of the severe potassium disturbances, 32.3 % were drug-induced, and 23 % were lethal. We identified previously undescribed pharmacological causes of hyperkalemia (risedronate, doxazosin) and hypokalemia (acyclovir, teicoplanin, cefepime, meropenem, dexketoprofen colistimethate). Significant predictor factors associated with drug-induced hyperkalemia were the use of polypharmacy (>5 drugs), age (>74 years), sex (female) and kidney disease (glomerular filtration rate <60 ml/min) with the presence of ≥4 comorbid conditions. The only predictor of drug-induced hypokalemia was the use of >5 drugs. The triggering factor associated with drug-induced hyperkalemia and hypokalemia was azotemia and hypoalbuminemia, respectively.

Conclusions

Drug-induced life-threatening potassium disturbances remain a relevant problem. Potential strategies for prevention are to avoid polypharmacy, early discontinuation of treatment of drugs causing hyperkalemia or nephrotoxicity in cases of various clinical situations (cardiac descompensation, infection, hypovolemia) or obstructive causes, and insistence on albumin control during hospitalization.     

Hypomagnesaemia/hypokalemia associated with the use of esomeprazole

Magnesium homeostasis is essential for many intracellular processes and depends on dynamic interplay of intestinal absorption, exchange with the bone reservoir, and renal excretion. Hypomagnesaemia may arise from various disorders. We review the case of a 59 year-old man whose only complaint was irritability with a routine analysis showing hypomagnesaemia and hypokalemia while using esomeprazole, a proton pump inhibitor (PPI). Fractional magnesium excretion was low, excluding excessive renal loss. Potassium excretion was 80 mEq/24 Hr in the presence of hypokalemia suggesting hypomagnesaemia-induced kaliuresis as its cause. Hypomagnesaemia partially resolved after oral magnesium supplementation. Esomeprazol suppression corrected hypomagnesaemia. A causal relationship with esomeprazol use was supported by the recurrence of hypomagnesaemia after rechallenge. We review the literature on hypomagnesaemia due to the use of proton pump inhibitors. In the past decade our understanding of transcellular magnesium transport was enhanced by the discovery of the magnesium channel, transient receptor potential (TR PM) 6 and 7 and other proteins that play an important role in its transport. In this light we discuss the possible etiology of proton pump inhibitor related hypomagnesaemia/hypokalemia.     

Molecular insights from dysregulation of the thiazide‐sensitive WNK/SPAK/NCC pathway in the kidney: Gordon syndrome and thiazide‐induced hyponatraemia

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Diuretics in the treatment of hypertension. Part 2: loop diuretics and potassium-sparing agents

Introduction: Diuretics enhance the renal excretion of Na⁺ and water due to a direct action at different tubular sites of the nephron where solute re-absorption occurs.

Areas covered: This paper focuses on the mechanism of action, pharmacodynamics, antihypertensive effects, adverse effects, interactions and contraindications of loop diuretics and potassium-sparing agents (including mineralocorticoid receptor antagonists (MRAs) and epithelial Na⁺ channel blockers).

Expert opinion: Loop diuretics are less effective than thiazide diuretics in lowering blood pressure, so that their major use is in edematous patients with congestive heart failure (HF), cirrhosis with ascites and nephritic edema. MRAs represent a major advance in the treatment of resistant hypertension, primary and secondary hyperaldosteronism and in patients with systolic HF to reduce the risks of hospitalization and of premature death. Potassium-sparing diuretics when coadministered with diuretics (thiazides and loop diuretics) working at more proximal nephron locations reduce the risk of hypokalemia and hypomagnesemia and the risk of cardiac arrhythmias. At the end of the article, the basis for the combination of diuretics with other antihypertensive drugs to achieve blood pressure targets is presented.     

Decreased renal excretory capacity of uric acid in rats fed a low sodium diet under consecutive administration of thiazide diuretics

The effect of consecutive treatments with thiazide diuretics on renal handling of uric acid was investigated with clearance experiments using rats. Two weeks of oral administration of trichlormethiazide (2 mg/kg, twice a day) in rats fed an ordinary diet caused no change in the uric acid excretory capacity. However, a week of oral administration of trichlormethiazide (0.1, 0.5 and 2 mg/kg, twice a day) in rats maintained on a purified diet containing low sodium amounts decreased the fractional excretion of uric acid. At 2 mg/kg, the decrease of inulin clearance developed clearly. Similar treatments with hydrochlorothiazide (10 mg/kg) and cyclopenthiazide (0.5 mg/kg) also decreased the inulin clearance and the fractional excretion of uric acid. Administration of the above diuretics during sodium deprivation resulted in a marked rise of the hematocrit and hypokalemia. Purified diet containing low sodium amounts alone did not change the uric acid excretory capacity as compared to the ordinary diet. Trichlormethiazide treatment and continued sodium deprivation caused marked losses of body weight and food intake and promotions of urine output and water intake. Histologically, hyperplasia of the cells and tubular dilatation at macula densa were slightly developed during sodium deprivation. With these severe changes, dilatation of the proximal tubules with flattened and regenerated epithelium was shown by the trichlormethiazide treatment (0.5 mg/kg). From these results, the characteristics of chronic treatment with thiazide diuretics acting on renal uric acid retention could be understood in the rat under sodium deprivation.     

POPULATION-BASED SURVEY OF HUMAN SODIUM AND POTASSIUM EXCRETION

1. During the 1989 National Heart Foundation Risk Factor Prevalence Survey a subsample in Hobart collected 24 h urine samples to measure electrolyte excretion. 2. The ranges were 30-344 mmol/24 h for Na+ excretion (mean 160 mmol/24 h for men, 124 mmol/24 h for women), and 25-119 mmol/24 h for K+ excretion (mean 77 mmol/24 h for men, 68 mmol/24 h for women). 3. As in other surveys, women excreted about 20-25% less Na+ and K+ than men, although there was no significant sex difference in the ratio of Na+/K+ excretion. 4. The recommended dietary intake (RDI) for Na+ and K+ was followed simultaneously by 19% of subjects, and 13% had a 24 h urinary Na+/K+ ratio less than or equal to 1.0. 5. Observance of the RDI limited the value of iodized salt for goitre prophylaxis. 6. Sodium excretion rates were outside the therapeutic range of thiazide diuretics in 22% of subjects. 7. Diet groups for long-term prospective cohort studies to test the prophylactic value of avoiding salt could apparently be recruited from existing subsamples of the population.     

Hypotensive and uric acid-retaining effects of trichlormethiazide under dietary sodium restriction in spontaneously hypertensive rats

In order to evaluate both the hypotensive and uric acid-retaining effects of thiazide diuretics in an animal model with hypertension, the effects of trichlormethiazide were studied using spontaneously hypertensive rats (SHR) under dietary sodium restriction. Trichlormethiazide was dosed daily for two weeks at 0.05, 0.5, 3 and 10 mg/kg, p.o. All doses caused obvious natriuresis, while an increase of urine volume was observed only at 3 and 10 mg/kg. The hypotensive effect, which was estimated at day 6 and 13, was recognized at doses of more than 0.5 mg/kg. At the end of the dosing, the hematocrit value of all medicated groups rose, and both the uric acid excretory capacity, estimated by the clearance values of inulin and uric acid, and the plasma potassium level clearly decreased at 3 and 10 mg/kg. A detailed study using a dose of 3 mg/kg showed shifts of the cumulative sodium and potassium balances to negative directions against the control group. Thus, trichlormethiazide-treated SHR under dietary sodium restriction showed both a hypotensive effect which might be due to the natriuresis and a tendency toward undesirable side effects such as hypokalemia and hyperuricemia. As there is no practical method in animal studies for simultaneously proving hypotensive and uric acid-retaining effects of diuretic antihypertensives, the findings of the present study might aid in the evaluation of diuretics more useful than the thiazides.     

Mechanism of action of xipamide and its classification as a "low ceiling diuretic". Pharmacodynamic-pharmacokinetic studies in healthy volunteers and in kidney and liver patients

Xipamide (CAS 14293-44-8) shows structural features comparable with the thiazide- as well as the class of loop diuretics. According to earlier findings this diuretic, in contrast to the thiazides, should not decrease the glomerular filtration rate (GFR) and be effective even in patients with advanced renal failure. Therefore recently the question, which class of diuretics xipamide should be related to, has been increasingly discussed. In order to solve this issue, the diuretic effect of xipamide was assessed in healthy volunteers once without and once under strict water and salt restriction. Additionally, changes in GFR were monitored by means of measurement of the creatinine clearance. Kinetic parameters were determined in plasma and urine; further, in patients with liver cirrhosis, renal elimination kinetics of the diuretic were correlated with the concentration of direct plasma bilirubin, as a marker of cholestasis, at the beginning of a treatment with xipamide, 40 mg qd. The investigations proved that xipamide, like a typical thiazide diuretic, gives rise to a temporary decrease in GFR of about 30 %, provided the renin-angiotensin-aldosterone system of the volunteer is activated by previous salt and water restriction. Xipamide leads to an increase of K+ and Mg2+ excretion, but to a decrease of Ca2+ excretion in urine, a charactaristical feature of the thiazide-like diuretics. The correlation between Na+ excretion and drug excreted in urine over time showed a functional graph that is characteristic for a "low ceiling" thiazide diuretic. In patients with renal failure FE(Na) was increased when related to the GFR-adjusted drug excretion rate, whereas it was diminished in conditions with decreased effective circulating volume like in liver cirrhosis with ascites. It could be shown that the elimination kinetics of xipamide are determined by renal drug clearance, which proportionally decreases with GFR. In patients with liver failure, a decrease of non-renal drug clearance went along with an increase in urinary drug excretion. The amount of drug excreted in urine (Ae) proportionally increased with the concentration of the patients' direct plasma bilirubin. Thus, from a pharmacological as well as clinical point of view xipamide acts like a thiazide diuretic. As could be shown for other thiazides some time ago, xipamide is effective not only in patients with cardiovascular diseases, but also in those with advanced renal failure.     

Renal failure with potassium-sparing diuretics

In one year 19 patients aged 73 SD 8 yr were referred with renal failure (plasma creatinine 0.14-0.52 mmol/l; urea 7.9-39.5 mmol/l; potassium 2.9-6.1 mmol/l, who were taking amiloride/hydrochlorothiazide (ten), amiloride alone (one) or triamterene/hydrochlorothiazide (eight). Six patients were taking other diuretics. Sixteen patients were being treated for hypertension and three for fluid retention; five hypertensive patients were also taking non-steroidal anti-inflammatory drugs (NSAID). Four patients were hypokalaemic, three were volume-depleted. All potassium-sparing diuretics and NSAID were stopped (four required another diuretic). Six-100 days later renal function was improved in 17 patients, unchanged in one and one patient had died of uraemia. Blood pressure was satisfactory on no therapy in 11 patients and two normotensive patients were oedema-free. In elderly patients with renal impairment potassium-sparing diuretics may cause renal failure, sometimes secondary to hypovolaemia, and NSAID may potentiate the effect.     

Cost-effectiveness of antihypertensive treatment: metoprolol versus thiazide diuretics

The aim of the present analysis was to calculate the cost-effectiveness of metoprolol versus thiazide diuretics in middle-aged men with mild to moderate uncomplicated hypertension. The analysis was based on the Metoprolol Atherosclerosis Prevention in Hypertensives (MAPHY) study, a randomised trial which showed a significantly lower risk for coronary events in patients taking metoprolol than in patients on thiazide diuretics. The main analysis was based on Swedish costs, but the costs were also varied in a special sensitivity analysis. Metoprolol was shown to be cost-saving compared with thiazide diuretics when both direct and indirect costs of morbidity were included. When only direct costs were included, the cost per life-year gained was $US2400. The result of the present analysis suggests that metoprolol is to be preferred to thiazide diuretics from a cost-effectiveness standpoint in the treatment of mild to moderate hypertension in middle-aged men. These findings regarding cost-effectiveness should, however, not be extrapolated to patient groups not included in the MAPHY trial.     

Current concepts in clinical therapeutics: congestive heart failure

The epidemiology and etiology, pathophysiology, diagnosis, and treatment of congestive heart failure (CHF) are reviewed. CHF affects as many as 4 million Americans and is one of the most prevalent causes of death in hospitalized patients. Major risk factors for developing CHF include advanced age, male sex, hypertension, coronary artery disease, smoking, hypercholesterolemia, diabetes mellitus, and rheumatic heart disease. Heart failure results from decreased intrinsic myocardial contractility caused by one or more of three changes: (1) altered adrenergic nervous system function, (2) impaired delivery of calcium to contractile elements in the heart, and (3) reduced myosin-ATPase activity in the myocardium. The disease is progressive, and no intervention has yet been found to stop it effectively. CHF is diagnosed based on subjective signs and symptoms and objective assessment using auscultation, ECG, chest roentgenogram, laboratory tests, and noninvasive and invasive tests. Treatment of CHF begins with restriction of physical activity and sodium intake. Pharmacologic interventions start with either digitalis glycosides or thiazide diuretics; both may be used concomitantly as the disease progresses. Current studies are focusing on the use of angiotensin-converting enzyme inhibitors as first-line agents for CHF. When CHF worsens, loop diuretics are substituted for or added to the thiazide diuretics, and vasodilators are added to reduce the workload on the heart. Other inotropic agents, including the new bipyridine derivatives, may also be used. In patients not responding to these and other aggressive therapeutic interventions, cardiac transplantation is the only option. Despite advances in management of CHF, little improvement in overall survival has been demonstrated, and no intervention has stopped or reversed the progression of CHF.     

Quantifying the effects of diuretics and β-adrenoceptor blockers on glycaemic control in diabetes mellitus – a systematic review and meta-analysis

Aims

Although there are reports that β-adrenoceptor antagonists (beta-blockers) and diuretics can affect glycaemic control in people with diabetes mellitus, there is no clear information on how blood glucose concentrations may change and by how much. We report results from a systematic review to quantify the effects of these antihypertensive drugs on glycaemic control in adults with established diabetes.

Methods

We systematically reviewed the literature to identify randomized controlled trials in which glycaemic control was studied in adults with diabetes taking either beta-blockers or diuretics. We combined data on HbA_1c and fasting blood glucose using fixed effects meta-analysis.

Results

From 3864 papers retrieved, we found 10 studies of beta-blockers and 12 studies of diuretics to include in the meta-analysis. One study included both comparisons, totalling 21 included reports. Beta-blockers increased fasting blood glucose concentrations by 0.64 mmol l⁻¹ (95% CI 0.24, 1.03) and diuretics by 0.77 mmol l⁻¹ (95% CI 0.14, 1.39) compared with placebo. Effect sizes were largest in trials of non-selective beta-blockers (1.33, 95% CI 0.72, 1.95) and thiazide diuretics (1.69, 95% CI 0.60, 2.69). Beta-blockers increased HbA_1c concentrations by 0.75% (95% CI 0.30, 1.20) and diuretics by 0.24% (95% CI −0.17, 0.65) compared with placebo. There was no significant difference in the number of hypoglycaemic events between beta-blockers and placebo in three trials.

Conclusions

Randomized trials suggest that thiazide diuretics and non-selective beta-blockers increase fasting blood glucose and HbA_1c concentrations in patients with diabetes by moderate amounts. These data will inform prescribing and monitoring of beta-blockers and diuretics in patients with diabetes.