Diuretic-induced hypokalaemia: an updated review.

Diuretic-induced hypokalaemia is a common and potentially life-threatening adverse drug reaction in clinical practice. Previous studies revealed a prevalence of 7%-56% of hypokalaemia in patients taking thiazide diuretics. The clinical manifestations of hypokalaemia due to diuretics are non-specific, varying from asymptomatic to fatal arrhythmia. Diagnosis of hypokalaemia is based on the level of serum potassium. ECG is useful in identifying the more severe consequences. A high dosage of diuretics and concomitant use of other drugs that increase the risk of potassium depletion or cardiac arrhythmias can increase the risk of cardiovascular events and mortality. Thiazide-induced potassium depletion may cause dysglycaemia. The risk of thiazide-induced hypokalaemia is higher in women and in black people. Reducing diuretic dose and potassium supplementation are the most direct and effective therapies for hypokalaemia. Combining with a potassium-sparing diuretic or blocker of the renin-angiotensin system also reduces the risk of hypokalaemia. Lowering salt intake and increasing intake of vegetables and fruits help to reduce blood pressure as well as prevent hypokalaemia.

Safety implications of combining ACE inhibitors with thiazides for the treatment of hypertensive patients.

INTRODUCTION: ACE-inhibitors (ACEI) and diuretics are the typical first-line antihypertensive drugs with complementary mechanisms of action. The present paper is summarizing the evidence supporting the efficacy of their combination in a broad range of hypertensive patients. AREAS COVERED: This source of data is different trials investigating the use of ACEI and diuretics in different populations of patients. The available evidence supports some advantage for thiazide-type compounds (chlortalidone-CHT and indapamide-IND) in the prevention of major CV complications. In terms of safety, hydrochlorothiazide (HCTZ) and indapamide are associated with a lesser rate of hypokalemia and abnormalities of metabolic profile (glucose control, uric acid levels, serum potassium levels). As far as the results of clinical trials, the most relevant studies are involving the combination of benazepril or perindopril with HCTZ (benazepril) or IND (Perindopril) respectively. All these studies have resulted in a favorable clinical outcome. In terms of safety profile, the combination of ACEi and diuretic is safe and comparable with that of ACEi and calcium channel blockers with no differences in the rate of major adverse events (cough or angioedema) and a lower rate of ankle edema. EXPERT OPINION: The combination of ACEi and diuretic is safe and well-tolerated and should be considered among the first-line treatments in most of the patients with hypertension.

First-line drugs for hypertension.

BACKGROUND: This is the first update of a review published in 2009. Sustained moderate to severe elevations in resting blood pressure leads to a critically important clinical question: What class of drug to use first-line? This review attempted to answer that question. OBJECTIVES: To quantify the mortality and morbidity effects from different first-line antihypertensive drug classes: thiazides (low-dose and high-dose), beta-blockers, calcium channel blockers, ACE inhibitors, angiotensin II receptor blockers (ARB), and alpha-blockers, compared to placebo or no treatment.Secondary objectives: when different antihypertensive drug classes are used as the first-line drug, to quantify the blood pressure lowering effect and the rate of withdrawal due to adverse drug effects, compared to placebo or no treatment. SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials up to November 2017: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We contacted authors of relevant papers regarding further published and unpublished work. SELECTION CRITERIA: Randomized trials (RCT) of at least one year duration, comparing one of six major drug classes with a placebo or no treatment, in adult patients with blood pressure over 140/90 mmHg at baseline. The majority (over 70%) of the patients in the treatment group were taking the drug class of interest after one year. We included trials with both hypertensive and normotensive patients in this review if the majority (over 70%) of patients had elevated blood pressure, or the trial separately reported outcome data on patients with elevated blood pressure. DATA COLLECTION AND ANALYSIS: The outcomes assessed were mortality, stroke, coronary heart disease (CHD), total cardiovascular events (CVS), decrease in systolic and diastolic blood pressure, and withdrawals due to adverse drug effects. We used a fixed-effect model to to combine dichotomous outcomes across trials and calculate risk ratio (RR) with 95% confidence interval (CI). We presented blood pressure data as mean difference (MD) with 99% CI. MAIN RESULTS: The 2017 updated search failed to identify any new trials. The original review identified 24 trials with 28 active treatment arms, including 58,040 patients. We found no RCTs for ARBs or alpha-blockers. These results are mostly applicable to adult patients with moderate to severe primary hypertension. The mean age of participants was 56 years, and mean duration of follow-up was three to five years.High-quality evidence showed that first-line low-dose thiazides reduced mortality (11.0% with control versus 9.8% with treatment; RR 0.89, 95% CI 0.82 to 0.97); total CVS (12.9% with control versus 9.0% with treatment; RR 0.70, 95% CI 0.64 to 0.76), stroke (6.2% with control versus 4.2% with treatment; RR 0.68, 95% CI 0.60 to 0.77), and coronary heart disease (3.9% with control versus 2.8% with treatment; RR 0.72, 95% CI 0.61 to 0.84).Low- to moderate-quality evidence showed that first-line high-dose thiazides reduced stroke (1.9% with control versus 0.9% with treatment; RR 0.47, 95% CI 0.37 to 0.61) and total CVS (5.1% with control versus 3.7% with treatment; RR 0.72, 95% CI 0.63 to 0.82), but did not reduce mortality (3.1% with control versus 2.8% with treatment; RR 0.90, 95% CI 0.76 to 1.05), or coronary heart disease (2.7% with control versus 2.7% with treatment; RR 1.01, 95% CI 0.85 to 1.20).Low- to moderate-quality evidence showed that first-line beta-blockers did not reduce mortality (6.2% with control versus 6.0% with treatment; RR 0.96, 95% CI 0.86 to 1.07) or coronary heart disease (4.4% with control versus 3.9% with treatment; RR 0.90, 95% CI 0.78 to 1.03), but reduced stroke (3.4% with control versus 2.8% with treatment; RR 0.83, 95% CI 0.72 to 0.97) and total CVS (7.6% with control versus 6.8% with treatment; RR 0.89, 95% CI 0.81 to 0.98).Low- to moderate-quality evidence showed that first-line ACE inhibitors reduced mortality (13.6% with control versus 11.3% with treatment; RR 0.83, 95% CI 0.72 to 0.95), stroke (6.0% with control versus 3.9% with treatment; RR 0.65, 95% CI 0.52 to 0.82), coronary heart disease (13.5% with control versus 11.0% with treatment; RR 0.81, 95% CI 0.70 to 0.94), and total CVS (20.1% with control versus 15.3% with treatment; RR 0.76, 95% CI 0.67 to 0.85).Low-quality evidence showed that first-line calcium channel blockers reduced stroke (3.4% with control versus 1.9% with treatment; RR 0.58, 95% CI 0.41 to 0.84) and total CVS (8.0% with control versus 5.7% with treatment; RR 0.71, 95% CI 0.57 to 0.87), but not coronary heart disease (3.1% with control versus 2.4% with treatment; RR 0.77, 95% CI 0.55 to 1.09), or mortality (6.0% with control versus 5.1% with treatment; RR 0.86, 95% CI 0.68 to 1.09).There was low-quality evidence that withdrawals due to adverse effects were increased with first-line low-dose thiazides (5.0% with control versus 11.3% with treatment; RR 2.38, 95% CI 2.06 to 2.75), high-dose thiazides (2.2% with control versus 9.8% with treatment; RR 4.48, 95% CI 3.83 to 5.24), and beta-blockers (3.1% with control versus 14.4% with treatment; RR 4.59, 95% CI 4.11 to 5.13). No data for these outcomes were available for first-line ACE inhibitors or calcium channel blockers. The blood pressure data were not used to assess the effect of the different classes of drugs as the data were heterogeneous, and the number of drugs used in the trials differed. AUTHORS' CONCLUSIONS: First-line low-dose thiazides reduced all morbidity and mortality outcomes in adult patients with moderate to severe primary hypertension. First-line ACE inhibitors and calcium channel blockers may be similarly effective, but the evidence was of lower quality. First-line high-dose thiazides and first-line beta-blockers were inferior to first-line low-dose thiazides.

[Effects of the combination of angiotensin receptor blockers and thiazide diuretics on laboratory values (levels of serum potassium, sodium, and uric acid)].

The combination of angiotensin receptor blockers (ARB) and a thiazide diuretic (hereafter, ARB/diuretic) is expected to improve patient adherence and increase the therapeutic effects because of the lower number of pills that require to be administered. In addition, an ARB/diuretic combination alleviates hypokalemia that frequently develops in patients receiving thiazide diuretics. In this study, we used electronic medical records to investigate the laboratory values (serum levels of potassium, sodium, and uric acid) of 194 ambulatory and hospitalized patients at the Gifu Municipal Hospital who received ARB/diuretic combination therapy for the first time between February 2010 and September 2012. According to the grade of classification of low serum potassium and sodium levels, the serum potassium level in one patient was grade 3 and the serum sodium level in two patients was grade 3 after the initiation of ARB/diuretic combination therapy. After administration of ARB/diuretic combination therapy, two patients received potassium supplements because their serum potassium levels decreased below the reference value. Similarly, one patient received a sodium supplement because of a decrease in the sodium level below the reference value. Uric acid level increased above the reference value after administration of the ARB/diuretic combination therapy in one patient; thus, this patient received antihyperuricemic agents. Therefore, pharmacists must carefully monitor the serum levels of potassium, sodium, and uric acid, particularly in the first six months after the initiation of ARB/diuretic combination therapy.

Prevention of thiazide-induced hypokalemia without magnesium depletion by potassium-magnesium-citrate.

Thiazide can cause magnesium depletion, which may exaggerate renal potassium wasting and hypokalemia. The purpose of this double-blind, randomized trial was to compare the metabolic effects of potassium-magnesium-citrate (K-Mg-citrate) and potassium chloride (KCl) during long-term treatment with thiazide. Twenty-two normal volunteers received hydrochlorothiazide 50 mg/d. Ten subjects concurrently took K-Mg-citrate (42 mEq K/d and 21 mEq Mg/d), and 12 subjects were given KCl 42 mEq/d. Serum potassium concentration remained unchanged during K-Mg-citrate supplementation, with a change from baseline of 21.7% over 6 months, compared with 26.4% with KCl supplementation. Serum electrolytes were normal and not significantly different between K-Mg-citrate and KCl. During K-Mg-citrate treatment, serum magnesium increased significantly by about 10%, associated with an adequate increase in urinary magnesium and a nonsignificant increase in monocyte and free muscle magnesium. Serum magnesium was unchanged, and monocyte and free muscle magnesium showed a nonsignificant decline during KCl supplementation. K-Mg-citrate provided an alkali load, increasing urinary pH, and reducing urinary undissociated uric acid. It also increased urinary citrate and tended to lower the saturation of calcium oxalate. KCl supplementation lacked these actions. K-Mg-citrate prevents thiazide-induced hypokalemia without provoking metabolic alkalosis. It seems to prevent magnesium depletion. By providing an alkali load, it retards the propensity for the crystallization of uric acid and probably of calcium oxalate. Though not conclusive, KCl supplementation may be less effective than K-Mg-citrate in maintaining normokalemia because of a subtle magnesium wasting. Moreover, KCl is devoid of protective action toward crystallization of stone-forming salts.