Relation Between Low Dose of Hydrochlorothiazide, Antihypertensive Effect and Adverse Effects

Abstract

Thiazide diuretics are widely used in the drug treatment of hypertension but their dose-response curves for the antihypertensive and adverse metabolic effects differ. To characterize the lower end of the dose-response curve a double-blind, parallel group trial was performed as multicentre study in Scandinavia. One hundred and eleven patients with newly diagnosed or previously treated mild to moderate hypertension (untreated diastolic blood pressure of 95-115 mmHg after 4 weeks placebo) were randomly allocated to various doses of hydrochlorothiazide (3, 6, 12.5 or 25 mg) or placebo for 6 weeks. Blood pressure and biochemical variables (plasma renin activity, serum potassium, magnesium, urate, fasting glucose, total cholesterol, HDL-cholesterol, triglycerides and apolipoproteins A1 and B were measured. 12.5 mg hydrochlorothiazide had a borderline effect on blood pressure whilst 25 mg had a definite antihypertensive effect. Biochemical changes were seen in plasma renin activity, serum potassium and urate after the 12.5 and 25 mg dose. Three and 6 mg had no effect on blood pressure or metabolic parameters.

Hydrochlorothiazide Versus Chlorthalidone

“…56 -58 In one study, 111 patients with hypertension were randomly assigned to placebo or 3, 6, 12.5, or 25 mg HCTZ for 6 weeks. 58 SBP was reduced by 2.1, 3.8, 6.4, 6.5, and 12.0 mm Hg by these respective doses (Figure 2). Another study found reductions in SBP of 29, 21, 32, and 24 mm Hg in 51 elderly patients randomly assigned to 25 mg daily, 25 mg twice daily, 50 mg daily, and 50 mg twice daily, respectively.…”

“…Effects of HCTZ and chlorthalidone on SBP as a function of daily dose (mg). Values for HCTZ of 3, 6, 12.5, and 25 mg were from one study, 58 whereas results for 50 and 100 mg were derived from 3 other studies. 67,68,70 Data for chlorthalidone were from a single study.…”

“…Another study found reductions in SBP of 29, 21, 32, and 24 mm Hg in 51 elderly patients randomly assigned to 25 mg daily, 25 mg twice daily, 50 mg daily, and 50 mg twice daily, respectively. 55 Five important principles are evident with HCTZ dosing: (1) some patients will respond to doses of 12.5 mg daily, (2) doses Ͼ25 mg daily often lower BP only slightly more than does 25 mg (ie, a relatively flat dose response), (3) hypokalemia is dose related, and the risk increases with dose, 53,57,58 (4) there is a great deal of variability in response with some patients, requiring doses of 25 to 50 mg before substantial antihypertensive effects are observed, 22,52,53 and the reduction in BP is greater when baseline BP is highest.…”

Thiazide Diuretics, Potassium, and the Development of Diabetes

“…14 The maximal potassium-depleting effect does not seem to be drug dependent or related to the total duration of exposure to the drug. 13,[15][16][17] However, there seems to be a dose-dependent effect regardless of thiazide diuretic used. Some reports suggest that doses of 12.5 to 25 mg daily of hydrochlorothiazide or chlorthalidone may produce less hypokalemia than doses of Ն50 mg daily.…”

Management in general practice of hypertensive patients poorly controlled with a fixed-dose renin–angiotensin system inhibitor and diuretic combination: results from a French national survey

“…Other authors have demonstrated that this 25 mg dose was significantly more effective than the 12.5 mg dose at lowering BP, and also note the absence of any substantial increase above 50 mg. 23 It should also be noted that it is only above 25 mg that HCTZ significantly increases basal plasma renin activity. 24 In a previous study, we demonstrated that the prescription of a combination of valsartan þ 25 mg HCTZ in patients who were not controlled by a combination of ARB þ 12.5 mg HCTZ normalized an additional 23% of patients. 25 In the present study, the majority of doctors who chose to increase the dose in patients receiving the two drugs at low doses increased the dose of both the RAS inhibitor and the diuretic.…”