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At least 19 recordsLinked to original sources

PubMed1992

Effectiveness of antihypertensive medications in office and ambulatory settings: a placebo-controlled comparison of atenolol, metoprolol, chlorthalidone, verapamil, and an atenolol-chlorthalidone combination.

In a double-blind, crossover study, five white men with mild-to-moderate hypertension received placebo and fixed doses of atenolol, metoprolol, chlorthalidone, verapamil, and the combination of atenolol and chlorthalidone in a quasi-random order. Daily dosages were: atenolol, 100 mg; metoprolol, 200 mg; chlorthalidone, 50 mg; verapamil, 240 mg; and the same doses of atenolol and chlorthalidone in combination. Standard office and daytime ambulatory blood pressures were assessed at the end of each month-long trial. Atenolol, metoprolol, chlorthalidone, and verapamil controlled office blood pressure with similar reductions. Verapamil did not lower ambulatory blood pressure at this dose (which is lower than is now commonly used), but reductions in ambulatory blood pressure were similar for atenolol, metoprolol, and chlorthalidone. The combination of atenolol and chlorthalidone maintained blood pressure control more effectively than the single drug treatments in both office and ambulatory settings, and the combined hypotensive effects were additive. However, reductions in the office due to the combination appeared to overestimate hypotensive effectiveness in the ambulatory setting. This study suggests that the effectiveness of commonly prescribed antihypertensive regimens varies according to setting as well as drug, and that assessment of treatment effectiveness can be improved by automated ambulatory blood pressure monitoring.

Adult↗

PubMed1975

Binding-site interaction of chlorthalidone and acetazolamide, two drugs transported by red blood cells.

When 14C-chlorthalidone was administered orally to 2 healthy volunteers, the total recovery of radioactivity in urine (about 75 percent) and feces was close to 100 percent. Most of the label recovered in the blood was bound to the blood cells. When the procedure was repeated while the 2 subjects were receiving acetazolamide, the excretion of labeled material in urine and feces was essentially unchanged, but the blood cells contained less and the plasma more of the blood radioactivity. The half-life of the radioactivity in plasma and blood cells had decreased by about 65 percent. Intravenous administration of acetazolamide (single dose) to 2 other subjects who had received 14C-chlorthalidone orally resulted in a marked drop in the blood cell radioactivity, whereas that in plasma increased. The affinity of chlorthalidone for red blood cells was further evidenced on incubation of 14C-chlorthalidone with human blood. Of the incubated radioactivity, 94 percent to 99 percent was recovered in the erythrocytes. Preincubation of the blood samples with acetazolamide prior to the addition of 14C-chlorthalidone, as well as incubation of acetozolamide in blood samples previously incubated with 14C-chlorthalidone, demonstrated that acetazolamide is able to inhibit and to displace chlorthalidone from blood cells. There are several lines of evidence indicating that chlorthalidone is transported attached to the erythrocyte carbonic anhydrase.

Acetazolamide↗

PubMed1976

Interindividual differences in chlorthalidone concentration in plasma and red cells of man after single and multiple doses.

A gas chromatographic method has been employed to determine chlorthalidone in plasma and whole blood after therapeutic doses. Radioactively labelled chlorthalidone was used for in vitro studies of the uptake of chlorthalidone from plasma by red blood cells. Chlorthalidone was markedly concentrated in red cells and as a compartment they would account for at least 30% of total drug in the body after multiple doses. The ratio between the plasma and red cell concentration of chlorathidone varied between individuals. After a single oral dose of 50 mg in 6 healthy volunteers chlorthalidone was eliminated with a half-life of 51 to 89 hours. The apparent volume of distribution varied between 3 and 13 1/kg and the clearance between 53 and 145 ml/min. The mean steady-state plasma concentrations during treatment with a standard dose of 50 mg daily (n = 10) varied 5-fold between individuals. During the steady state approximately 50% of the daily dose was excreted unchanged in the urine during 24 hrs. The plasma levels observed in patients were higher than those preducted from the single oral dose studies in healthy volunteers.

Adult↗

PubMed1976

Cardiovascular response to exercise under increasing doses of chlorthalidone.

Five male subjects with essential hypertension received chlorthalidone at each of four dose levels (25, 50, 100, and 200 mg/day) for eight week periods each preceded by an eight week placebo period. Dosage order was randomized and double-blind. During the last week of each active and placebo period an upright bicycle exercise study was carried out at three loads (100, 200, 300 kpm/min) for 6 min each. Oxygen consumption at the maximal workload was 42% of predicted at a heart rate of 170. During placebo therapy, increasing workloads were associated with a progressive increase in blood pressure, heart rate, and pressure-rate index (systolic pressure times heart rate). With increasing doses of chlorthalidone up to 100 mg/day, there was a progressive reduction in blood pressure and pressure-rate index. At 200 mg/day there were paradoxical increases in diastolic pressures, heart rates and pressure-rate indices above values observed at 100 mg/day. With increasing doses of chlorthalidone, there was a progressive increase in arterial blood CO2 content and pH. Increasing workloads were associated with increased arterial blood lactate and decreased arterial blood lactate and decreased arterial blood pH. The changes in lactate and pH were not different at the different dose levels. The best antihypertensive effect in these exercising subjects was observed at a daily dose of 100 mg of chlorthalidone. The exercise response was useful in the determination of potentially adverse hemodynamic consequences of the larger dose of chlorthalidone.

Adult↗

PubMed1976

Effects of chlorthalidone on serum and total body potassium in hypertensive patients.

Total body potassium has been estimated in 26 hypertensive patients who were hypokalaemic as a result of long-term chlorthalidone treatment (mean 20.5 months), while they were on chlorthalidone and 4 weeks after this had been discontinued. The mean difference amounted to only 95 mEq (not significant). In 6 additional patients not previously treated with chlorthalidone, serial total body potassium estimations revealed a mean potassium deficiency of 245 mEq after 33 days and of 106 mEq after 100 days. These results suggest that the mechanism causing the initial potassium loss is partly reversed or compensated later on. In patients with uncomplicated hypertension, no significant potassium deficiency was detected during long-term treatment. Eighteen of our patients received 39 mEq potassium chloride supplements daily for 4 weeks; this caused a mean rise in serum potassium from 3.23 mEq/l to 3.38 mEq/l (not significant). Total body potassium did not change at all. We conclude that potassium chloride supplements are not an effective treatment of hypokalaemia in this condition. Correction of the extracellular pH by ammonium chloride in 6 patients on chlorthalidone, who demonstrated a slight metabolic alkalosis, gave rise to a mean increase in plasma potassium from 2.78 mEq/l to 2.96 mEq/l (not significant). The hypokalaemia in hypertensive patients on long-term chlorthalidone treatment cannot be explained by either a potassium deficiency or the change in extracellular pH.

Adult↗

PubMed1992

[An open comparative study of captopril + hydrochlorothiazide versus chlorthalidone for the treatment of mild and moderate primary hypertension].

PURPOSE: To compare the antihypertensive and metabolic effects of captopril combined with hydrochlorothiazide (C+HCTZ) versus chlorthalidone (CT) in mild and moderate primary hypertensive patients. METHODS: Fifty five patients, without treatment or treated with 15 days placebo were randomized for treatment with the combination of captopril 50mg and hydrochlorothiazide 25mg (n = 29) against chlorthalidone (n = 26). The clinical evaluation was done during placebo and monthly throughout three months, and the laboratory tests were done before and at the end of the study. RESULTS: The blood pressure were similar between groups during placebo period (C + HCTZ: 161 +/- 25/102 +/- 6-CT: 155 +/- 18/101 +/- 6 mmHg); the diastolic blood pressure decreases significantly at first month already in the group C + HCTZ (89 +/- 8 mmHg) compared to group CT (94 +/- 8 mmHg, p < 0.05). The percentile diastolic and mean blood pressure dropped, in average, 12% in C + HCTZ group and in CT varied between 7 (1st and 2nd month) to 11% (3rd month). Without statistical difference, the blood pressure normalization was obtained in 69% of the patients with the association captopril and diuretic and in 50% of the patients in the chlorthalidone group. It was observed a significant reduction of potassium in patients treated with chlorthalidone (4.2 +/- 0.7 to 3.7 +/- 0.4 mEq/L, p < 0.01) that was not observed with the captopril and the thiazide associated. The last treatment also significantly reduced the cholesterol levels (219 +/- 39 mg/dl to 202 +/- 39 mg/dl, p < 0.04). CONCLUSION: Our results indicate that captopril combined with low diuretic dose normalize the blood pressure in 69% mild to moderate primary hypertensive patients, and acts faster than chlorthalidone in this control. In addition has metabolic benefits reducing cholesterol levels with no alteration in potassium levels.

Adolescent↗

PubMed1977

Chlorthalidone analysis using carbonic anhydrase inhibition.

Chlorthalidone was analyzed in the concentration range of 0.1-3.0 microgram/ml with a precision of +/- 0.05 microgram/ml. Chlorthalidone inhibition of the enzymatic hydrolysis rate of p-nitrophenyl acetate by bovine erythrocyte carbonic anhydrase was used as a basis for the determination. The amount of p-nitrophenol formed was measured by monitoring the absorbance at 400 nm, and its formation rate was proportional to the chlorthalidone concentration. The mixing of the enzyme, substrate, and sample, the incubation of the reaction mixture, and the recording of the absorbance were automated. A survey of urine samples from 26 normal human subjects did not reveal any endogenous substances that interfered with the assay. Analyses of urine samples from six subjects after oral administration of 100 mg of chlorthalidone indicated rapid absorption and a biphasic elimination. The alpha-phase half-life was 1.5 hr, and the beta-phase half-life was 35 hr.

Autoanalysis↗

PubMed1979

Automated analysis of chlorthalidone.

Chlorthalidone inhibition of the enzymatic hydrolysis rate of p-nitrophenyl acetate by bovine erythrocyte carbonic anhydrase was used as a basis for chlorthalidone determination in plasma and urine. For urinary samples, a completely automated, continuous flow system was developed to extract the samples and perform the enzymatic reaction. Over 100 samples per day could be assayed by one person. The assay had a sensitivity of 0.5 micrograms/ml and thus could determine urinary concentrations after a therapeutic chlorthalidone dose. To determine plasma concentrations after a therapeutic dose, a manual extraction procedure was used in combination with a second continuous flow system for the enzymatic reaction. This system was optimized to detect the lowest chlorthalidone concentration allowed by the enzymatic inhibition constant and could detect 25 ng/ml.

Animals↗

PubMed1979

Absolute bioavailability of chlorthalidone in man: a cross-over study after intravenous and oral administration.

Seven normal human volunteers each received a constant-rate infusion of chlorthalidone for 2 h, and the same (commonly 50 mg) single oral dose on separate occasions. The concentration of unchanged chlorthalidone was analyzed over a 100 to 220 h period in plasma, red blood cells, urine and faeces after both dosage forms. A three compartment model was required to describe the intravenous plasma concentrations in five of the subjects. A two compartment model sufficed to account for the decay of the oral plasma concentrations in all seven subjects. The mean plasma t1/2 after i.v. dosing was 36.5 h (+/- 10.5 SD), and the mean plasma t1/2 after oral doses was 44.1 h (+/- 9.6 SD). The mean red blood cell concentration t1/2 after i.v. doses was 46.4 h (+/- 9.9 SD), and the mean red blood cell t1/2 after the oral doses was 52.7 h (+/- 9.0 SD). The shorter i.v. half-live was not equally manifest in all subjects, being mainly apparent in three of them. In all cases the urinary excretion rate plots were parallel to the plasma concentration curves. As the faster decay after i.v. administration was not accompanied by increased renal clearance, the difference must have been due to non-renal mechanism. The mean total of 65.4 (+/- 8.6 SD) % of the intranvenous dose was excreted in urine over infinite time, whereas the mean total excretion after the oral dose was 43.8 (+/- 8.5 SD) %. Faecal excretion ranged from 1.3--8.5% of dose in the i.v. study to 17.5--31.2% of dose in the oral study. The sum of the amounts present in urine plus faeces pointed strongly to an important metabolic route of elimination of chlorthalidone. Bioavailability estimates (F) from three sets of data were--a mean F of 0.61 from plasma concentrations, 0.67 from urinary excretion measurements and 0.72 from the erythrocyte concentrations. Simulations with a non-linear model indicated lesser validity of the estimate from erythrocyte concentrations. It was concluded that the average of plasma and urine data, F = 0.64, yielded the best estimate of the oral availability of chlorthalidone 50 mg in man.

Administration, Oral↗

PubMed1975

Intrapatient comparison of treatment with chlorthalidone, spironolactone and propranolol in normoreninemic essential hypertension.

The effects of chlorthalidone, spironolactone and propranolol in reducing blood pressure were compared in the same 11 normoreninemic hypertensive patients. All three drugs decreased the blood pressure significantly and no agent had a superior blood pressure-lowering effect. The blood pressure did not normalize. The data suggest that no one variable--volume factors, relative hyperactivity of the renin-aldosterone system or beta-adrenergic hyperactivity--is the prime mover in normoreninemic hypertension. Long-term treatment with chlorthalidone resulted in slight hyperreninism (26.3 +/- 4.9 ng-ml-1-3 hours-1) (mean +/- standard error) with concomitant changes in plasma aldosterone (23.0 +/- 3.2 ng-100 ml-1). The body weight decreased significantly (--1.8 kg, P less than 0.005). Plasma potassium concentrations were low (3.2 +/- 0.1 mEq-liter -1). Creatinine clearance was unimpaired (117 +/- 6 ml-min-1). Treatment with spironolactone resulted in more marked hyperreninism (47.0 +/- 14.3 ng-ml-1-3 hours-1) and hyperaldosteronism (61.9 +/-11.8 ng-100 ml-1). The body weight decreased significantly (--1.9 kg, P less than 0.004). Significant hyperkalemia occurred (4.4 +/- 0.1 mEq-liter-1). The glomerular filtration rate decreased significantly to 93 +/- 3 ml-min-1 (P less than 0.004). Treatment with propranolol resulted in marked suppression of the plasma renin activity (1.8 +/- 0.2 ng-ml-1-3 hours-1) and plasma aldosterone levels (8.9 +/- 1.3 ng-100 ml-1). A significant increase in body weight occurred (+2.3 kg, P less than 0.013). The plasma potassium concentration increased to a level not significantly different from the value found after treatment with spironolactone (4.2 +/- 0.1 mEq-liter-1). The creatinine clearance decreased significantly to 99 +/- 5 ml-min-1 (P less than 0.008). Hyperreninemia (by spironolactone and chlorthalidone), effective hyperaldosteronism (by chlorthalidone) and volume retention (by propranolol) are considered to represent expressions of mechanisms counteracting the depressor effects of these different pharmacologic maneuvers, leading to the maintenance of supranormal blood pressure.

Adult↗

PubMed1978

Determination of chlorthalidone in plasma, urine and red blood cells by gas chromatography with nitrogen detection.

A sensitive and selective gas chromatographic method is described for determining the diuretic and antihypertensive drug chlorthalidone in plasma, urine and erythrocytes. Use is made of an alkali flame ionization detector (nitrogen detector), and the chlorthalidone and internal standard are chromatographed as methyl derivatives. Down to 10 ng of drugs in the biological sample can be measured accurately, with a standard deviation of 5%. Because the concentration of chlorthalidone found in erythrocytes is 50-100 times higher than that in plasma, the influence of haemolysis on the plasma concentration has been investigated. In addition, a pharmacokinetic study with human volunteers revealed that the apparent concentration of the drug found in plasma can be much too low (by more than 50%), if the plasma is not separated from the erythrocytes immediately after venipuncture. Precautions to be observed to ensure correct handling of blood samples (so that results for plasma concentrations will be reliable) are stressed. The findings have application in kinetic studies on chlorthalidone.

Chlorthalidone↗

PubMed1976

Increase in serum-lipids during treatment of hypertension with chlorthalidone.

Fasting concentrations of serum cholesterol and triglyceride were measured before and during therapy in 63 patients with uncomplicated primary (essential) hypertension. The patients were divided into two groups, and diet therapy was applied equally to both groups. One group of 31 patients received no other therapy; the other 32 received chlorthalidone in addition to diet. Diet therapy consisted of no added sodium, caloric restriction if overweight, and consumption of foods low in lipids. On diet therapy alone serum-cholesterol fell by 11 mg/dl (P less than 0-02 vs pretreatment value) and serum-triglyceride was unchanged. When chlorthalidone was prescribed in addition to diet, serum cholesterol rose by 12 mg/dl and triglyceride by 36 mg/dl (P less than 0-005 vs pretreatment value for both). Serum-lipids were similar in the two groups before treatment; during therapy both serum cholesterol (P less than 0-05) and triglyceride (P less than 0-005) concentrations were higher in the chlorthalidone group. Thus, despite the prescription of lipid-lowering and calorie-restricted diets, serum-lipids became slightly raised when chlorthalidone was used as the sole drug in the treatment of hypertension.

Chlorthalidone↗

PubMed1979

Atenolol and chlorthalidone in combination for hypertension.

1 The hypotensive effect of single daily dosing with atenolol 100 mg and chlorthalidone 25 mg given alone or in combination has been assessed in a double-blind, crossover, placebo controlled trial in fifteen hypertensive patients. 2 Average lying blood pressures were: Placebo 155.4/103.9 mm Hg, atenolol 134.6/85.8 mm Hg, chlorthalidone 139.5/90.1 mm Hg, combination 127.7/82.5 mm Hg. 3 The effect of the combination therapy in reducing lying diastolic pressure compared with placebo (a fall of 21.4 mm Hg) was significantly less than the 31.9 mm Hg fall predicted from the sum of the individual effects (P = 0.01). 4 Observations on blood pressure at rest and under mental, isometric and bicycle ergometer stress were made pre-dose and post-dose for a 12 h period at the end of the last treatment period. 5 Lying blood pressure declined from the zero hour (pre-dose) reading on all treatments to a low at 15.00--18.00 h and then rose again. 6 The rise in systolic blood pressure after isometric exercise and mental stress was of a similar magnitude with all four treatment regimes. 7 Atenolol, alone and in combination with chlorthalidone, reduced the blood pressure and the pulse rate increase on exercise 2 h post-dose when compared with readings 24 h post-dose. 8 Once daily dosing with a combination of atenolol and chlorthalidone produced a fall in supine blood pressure over a 24 h period but the effect on exercise induced changes was not uniform over this period.

Adolescent↗

PubMed1992

Chlorthalidone reduces vascular hyperresponsiveness in DOCA-salt hypertensive rats.

The mechanisms of anti-hypertensive effect of diuretics remain unknown. The purpose of this study was to test the hypothesis that long-term treatment with chlorthalidone decreases the responsiveness of resistance vessels to neurohormones. The study was performed in deoxycorticosterone acetate (DOCA)-salt hypertensive rats with and without treatment with chlorthalidone (Chlor. 8 mg/day, for 20 days). Resting mean arterial pressure in freely moving state was significantly reduced in DOCA-salt-Chlor rats when compared to DOCA-salt rats (116 +/- 3 vs 147 +/- 7 mmHg, respectively). Chlorthalidone treatment reduced the high plasma sodium content observed in DOCA-salt rats to the same levels observed in normotensive control groups. Results obtained in isolated perfused mesenteric arteries showed: a) the increase in perfusion pressure elicited by norepinephrine (NE), serotonin (SE) and vasopressin (VP) was significantly greater in DOCA-salt than in DOCA-salt + Chlor rats or control normotensive rats; b) the endothelium removal increased the pressor responses to NE, SE and VP in a similar way in all groups. These data provide evidence that long-term chlorthalidone treatment reduces vascular hyperresponsiveness to these neurohormones. In addition, these results indicate that this reduction in vascular hyperresponsiveness, associated with a decrease in extracellular sodium level, could be a possible mechanism by which the diuretics reduce the high blood pressure.

Animals↗

PubMed1975

[Spironolactone combined with chlorthalidone in the treatment of essential arterial hypertension].

The antihypertensive effect and the tolerance of the association of spironolactone and chlorthalidone were evaluated clinically and by numerous laboratory examinations in a group of 18 patients affected with non-complicated essential hypertension. All the patients were treated for 30 consecutive days with chlorthalidone (100 mg/day) and then for another 30 days with the two drugs administered contemporaneously (100 mg/day of spironolactone + 100 mg/day chlorthalidone). The balanced combination of the two drugs showed to be significantly more active than the treatment with just chlorthalidone and the margin of safety wider; the therapeutic activity showed to be independent from the variations of the plasma renin activity.

Aged↗

PubMed1978

Dose response to chlorthalidone in patients with mild hypertension. Efficacy of a lower dose.

A multicenter study of chlorthalidone was performed to determine the relative antihypertensive efficacy and side effects of doses lower than those usually recommended for therapy. After a 4-wk placebo control period 100 patients with mild hypertension were randomly assigned doubleblind to 12.5-, 25-, 50-, or 75-mg regimens of chlorthalidone or to placebo for 12 wk. The groups of patients taking 25, 50, and 75 mg had declines in blood pressure which were not significantly different from each other. Serum potassium decreased in the 50- and 75-mg groups but not significantly in the 25-mg group. We conclude that chlorthalidone, 25 mg daily, was at least as effective for hypertension as 50 and 75 mg with less perturbation of potassium. Use of smaller initial diuretic doses may provide equal efficacy with fewer side effects for many patients.

Adult↗

PubMed1979

Atenolol and chlorthalidone on blood pressure, heart rate, and plasma renin activity in hypertension.

The antihypertensive effect of atenolol, with and without chlorthalidone, on hypertension was assessed in an outpatient as well as in an inpatient study. In the outpatient study atenolol alone induced decreases in systolic and diastolic BP amounting to 20 and 15 mm Hg. Maximal response of BP and HR developed within a week at the lowest dose used (100 mg twice daily). Combined atenolol-chlorthalidone treatment decreased lying and standing systolic BP by 7 and 14 mm Hg more than atenolol alone, but diastolic BP was decreased little more. In the inpatient study the addition of atenolol to chlorthalidone therapy in a dose of 100 mg twice daily resulted in a maximal decrease in BP within 3 days. At this dose PRA was lowered only slightly. Larger doses did not lead to any significant further decrease in BP, whereas PRA fell progressively. Our results indicate that, in contrast to nonselective blockade, specific beta-1-adrenoceptor blockade by atenolol is capable of inducing a distinct antihypertensive effect, unrelated to suppression of PRA. The decrease in PRA after larger doses of atenolol was not accompanied by a further decrease in BP. Because diuretic-induced renin release plays a role in the maintenance of the BP, our findings suggest that at higher dosages a hypertensive effect of the beta blocker compensated for the hypotensive effect of the decrease in PRA.

Adult↗

PubMed1978

Chlorthalidone-induced syndrome of inappropriate secretion of antidiuretic hormone.

A 60-year-old woman who had been instructed to increase her water intake because of nephrolithiasis developed the syndrome of inappropriate secretion of antidiuretic hormone when treated with chlorthalidone for mild hypertension. Serum osmolality was 235 mOsm/kg with concomitant urine osmolality of 490 mOsm/kg. When serum sodium decreased to 110 mEq/liter, plasma antidiuretic hormone (ADH) was elevated at 30 pg/ml. The syndrome resolved when chlorthalidone was discontinued together with fluid intake restriction. Plasma ADH returned to normal (less than 0.5 pg/ml) after three days of treatment. The favorable outcome in this patient is attributed to early recognition of the syndrome, which might occur even with nonthiazide diuretics such as chlorthalidone.

Chlorthalidone↗