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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↗

PubMed1985

Relative bioavailability of chlorthalidone in humans after single oral doses.

The relative bioavailability of chlorthalidone from rapidly dissolving, stabilized, amorphous 15- and 25-mg formulations was compared in 24 normal adult male volunteers to the 25-mg market standard tablet and a 25-mg oral reference solution. When adjusted for dose, the experimental formulations were 116 and 104% of the calculated mean area under the curve for chlorthalidone reference solution compared to 81% for the tablet of the innovator. Likewise, the dose-adjusted mean peak blood levels for the 15- and 25-mg experimental tablets and the 25-mg tablet of the innovator were 112, 105 and 78% of the reference solution, respectively. Mean times-to-peak blood concentrations were 8.4 h for the 25-mg and 9.1 h for the 15-mg amorphous formulations compared to 9.2 h for the oral reference solution and 11.8 h for the market standard tablet. Drug concentrations declined monoexponentially with harmonic mean half-lives ranging from 47 to 55 h and intrinsic clearances ranging from 0.13 to 0.18 L/h regardless of formulation. The dose-adjusted relative bioavailability for the experimental formulations was not significantly different from the oral reference solution, whereas the market standard tablet was significantly (p less than 0.0001) lower than the reference solution. The urinary excretion of chlorthalidone was generally greater following the stabilized amorphous formulations than either the tablet of the innovator or the reference solution. The results of this research show that a rapidly dissolving chlorthalidone tablet can be formulated that shows complete relative bioavailability in humans.

Adult↗

PubMed1981

Chlorthalidone in mild hypertension - dose response relationship.

The dose response curve for 25, 50, 75 and 100 mg doses of chlorthalidone was studied in double blind fashion over an 8 week period in patients who presented with untreated mild hypertension. One hundred and thirty four patients completed this multicentre, family practice study. After 2 week's medication, a decline in blood pressure was noted in all dosage groups and this was maximal by 4 weeks. At 8 weeks all doses of chlorthalidone induced a significant reduction in both systolic and diastolic blood pressure (mean -18 and -10 mmHg respectively). Amongst the 4 dosage groups, no differences in response were noted resulting in a flat dose response curve. During the study, mean blood urea and serum uric acid rose whilst serum potassium fell, the urea and potassium being least affected in the 25 mg dosage group. As the dosage of chlorthalidone increased, so the tendency for abnormal laboratory values increased. Unwanted effects sought during the study were relatively few in number. No clear dose response relationship was evident although the positive responses in the 25 mg dosage group were less than in the higher dosages. These results suggest that 25 mg chlorthalidone is the optimum dosage for initiation of therapy in patients with mild to moderate hypertension. This dosage is associated with less adverse biochemical changes and unwanted effects than the higher dosage studied.

Adult↗

PubMed1983

Comparative pharmacokinetic profiles of metoprolol and chlorthalidone administered alone or in combination to healthy volunteers.

A potential pharmacokinetic interaction between the beta-blocking drug, metoprolol, and the diuretic, chlorthalidone, has been investigated in three single or multiple dose studies in healthy volunteers. The pharmacokinetic profile of metoprolol 100 mg was not affected by pretreatment with or co-administration of chlorthalidone 25 mg twice daily. Similarly, the pre-dosing steady-state level of chlorthalidone during chronic treatment and its blood level profile after a single 25 mg dose were not affected by metoprolol. The bioavailabilities of the 2 drugs administered in combination were identical to those observed when each drug was administered alone. These studies demonstrate that there is no pharmacokinetic interaction between metoprolol and chlorthalidone when doses of 100 and 25 mg, respectively, are co-administered twice daily.

Chlorthalidone↗

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↗

PubMed1986

Cadralazine and chlorthalidone as a second-step drug with atenolol in hypertensive patients: differences in blood pressure control during exercise.

The long-term efficacy of a new vasodilator, cadralazine (ISF 2469), and chlorthalidone have been compared in 20 hypertensive patients not adequately controlled by atenolol. After 4 weeks of treatment with atenolol 100 mg once daily, patients whose diastolic blood pressure was greater than 95 mmHg were randomly divided into two groups to receive in addition to atenolol, either cadralazine 15 mg once daily or chlorthalidone 25 mg once daily. Both treatments were administered for 6 months. At the end of treatment with atenolol and after 3 and 6 months of combination therapy, blood pressure and heart rate were measured at rest and during bicycle exercise 24 h after the last dose. Compared to atenolol alone, both cadralazine and chlorthalidone caused a significant and similar reduction in resting blood pressure. Both groups showed an increase in diastolic blood pressure during exercise while receiving atenolol alone. The addition of chlorthalidone did not modify the pressor response to exercise, whereas patients taking cadralazine had a decrease in exercise diastolic blood pressure, which was fully evident after 6 months of therapy. The reduction in exercise diastolic blood pressure induced by cadralazine was proportional to the increase in exercise heart rate, suggesting a fall in peripheral vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1987

Plasma renin activity does not predict the antihypertensive efficacy of chlorthalidone.

It has been established that angiotensin II stimulation may limit the antihypertensive potential of diuretic therapy in some patients. It is less clear, however, whether renin-angiotensin II stimulation is the cause of the flat blood pressure dose-response relationship to diuretics. To investigate this, 75 out-patients with essential hypertension were treated with chlorthalidone 12.5, 25 or 50 mg o.d. for 3 weeks, in a double-blind, placebo controlled cross-over study. Chlorthalidone significantly reduced blood pressure in all the groups, a plateau being reached at 25 mg o.d. Similarly, plasma renin activity was increased by each dose level of chlorthalidone, but it showed a different trend, being increased to a comparable extent at 12.5 mg and 25 mg o.d., and still higher at 50 mg o.d. Thus, greater stimulation of renin was coincident with the levelling of the blood pressure response to chlorthalidone. However no significant correlation was found between interindividual plasma renin activity and change in blood pressure, either in the entire series, or in each treatment subset. The data suggest overall that renin stimulation may influence the characteristic dose-hypotensive response relationship to diuretic agents in antihypertensive therapy, but it is unlikely that measurement of individual plasma renin activity will provide an useful guide to the optimal dose of a diuretic agents.

Adult↗

PubMed1988

Addition of chlorthalidone to slow-release nifedipine in the treatment of arterial hypertension: a controlled study versus placebo.

The use of calcium antagonists and diuretics in combination for treatment of hypertension is controversial. In a single-blind study 16 patients (8 men, 8 women, age range 39 to 62 years) with primary hypertension of mild to moderate degree were given slow-release nifedipine 20 mg twice daily for 6 weeks, thereafter either chlorthalidone 25 mg (Group A) or placebo (group B) daily was randomly added for a further 6-week period. Blood pressure (BP), heart rate, plasma renin activity (PRA), aldosterone, and 24 hour urinary electrolytes were evaluated. Nifedipine decreased supine BP from 159/92 +/- 16/8 to 151/89 +/- 10/6 mmHg in group A and from 162/94 +/- 20/12 to 145/85 +/- 14/6 mmHg in group B. A further fall to 139/84 +/- 7/6 mmHg (p less than .05) was observed after addition of chlorthalidone. PRA significantly increased with combined treatment compared to baseline (3.3 +/- 0.8 to 9.9 +/- 3.3 ng/ml/hr; p less than 0.05). A slight reduction of 24-hour urinary calcium was observed after the addition of chlorthalidone. These data indicate that the combination of nifedipine and chlorthalidone might be beneficial in the treatment of arterial hypertension.

Adult↗

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↗

PubMed1994

The effect of chlorthalidone on ventricular ectopic activity in patients with isolated systolic hypertension. The SHEP Study Group.

In an ancillary study of the Systolic Hypertension in the Elderly Program (SHEP), the effects of diuretics on ventricular ectopic activity were investigated in 186 patients with isolated systolic hypertension. Ventricular premature complexes (VPCs) were examined as the number of VPCs/24 hours, presence of > or = 1 VPC, presence of > or = 10 VPCs/24 hours, and presence of VPC pairs or ventricular tachycardia. Significant changes in VPCs were not observed either in the 92 patients randomized to chlorthalidone stepped-care (12.5 and 25 mg/day) or in the 94 placebo-treated patients (p > 0.1 for all VPC definitions and both groups). Serum potassium decreased from 4.4 +/- 0.5 to 4.1 +/- 0.5 mEq/liter (p = 0.002) in the chlorthalidone group and did not change (4.4 +/- 0.5 to 4.5 +/- 0.4 mEq/liter) in the placebo group. Potassium was prescribed routinely for confirmed hypokalemia < 3.5 mEq/liter. A relation between serum potassium and VPC or change in serum potassium and change in VPC was not observed in the chlorthalidone group. In summary, in patients with isolated systolic hypertension, chlorthalidone in doses that are effective in decreasing stroke and cardiovascular event rates (12.5 or 25 mg/day), did not increase VPCs.

Aged↗

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↗

PubMed1988

Chlorthalidone reduces calcium oxalate calculous recurrence but magnesium hydroxide does not.

We examined the effectiveness of chlorthalidone or magnesium hydroxide in the prevention of recurrent calcium oxalate kidney calculi. In a double-blind random allocation design daily dosages of 25 or 50 mg. chlorthalidone, 650 or 1,300 mg. magnesium hydroxide, or an identical placebo were administered. All groups showed significantly decreased calculous events compared to the pretreatment rates. During the trial 56.1 per cent fewer calculi than predicted developed in the placebo group (p less than 0.01), whereas the groups receiving low and high dosage magnesium hydroxide showed 73.9 and 62.3 per cent fewer calculi, respectively (p less than 0.001 and less than 0.01, respectively). Chlorthalidone treatment resulted in a 90.1 per cent decrease from predicted rates and both dosages yielded similar results. When the treatments were compared chlorthalidone was significantly better than the placebo or magnesium hydroxide (p less than 0.01). The large decreases in calculous events seen when placebo or ineffective therapy was given underscore the positive treatment bias that occurs when historical controls are used and they demonstrate the need for proper experimental design.

Calcium Oxalate↗

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↗

PubMed2003

Antihypertensive therapy with verapamil SR plus trandolapril versus atenolol plus chlorthalidone on glycemic control.

BACKGROUND: There is evidence that diuretics and beta blockers impair glucose tolerance, whereas calcium channel blockers and angiotensin converting enzyme blockers lack this metabolic effect. We compared the effect of a combination therapy with a nondihydropyridine calcium channel blocker plus an angiotensin converting enzyme inhibitor and a beta blocker plus a diuretic on hemoglobin A(1c) (Hb A(1c)) in patients with type 2 diabetes and mild-to- moderate hypertension. METHODS: A total of 463 hypertensive outpatients with non-insulin treated type 2 diabetes on stable antidiabetic therapy for at least 3 months and with HbA(1c) between 6.5% and 10% were recruited. In a randomized, double blind trial patients were treated for 20 weeks with fixed combinations of verapamil sustained release (SR) plus trandolapril and of atenolol plus chlorthalidone following a 2-week placebo run-in period. The main outcome measures were HbA(1c), fasting plasma glucose, and fructosamine levels as well as systolic and diastolic blood pressure. RESULTS: HbA(1c) remained stable at 7.9% after administration of verapamil SR plus trandolapril and increased from 7.8% to 8.6% with atenolol plus chlorthalidone; the differences between treatment groups were significant at 4, 12, and 20 weeks of treatment and at last visit (P <.0001). Mean blood pressure fell from 169/96 to 150/85 and from 168/95 to 145/83 mm Hg after administration of verapamil SR plus trandolapril and atenolol plus chlorthalidone, respectively. Both combinations were well tolerated. CONCLUSIONS: HbA(1c) and other parameters of short- and long-term glycemic control were in a more favorable range after antihypertensive treatment with verapamil SR plus trandolapril as compared with atenolol plus chlorthalidone.

Adrenergic beta-Antagonists↗

PubMed1993

Chlorthalidone attenuates the reduction in total cholesterol and small, dense LDL cholesterol subclass associated with weight loss.

Thiazide diuretics are known to raise total and LDL cholesterol. To assess whether chlorthalidone affected levels of putatively atherogenic small, dense LDL (LDL 3), we conducted a 12 week double blind randomized, placebo controlled clinical trial in 34 nonsmoking men aged 35 to 57 years with mild hypertension (DBP 90 to 104 mm Hg). Our a priori hypothesis that chlorthalidone raised LDL 3 levels was not confirmed. However, the fall in LDL 3 (P = .03) and total cholesterol (P = .08) associated with weight loss was attenuated by chlorthalidone. Since weight loss is commonly prescribed during the clinical management of hypertensives with concomitant hypercholesterolemia, consideration should be given to the attenuating effect of chlorthalidone on cholesterol reduction in the management of these patients.

Adult↗

PubMed1989

Chlorthalidone does not increase the hypotensive effect of nifedipine in essential hypertensives: a crossover multicentre study.

To determine whether the combination of nifedipine + chlorthalidone exerts an additive antihypertensive effect when compared with single-drug treatment, we studied 66 uncomplicated essential hypertensives, with diastolic blood pressure of greater than 100 and less than 115 mmHg. At the end of a 1-month washout placebo period, using a double-blind crossover design, the patients were randomly allocated to nifedipine (20 mg twice a day), chlorthalidone (25 mg once a day), the two drugs combined at the same doses and the corresponding placebo. Compared with the randomly allocated placebo, the three active treatments significantly reduced blood pressure without changing the heart rate or body weight. Both the absolute and percentage decreases in mean blood pressure induced by nifedipine and the combination compared with placebo were similar and significantly greater than those induced by chlorthalidone. Taken together, these data show that the combination of nifedipine + chlorthalidone does not exert any additive antihypertensive effect compared with nifedipine alone. This finding indicates that the combination of a dihydropyridine calcium antagonist + a thiazide diuretic is probably devoid of any particular clinical significance in the treatment of uncomplicated essential hypertensives.

Adult↗

PubMed1995

Influence of indapamide and chlorthalidone on reperfusion-induced ventricular fibrillation in isolated guinea pig hearts.

The delayed rectifier potassium current (IK) is a major repolarizing current in guinea pig ventricular myocytes. Blockade of IK or other repolarizing currents is of increasing interest for development of antiarrhythmic drugs; however, these interventions may also be proarrhythmic. In the present study, we compared the potential antiarrhythmic properties of indapamide and chlorthalidone, two structurally related sulfonamide diuretics which differ in their ability to block the slow component of the delayed rectifier (IKs) in isolated, buffer-perfused guinea pig hearts. Hearts underwent 30-min global no-flow ischemia and 10-min reperfusion. Dose-response (10(-7)-10(-4) M) effects of indapamide or chlorthalidone on reperfusion-induced arrhythmias, coronary flow, and heart rate (HR) were evaluated in a randomized blinded fashion. There was no significant difference in the incidence of ventricular fibrillation (VF) for either compound as compared with untreated controls. However, VF duration was reduced to < 40 s in all hearts treated with indapamide 10(-4) M). Mean VF duration with indapamide 10(-4) M was 31 +/- 4 versus 70 +/- 40 s in controls (p < 0.05). Chlorthalidone did not protect against reperfusion-induced arrhythmias. HR was unchanged with either compound; coronary flow during the control perfusion period increased approximately 43% with indapamide 10(-4) M (p < 0.05 vs. all treatment groups). These results demonstrate that indapamide, but not chlorthalidone, confers significant protection against reperfusion-induced VF in this experimental preparation and suggest that selective block of IKs may be antiarrhythmic.

Analysis of Variance↗