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PubMed1982

Evidence for an extrarenal action of chlorothiazide on serum potassium.

The effects of chlorothiazide and furosemide on serum potassium were studied in fasting anuric patients maintained by chronic hemodialysis and compared to a control period when no drug was administered. Serum potassium levels were significantly lower following oral chlorothiazide (15 mg/kg body weight) than during the control period. After intravenous furosemide (1 mg/kg body weight), potassium levels were midway between those of the chlorothiazide and control periods, but statistical significance was not attained. Comparing the three study periods, there were no significant differences in the changes in body weight, blood pressure, blood pH, hematocrit, urea, glucose, sodium, albumin, insulin, plasma renin activity and aldosterone. This suggests that an extrarenal action of chlorothiazide on the cell membrane promotes cellular uptake of potassium.

Chlorothiazide↗
PubMed1963

EFFECT OF CHLOROTHIAZIDE ON CESIUM-137 EXCRETION IN HUMAN SUBJECTS.

The therapeutic value of the diuretic, chlorothiazide (Diuril), in reducing the body burden of cesium-137 in human subjects was investigated. Two subjects were given chlorothiazide, 2 g./day, following a single oral intake of cesium-137. The urinary excretion and the per cent retention of cesium-137 were compared with similar data obtained from two control subjects. Although chlorothiazide produced a marked potassium diuresis, it had no significant effect in reducing the body burden of cesium.Analysis was made of the rate of turnover of cesium and potassium in the two control subjects, who were followed up for 320 days. The biological half-lives, T(b), of K were 42 and 41 days. In both subjects a small fraction of the cesium-137 was rapidly excreted. The remainder (88% and 83% in the two cases) was excreted at a slower constant rate. The concentrations further decreased to 44% and 41.5% in 90 and 155 days, respectively.

Acetazolamide↗
PubMedDate not supplied

Bioavailability of chlorothiazide from 50, 100, and 250 MG solution doses.

The bioavailability of chlorothiazide was examined following single oral solution doses to eight healthy male volunteers. Drug was administered in 250 ml of water after overnight fast. Bioavailability was determined by measuring 72 h urinary recovery of unchanged drug. Mean urinary recovery from 50, 100, and 250 mg doses was, respectively, 28.3, 47.0 and 83.3 mg, representing 56.4, 47.0, and 33.3 per cent of the administered dose. The correlation coefficient between dose size and percentage recovery was -0.662. These results add support to previous suggestions that the absorption of chlorothiazide from the gastrointestinal tract is saturable, and that the availability of chlorothiazide may be similar to that of hydrochlorothiazide when these compounds are administered in the same dosage range.

Adult↗
PubMedDate not supplied

Thiazides XI: partitioning of chlorothiazide in red blood cells after oral administration.

Uptake of chlorothiazide by red blood cells after oral drug administration was investigated. Chlorothiazide was administered to normal healthy volunteers as a solution or a tablet. Frequent blood samples were collected and analysed by a specific HPLC method. The results indicate that there is a significant uptake of chlorothiazide by red blood cells, resulting in a higher blood AUC compared to plasma AUC.

Administration, Oral↗
PubMed1982

Thiazides IV: Comparison of dissolution with bioavailability of chlorothiazide tablets.

Based on the initial dissolution rate profiles in water, a slow-dissolving, an intermediate-dissolving, and a fast-dissolving chlorothiazide 250-mg tablet were selected for the bioavailability and bioequivalence study. In addition, two marketed 500-mg chlorothiazide tablets were studied. The three 250-mg tablets were bioequivalent, as were the two 500-mg tablets. Therefore, the dissolution test conditions were modified to associate in vitro dissolution with in vivo performance of the product. Based on these results, it was concluded that a dissolution of 75% in 60 min by paddle method at 75 rpm in pH 7.4 phosphate buffer can be used as a quality assurance test for 250- and 500-mg chlorothiazide tablets.

Biological Availability↗
PubMed1976

A comparison of the effects of chlorothiazide and of metolazone in the treatment of hypertension.

1. A cross-over study was done in twenty patients with hypertension to compare the effects of chlorothiazide (0-5 g twice daily) and metolazone (5 mg daily) in combination with other anti-hypertensive agents. 2. Compared with absence of diuretic therapy, chlorothiazide and metolazone both produced significantly lower blood pressures. 3. Blood pressures on metolazone tended to be lower than on chlorothiazide but this difference was not statistically significant. 4. Both diuretics significantly lowered serum potassium concentrations and total body potassium to a similar degree, but the serum potassium did not fall below the normal range in any patient and no potassium supplements were needed. No electrocardiographic changes suggestive of hypokalaemia were noted. 5. Small but significant increases in serum bicarbonate, calcium, urea and acid were observed with both diuretics. 6. Patient acceptance was excellent and no adverse effects were encountered.

Adult↗
PubMed1961

Action of chlorothiazide on the distribution excretion and hypotensive effect of pempidine in man.

When chlorothiazide is given to hypertensive patients who are receiving pempidine a rise in plasma pempidine concentration occurs and this is proportionately greater than the additional fall in blood pressure. After pempidine has been added to human whole blood in vitro or in vivo the ratio of the pempidine concentration in the red cells to that in the plasma falls in the course of 1 hr from an initial value greater than 2 to about 1.2. If chlorothiazide is present also, however, the ratio remains constant at 0.7. Changes in the plasma pempidine concentration in vivo probably result from the binding of pempidine to plasma protein in the presence of chlorothiazide. This has been observed in vitro by a dialysis technique.

Antihypertensive Agents↗
PubMed1991

[Metabolic effects of chlorothiazide and propranolol on essential hypertension--a double-blind, cross-over design clinical trial].

Several studies have shown that antihypertensive drugs therapy could reduce morbidity and mortality of hypertension related complication such as stroke, congestive heart failure and renal failure, but there was no significant reduction of coronary heart disease. The benefit of the treatment on morbidity and mortality may be counterbalanced by adversed metabolic effects of long-term therapy. The purpose of this study is to evaluate the blood pressure-lowering and adverse metabolic effects of chlorothiazide and propranolol monotherapy. A double-blind, cross-over design clinical trial was performed for 42 cases (22 males and 20 females) with the mean age of 52 (from 30 to 59 years old). After 2 weeks run-in period, the patients were assigned to group A and B with age and sex stratification. Chlorothiazide and propranolol were given for 12 weeks in alternative with 2 weeks placebo washout period. Our studies have shown that, chlorothiazide and propranolol could reduce both systolic and diastolic blood pressure significantly. But they also associated with adverse metabolic effects. Serum uric acid and triglyceride increased and decreased the concentration of high density lipoprotein cholesterol (HDL-C). Those changes could counterbalance the benefit of blood pressure-lowering effect of antihypertension. Carefully monitoring the adverse metabolic effects closely is necessary in therapy with these drugs.

Adult↗
PubMed1978

The mechanism of chlorothiazide-induced carbohydrate intolerance.

In order to establish the mechanism(s) of chlorothiazide-induced hyperglycemia, measurements of blood glucose, plasma insulin, liver glycogen and hepatic cyclic adenosine 3':5'-monophosphate (cyclic AMP) levels, and liver phosphodiesterase activity were made in rats administered 10, 25, 50 or 100 mg/kg of the drug. Comparison of data obtained on these animals with those from controls revealed significant and dose-dependent increases in blood glucose, decreases in liver glycogen, increases in hepatic cyclic AMP and inhibition of phosphodiesterase. Although basal insulin levels were significantly increased at the two higher doses of chlorothiazide, ratios of blood glucose/plasma insulin levels showed suppression of insulin secretion at all four doses. However, this suppression was not dose-related. All effects of the drug were maximal at 2 hours after subcutaneous administration. The results of this investigation indicate that the primary mechanism of chlorothiazide-induced carbohydrate intolerance is cyclic AMP-mediated stimulation of glycogenolysis and inhibition of glycogenesis. Suppression of insulin secretion is secondary but probably contributes to the hyperglycemia.

Animals↗
PubMed1979

The effects of long-term oral treatment with chlorothiazide or furosemide on hereditary diabetes insipidus in rats.

The polyuria of homozygous Brattleboro (BB) female rats is halved when they are given chlorothiazide (about 250 mg/day) or furosemide (about 60 mg/day) orally for one day. The effect of chlorothiazide is still found after 16 days of treatment, whereas the effect of furosemide entirely disappears within 5 days. Both diuretics induce chronically increased plasma renin activity (PRA) and decreased natriuresis as long as they are added to the diet; the effect on Na is more evident during furosemide treatment. Urinary urea content as well as urinary osmolality are increased by chlorothiazide and "free water" output is normalized. Furosemide does not affect urea content and decreases urinary osmolality from the start, as compared to untreated BB homozygotes; it raises "free water" output above BB values.

Animals↗
PubMed1966

A comparison of the effects of chlorothiazide, quinethazone and placebo on student volunteers and on rats: a teaching exercise.

Medical student participation in a controlled doubleblind clinical bioassay provides an effective introduction to clinical pharmacology and perhaps the best stimulus to the future rational evaluation and use of drugs. In one such exercise, 27 volunteers were divided into three groups: one received 50 mg. quinethazone, one 500 mg. chlorothiazide and the third a lactose placebo. Urine was collected for three 90-minute periods, volume and pH being recorded; sodium and potassium were measured with a flame photometer, and chloride by the Volhard technique. Although this study was primarily a comparative bioassay of two established diuretics against a placebo, no previous direct comparisons of these diuretics could be found in the literature. The diuretic activity of chlorothiazide and quinethazone compared to placebo therapy was confirmed in both humans and rats, the use of controls was illustrated, and a higher mean sodium-potassium ratio for quinethazone than for chlorothiazide was demonstrated.

Animals↗
PubMed1976

Effect of chlorothiazide on the pharmacokinetics of lithium in plasma and erythrocytes.

The effect of chlorothiazide on the pharmacokinetics of lithium in both plasma and RBCs was studied in normal adult males. This was accomplished by administering single, 300 mg. doses of lithium carbonate alone and concurrently with chlorothiazide (0.5 grams/day for one week). Thiazide administration resulted in increases in plasma and RBC concentrations of 26.2 and 25.4%, respectively, as well as a 26.5% decrease in renal lithium clearance. The data were analyzed in terms of a two compartment pharmacokinetic model as previously reported (8). The results of this analysis showed that the change in renal lithium clearance could be accounted for by a 24.1% reduction in the value of ke, the excretion rate constant. It was also shown that changes in plasma lithium concentration during chronic lithium therapy would be expected to increase by 25-30% when chlorothiazide therapy is employed. The model also predicts that changes in RBC concentrations would parallel those occurring in plasma and thus no change in the RBC/plasma lithium ratio would be expected.

Adult↗
PubMed1977

Adjustment of lithium dose during lithium-chlorothiazide therapy.

There has been a long-held belief that lithium salts cannot be used in the presence of thiazide diuretics. Recently, however, thiazides have been demonstrated to be not only safe, but actually indicated in two situations in which lithium salts are used. The first is in the treatment of lithium-induced nephrogenic diabetes insipidus and the second is in severe manic depressive illness in which high doses of lithium do not produce therapeutic serum or intraeythrocytic lithium concentrations. This new information now makes it possible for some manic depressive patients with serious medical illnesses (such as hypertension or congestive heart failure), in whom thiazide diuretics are routinely used, to be treated cautiously with lithium carbonate. This paper analyzes data from 13 patients taking lithium carbonate and varying doses of chlorothiazide in order to indicate the approximate magnitude of downward adjustment of daily lithium dose which the clinician must make to safely give 500, 750, and 1,000 mg/day of chlorothiazide.

Chlorothiazide↗
PubMed1979

Bioavailability of chlorothiazide tablets in humans.

A urinary excretion bioavailability study was conducted in 12 healthy male subjects to evaluate three 250-mg and three 500-mg chlorothiazide tablet products. The study was a crossover design, and urine samples were collected 1, 2, 3, 4, 6, 8, 12, and 24 hr after administration of each dose. The resulting data were statistically analyzed for significant differences in cumulative percent of dose excreted at each sampling time, total drug recovery after 24 hr, maximum excretion rate, and time of maximum excretion rate. No statistically significant differences were found between the three 250-mg tablets tested. The urinary drug recovery after administration of one of the 500-mg products was significantly (p less than 0.05) lower than that from the other two 500-mg tablets. The total mean recovery from each product ranged from only 11 to 20%, indicating that in general chlorothiazide was not well absorbed following oral administration. Attempts at correlating the urinary excretion data with the dissolution rate determinations were not successful.

Adult↗
PubMed1981

In vivo-in vitro correlations with a commercial dissolution simulator. I: Methenamine, nitrofurantoin, and chlorothiazide.

Dissolution profiles were determined for nine methenamine, 14 nitrofurantoin, and six chlorothiazide dosage forms using a dissolution simulator. Various in vivo-in vitro correlations were examined. The best correlation for methenamine was between the maximum urinary excretion rate and the time for 15% dissolution. A good correlation for the 50-mg nitrofurantoin tablets was also found between cumulative percent of drug excreted in 12 hr and the percent dissolved in 1 hr. There were no significant correlations for the 100-mg nitrofurantoin dosage forms. Good correlations were also observed for the 250- and 500-mg chlorothiazide tablets between the percent of drug dissolved in 1 min or the time for 15% dissolution and the maximum excretion rate.

Absorption↗
PubMed1989

Effect of temperature and fat content on the solubility of hydrochlorothiazide and chlorothiazide in milk.

The solubility of hydrochlorothiazide and chlorothiazide in milk has been studied. Experiments were carried out at 5, 15, 25, and 37 degrees C on a buffer solution of pH 6.5, a 2.6% solution of casein, bovine skim milk samples, and bovine milk samples with fat contents of 0.75, 1.70, and 3.50%. The "total" solubility of both drugs in the media studied was higher than the buffer solubility. The highest "total" solubility for both drugs was observed in skim milk. Based on binding data of thiazides to milk, the "total" solubility was split into "free" and "bound" solubility. The increases of solubility noted cannot be explained on the basis of drug-milk binding data. The enhancement of solubility was attributed to the increase of intrinsic solubility of drugs in milk. Results of the thermodynamic analysis of solubility data showed that a different solubilization process of hydrochlorothiazide may be responsible for the high solubility values found in skim milk for this drug. In contrast, the thermodynamic parameters of chlorothiazide in all types of milk are similar, indicating a common solubilization mechanism. The biopharmaceutical significance of the findings is discussed in light of the freeze-dried drug-milk formulations and coadministration of drugs with milk in general.

Animals↗
PubMed1975

Mechanism of immediate hemodynamic effects of chlorothiazide.

The mechanism of the immediate hemodynamic effects of intravenous chlorothiazide (25 mg. per kilogram) was studied in 22 anesthetized open-chest dogs. Within 20 minutes after administration, cardiac output and stroke volume significantly fell; this was associated with decreased central venous and left ventricular end-diastolic pressures. That these hemodynamic effects were caused by, and dependent upon, volume loss through diuresis (eightfold increase in urine volume) was shown: by a return of these measurements to control levels when the volume loss (by diuresis) was corrected with 6 per cent Dextran; by prevention of the hemodynamic changes in chlorthiazide-treated dogs previously prepared with ureterocaval anastomosis; and by confirming these same hemodynamic effects by quantitatively equivalent hemorrhage. Thus, the immediate diuresis produced by chlorothiazide resulted in a contracted plasma volume (increased hematocrit and serum protein concentration) which, in turn, diminished cardiac venous return, central filling pressures, stroke volume, and cardiac output. There was no evidence demonstrated to indicate any direct myocardial effect or peripheral venodilation induced by thiazide.

Animals↗
PubMed1975

Dissociation of calcium and sodium clearances in patients with hypoparathyroidism by infusion of chlorothiazide.

Previous reports have identified a deficient hypocalciuric response to chronic treatment with thiazide diuretics in patients with hypoparathyroidism. The present study was designed to ascertain if the acute response to thiazide diuretics is impaired in hypoparathyroidism. Five normal subjects and five patients with hypoparathyroidism were studied with the renal clearance technique during water diuresis. In normal subjects the clearance of calcium/clearance of sodium was 0.98 +/- 0.14 before, and 0.33 +/-0.03 during the intravenous infusion of chlorothiazide. In patients with hypoparathyroidism the corresponding ratios were 1.69 +/- 0.27 and 0.57 +/- 0.10. In both groups the drug-induced fall in clearance was 65% of control. The concentration of chlorothiazide in plasma and its rate of excretion were comparable in both groups. It is concluded that the acute action of thiazides is not impaired in hypoparathyroidism.

Adolescent↗