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At least 19 recordsLinked to original sources
PubMed1980

Antihypertensive efficacy of alpha-methyldopa, chlorothiazide and Supres-150 (alpha-methyldopa-chlorothiazide).

Twenty-two white men and two white women with uncomplicated essential hypertension participated in a randomized double-blind trial comparing placebo with alpha-methyldopa (750 mg/d orally) and chlorothiazide (450 mg/d orally), alone or in combination. There were no significant differences in blood pressures as measured with the patients lying down; however, with the patients standing the systolic, diastolic and mean arterial blood pressures were significantly lower (P < 0.05) after treatment with alpha-methyldopa or the combination product. The higher the blood pressure before treatment, the greater the fall with treatment. Adverse effects were infrequent.

Adult↗
PubMed1975

Clarification of the site of action of chlorothiazide in the rat nephron.

The saluretic effect of the thiazide diuretics has been attributed to inhibition of sodium reabsorption in the distal nephron of the kidney. Recent micropuncture studies have shown, however, that chlorothiazide administration can also inhibit sodium reabsorption in the proximal convolution. To clarify the site of the saluretic effect of chlorothiazide, these micropuncture studies examined the effect of chlorothiazide on chloride transport in the nephron. The effect of chlorothiazide on chloride transport was studied because chlorothiazide's effectiveness as a saluretic is largely due to its ability to enhance sodium chloride excretion; if only changes in sodium transport are examined, it would be then difficult to determine if sodium as bicarbonate or as chloride is affected, since chlorothiazide can inhibit carbonic anhydrase. One group of rats was studied before and after 15 mg/kg per h chlorothiazide. For comparison, another group of rats was studied before and after 2 mg/kg per h benzolamide, a carbonic anhydrase inhibitor. Fractional chloride delivery from the proximal tubule was similarly increased in both groups from 59.4 to 71.0% by chlorothiazide administration, Pless than 0.0001, and from 54.3 to 68.2% by benzolamide administration, P less than 0.001. The increased delivery very of chloride from the proximal tubule was largely reabsorbed before the early distal tubule as fractional chloride delivery to this site increased only from 5.08 to 7.40% after chlorothiazide administration, P less than 0.001, and from 4.50 to 6.29% after benzolamide administration, P less than 0.01. Benzolamide had no effect on chloride reabsorption in the distal convoluted tubule. However, chlorothiazide administration resulted in a marked decrease in distal tubular chloride reabsorption, the fraction of filtered chloride present at the late distal tubule incresing from 1.24 to 6.25%, P less than 0.001. Fractional chloride excretion in the urine increased from 0.29 to 3.44%, P less than 0.001, after chlorothiazide, but did not change after benzolamide. The influence of chlorothiazide on proximal chloride transport presumably is related to its ability to inhibit renal carbonic anhydrase. However, it is not the effect of chlorothiazide in the proximal convolution but rather its effect in the distal convoluted tubule which is primarily responsible for its ability to be an effective saliuretic.

Animals↗
PubMed1981

Saturable kinetics of intravenous chlorothiazide in the rhesus monkey.

A range of bolus doses of 14C-chlorothiazide and unlabeled drug (6.7-30 mg/kg) were administered to each of three unanesthetized rhesus monkeys with and without concurrent probenecid dosing. Plasma up to 4 h and urine up to 24 h were sampled frequently. Apparent terminal plasma half-lives ranged from 18 to 25 min in the absence of probenecid. No apparent trend was noted for the volume of distribution of the central compartment calculated from estimated plasma concentrations at time zero. For chlorothiazide studies, an average of 92% of the dose was recovered in urine by 24 hr. Plasma and urinary clearances at low doses were 20 to 50% higher than those found with higher doses. These dose-dependent clearances for chlorothiazide were found at doses parallel to the most often prescribed clinical doses in humans on a g chlorothiazide per kg body weight basis. Clearances in the presence of probenecid decreased two- to four-fold over those seen without probenecid. Incremental renal clearances of chlorothiazide in the studies with and without probenecid were also evaluated. Curvilinear segments characteristic of dose-dependent kinetics were demonstrated in graphs of urinary excretion rate versus plasma concentrations. Values of Michaelis-Menten constants Vmax and Km were calculated for renal excretion of chlorothiazide by active transport after intravenous doses in all three monkeys. The contribution of glomerular filtration to chlorothiazide renal clearance was found to be negligible. Values of the constant KI (the concentration of the probenecid competitive inhibitor of chlorothiazide, which double the apparent Km value of chlorothiazide) were calculated using the previously calculated Vmax and Km values.

Animals↗
PubMed1982

Influence of food and fluid volume on chlorothiazide bioavailability: comparison of plasma and urinary excretion methods.

The bioavailability of chlorothiazide from oral tablets was examined under fasting and nonfasting conditions in healthy male volunteers. Bioavailability was determined from urinary excretion data and plasma chlorothiazide concentrations. Two fasting treatments and one nonfasting treatment yielded similar plasma chlorothiazide profiles, characterized by sharply ascending and descending segments until 12-13 hr postdosing, followed by a prolonged period with variable and erratic chlorothiazide levels. A triexponential function that adequately described mean data from each treatment could not be applied to individual plasma curves because of their variable nature. Chlorothiazide absorption was not influenced by different accompanying water volumes in fasted individuals but was doubled when tablets were administered immediately after a standard meal. Urinary excretion of chlorothiazide correlated well with plasma drug concentrations; 48-hr urinary recovery accounted for 24.7% of a 500-mg dose in nonfasted subjects compared to 12.3 and 14.9% in fasted subjects receiving the drug with 20 and 250 ml of water, respectively. Observed relationships between chlorothiazide dosage and absorption efficiency are consistent with previous suggestions that chlorothiazide absorption from the GI tract is saturable and site specific.

Adult↗
PubMed1997

Cellular mechanisms of chlorothiazide and cellular potassium depletion on Mg2+ uptake in mouse distal convoluted tubule cells.

The use of the distally-acting diuretic, chlorothiazide, has been reported to have important effects on renal magnesium handling. The cellular mechanisms of chlorothiazide action on Mg2+ uptake was investigated in immortalized mouse distal convoluted tubule (MDCT) cells. Intracellular free Mg2+ concentration was determined by microfluorescence. Mg2+ transport was measured as a function of change in intracellular Mg2+ concentration with time following placement of Mg2+-depleted cells into a buffer containing 1.5 mM magnesium. The uptake rate of Mg2+ into Mg2+-depleted cells was 179 +/- 28 nM/second. Mg2+ uptake was dependent on the membrane voltage as membrane hyperpolarization enhanced uptake whereas depolarization diminished transport. Chlorothiazide increased Mg2+ uptake by 58%, from 179 +/- 28 to 283 +/- 23 nM/second. The ability of chlorothiazide to stimulate Mg2+ uptake in MDCT cells was concentration-dependent and related to the diuretic-induced hyperpolarization of the plasma membrane. These studies support the notion that acute chlorothiazide administration enhances renal magnesium conservation through its effects on Mg2+ transport within the distal convoluted tubule. Since chronic chlorothiazide administration may result in hypokalemia as well as hypomagnesemia, Mg2+ uptake was determined in potassium-depleted MDCT cells. Mg2+ uptake was diminished, 80 +/- 24 nM/second, in potassium depleted cells. Hyperpolarization of the plasma membrane with the cell permanent anion, SCN-, corrected Mg2+ uptake in potassium depleted cells suggesting that the basis for diminished uptake may, in part, be due to depolarization of the membrane voltage. In summary, acute chlorothiazide stimulates Mg2+ transport in MDCT cells. We postulate that chronic chlorothiazide use may lead to hypokalemia that in turn diminishes Mg2+ transport in the distal tubule resulting in urinary magnesium-wasting.

Animals↗
PubMed1993

The effect of chlorothiazide on bone-related biochemical variables in normal post-menopausal women.

OBJECTIVE: To evaluate the effects of short-term administration of chlorothiazide on fasting urinary hydroxyproline, an index of bone resorption, and other bone-related biochemical parameters in normal post-menopausal women. DESIGN: Subjects served as their own control before and after chlorothiazide treatment. SETTING: Subjects were recruited by advertisement. PARTICIPANTS: Thirteen healthy post-menopausal women with a mean age of 65 years. INTERVENTION: Each subject was given chlorothiazide 500 mg bd po for 7 days. Fasting blood and urine samples were obtained immediately before the commencement of chlorothiazide (day 1) and 2 and 7 days after starting chlorothiazide. RESULTS: Chlorothiazide decreased the urinary calcium/creatinine (mean value day 1, 0.267; day 2, 0.143; day 7, 0.135; P < 0.001) and hydroxyproline/creatinine (day 1, 0.0192; day 2, 0.0145; day 7, 0.0139; P < 0.02) molar ratios. CONCLUSION: Chlorothiazide decreases fasting urinary hydroxyproline, a marker of bone resorption in post-menopausal women. This observation supports a potential role for thiazide diuretics in the prevention of osteoporosis. The observed fall in urinary hydroxyproline is of the same order as that seen after treatment with estrogen or calcium supplements.

Acid-Base Equilibrium↗
PubMed1981

[Diuretics and vascular risk factors. Comparison between tienilic acid and chlorothiazide (author's transl)].

Tienilic acid (250 mg/day) was compared with chlorothiazide (500 mg/day) in 25 hypertensive patients in a randomized cross-over study (2 periods of 2 months). Mean supine arterial pressure was lower with tienilic acid than with chlorothiazide (106 +/- 3 vs 111 +/- 3 mm Hg, p less than 0.05) whereas no difference could be noted in body weight, natriuresis and plasma renin activity. Glucose tolerance tests were altered in the same fashion. Serum cholesterol (234 with tienilic acid and 239 mg/dl with chlorothiazide) and serum triglyceride levels (178 with tienilic acid and 179 mg/dl with chlorothiazide) were not different. Serum urate concentrations were lower with tienilic acid (4.8 mg/dl) than with chlorothiazide (7.8 mg/dl) whereas fractional excretion of urate was much higher with tienilic acid (17 +/- 2%) than with chlorothiazide (7 +/- 2%). Thus, the only metabolic advantage of tienilic acid over chlorothiazide is its hypouricemic effect which warrants long term studies to evaluate its vascular prognostic significance.

Adult↗
PubMed1985

Effect of chlorothiazide on serial measurements of exchangeable sodium and blood pressure in spontaneously hypertensive rats.

Chlorothiazide (100 mg/kg body weight) was given by gavage daily to spontaneously hypertensive rats for 4 weeks. Another group of spontaneously hypertensive rats was given only tap water and served as control. Measurements of total exchangeable sodium, blood pressure and weight were performed for 2 weeks before and for 4 weeks during treatment. Before treatment, exchangeable sodium, blood pressure and weight were similar in the two groups of rats. Chlorothiazide significantly attenuated the blood pressure increase in spontaneously hypertensive rats, the effect being most marked during the first 2 1/2 weeks of treatment and less thereafter. Rats in the chlorothiazide-treated group gained weight more slowly than did those of the control group. Exchangeable sodium, expressed as mmol/kg body weight, did not differ significantly between the two groups at any stage. When exchangeable sodium was expressed as mmol/rat, there was a more gradual rise in the chlorothiazide-treated animals, in accordance with their slower gain in weight. There was no temporal association between the antihypertensive effect of chlorothiazide and changes in exchangeable sodium. Thus whereas chlorothiazide treatment of spontaneously hypertensive rats slows the increase of both weight and exchangeable sodium, other mechanisms are apparently responsible for the antihypertensive action of the drug.

Animals↗
PubMed1996

Cardiomegaly and vasoactive hormones in rats with chronic myocardial infarction: long-term effects of chlorothiazide.

1. The effects of prolonged chlorothiazide treatment of left ventricular failure on cardiac hypertrophy, circulating vasoactive hormones and exchangeable body sodium were examined in rats with chronic myocardial infarction induced by left coronary artery ligation. Chlorothiazide therapy commenced either immediately or 2 weeks after infarction. For 4 weeks, the rats were given either chlorothiazide (50 mg day-1 kg-1) in their drinking water or drinking water alone. 2. Cardiac weight increased in untreated rats with infarction in comparison with sham-operated controls, indicating the presence of chronic left ventricular dysfunction, although exchangeable body sodium, plasma renin activity, plasma vasopressin and plasma osmolality remained unchanged. 3. Chlorothiazide raised haematocrit and plasma renin activity equally in rats with and without infarction, although exchangeable body sodium, plasma vasopressin and plasma osmolality were not changed by the treatment. Plasma atrial natriuretic peptide was 2-fold higher in rats with infarction and this response was not affected by chlorothiazide treatment. Chlorothiazide therapy did not prevent or reverse cardiac hypertrophy. 4. Chronic diuretic therapy in this experimental model of heart failure did not reduce extracellular sodium, plasma vasopressin or the extent of ventricular hypertrophy, possibly because the condition was associated with activation of the renin-angiotensin system.

Animals↗
PubMedDate not supplied

Absorption and disposition kinetics of chlorothiazide in protein-calorie malnutrition.

The influence of dietary protein deficiency on the absorption and disposition kinetics of chlorothiazide was investigated in male Sprague-Dawley rats fed for 4 weeks on a 23 per cent (control) or a 5 per cent (low) protein diet ad libitum. Chlorothiazide in plasma and urine was determined by a sensitive and specific HPLC assay. Following an intravenous dose of 10 mg kg-1 chlorothiazide, there was a significant decrease in the total plasma clearance (Cl) per kg of body weight from 1.80 +/- 0.15 to 1.29 +/- 0.15 l h-1 kg-1 and apparent steady-state volume of distribution from 0.65 +/- 0.13 to 0.38 +/- 0.07 l kg-1 in the protein-deficient rats. However, no significant difference was found in the two groups of animals with respect to mean residence time (MRT) and free fraction of drug in plasma. The mean harmonic half-life was increased from 72 to 91 min in the protein-deficient rats. The urinary recovery of unchanged chlorothiazide in 48 h was essentially complete in both groups of animals. The absorption of chlorothiazide, as assessed by the mean urinary recovery of unchanged drug after oral administration, was 66 per cent and 68 per cent in normal and protein-deficient rats, respectively.

Animals↗
PubMed1981

Chlorothiazide absorption from solution and tablet dosage forms in dogs.

The bioavailability of an aqueous solution of chlorothiazide and three commercially available chlorothiazide tablets was assessed in adult mongrel dogs. In two crossover urinary excretion studies, six fasting dogs received single 500-mg doses of chlorothiazide as an aqueous solution, one 500-mg originator tablet on two separate occasions (Tablets A-1 and A-2), two 250-mg originator tablets (Tablet B), or one 500-mg generic tablet (Tablet C). 6-Amino-4-chlorobenzene-1,3-disulfonamide )chloraminophenamide), a pharmacologically active hydrolysis product of chlorothiazide was not detected in any urine sample. Urinary recoveries of chlorothiazide after oral administration, expressed as the mean (range) percent of the dose, was only 22.0 (8.41-33.9), 15.7 (10.2-25.0), 20.7 (7.25-31.0), 18.5 (8.72-33.2), and 21.9% (6.69-41.1%) for the aqueous solution and Tablets A-1, A-2, B, and C, respectively. Considerable interindividual variation and some intraindividual variation were observed. No statistically significant difference in bioavailability existed among the aqueous solution and Tablets A-2 and B, between Tablets A-1 and C, and between Tablets A-1 and A-2.

Animals↗