Errors in chlorothiazide bioavailability estimates based on a Bratton--Marshall colorimetric method for chlorothiazide in urine.
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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↗
Apparent dose-dependent absorption of chlorothiazide in dogs.
The purpose of this study was to determine the effect of oral dose on the absorption of chlorothiazide in the dog. Chlorothiazide was quantitatively excreted in the urine after administration of 50-mg and 250-mg intravenous doses. In contrast, the urinary recovery of chlorothiazide after oral administration showed appreciable interanimal variation and decreased from 70.4% to 26.7% on the average as the oral dose was increased from 125 mg to 750 mg. Oral administration of a single 15-mg dose of propantheline bromide (a potent inhibitor of gastric emptying and intestinal motility) at--1 hr increased the absorption of a 250 mg oral dose of chlorothiazide in three out of four dogs. These results suggest that chlorothiazide absorption is dose dependent and apparently site specific.
Administration, Oral↗
Chronic effects of chlorothiazide on reabsorption by the proximal tubule of the rat.
1. The renal response to a low-sodium diet alone and a low-sodium diet plus the daily oral administration of chlorothiazide was examined in rats. Sodium restriction resulted in a decrease in sodium excretion until day 4, after which it remained constant. The administration of chlorothiazide resulted in an initial natriuresis. By day 6, however, the natriuresis had abated and thereafter sodium excretion remained the same as that of the low sodium group. 2. After the animals were in balance on their respective regimens, clearance and micropuncture studies were performed. The glomerular filtration rate was lower in the chlorothiazide-treated rats than in control rats and/or in the low-sodium group. End proximal tubule TF/Pinulin ratios were higher in the diuretic-treated animals than in control rats. TF/Pinulin ratios in low-sodium animals were lower than in the diuretic-animals but higher than in control rats. 3. These studies demonstrate that the escape from the chronic effects of chlorothiazide is due to a decrease in the glomerular filtration rate and to an increase in fractional reabsorption in the proximal tubule, resulting in a reduction in delivery of filtrate to the cortical diluting segment where chlorothiazide exerts its major inhibitory effect.
Animals↗
Interrelationship of chlorothiazide and parathyroid hormone: a micropuncture study.
Sodium and calcium are normally reabsorbed in parallel in the renal tubule. Both parathyroid hormone (PTH) and thiazide diuretics may influence this relationship. This study was designed to show whether the dissociation of Na from Ca transport produced by thiazides is dependent upon the presence of PTH. Hydropenic thyroparathyroidectomized (TPTX) dogs were given chlorothiazide alone and together with PTH. Chlorothiazide alone significantly increased fractional excretion of sodium (0.5 +/- 0.3-5.6 +/- 0.3%) and calcium (0.74 +/- 0.18-1.4 +/- 0.24%). However, the Ca/Na excretion ratio fell markedly from 1.57 to 0.24%. Micropuncture revealed this dissociation to occur at the distal tubule. Proximal reabsorption of water, sodium, and calcium were inhibited to an equal extent. However, distal fractional sodium reabsorption fell 10% whereas calcium reabsorption remained unchanged following chlorothiazide administration in TPTX animals. When phosphaturic doses of PTH were administered with chlorothiazide, no significant changes were observed in calcium or sodium reabsorption. It is concluded that PTH plays no role in the dissociation of sodium from calcium reabsorption resulting from acute chlorothiazide administration.
Animals↗
The role of volume contraction in the hypocalciuric action of chlorothiazide.
Thiazide-induced hypocalciuria usually requires two to four days of drug treatment for its full expression. The present experiments were designed to test the possibility that an immediate hypocalciuria could be produced in subjects whose extracellular volumes were already contracted. In previously untreated subjects, chlorothiazide (2 g/day) did not produce hypocalciuria on the first day of treatment. Hypocalciuria occurred on the second day and was somewhat enhanced on the third and fourth days of treatment. In subjects pretreated with furosemide (40 mg two or three times a day for two days), chlorothiazide produced hypocalciuria on the first day of its use. Under the influence of chlorothiazide, there was a strong linear correlation between the changes in the excretion of calcium and sodium. The results are consistent with the idea that chlorothiazide enhances the ratio of calcium to sodium reabsorptions and that this tendency for absolute hypocalciuria can be overridden by a large natriuretic response to the drug. Volume contraction, which minimizes the natriretic response to diuretics, allows a more immediate and pronounced hypocalciuric response to thiazides.
Adult↗
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↗
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↗
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↗
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↗
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↗
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↗
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↗
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↗
Relative effectiveness of chlorothiazide, reserpine and hydrallazine in spontaneously hypertensive rats.
1. Previous studies in this laboratory indicated that a mixture of anti-hypertensive agents in the drinking water controlled the blood pressure of spontaneously hypertensive rats (SHR). The present study was designed to determine which of the agents exerted the greatest anti-hypertensive effect. 2. Treatment was begun at 12 weeks of age in groups of eleven to seventeen rats with one of the following drugs: reserpine, chlorothiazide or hydrallazine. Blood pressures were recorded by the tail method under light ether anaesthesia every 2 weeks until the rats were approximately 70 weeks of age. 3. At 50 weeks of age, blood pressure of chlorothiazaide-treated rats averaged 40 mmHg below untreated control SHR; reserpine-treated SHR were also 40 mmHg lower than control rats, and hydrallazine-treated SHR were 85 mmHg below the control rats. 4. Rats in all groups gained weight normally and appeared in good health. Although all drugs were active, hydrallazine was considerably more effective than chlorothiazide or reserpine in the SHR.
Animals↗
Effects of furosemide and chlorothiazide on blood pressure and plasma renin activity.
Short (2 weeks) and long (12 weeks) term effects of furosemide and chlorothiazide on blood pressure, plasma renin activity, and uric acid concentration were studied in 69 hypertensive patients. Both treatments caused significant reductions in blood pressure and increases in plasma renin activity and uric acid at 2 and 12 weeks in 6) normal renin patients; there was no difference between the effects of furosemide and that of chlorothiazide. Reduction in blood pressure in eight low renin patients who showed smaller changes in plasma renin activity and uric acid was not significant at 2 weeks but significant after 12 weeks of treatment.
Adult↗
Potentiation of the response to vasopressin (pitressin) by treatment with a combination of chlorpropamide and chlorothiazide in Brattleboro rats with hereditary hypothalamic diabetes insipidus.
1 The effect of a combination of chloropropamide and chlorothiazide in Brattleboro rats with hereditary hypothalamic diabetes insipidus (DI) treated with low doses of vasopressin (Pitressin tannate in oil) was investigated with particular reference to the time course of response from the initiation of treatment. 2 Analysis of the relationship between water intake and body weight indicated no real correlation and body weight accounted for only 4.4% of the variation in water intake. It was therefore decided to use whole body responses as the index in preference to the response per unit body weight. 3 The daily administration of 5 mg chlorpropamide combined with chlorothiazide in the drinking water (4 mg/1) to Pitressin-treated DI rats potentiated the response to small doses of vasopressin (25 and 50 mu Pitressin/24 hours). Water intake was reduced by the drug combination by an average of 12.35 ml/24 h, but only on the second day of treatment was the decrease of any real magnitude (30 ml/24 h but otherwise 9 ml/24 h or less). Analysis of urine volume measurements gave similar results to those obtained for water intake and the potency ratio measured in terms of free water clearance was 1.26 (agreeing closely with the ratio for water intake which was 1.24). 4 A reduction in the solute excretion was observed only in those DI rats treated with the higher dose of Pitressin (50 mu/24 h) combined with the two drugs. 5 Possible reasons for the discrepancy between the effect of the combination of chlorpropamide and chlorathiazide on water metabolism in the DI rat and the DI patient are discussed.
Animals↗
Double-blind trial of antihypertensive effect of chlorothiazide in severe renal failure.
A randomised double-blind crossover trial was done to assess the efficacy of chlorothiazide as an antihypertensive drug in patients with severe renal failure. There was a significant reduction in standing (mean drop 13/6 mm Hg) and supine (mean drop 13/5 mm Hg) blood-pressure, without postural hypotension. Chlorothiazide has a place in the management of hypertension in patients with severe renal failure and its antihypertensive effect is probably due to a change in peripheral vascular resistance and not to volume contraction.
Adult↗