Errors in chlorothiazide bioavailability estimates based on a Bratton--Marshall colorimetric method for chlorothiazide in urine.
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Co-operative clinical trial of alpha-methyldopa. 3. Double-blind control comparison of alpha-methyldopa and chlorothiazide, and chlorothiazide and rauwolfia.
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Chlorothiazide↗
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↗
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↗
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↗
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↗
Effect of magnesium depletion and potassium depletion and chlorothiazide on intracellular pH in the rat, studied by 31P NMR.
1. Both dietary magnesium depletion and potassium depletion (confirmed by tissue analysis) were induced in rats which were then compared with rats treated with chlorothiazide (250 mg/kg diet) and rats on a control synthetic diet. 2. Brain and muscle intracellular pH was measured by using a surface coil and [31P]-NMR to measure the chemical shift of inorganic phosphate. pH was also measured in isolated perfused hearts from control and magnesium-deficient rats. Intracellular magnesium status was assessed by measuring the chemical shift of beta-ATP in brain. 3. There was no evidence for magnesium deficiency in the chlorothiazide-treated rats on tissue analysis or on chemical shift of beta-ATP in brain. Both magnesium and potassium deficiency, but not chlorothiazide treatment, were associated with an extracellular alkalosis. 4. Magnesium deficiency led to an intracellular alkalosis in brain, muscle and heart. Chlorothiazide treatment led to an alkalosis in brain. Potassium deficiency was associated with a normal intracellular pH in brain and muscle. 5. Magnesium depletion and chlorothiazide treatment produce intracellular alkalosis by unknown mechanism(s).
Acid-Base Equilibrium↗
Cellulose phosphate and chlorothiazide in childhood idiopathic hypercalciuria.
A calcium loading test performed on seven of eight children with idiopathic hypercalciuria identified the hyperabsorptive form of hypercalciuria in five and renal hypercalciuria in one. The type of hypercalciuria was not identified in the other patient. Three children presented with hematuria without calculus formation. Chlorothiazide reduced the urinary calcium excretion level in two of six patients to the normal range. The addition of cellulose phosphate to chlorothiazide reduced the urinary calcium excretion level to the normal range in those four patients who showed an incomplete response to chlorothiazide alone. There was clinical improvement with cellulose phosphate in another child whose symptoms did not disappear after chlorothiazide had reduced urinary calcium level to the normal range. Cellulose phosphate is effective in children with recurrent stone formation who have shown inadequate response to chlorothiazide.
Administration, Oral↗
Renal tubular secretion and effects of chlorothiazide, hydrochlorothiazide and clopamide: a study in the avian kidney.
The relationship between renal tubular secretion and saluretic effects of two thiazides (chlorothiazide and hydrochlorothiazide) and clopamide was studied using a modified Sperber technique. The distribution of carbonic anhydrase in the avian kidney was studied by a histochemical method. The modified Sperber technique allows an absolute estimation of the tubular excretion efficiency of a substance, as determined by its True Tubular Excretion Fraction (TTEF). The TTEF values were for chlorothiazide 59%, hydrochlorothiazide 22% and clopamide 10%. Thus, they were all actively secreted by renal tubular cells; most likely through organic anion transport since novobiocin markedly reduced the TTEF values. After infusion of the diuretics into the renal portal system on one side there was only a small ipsilateral excess natriuresis and chloruresis, in spite of their different tubular excretion efficiencies. For hydrochlorothiazide, and especially for chlorothiazide the saluretic effect therefore appears to be largely independent of the tubular fluid concentration of the diuretic and primarily evoked from the peritubular side of the avian nephron. This is a sharp contrast to the primarily luminally induced saluretic effects of furosemide, ethacrynic acid and piretanide. Only chlorothiazide caused an ipsilateral excess excretion of potassium and bicarbonate, probably due to inhibition of carbonic anhydrase since similar effects were seen after acetazolamide. This effect was coupled to tubular secretion of the diuretic, and probably reflects an inhibition of carbonic anhydrase in cortical distal tubules, where the enzyme is present in the apical region of most cells and could be reached by chlorothiazide present in the tubular fluid.
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↗
Reversal of vitamin-D2-induced hypercalciuria by chlorothiazide.
To test the effects of chlorothiazide on vitamin-D2-induced hypercalciuria, we carried out 17 metabolic studies lasting 12 days each in adult Sprague-Dawley male rats. Three groups were studied: (A) control rats receiving only the vitamin-D2 vehicle; (B) vitamin-D2-treated rats receiving 50 IU/day; and (C) rats treated in the same manner as group B with the addition of chlorothiazide 20 mg/day for the last 6 days of the study. Urine was collected during the last 3 days, and a blood sample was obtained at the end of each study period. Analysis of the data showed that there were no significant differences between the groups in changes of serum calcium concentration (A, 6.1 +/- 0.1 mg/dl; B, 6.1 +/- 0.2 mg/dl; C, 6.0 +/- 0.2 mg/dl), serum creatinine concentration (A, 0.5 +/- 0.07 mg/dl; B, 0.52 +/- 0.08 mg/dl; C, 0.48 +/- 0.04 mg/dl), and creatinine clearance (A, 4.8 +/- 0.7 ml/min/kg; B, 5.2 +/- 1.2 ml/min/kg; C, 4.9 +/- 0.5 ml/min/kg). The administration of vitamin-D2 significantly increased the urinary calcium excretion from 6.7 +/- 1.0 mg/kg/day to 19.5 +/- 9.7 mg/kg/day (p less than 0.02), but the calciuria was inhibited in group C rats by the addition of chlorothiazide, which restored urinary calcium excretion to 6.8 +/- 2.5 mg/kg/day (p less than 0.02). Evaluation of the ratio of calcium/creatinine excretion (A, 0.19 +/- 0.03; B, 0.53 +/- 0.25; C, 0.20 +/- 0.07) and calcium/sodium excretion (A, 0.22 +/- 0.05; B, 0.48 +/- 0.25; C, 0.19 +/- 0.04) further confirmed these effects of vitamin-D2 and chlorothiazide on urine calcium excretion. We conclude that in rats conventional doses of vitamin-D2 consistently induce marked hypercalciuria, even without hypercalcemia, and that this hypercalciuria can be effectively prevented by chlorothiazide.
Animals↗
Effect of calcium, furosemide and chlorothiazide on net volume reabsorption and basolateral membrane potential of the distal tubule.
In the distal tubule of the isolated kidney of Amphiuma net volume reabsorption (split-oil droplet method) and basolateral membrane potential (psi b) were measured. Luminal perfusion solution could be changed rapidly from 108 mmol . 1-1 NaCl plus 0.1 mmol . 1-1 calcium to solutions containing 103 or 97 mmol . 1-1 NaCl plus 3.6 or plus 7.2 mmol . 1-1 calcium. Furthermore, 10(-4) mol . 1-1 furosemide or chlorothiazide were applied luminally. (1) Addition of 7.2 mmol . 1-1 calcium hyperpolarized psi b from -73.4 mV to -108.3 mV and inhibited net volume reabsorption. (2) Similarly, when furosemide was injected, psi b was hyperpolarized and net volume reabsorption reduced. Application of both high calcium and furosemide further inhibited volume reabsorption. (3) The effects of chlorothiazide were similar to those of furosemide. However, when both high calcium and chlorothiazide were administered psi b and volume reabsorption were almost normalized. (4) The data are consistent with the hypothesis that calcium and the diuretics interfere primarily with chloride uptake across the luminal membrane and thus reduce sodium chloride transport. When chlorothiazide in the presence of high luminal calcium almost normalized chloride transport, it is likely that its effects were by stimulating calcium transport and thus increasing intracellular calcium activity.
Animals↗
Effect of angiotensin II-induced changes in perfusion flow rate on chlorothiazide transport in the isolated perfused rat kidney.
Angiotensin II was used as a probe to study the effect of changes in perfusate flow rate on the renal clearance parameters of chlorothiazide in the isolated perfused rat kidney. Perfusion studies were performed in five rats with no angiotensin II present in the perfusate and in five rats with a 1-4 ng/min infusion of angiotensin II into the perfusate. Angiotensin II had a dramatic effect on the renal hemodynamics, resulting in a 43% decrease in perfusate flow, a 16% decrease in glomerular filtration rate (GFR), and a 45% increase in filtration fraction. Values for the fractional excretion of glucose were low and consistent, with or without angiotensin II. Although the unbound fraction (fu) of chlorothiazide was unchanged between treatments, the renal (CLr) and the secretion clearances were reduced by about 50% in the presence of angiotensin II; the excretion ratio [ER = CLr/(fu.GFR)] was reduced by 38% with angiotensin II present in the perfusate. Analysis of the data was complicated by the presence of a capacity-limited transport for renal tubular secretion. Transport parameters (+/- SD) were obtained and the corrected intrinsic secretory clearance [(Vmax/GFR)/Km] of chlorothiazide was 123 +/- 18 without angiotensin II vs. 72.8 +/- 30.0 with angiotensin II. These results demonstrate that alterations in organ perfusion can significantly reduce the clearance parameters of chlorothiazide in the rat IPK. These flow-induced changes in intrinsic secretory transport may reflect perturbations other than that of perfusion flow rate alone.
Angiotensin II↗
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↗
The effect of beta-adrenoceptor blockers on the absorption and excretion of chlorothiazide in man.
The effect of beta-adrenoceptor blockers on the absorption and elimination of the diuretic chlorothiazide was studied in healthy subjects. A week of pretreatment with either pindolol (10 mg twice daily) or propranolol (80 mg twice daily) resulted in significant reduction in 36 h mean cumulative urinary recovery of chlorothiazide in two groups of six subjects compared with a control (untreated) group. A week of pretreatment with atenolol (100 mg daily) did not significantly alter 36 h cumulative urinary excretion in another group of six subjects. None of the beta-blockers significantly changed chlorothiazide half-life. It is suggested that the non-selective (as opposed to the cardioselective) beta-blockers reduce chlorothiazide absorption by the mechanism(s) discussed.
Adrenergic beta-Antagonists↗
Gastrointestinal absorption of chlorothiazide: evaluation of a method using salicylazosulfapyridine and acetaminophen as the marker compounds for determination of the gastrointestinal transit time in the dog.
Gastrointestinal absorption properties of chlorothiazide was investigated in dogs by a double-marker method using acetaminophen and salicylazosulfapyridine as the markers. The mean absorption time of acetaminophen (MATAAP) and the time for first appearance of sulfapyridine in plasma (TFASP) were used for the assessment of gastric emptying and oro-colonic transit times, respectively. Chlorothiazide absorption efficiency was increased by pretreatment with atropine sulfate. There was a good correlation between MATAAP and the extent of bioavailability of chlorothiazide, however, there was no correlation between TFASP and the extent of bioavailability of the drug. These results indicate that chlorothiazide absorption takes place primarily in a limited segment of the upper small intestine, supporting the assumption reported previously. This double-marker method seems to be a useful tool for the investigation of the relationship between drug absorption and its gastrointestinal transit.
Acetaminophen↗
Effects of chlorothiazide, furosemide and PTH on Na+ and Ca2+ handling in isolated perfused kidneys of the spontaneously hypertensive rat.
The role of the kidney in a disturbed calcium metabolism in spontaneously hypertensive rats (SHR) was investigated. The hemodynamics of isolated perfused SHR kidneys were not basically altered compared to Wistar-Kyoto (WKY) control kidneys. Renal calcium handling by isolated perfused WKY and SHR kidneys at 12 weeks of age was not significantly different. In addition, the effects of chlorothiazide and furosemide on renal calcium handling were studied in isolated perfused kidneys from both rat strains. Both diuretics increased glomerular filtration rate, diuresis and excretion of sodium and calcium. However, both diuretics stimulated diuresis and calcium excretion significantly less in SHR than in WKY kidneys. The calciuric action of chlorothiazide was completely abolished by administration of human-parathyroidhormone (hPTH), while the natriuric effect was unchanged by hPTH. This observation suggests that a hypocalciuric action of chlorothiazide 'in vivo' is possibly mediated by PTH. Our study suggests that the kidney is not responsible for the disturbance in calcium metabolism in SHR. A surprising finding is that the SHR kidney was less responsive to the diuretics furosemide and chlorothiazide than the kidney of the WKY control.
Animals↗