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PubMed1979

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↗
PubMed1975

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↗
PubMed1989

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↗
PubMed1986

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↗
PubMed1982

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↗
PubMed1982

Effect of chlorothiazide on renal calcium and magnesium handling in the hamster.

Recollection micropuncture and clearance studies were performed on 21 thyroparathyroidectomized hamsters to characterize the effect of chlorothiazide on tubular sodium, calcium, and magnesium transport. Acute administration of chlorothiazide resulted in a marked natriuresis while urinary calcium excretion fell and magnesium remained unchanged. The fraction of sodium, calcium, and magnesium remaining at the late proximal tubule increased modestly from 65 +/- 4 to 75 +/- 3, 68 +/- 3 to 75 +/- 4, and 78 +/- 4 to 85 +/- 2%, respectively. Distal tubular fluid to ultrafilterable plasma (TF/UF) sodium concentration rose from 0.24 +/- 0.03 to 0.44 +/- 0.04 whereas distal TF/UFCa concentration fell from 0.58 +/- 0.05 to 0.38 +/- 0.06. The fraction of sodium remaining at the distal tubule rose from 4.0 +/- 1.4 to 10.0 +/- 1.4% while that of calcium decreased from 10.2 +/- 1.1 to 7.6 +/- 1.2% following administration of chlorothiazide. No change was observed in distal delivery of magnesium. Thus chlorothiazide acted in the distal tubule to decrease sodium reabsorption, enhance calcium transport, and had little effect on distal magnesium reabsorption. These data are consistent with the distal tubular action of chlorothiazide which is independent of parathyroid hormone.

Animals↗
PubMed1975

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↗
PubMed1983

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↗
PubMed1981

High-pressure liquid chromatographic determination of chlorothiazide and hydrochlorothiazide in plasma and urine: preliminary results of clinical studies.

High-pressure liquid chromatographic procedures were developed for the determination of chlorothiazide and hydrochlorothiazide in plasma and urine. The plasma assay incorporates a preextraction procedure that eliminates interference by endogenous substances. Chromatography is carried out on an octadecyl reversed-phase column. Mobile phases are 15% methanol in 0.01 M acetic acid for plasma and 4% acetonitrile in 0.01 M sodium perchlorate, adjusted to pH 4.6, for urine. At a flow rate of 2.5 ml/min, the retention times for chlorothiazide and hydrochlorothiazide are 3.5 and 4.6 min for plasma and 10.5 and 13.5 min for urine, respectively. Preliminary results of a clinical study in fasting male volunteers showed that the plasma levels and urinary excretion rate of chlorothiazide peaked at 1-2 hr following a 500-mg oral dose and subsequently declined irregularly. On the other hand, the plasma levels and urinary excretion rate of hydrochlorothiazide peaked at 2-3 hr following a 50-mg oral dose and subsequently declined in biphasic fashion. Urinary excretion rates of both chlorothiazide and hydrochlorothiazide closely resemble their concentration profiles in plasma.

Chlorothiazide↗
PubMed1981

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↗
PubMed1992

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↗
PubMed1976

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↗
PubMed1987

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↗
PubMed1981

Urinary zinc in relation to other cations and flow during volume expansion and intravenous chlorothiazide.

Urinary excretion of zinc, sodium, potassium, and calcium was studied in anesthetized dogs under conditions of volume expansion by saline infusion and volume expansion plus chlorothiazide administration. Zinc excretion was positively correlated to the fractional water excretion, as well as to th excretion of the other cations, during volume expansion. Chlorothiazide administration during volume expansion increased the zinc, sodium, and potassium excretion without changing that of calcium. The enhanced zinc excretion during chlorothiazide diuresis was equal to that expected on the basis of the increase in fractional water excretion alone. The urinary concentration of zinc appeared inversely related to the urine flow rate, reaching a minimum below that of the plasma ultrafilterable zinc concentration. The ratio of the clearance of zinc to that of sodium was 0.28, indicating a greater degree of net reabsorption for zinc than for calcium. These findings suggest that zinc and sodium reabsorption may be inhibited to a similar degree at chlorothiazide-sensitive sites in the tubule. Furthermore, the zinc reabsorptive mechanism seems capable of lowering urinary zinc concentration below that of ultrafiltrate and appears related in some way to sodium reabsorption.

Animals↗
PubMed1990

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↗
PubMed1987

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↗
PubMed1988

Renal transport kinetics of chlorothiazide in the isolated perfused rat kidney.

The effect of protein binding on the renal excretion of chlorothiazide was examined in the isolated perfused rat kidney. Drug studies were performed in three rats at 6.00% bovine serum albumin + 0% dextran and in three rats at 0.25% bovine serum albumin + 3.83% dextran. Chlorothiazide was introduced into the recirculating perfusate at an initial concentration of 100 micrograms/ml, and was assayed using high-performance liquid chromatography. Functional viability of the kidney was assessed by measuring the fractional excretion of sodium and glucose, and the glomerular filtration rate. The protein binding of drug in perfusate was determined by equilibrium dialysis. These experimental conditions resulted in an approximate 14-fold increase of percent free (from 5.3-72.0%), and a 3-fold increase of renal (from 1.03-3.30 ml/min) and secretion (from 1.01-2.83 ml/min) clearances. The data were best fitted by a model in which one Michaelis-Menten term was used to describe active transport, and secretion was dependent upon free concentrations of chlorothiazide in the perfusate. The maximum velocity of secretion (Vm = 85.6 micrograms/min) and Michaelis constant (Km = 2.1 micrograms/ml) of chlorothiazide was estimated using a nonlinear least-squares regression program. These results suggest that for compounds of low renal extraction, free drug concentrations are the driving force for carrier-mediated tubular secretion.

Animals↗
PubMed1980

The renin-aldosterone system in low-dose chlorothiazide treatment of hypertensive subjects.

Eight patients with essential hypertension were treated with chlorothizide 250 mg daily for 4 weeks with 500 mg daily for further 8 weeks. Both systolic and diastolic blood pressures (BP) decreased significantly during the lower dosage (p < 0.05). Only the diastolic BP continued decrease during the higher dosage regimen of chlorothiazide (p < 0.05). Plasma renin activity (PRA) and plasma aldosterone (PA) did not increase during the lower dosage of chlorothiazide. During 4 weeks on the dosage of 500 mg of chlorothiazide daily, PRA increased by 79 per cent (p < 0.001) and PA by 66 per cent (p < 0.001) from the level of the lower dosage. During the next 4 weeks, no changes in PRA or PA were seen. The result shows the strong compensatory activation renin-aldosterone system on the usual chlorothiazide therapy. In spite of a decrease in BP, the lower dosage was not accompanied with any significant compensation. Renin-aldosterone system during diuretic therapy not only causes the so-called false tolerance to antihypertensive effect, but also potentiates the loss of potassium. This can best be avoided by using the minimal effective dosage of the diuretic drug.

Adolescent↗