Administration Of Hydrochlorothiazide Research Articles

Response of Thiazide-lnduced Hypokalemia to Amiloride

The effects of amiloride hydrochloride on thiazide-induced hypokalemia were evaluated. In metabolic balance studies, amiloride reversed thiazide-induced urinary potassium loss, restored plasma bicarbonate concentration and pH to pretreatment levels, and produced further increases in aldosterone secretion. Effects of long-term administration of hydrochlorothiazide and an amiloride-hydrochlorothiazide combination were compared in outpatients who had experienced thiazide-induced hypokalemia while receiving oral potassium supplements. After eight weeks, those given hydrochlorothiazide alone had an average serum potassium level of 3.01 +/- 0.08 mEq/L). Those given the amiloride-hydrochlorothiazide combination had an average serum potassium level of 3.75 +/- 0.008 mEq/L, not significantly different from the control value (3.82 +/- 0.08 mEq/L). Both groups had increased plasma aldosterone concentrations and plasma renin activity. The potassium-conserving effect of amiloride persisted with extended therapy.

The antidiuretic effect of chronic hydrochlorothiazide treatment in rats with diabetes insipidus: water and electrolyte balance.

1. The antidiuretic effect of hydrochlorothiazide in diabetes insipidus was investigated in rats with the hereditary hypothalamic form of the disease (Brattleboro rats). 2. Administration of hydrochlorothiazide in the food resulted in a marked fall in urine volume and a corresponding rise in osmolality. These effects persisted throughout the period of treatment (6-7 days). 3. Body weight and extracellular volume were significantly reduced in the thiazide-treated rats. 4. Hydrochlorothiazide caused an increase in urinary sodium excretion only on the first day of treatment. The resulting small negative sodium balance (in comparison with untreated rats) remained statistically significant for 2 days only. Thiazide-treated rats gradually developed a potassium deficit which was statistically significant from the fourth day of treatment. 5. Total exchangeable sodium, measured after 7 days of thiazide treatment, was not significantly different from that of untreated rats. However, plasma sodium was reduced in thiazide-treated animals, whereas erythrocyte sodium concentration was elevated. 6. It is concluded that the antidiuresis resulting from chronic hydrochlorothiazide administration is associated with a reduction in extracellular volume, but not with a significant overall sodium deficit. Hydrochlorothiazide appears to cause a redistribution of the body's sodium such that the amount of sodium in the extracellular fluid compartment is reduced.

The antidiuretic effect of chronic hydrochlorothiazide treatment in rats with diabetes insipidus: renal mechanisms.

1. Brattleboro rats with hereditary diabetes insipidus were maintained in metabolism cages for 12–14 days. During the final 5–7 days hydrochlorothiazide was added to the food of half the animals, resulting in a sustained antidiuresis. At the end of this time all rats were anaesthetized and their renal function was investigated. 2. Water, sodium and potassium excretion rates during anaesthesia were similar to their respective values during the final period in metabolism cages. 3. Total glomerular filtration rate and superficial nephron filtration rate were similar in untreated and thiazide-treated animals. Fractional fluid reabsorption in proximal convoluted tubules, as measured by tubular fluid/plasma inulin concentration ratios in late surface convolutions, was moderately increased in the thiazide-treated rats, and was associated with a small reduction in the volume of fluid delivered to more distal nephron segments. 4. The osmolality of renal papillary interstitial fluid from thiazide-treated rats was considerably greater than that from untreated animals. There was also a small increase in papillary fluid sodium concentration. 5. It is concluded that the mechanism of the sustained antidiuresis during chronic hydrochlorothiazide administration in diabetes insipidus differs from that of the acute response. The changes in proximal tubular function during chronic thiazide treatment only partially account for the reduction in urine volume; it seems probable that the raised papillary osmolality, by enhancing water reabsorption at sites beyond the proximal tubule, makes a greater contribution to the antidiuresis.

Riboflavin Analogues: A Novel Class of Antihypertensive Drugs

1. Riboflavin analogues were tested in three hypertensive rat models: the DOCA-salt hypertensive rat, spontaneously hypertensive rats (SHR) and Dahl S rats. 2. When 1.6 mg of 7,8-dimethyl-10-formyl-methylisoalloxazine (FMI) or 7,8-dimethyl-10-(2′-hydroxyethyl)isoalloxazine (HEI) was administered with 3.0 mg of DOCA twice weekly for 9 weeks, the systolic blood pressure (SBP) of the unanaesthetized rats rose to only 136 ± 5 mmHg compared with 165 ± 5 mmHg during DOCA treatment alone. The analogues blunted the retention of iliopsoas muscle Na+ and water due to DOCA. 3. In subsequent studies, the more potent riboflavin analogue 7,8-dimethyl-10-(3-chlorobenzyl)isoalloxazine (CBI) was employed. Administration of 0.5 mg of CBI/100 g body wt. twice weekly for 7 weeks lowered the SBP of the unanaesthetized SHR from 188 ± 7 mmHg to 148 ± 2 mmHg. The rats tolerated the medication well. CBI was more effective than hydrochlorothiazide, which at 2.2 mg/100 g body wt. daily only lowered the SBP to 167 ± 5 mmHg. The combined administration of CBI and hydrochlorothiazide produced an additive effect in that the SBP was reduced to 126 ± 4 mmHg. 4. CBI treatment resulted in a 36% and 11% decrease in the iliopsoas muscle Na+ concentration and water content respectively, suggesting that the untreated SHR is retaining Na+. The hydrochlorothiazide-treated SHR exhibited elevated levels of serum aldosterone. There was a profound suppressive effect of CBI on the secondary hyperaldosteronism generated by hydrochlorothiazide which was also reflected in the iliopsoas muscle K+ concentration. 5. In contrast to the SHR, the administration to the Dahl S rats of CBI for 8 weeks at 0.5 mg/100 g body wt. twice weekly reduced neither their SBP nor their iliopsoas muscle Na+ and water contents. 6. These results are consistent with our hypothesis that the antihypertensive actions of the riboflavin analogues are closely associated with their ability to modify the effects of mineralocorticoids on Na+ balance. These data suggest that riboflavin analogues also decrease aldosterone production and may function as dual-mechanism diuretic agents with K+ sparing properties and thus act as a novel class of antihypertensive drugs.

Plasma active and inactive renin and urinary kallikrein in normal subjects in response to hydrochlorothiazide, spironolactone or aldosterone administration.

The aim of this study has been to see whether acute variations in the proportions of circulating active and inactive renin in normal subjects were related to concurrent changes in the excretion of urinary kallikrein. Hydrochlorothiazide (50 mg/day) was given to 6 normal volunteers for 6 days; another group of 6 normal subjects received spironolactone (300 mg/day) for 6 days whereas synthetic aldosterone (0.5 mg/day) was administered i.m. for three days to 3 normal subjects. Both diuretics induced a sharp rise in active and total renin and a significant transient decrease in inactive renin so that the active: total renin proportion significantly increased. Urinary kallikrein excretion did not significantly change in either group. Parenteral administration of aldosterone induced a striking fall in all renin components without changing the proportions of active and inactive renin whereas urinary kallikrein excretion increased. These results indicate that changes in active: total renin proportions can occur without parallel variations in urinary kallikrein excretion. The latter cannot be used, therefore, as a reliable index of the possible role of renal kallikrein as activator in-vivo of inactive renin in man.

Prevention of calcium nephrolithiasis with low-dose thiazide, amiloride and allopurinol

We report 5 years' experience with low-dose hydrochlorothiazide, 50 mg/day and amiloride, 5 mg/day, in 519 patients with recurrent calcium nephrolithiasis. Additional treatment with allopurinol, 100 mg/day, was prescribed for approximately 50 percent of the patients. All patients had active stone formation, having 3,464 stones in 3,126 patient-years (6.67 stones per patient, 1.10 stones per year). Hypercalciuria was present in 65 percent of the patients and hyperuricosuria in 24 percent. The administration of low-dose hydrochlorothiazide was effective in reducing urinary calcium excretion in most patients. It is possible that the hypocalciuric effect of hydrochlorothiazide were enhanced by amiloride, an agent which has been shown to cause hypocalciuria when given alone. Significant side effects requiring discontinuation of the drug were observed in only 5 percent of the patients. During 872.8 patient-years of treatment, only 53 new stones were formed (0.10 stones per patient, 0.06 stones per year) in contrast with the 916 predicted ones. The difference (chi-square) is statistically significant (p < 0.001). These results show that the administration of low-dose hydrochlorothiazide and amiloride, either alone or in association with allopurinol, is clinically effective in reducing the rate of recurrence of calcium nephrolithiasis.

Thiazide-induced hyponatremia associated with death or neurologic damage in outpatients

Seven elderly patients were encountered who had been taking thiazides or thiazide-like diuretics (hydrochlorothiazide, polythiazide or metolazone) for less than 16 days and who presented with severe symptomatic hyponatremia (serum sodium = 105 ± 6 meq/liter). In five patients, urine sodium + potassium was 156 meq/liter whereas that in serum was 108 meq/liter (P < 0.01). All patients had central nervous manifestations of hyponatremia (seizures, stupor, coma, extensor plantar response) and all but one were treated with 3 percent sodium chloride to raise the serum sodium level above 130 meq/liter within 44 hours. Three patients died, two had permanent paralysis, and two recovered. Other causes of the neurologic dysfunction were ruled out by negative lumbar punctures, brain scan and computerized axial tomography (CAT) scan. In all, serum creatinine was below 1.1 mg/dl. The patients who recovered were studied. In two patients, the administration of oral metolazone (10 mg/day for two days) or hydrochlorothiazide (100 mg/day for two days) with ad libitum water intake resulted in decrements in serum sodium of 13 to 18 meq/liter in 36 hours. In both, serum sodium levels fell below 125 meq/liter with resultant symptoms. In one patient, the response to a standard oral water loading test was studied before and after 10 mg of metolazone administration. After metolazone therapy, the percent excretion of a standard oral water load in 4 hours fell from 65 percent to 15 percent, minimal urine osmolality, which had been 130 to 371 mosmol/kg, increased to 371 mosmol/kg, free water clearance fell from 2.25 to −0.25 ml/min and urine sodium excretion increased from 62 to 159 μeq/min. Plasma antidiuretic hormone (ADH) levels were undetectable before and after the administration of metolazone but rose after overnight dehydration. Thus, metolazone resulted in impaired ability to dilute the urine and excrete a water load, with 256 percent increase in urine sodium loss. Therefore, in a susceptible subgroup of outpatients, thiazides may rapidly induce severe hyponatremia with permanent neurologic damage or death.

Endocrine profile in the long-term phase of converting-enzyme inhibition.

Captopril is a potent antihypertensive whose mechanism of action may involve changes in several vasoactive hormonal systems (renin-angiotensin, kallikrein-kinin, prostaglandin). Since these potential mediators of the captopril hypotensive effect may vary with duration of therapy, we studied the changes in these vasoactive systems during the short- and long-term phases of captropril treatment in 31 patients with essential hypertension, most of whom were treated for over 9 mo. We related the captopril blood pressure-lowering effect to changes in these systems, and also determined whether sodium restriction and diuretic therapy had any modifying effect. During short-term administration of captopril in the sodium-restricted state, supine diastolic blood pressure (SDBP) fell 18 ± 2 mm Hg (p < 0.01), and was associated with decrements in angiotensin II (A II) (−9 ± 3 pg/ml) and increments in plasma kinins (1.0 ± 0.2 ng/ml) (p < 0.05). During long-term administration of captopril and hydrochlorothiazide (HCTZ), the fall in blood pressure (−23 ± 2 mm Hg, p < 0.01) was sustained for at least 9 mo of therapy. Combined capotopril and HCTZ therapy results in a greater reduction in SDBP (−23 ± 2 mm Hg) than with captopril alone (−11 ± 2 mm Hg) (p < 0.01). In contrast to the immediate hormonal changes, during long-term therapy plasma A II levels were slightly higher than control (11 ± 3 pg/ml) presumably because of a reactive increase in plasma renin activity, and plasma kinins continued to rise (2.6 ± 1.0 ng/ml, p < 0.01), while prostaglandin E2 metabolites were also elevated (20 ± 8 pg/ml, p = 0.0083). Captopril is therefore a potent antihypertensive agent when used in combination with sodium restriction or a diuretic. During the short-term phase of administration, the fall in blood pressure is associated with reduction in A II generation and an increase in kinin levels. In the long-term phase, however, A II seems to play a smaller role, if any, while kinins and potentially prostaglandins assume a more prominent role in mediating the captopril hypotensive effect. Clinical Pharmacology and Therapeutics (1980) 28, 499–508; doi:10.1038/clpt.1980.194

A micropuncture study of proximal tubular function after acute hydrochlorothiazide administration to Brattleboro rats with diabetes insipidus.

1. Renal function in anaesthetized Brattleboro rats with hereditary hypothalamic diabetes insipidus was studied with micropuncture techniques before, and 1–3 h after, a single injection of hydrochlorothiazide. 2. In rats given hydrochlorothiazide and kept in sodium and water balance, total glomerular filtration rate and superficial nephron filtration rate were similar to values in control animals, whereas fractional fluid reabsorption in the proximal tubule (as evidenced by tubular fluid/plasma inulin concentration ratios) was slightly, but significantly, reduced. This suggests that hydrochlorothiazide may have a small direct inhibitory effect on proximal tubular reabsorption. 3. When rats were given hydrochlorothiazide and the resultant extra urinary sodium losses were not replaced, there was a marked antidiuresis. In these animals total glomerular filtration rate was reduced by 23% and superficial nephron filtration rate by 27% when compared with values in control rats. Fractional proximal tubular fluid reabsorption increased significantly whereas absolute proximal fluid reabsorption was unaffected. 4. It is concluded that the reduction in body sodium which follows acute hydrochlorothiazide administration over-rides any inhibitory effect of the drug on proximal tubular reabsorption, and leads instead to an increase in fractional fluid reabsorption at this site. This effect, combined with the fall in glomerular filtration rate, results in a greatly reduced delivery of fluid to the more distal nephron segments, and is probably largely responsible for the observed antidiuresis.

Estimating compliance with diuretic therapy: urinary hydrochlorothiazide-creatinine ratios in normal subjects.

We gave 21 healthy young men 100 mg of hydrochlorothiazide daily to determine whether or not urinary detection of the drug was feasible as a measure of compliance on a standard antihypertensive regimen. All subjects took the drug daily for 6 days, after which they were divided into four groups with differing patterns of medication administration. Urine hydrochlorothiazide and creatinine measurements were obtained to validate the urinary hydrochlorothiazide-creatinine ratio (UHCR) as an accurate quantitative index of compliance. The subjects achieved a constant level of UHCR of 13 +/- 3.0 within 48 hours of hydrochlorothiazide administration. The UHCR levels decreased to 5.0 +/- 0.8 48 hours after discontinuation of the drug (p less than 0.001). UHCR values in the range of 13 +/- 6 indicate that the subject has ingested hydrochlorothiazide 24 hours previously. The UHCR is a potentially useful means of assessing compliance in hypertensive patients taking hydrochlorothiazide.

Site of renal action of xipamide

Xipamide, hydrochlorothiazide, and furosemide were given to normal volunteers on a double-blind basis. During maximal water diuresis, there was a reduction in free water clearance and an increase in osmolar clearance after administration of xipamide and hydrochlorothiazide, but not in the case of furosemide. During maximal hydropenia, both xipamide and hydrochlorothiazide increased free water reabosorption in a linear relationship to osmolar clearance, while furosemide increased osmolar clearance with little change in free water reabsorption. It was concluded, therefore, that, as with hydrochlorothiazide, the site of action of xipamide was on the distal convoluted tubule, and that of furosemide on the loop of Henle.

Long-Term Efficacy of Captopril (SQ 14,225) In 2-Kidney Renal Hypertensive Rats

The effects of daily captopril therapy (30 mg/kg p.o.) given for one year on systolic blood pressure, heart rate and survival of 2-kidney renal hypertensive rats (2K-RHR) were examined. Captopril caused significant and sustained reductions in systolic blood pressure of 2K-RHR throughout the 1-year period with no important changes in heart rate. Simultaneous administration of the diuretic hydrochlorothiazide (HCTZ) enhanced the antihypertensive effect of captopril but did not normalize blood pressure, this despite no effect on blood pressure by HCTZ given alone. On the other hand, co-administration of guanethidine with captopril normalized blood pressure. Survival rates of 2K-RHR were highest in the rats receiving captopril plus HCTZ, next highest in rats receiving captopril alone and lowest in rats receiving water or HCTZ. The results demonstrate the long-term efficacy of captopril and suggest a sympathetic component in the maintenance of chronic 2-kidney renal hypertension.

The role of sodium depletion in hydrochlorothiazide-induced antidiuresis in Brattleboro rats with diabetes insipidus.

1. The mechanism of the antidiuretic effect of hydrochlorothiazide in diabetes insipidus was studied in anaesthetized Brattleboro rats with the hereditary hypothalamic form of the disease. 2. The antidiuresis caused by acute administration of hydrochlorothiazide followed an increase in sodium excretion and was associated with a significant fall in the plasma sodium concentration. There were concomitant falls in effective renal plasma flow and glomerular filtration rate. 3. When sodium depletion was prevented by adjusting the infusion of sodium chloride, the falls in plasma sodium concentration, effective renal plasma flow and glomerular filtration rate were abolished. Under these circumstances there was an increase in urine volume, which suggests that hydrochlorothiazide may inhibit fractional fluid reabsorption in the proximal convoluted tubule. 4. The results indicate that the antidiuresis caused by hydrochlorothiazide in diabetes insipidus results, at least in part, from falls in effective renal plasma flow and glomerular filtration rate. These in turn seem to be entirely secondary to the drug-induced sodium depletion.

Antihypertensive Effect of Trichlormethiazide in Spontaneously Hypertensive Rats

Antihypertensive and diuretic effects of trichlormethiazide (TCM) were investigated in the spontaneously hypertensive rats (SHR). The antihypertensive effect of TCM in an acute experiment was observed in male SHR only at a dose over 10 mg/kg given intraperitoneally and not in female SHR and normotensive Kyoto Wistar rats. to a subacute experiment (6 weeks), TCM retarded the development of hypertension in the male SHR loaded with 1% saline solution at an oral dose over 1 mg kg−1 day−1 and such had a diuretic effect. Oral administration of TCM and hydrochlorothiazide (HCT) at 10 mg kg−1 day−1 retarded the development of hypertension in the saline loaded female SHR to the same degree, but the relationship between antihypertensive and diuretic effects of both compounds was obscure. Except for decreases of water contents in the thoracic artery and wet weights of hearts, the electrolyte, uric acid, catecholamine and 5-hydroxytryptamine contents in the serum or/and organs were not affected by either TCM or HCT. It is concluded that the antihypertensive effect of TCM and HCT can be observed in SHR with a saline-load, and that the effect may be due to diuretic actions in the male. The relationship was not apparent in female SHR.

Drug-induced hyponatraemia in psychogenic polydipsia

Two patients with psychogenic polydipsia developed hyponatraemia, one in association with administration of hydrochlorothiazide and the other with that of tolbutamide. It is suggested that the increased fluid intake in such patients may make them more susceptible to the development of hyponatraemia from thiazide or sulphonylurea compounds.

Effect of hydrochlorothiazide on phosphorus during treatment with diphosphonate.

The effects of probenecid and hydrochlorothiazide on renal handling of phosphorus during hyperphosphatemia induced by diphosphonate (ethane-1-hydroxy-1, 1-diphosphonate, EHDP) was studied. Measurements of calcium, phosphorus, and creatinine clearance were performed in 2 sessions on each of 3 consecutive days in 10 normal fasting volunteers during the morning hours from 8 A.M. to 12 noon. During 2 to 3 wk thereafter, each subject was treated with EHDP, 30 mg/kg/day. The second group of studies were performed in the same manner as the first except the EHDP administration was continued throughout. EHDP caused elevation of serum phosphorus in all cases. Probenecid did not affect urine phosphorus. Hydrochlorothiazide caused a transient phosphaturia of similar magnitude in the EHDP treated and untreated states. Creatinine clearance was not affected by any of the treatments and urine calcium was decreased by EHDP. It was concluded that hydrochlorothiazide inhibits tubular reabsorption of phosphorus but that it does not affect the mechanism whereby EHDP causes increased tubular reabsorption of phosphorus. Chronic administration of hydrochlorothiazide along with EHDP may inhibit hyperphosphatemia and may change the bone effects of EHDP.

Evaluation of antihypertensive agents in the stress-induced hypertensive rat

Hypertension was induced in male, albino, Sprague-Dawley rats by exposure to environmental stimuli consisting of motion, noxious sounds and flashing lights at intervals over a period of ten weeks. Systolic blood pressure levels exceeded 150 mm Hg by the end of this period and remained elevated for 20 weeks after cessation of exposure to these noxious stimuli. The stress-induced hypertensive rat was found to be a useful model for the screening of antihypertensive drugs. Decreases in systolic pressure occured following administration of guanethidine, catapres, chlorisondamine, hydralazine, hydrochlorothiazide, phentolamine, propranolol, or sotalol, s.c. to these hypertensive animals. This rat model of hypertension offers the advantages of longevity, stability and is acquired without drug administration or genetic management.

Hydrochlorothiazide-Induced Water Intoxication in Myxedema

HYPOTHYROIDISM is commonly associated with asymptomatic hyponatremia. Infrequently, patients with myxedema may develop severe hyponatremia and water intoxication. To our knowledge, water intoxication in myxedema following oral administration of hydrochlorothiazide has not been reported. We have seen such a patient who developed severe hyponatremia and water intoxication with mental confusion following oral administration of this drug. <h3>Report of a Case</h3> A 46-year-old man entered our hospital with a four-week history of upper respiratory tract infection, followed by hoarseness, facial swelling, puffy eyelids, swollen hands and legs, and exertional dyspnea. The patient was oriented and markedly obese. Blood pressure was 160/100 mm Hg; pulse, 76 beats per minute; temperature, 37.2 C (99 F); weight, 127.7 kg (281 lb); height, 183 cm (6 ft). The face and periorbital areas were puffy. The thyroid gland was not palpable. The heart was enlarged. The skin was cool and dry; mild pitting ankle edema was

Changes in renal urate handling after prolonged thiazide treatment

The effect of prolonged thiazide diuretic administration on renal urate handling was examined in 10 normal men, before and after 2 weeks of oral hydrochlorothiazide administration. Whereas urate excretion per unit of glomerular filtration rate (GFR) usually remained unchanged, urate clearance (C urate:GFR) decreased slightly but significantly after the administration of hydrochlorothiazide because of increased plasma urate concentrations in some subjects. To assess the relative importance of intact tubular secretion of urate in producing this response, each participant was given pyrazinamide (PZA), an agent that inhibits urate secretion. The decrement in urate excretion: GFR produced by PZA (PZA-suppressible urate excretion) did not change after the administration of hydrochlorothiazide, but the decrement in C urate: GFR (PZA-suppressible urate clearance) decreased significantly. Residual urate excretion rates and clearance values after secretory inhibition by PZA remained unchanged after hydrochlorothiazide was given. These results suggest that the excretion of secreted urate was blunted after prolonged treatment with hydrochlorothiazide. Whether this resulted from an inhibition of tubular secretion or from increasingly avid reabsorption of urate at a postsecretory tubular site presently is unclear.

Prolonged administration of hydrochlorothiazide on cardiac function in beagle dogs.

ConclusionsChronic administration of hydrochlorothiazide (10 mg/kg, po for 12 months) to beagle dogs failed to produce any alterations in blood pressure and heart rate, despite a significant reduction in cardiac output, stroke volume, and stroke work. Analysis of ventricular function curves indicates a diminution in contractility of the myocardium in the treated animals. It is concluded from this investigation that the adverse effects of HCT on the myocardium in the face of increased total peripheral resistance noted in this study may warrant careful reevaluation of this agent in cardiovascular therapy.This study was supported by Public Health Service Grant GM-15587. The authors express their appreciation to Dr. John E. Baer of Merck Institute of Therapeutic Research, West Point, PA, for generously supplying hydrochlorothiazide, and to Messrs. Charles Parham and David Snyder for their valuable technical assistance.