Diuretic; calcium-activated potassium (KCA) channel

One type of thiazide diuretic is hydrochlorothiazide. It works on the kidneys to lessen sodium (Na) reabsorption in the distal tubule, which lowers blood volume. By vying for chloride ion sites on the electrically neutral Na+-Cl cotransporter, the primary site of action in the nephron takes place. Hydrochlorothiazide can induce natriuresis with concurrent water loss by obstructing sodium ion transport in the distal convoluted tubules. At this point, thiazides improve calcium reabsorption without affecting sodium transport. Hydrochlorothiazide is also expected to lower peripheral vascular resistance through other methods [1].

In adult male Sprague Dawley mice, hydrochlorothiazide (HCTZ; oral; 12.5 mg/kg/d; 8 weeks) decreases the expression of AT1, TGF-β, and Smad2 in cardiac tissue, improves cardiac function, and decreases cardiac interstitial fibrosis and collagen volume fraction. Hydrochlorothiazide also lowers aldosterone and angiotensin II levels in the plasma. Furthermore, in newborn rat ventricular fibroblasts, hydrochlorothiazide can prevent the production of TGF-β1 and Smad2 proteins that are stimulated by angiotensin II [2].

Thiazide and thiazide-like diuretics are among the most commonly used antihypertensives and have been available for over 50 years. However, the mechanism by which these drugs chronically lower blood pressure is poorly understood. Possible mechanisms include direct endothelial- or vascular smooth muscle-mediated vasodilation and indirect compensation to acute decreases in cardiac output. In addition, thiazides are associated with adverse metabolic effects, particularly hyperglycemia, and the mechanistic underpinnings of these effects are also poorly understood. Thiazide-induced hypokalemia, as well as other theories to explain these metabolic disturbances, including increased visceral adiposity, hyperuricemia, decreased glucose metabolism and pancreatic beta-cell hyperpolarization, may play a role. Understanding genetic variants with differential responses to thiazides could reveal new mechanistic candidates for future research to provide a more complete understanding of the blood pressure and metabolic response to thiazide diuretics.[1]

Aims: Our previous study indicates that hydrochlorothiazide inhibits transforming growth factor (TGF)-β/Smad signaling pathway, improves cardiac function and reduces fibrosis. We determined whether these effects were common among the diuretics and whether angiotensin II receptor type 1 (AT1) signaling pathway played a role in these effects.[2]
Methods: Heart failure was produced by ligating the left anterior descending coronary artery in adult male Sprague Dawley rats. Two weeks after the ligation, 70 rats were randomly divided into five groups: sham-operated group, control group, valsartan group (80 mg/kg/d), hydrochlorothiazide group (12.5 mg/kg/d) and furosemide group (20 mg/kg/d). In addition, neonatal rat ventricular fibroblasts were treated with angiotensin II.[2]
Results: After eight-week drug treatment, hydrochlorothiazide group and valsartan group but not furosemide group had improved cardiac function (ejection fraction was 49.4±2.1%, 49.5±1.8% and 39.9±1.9%, respectively, compared with 40.1±2.2% in control group), reduced cardiac interstitial fibrosis and collagen volume fraction (9.7±1.2%, 10.0±1.3% and 14.1±0.8%, respectively, compared with 15.9±1.1% in control group), and decreased expression of AT1, TGF-β and Smad2 in the cardiac tissues. In addition, hydrochlorothiazide reduced plasma angiotensin II and aldosterone levels. Furthermore, hydrochlorothiazide inhibited angiotensin II-induced TGF-β1 and Smad2 protein expression in the neonatal rat ventricular fibroblasts.[2]
Conclusions: Our study indicates that the cardiac function and remodeling improvement after ischemic heart failure may not be common among the diuretics. Hydrochlorothiazide may reduce the left ventricular wall stress and angiotensin II signaling pathway to provide these beneficial effects.[2]

Absorption, Distribution and Excretion
The bioavailability of orally administered hydrochlorothiazide is 65-75%, with a time to peak concentration (Tmax) of 1-5 hours and a peak plasma concentration (Cmax) of 70-490 ng/mL (dose 12.5-100 mg). When taken with food, bioavailability decreases by 10%, Cmax decreases by 20%, and Tmax is prolonged from 1.6 hours to 2.9 hours. Hydrochlorothiazide is excreted unchanged in the urine. The volume of distribution varies considerably among studies, ranging from 0.83-4.19 L/kg. The renal clearance of hydrochlorothiazide in patients with normal renal function is 285 mL/min. In patients with a creatinine clearance of 31-80 mL/min, the mean renal clearance of hydroxychlorothiazide is 75 mL/min; in patients with a creatinine clearance ≤30 mL/min, the mean renal clearance of hydroxychlorothiazide is 17 mL/min. Hydrochlorothiazide is well absorbed from the gastrointestinal tract, with an oral bioavailability of approximately 65-75%. While there are reports of variations in absorption rate and extent among different formulations, no studies have established the clinical significance (if any) of these absorption differences in patients taking hydrochlorothiazide long-term. Following an oral dose of 12.5-100 mg hydrochlorothiazide, peak plasma concentrations of 70-490 ng/mL can be achieved within 1-5 hours. Food reduces the rate and extent of absorption of hydrochlorothiazide capsules (Microzide). When hydrochlorothiazide capsules (Microzide) are taken with food, the bioavailability and peak plasma concentration decrease by approximately 10% and 20%, respectively. The time to peak plasma concentration is delayed by 1.3 hours (from 1.6 hours to 2.9 hours). Absorption of hydrochlorothiazide is reduced in patients with heart failure. Approximately 40-68% of the drug is bound to plasma proteins. The pharmacokinetics of hydrochlorothiazide are linear. Based on plasma drug concentration measurements over at least 24 hours, the plasma half-life of hydrochlorothiazide has been reported to be 5.6–15 hours. Hydrochlorothiazide appears to be unmetabolized and excreted unchanged in the urine. At least 61% of the drug has been reported to be cleared from the body within 24 hours. Increased plasma concentrations and prolonged elimination half-life of hydrochlorothiazide have been reported in patients with renal insufficiency. The effect of hemodialysis on drug clearance has not been determined. Thiazides can cross the placental barrier and are present in umbilical cord blood. Thiazides can be secreted into breast milk. (14)C-hydrochlorothiazide (hct) was administered orally (n=4) and intravenously (n=2) to healthy subjects. Gastrointestinal absorption was between 60% and 80%, with the majority occurring in the duodenum and upper jejunum. Radioactivity was primarily excreted in the urine, with no significant bile excretion observed. Urine radiochromatographic analysis indicated that over 95% of the absorbed or injected (14)C-hct was excreted unchanged. Plasma radioactivity showed a rapid decline in the first 10 hours after oral administration, but thereafter the radioactivity level indicated a slow decline. This phase was confirmed in one subject who received 75 mg of hydrochlorothiazide (HCT) orally. The concentration of HCT in plasma (determined by gas-liquid chromatography) conformed to a two-compartment model, with half-lives of 1.7 hours for the α phase and 13.1 hours for the β phase. HCT accumulated in blood cells, with an average intracellular to plasma radioactivity ratio of 3.5. Metabolism of HCT in two hypertensive patients on long-term medication was similar to that in healthy subjects after a single dose of 14C-HCT. A third patient with slightly elevated serum creatinine had a slower rate of HCT clearance than other patients. As in healthy subjects, patients excreted more than 95% of hydrochlorothiazide unchanged. For more complete data on absorption, distribution, and excretion of hydrochlorothiazide (6 items), please visit the HSDB record page. Hydrochlorothiazide is not metabolized.
Hydrochlorothiazide is not metabolized.
Excretion route: Hydrochlorothiazide is not metabolized, but is rapidly excreted by the kidneys. Hydrochlorothiazide can cross the placental barrier but not the blood-brain barrier, and is secreted into breast milk.
Half-life: 5.6 and 14.8 hours
Biological half-life
The plasma half-life of hydrochlorothiazide is 5.6–14.8 hours.
Based on plasma drug concentration determination over at least 24 hours, the reported plasma half-life of hydrochlorothiazide ranges from 5.6 to 15 hours.
The bioavailability of 50 mg hydrochlorothiazide tablets orally in healthy male volunteers was studied under fasting and non-fasting conditions. The pharmacokinetics of hydrochlorothiazide in plasma can be described by a triple exponential function, with mean half-lives determined by the three exponents being 1.0, 2.2, and 9.0 hours, respectively. Following oral administration of hydrochlorothiazide (HCT), plasma radioactivity shows a rapid decline in the first 10 hours, but thereafter the labeled levels indicate a slow decline phase. This slow decline phase was confirmed in a subject who received 75 mg of HCT orally. The plasma HCT concentration in this subject (determined by gas-liquid chromatography) conformed to a two-compartment model, with half-lives of 1.7 and 13.1 hours for the α and β phases, respectively.

Toxicity Summary
Identification and Uses: Hydrochlorothiazide is a white or off-white crystalline, odorless powder. Hydrochlorothiazide tablets are indicated for the treatment of congestive heart failure, cirrhosis, and edema associated with corticosteroid and estrogen therapy. It can also be used to treat hypertension, either alone or to enhance the efficacy of other antihypertensive drugs in severe hypertension. Additionally, hydrochlorothiazide tablets can be used to treat edema caused by various renal disorders, such as nephrotic syndrome, acute glomerulonephritis, and chronic renal failure. Human Studies: Clinical toxicity is relatively rare and may be caused by overdose, adverse reactions, or accidental hypersensitivity reactions. It may cause electrolyte disturbances, leading to arrhythmias and orthostatic hypotension, as well as metabolic disorders such as hyperglycemia and hyperuricemia. Furthermore, it may exacerbate hepatic and renal insufficiency, cause allergic reactions, hematologic disorders, acute non-cardiac pulmonary edema, and gastrointestinal irritation and central nervous system symptoms. Generally, diuretic exposure is not associated with teratogenicity. Some studies suggest a slight association with respiratory malformations. Other risks include fetal or neonatal jaundice and thrombocytopenia. Eight patients developed severe edema two weeks after abrupt discontinuation of hydrochlorothiazide. A positive incidence of squamous cell carcinoma of the skin and lips was observed in patients. Animal studies: Existing animal toxicity information comes from studies conducted by the U.S. National Toxicology Program. No teratogenic, embryotoxic, or fetal toxic effects were observed in rats. Toxicology and carcinogenicity studies were conducted by feeding male and female rats and mice with a diet containing hydrochlorothiazide. An increased incidence of hepatocellular tumors was observed in male mice in the high-dose group. Increased renal injury-related or secondary lesions were observed in rats in the administration group, including parathyroid hyperplasia, fibrous osteodystrophy, and multi-organ mineralization. Hydrochlorothiazide induced gene mutations in mouse lymphoma cells and sister chromatid exchange in Chinese hamster cells. In vitro experiments showed that hydrochlorothiazide did not induce chromosomal aberrations in Chinese hamster cells or sex-linked recessive lethal mutations in Drosophila. Hydrochlorothiazide induced mitotic recombination and nondisjunction in Aspergillus. It is not mutagenic against Salmonella Typhimurium or Escherichia coli. Hydrochlorothiazide is a thiazide diuretic that inhibits water reabsorption in nephrons by inhibiting the sodium-chloride cotransporter (SLC12A3) in the distal convoluted tubule. This protein is responsible for 5% of total sodium reabsorption. Normally, the sodium-chloride cotransporter transports sodium and chloride from the lumen into the epithelial cells of the distal convoluted tubule. The energy required for this process comes from the sodium ion gradient established by sodium-potassium ATPase on the basolateral membrane. After sodium ions enter the cell, they are transported to the basolateral interstitium by sodium-potassium ATPase, leading to an increase in interstitial osmotic pressure, thereby establishing an osmotic gradient for water reabsorption. Hydrochlorothiazide effectively reduces the osmotic gradient and water reabsorption in nephrons by blocking the sodium-chloride cotransporter.

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Effects during pregnancy and lactation
◉ Overview of use during lactation
A daily dose of 50 mg or less of hydrochlorothiazide is acceptable during lactation. High doses may cause a strong diuretic effect, thereby reducing breast milk production.
◉ Effects on breastfed infants
A 28-day-old infant, breastfed since birth, had no observed electrolyte abnormalities when the mother took 50 mg of hydrochlorothiazide orally daily.
◉ Effects on lactation and breast milk
Hydrochlorothiazide has been successfully used to suppress lactation at different postpartum periods, at doses of 100 mg in the morning and 50 mg in the afternoon, or 50 mg twice daily. Thiazides and similar diuretics, along with fluid restriction and chest binding, have been used to suppress postpartum lactation. The additional effects of diuretics on these effective lactation suppression measures have not been studied. There are currently no data on the effects of diuretics on established, sustained lactation.
Protein binding
Hydrochlorothiazide has a protein binding rate of 40-68% in plasma.
Hydrochlorothiazide has been shown to bind to human serum albumin.

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Toxicity Data
The oral LD50 of hydrochlorothiazide in mice and rats is greater than 10 g/kg.Interactions
Table: Potential Drug Interactions of Hydrochlorothiazide Tablets [Table #4429]Non-human Toxicity Values
Rabbit intravenous LD50: 461 mg/kg
Dog intravenous LD50: 250 mg/kg
Mouse subcutaneous LD50: 1470 mg/kg
Mouse intraperitoneal LD50: 578 mg/kg
For more complete data on the non-human toxicity values of hydrochlorothiazide (out of 11), please visit the HSDB record page.

[1]. Duarte, J.D. and R.M. Cooper-DeHoff, Mechanisms for blood pressure lowering and metabolic effects of thiazide and thiazide-like diuretics. Expert Rev Cardiovasc Ther, 2010. 8(6): p. 793-802.

[2]. Hydrochlorothiazide modulates ischemic heart failure-induced cardiac remodeling via inhibiting angiotensin II type 1 receptor pathway in rats. Cardiovasc Ther. 2017 Apr;35(2).

[3]. Inhibition of Co-Crystallization of Olmesartan Medoxomil and Hydrochlorothiazide for Enhanced Dissolution Rate in Their Fixed Dose Combination. AAPS PharmSciTech. 2018 Dec 17;20(1):3.

Crystals or white powder. (NTP, 1992)
Hydrochlorothiazide is a benzothiadiazine compound with the chemical name 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide, substituted with a chlorine atom at position 6 and a sulfonamide group at position 7. It is a diuretic used to treat hypertension and congestive heart failure. It is both an exogenous substance and an environmental pollutant, possessing both diuretic and antihypertensive effects. It is a benzothiadiazine compound, a sulfonamide compound, and an organochlorine compound.
Hydrochlorothiazide is the most commonly used thiazide diuretic. It is indicated for the treatment of edema and hypertension. While widely used, its use is declining with the rise of angiotensin-converting enzyme inhibitors (ACEIs). Many combination preparations contain hydrochlorothiazide and ACEIs or angiotensin II receptor blockers. Hydrochlorothiazide was approved by the U.S. Food and Drug Administration (FDA) on February 12, 1959. Hydrochlorothiazide is a thiazide diuretic. Its physiological action is achieved by increasing diuresis. Hydrochlorothiazide is a short-acting thiazide diuretic. Hydrochlorothiazide (HCTZ) is widely used to treat hypertension and edema. The drug's metabolites appear to preferentially bind to and accumulate within red blood cells. The drug is primarily excreted through the kidneys. Thiazide diuretics are generally considered typical representatives of this class of drugs. They reduce the reabsorption of electrolytes by the renal tubules, thereby increasing the excretion of water and electrolytes, including sodium, potassium, chloride, and magnesium. It has been used to treat a variety of conditions, including edema, hypertension, diabetes insipidus, and hypoparathyroidism. Thiazide diuretics are often considered typical representatives of this class of drugs. They reduce the reabsorption of electrolytes by the renal tubules, thereby increasing the excretion of water and electrolytes, including sodium, potassium, chloride, and magnesium. It has been used to treat a variety of conditions, including edema, hypertension, diabetes insipidus, and hypoparathyroidism. See also: hydrochlorothiazide; triamterene (component); hydralazine hydrochloride; hydrochlorothiazide (component); hydrochlorothiazide; methyldopa (component)... See more...

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Drug Indications
Hydrochlorothiazide can be used alone or in combination to treat congestive heart failure, cirrhosis, nephrotic syndrome, acute glomerulonephritis, chronic renal failure, and edema caused by corticosteroid and estrogen therapy. Hydrochlorothiazide can also be used alone or in combination to treat hypertension.

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Mechanism of Action
Hydrochlorothiazide is transported from the bloodstream to the distal convoluted tubule epithelial cells via organic anion transporters OAT1, OAT3, and OAT4. Then, hydrochlorothiazide is transported from these cells to the renal tubular lumen via multidrug resistance-associated protein 4 (MRP4). Under normal circumstances, sodium ions are reabsorbed by the distal convoluted tubule epithelial cells and pumped into the basolateral interstitium by sodium-potassium ATPase, thereby creating a concentration gradient between the epithelial cells and the distal convoluted tubule, promoting water reabsorption. Hydrochlorothiazide acts on the proximal end of the distal convoluted tubule, inhibiting the reabsorption of sodium chloride cotransporter (also known as solute carrier family 12 member 3, SLC12A3). Inhibition of SLC12A3 reduces the concentration gradient between epithelial cells and the distal convoluted tubule, thereby reducing water reabsorption.

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Therapeutic Uses
Antihypertensive; Diuretic; Sodium chloride cotransporter inhibitor
/Clinical Trials/ ClinicalTrials.gov is a registry and results database that catalogs human clinical studies funded by public and private institutions worldwide. This website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov contains summary information about the study protocol, including: disease or condition; intervention (e.g., the medical product, behavior, or procedure being studied); study title, description, and design; participation requirements (eligibility criteria); study location; contact information for the study location; and links to relevant information from other health websites, such as NLM's MedlinePlus (which provides patient health information) and PubMed (which provides citations and abstracts of academic articles in the medical field). Hydrochlorothiazide is listed in the database.
Hydrochlorothiazide tablets (USP) are indicated for the treatment of congestive heart failure, cirrhosis, and edema associated with corticosteroid and estrogen therapy. /Listed under US Product Label/
Hydrochlorothiazide tablets (USP) have also been found to be used to treat edema caused by various renal disorders, such as nephrotic syndrome, acute glomerulonephritis, and chronic renal failure. /Included under US Product Label/
For more complete data on the therapeutic uses of hydrochlorothiazide (7 types), please visit the HSDB record page.

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Drug Warnings
Hydrochlorothiazide has similar pharmacological effects, uses, and toxicities to thiazide antibiotics. The usual precautions for using thiazide antibiotics should be followed.
Some commercially available hydrochlorothiazide preparations contain sulfites, which may cause allergic reactions in certain susceptible individuals, including anaphylactic shock and life-threatening or mild asthma attacks. The overall prevalence of sulfite allergy in the general population is unknown but is likely low; this allergy appears to be more common in asthmatic patients than in non-asthmatic patients.
The following lists reported adverse reactions, arranged in descending order of severity within each category. …When moderate or severe adverse reactions occur, the dose of the thiazide antibiotic should be reduced or treatment should be discontinued.
Table: Adverse Reactions to Hydrochlorothiazide Tablets [Table #4432]

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Pharmacodynamics
Hydrochlorothiazide inhibits the reabsorption of sodium and water in the distal convoluted tubule, thereby increasing the excretion of water in the urine. Hydrochlorothiazide has a wide therapeutic window, and the dosage needs to be adjusted individually, ranging from 25 to 100 mg. Patients with impaired renal or hepatic function should use hydrochlorothiazide with caution.

C7H8CLN3O4S2

297.7391

296.964

C, 28.24; H, 2.71; Cl, 11.91; N, 14.11; O, 21.49; S, 21.54

58-93-5

Hydrochlorothiazid-d2;1219798-89-6;Hydrochlorothiazid-13C,d2;1190006-03-1;Hydrochlorothiazide-13C6;1261396-79-5； 58-93-5; 58-94-5

3639

White, or practically white crystalline powder
White to off-white crystalline powder

1.7±0.1 g/cm3

577.0±60.0 °C at 760 mmHg

273 °C

302.7±32.9 °C

0.0±1.6 mmHg at 25°C

1.632

-0.07

3

7

1

17

494

0

ClC1C([H])=C2C(=C([H])C=1S(N([H])[H])(=O)=O)S(N([H])C([H])([H])N2[H])(=O)=O

JZUFKLXOESDKRF-UHFFFAOYSA-N

InChI=1S/C7H8ClN3O4S2/c8-4-1-5-7(2-6(4)16(9,12)13)17(14,15)11-3-10-5/h1-2,10-11H,3H2,(H2,9,12,13)

6-chloro-1,1-dioxo-3,4-dihydro-2H-1lambda6,2,4-benzothiadiazine-7-sulfonamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product is not stable in solution, please use freshly prepared working solution for optimal results.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~50 mg/mL (~167.93 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (8.40 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (8.40 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (8.40 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)