In hypoxic environments, fold is inhibited in a temporary equilibrium manner by benzothiazines (0.4, 2, 10 μM). Biological cellulase 9 (CA9) and benzothiazine have corresponding Ki values of 8.0, 8.8, and 10 nM for CA9, CA2, and CA1 [2].

Benthhiazide (1, 1.5 mg/100 g BW) produces a considerable reduction in urinary calcium excretion and a dissociation of calcium and sodium excretion due to hyperprolactinemia [1].

Absorption, Distribution and Excretion
Absorbed in the digestive tract.
DIURESIS OCCURS WITHIN 2 HR & LASTS 12-18 HR.
THIAZIDES ARE ABSORBED FROM GI TRACT & OWE THEIR USEFULNESS LARGELY TO THEIR EFFECTIVENESS BY ORAL ROUTE. ABSORPTION IS RELATIVELY RAPID. MOST AGENTS SHOW DEMONSTRABLE DIURETIC EFFECT WITHIN HR AFTER ORAL ADMIN. /THIAZIDE DIURETICS/
IN GENERAL, THIAZIDES WITH RELATIVELY LONG DURATIONS OF ACTION SHOW PROPORTIONATELY HIGH DEGREE OF BINDING TO PLASMA PROTEINS & ARE REABSORBED BY RENAL TUBULES. ... DRUG PASSES READILY THROUGH PLACENTAL BARRIER TO FETUS. ALL THIAZIDES PROBABLY UNDERGO ACTIVE SECRETION IN PROXIMAL TUBULE. /THIAZIDE DIURETICS/
DISTRIBUTED IN EXTRACELLULAR SPACE & /CROSSES/ PLACENTA /& APPEARS IN CORD BLOOD/. ONSET OF DIURETIC ACTION...2 HR...PEAK EFFECT...3 TO 6 HR...APPROX DURATION OF /ACTION OF SINGLE DOSE 12-18 HR/. EXCRETED BY GLOMERULAR FILTRATION & ACTIVE SECRETION IN PROXIMAL TUBULE /HUMAN, ORAL/.
ONSET OF HYPOTENSIVE ACTION...3 TO 4 DAYS, &...ACTION DISSIPATES...1ST WK AFTER DISCONTINUING CHRONIC THERAPY. /APPEARS/ IN MILK OF NURSING MOTHERS /HUMAN, ORAL/.

Toxicity Summary
As a diuretic, benzthiazide inhibits active chloride reabsorption at the early distal tubule via the Na-Cl cotransporter, resulting in an increase in the excretion of sodium, chloride, and water. Thiazides like benzthiazide also inhibit sodium ion transport across the renal tubular epithelium through binding to the thiazide sensitive sodium-chloride transporter. This results in an increase in potassium excretion via the sodium-potassium exchange mechanism. The antihypertensive mechanism of benzthiazide is less well understood although it may be mediated through its action on carbonic anhydrases in the smooth muscle or through its action on the large-conductance calcium-activated potassium (KCa) channel, also found in the smooth muscle.

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the amount of benzthiazide in breastmilk. Intense diuresis with large doses may decrease breastmilk production. Other diuretics in low doses are preferred over benzthiazide.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information on benzthiazide was not found as of the revision date. Intense diuresis with thiazides and thiazide-like diuretics, fluid restriction and breast binding have been used to suppress postpartum lactation. The added contribution of the diuretic to these measures, which are effective in suppressing lactation, has not been studied. There are no data on the effects of diuretics on established, ongoing lactation.

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Protein Binding
30%

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Interactions
MANY DIABETIC PATIENTS REGULATED BY CHLORPROPAMIDE OR OTHER SULFONYLUREAS EXHIBIT IMPAIRED DIABETIC CONTROL WHEN ANY THIAZIDE DIURETIC IS ADDED TO DRUG REGIMEN. /THIAZIDE DIURETICS/
CONCURRENT ADMIN OF THIAZIDE DIURETICS & MONOAMINE OXIDASE INHIBITORS MAY INCR HYPOTENSION. /THIAZIDE DIURETICS/
...HYPOKALEMIA MAY INTENSIFY ACTION OF NEUROMUSCULAR BLOCKING AGENTS. ... POTASSIUM-DEPLETING DIURETICS ARE KNOWN TO CAUSE HYPOKALEMIA & MAY ENHANCE THIS EFFECT. /DIURETICS/
...CARDIAC GLYCOSIDE & DIURETIC; DIURETIC-INDUCED HYPOKALEMIA POTENTIATES CARDIOTOXICITY OF GLYCOSIDE. /DIURETICS/
For more Interactions (Complete) data for BENZTHIAZIDE (21 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 MOUSE ORAL GREATER THAN 5000 MG/KG
LD50 RAT ORAL GREATER THAN 10000 MG/KG
LD50 DOG ORAL GREATER THAN 5000 MG/KG
RABBIT INTRAVENOUS 410 MG/KG
For more Non-Human Toxicity Values (Complete) data for BENZTHIAZIDE (6 total), please visit the HSDB record page.

[1]. Hypercalciuria in hyperprolactinemic rats: effects of benzthiazide. Metabolism. 1986 Jul;35(7):668-72.

[2]. Rational drug repositioning guided by an integrated pharmacological network of protein, disease and drug. BMC Syst Biol. 2012 Jul 2;6:80.

Therapeutic Uses
Diuretics, Thiazide
IT IS ABOUT 10 TIMES AS POTENT ON MG BASIS AS CHLOROTHIAZIDE.
THIAZIDE DRUGS...USUALLY FIRST DRUG TO BE EMPLOYED IN TREATMENT OF HYPERTENSION. SINCE THIAZIDES INDUCE ONLY LIMITED (10%) REDN IN BLOOD PRESSURE THEY ARE USEFUL EITHER IN MILD CASES OF HYPERTENSION OR AS ADJUNCTIVE THERAPY TO OTHER DRUGS. /THIAZIDE DIURETICS/
THIAZIDE DIURETICS ARE EFFECTIVE AS ADJUNCTIVE THERAPY IN EDEMA ASSOC WITH CONGESTIVE HEART FAILURE, HEPATIC CIRRHOSIS, & CORTICOSTEROID & ESTROGEN THERAPY, AS WELL AS EDEMA DUE TO VARIOUS FORMS OF RENAL DYSFUNCTION...& SEVERE EDEMA DUE TO PREGNANCY. /THIAZIDE DIURETICS/
For more Therapeutic Uses (Complete) data for BENZTHIAZIDE (8 total), please visit the HSDB record page.

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Drug Warnings
THEY SHOULD...BE USED WITH CAUTION IN PT WITH IMPAIRED LIVER FUNCTION. /THIAZIDE DIURETICS/
PERIODIC SERUM ELECTROLYTE DETERMINATION SHOULD BE DONE ON ALL PATIENTS IN ORDER TO DETECT ELECTROLYTE IMBALANCE SUCH AS HYPONATREMIA, HYPOCHLOREMIC ALKALOSIS, & HYPOKALEMIA. /THIAZIDE DIURETICS/
THIAZIDE DIURETICS ARE CONTRAINDICATED IN ANURIA, PATIENTS HYPERSENSITIVE TO THESE & OTHER SULFONAMIDE DRUGS, & IN OTHERWISE HEALTHY PREGNANT WOMEN WITH OR WITHOUT MILD EDEMA. ...SHOULD BE USED WITH CAUTION IN PT WITH RENAL DISEASE, SINCE THEY MAY PPT AZOTEMIA. /THIAZIDE DIURETICS/
CLINICAL TOXICITY...USUALLY RESULTS FROM UNEXPECTED HYPERSENSITIVITY. CASES OF...PURPURA, DERMATITIS WITH PHOTOSENSITIVITY, DEPRESSION OF FORMED ELEMENTS OF BLOOD, & NECROTIZING VASCULITIS HAVE BEEN REPORTED. /THIAZIDE DIURETICS/
For more Drug Warnings (Complete) data for BENZTHIAZIDE (8 total), please visit the HSDB record page.

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Pharmacodynamics
Benzthiazide is used to treat hypertension and edema. Like other thiazides, benzthiazide promotes water loss from the body (diuretics). They inhibit Na⁺/Cl^- reabsorption from the distal convoluted tubules in the kidneys. Thiazides also cause loss of potassium and an increase in serum uric acid. Thiazides are often used to treat hypertension, but their hypotensive effects are not necessarily due to their diuretic activity. Thiazides have been shown to prevent hypertension-related morbidity and mortality although the mechanism is not fully understood. Thiazides cause vasodilation by activating calcium-activated potassium channels (large conductance) in vascular smooth muscles and inhibiting various carbonic anhydrases in vascular tissue.

C15H14CLN3O4S3

431.9374

430.983

91-33-8

2343

White to off-white solid powder

1.4176 (rough estimate)

680.6 °C at 760 mmHg

231-232° (U.S. patent); mp 238-239° (P'an)

365.4 °C

1.6100 (estimate)

4.869

2

7

5

26

739

0

NDTSRXAMMQDVSW-UHFFFAOYSA-N

InChI=1S/C15H14ClN3O4S3/c16-11-6-12-14(7-13(11)25(17,20)21)26(22,23)19-15(18-12)9-24-8-10-4-2-1-3-5-10/h1-7H,8-9H2,(H,18,19)(H2,17,20,21)

3-(benzylsulfanylmethyl)-6-chloro-1,1-dioxo-4H-1λ6,2,4-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

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 (~115.76 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.82 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 20.8 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: ≥ 2.08 mg/mL (4.82 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 20.8 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.)