ヒドロクロロチアジド

-0.07

log Kow = -0.07

-0.07

White, or practically white crystalline powder

White to off-white crystalline powder

less than 0.1 mg/mL at 72.5 °F (NTP, 1992)

722

In water, 722 mg/L at 25 °C

Soluble in ethanol at approximately 750 g/L; soluble in acetone, dilute ammonia; freely soluble in sodium hydroxide solution, n-butylamine, dimethylformamide; sparingly soluble in alcohol; insoluble in ether, chloroform, dilute mineral acids

Soluble in sodium hydroxide solution

Freely soluble in sodium hydroxide solution, in n-butylamine and in dimethylformamide; sparingly soluble in methanol; insoluble in dilute mineral acids

523 to 527 °F (NTP, 1992)

266-268

273-275 °C

274 °C

Crystals or white powder. (NTP, 1992)

Solid

Stable under recommended storage conditions.

Commercially available hydrochlorothiazide tablets have an expiration date of 3 or 5 years following the date of manufacture depending on the packaging.

This chemical does not meet GHS hazard criteria for 1.5% (3 of 198) of reports.

Danger

H302 (63.1%): Harmful if swallowed [Warning Acute toxicity, oral]；H317 (33.3%): May cause an allergic skin reaction [Warning Sensitization, Skin]；H334 (33.3%): May cause allergy or asthma symptoms or breathing difficulties if inhaled [Danger Sensitization, respiratory]；H372 (28.3%): Causes damage to organs through prolonged or repeated exposure [Danger Specific target organ toxicity, repeated exposure]

P233, P260, P261, P264, P270, P271, P272, P280, P284, P301+P317, P302+P352, P304+P340, P319, P321, P330, P333+P317, P342+P316, P362+P364, P403, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 198 reports by companies from 32 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.；Reported as not meeting GHS hazard criteria per 3 of 198 reports by companies.；There are 31 notifications provided by 195 of 198 reports by companies with hazard statement code(s).；Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. For more detailed information, please visit ECHA C&L website.

Hazard Traits - Carcinogenicity；Authoritative List - IARC Carcinogens - 1；Report - regardless of intended function of ingredient in the product

Hydrochlorothiazide: Does not have an individual approval but may be used under an appropriate group standard

IMAP assessments - 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-, 1,1-dioxide: Environment tier I assessment；IMAP assessments - 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-, 1,1-dioxide: Human health tier I assessment

SYMPTOMS: Acute symptoms may include dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. May also cause hypersensitivity reactions, skin and mucous membrane irritation. Long term effects may include adverse hematologic reactions including aplastic anemia.；ACUTE/CHRONIC HAZARDS: This compound may cause skin and mucous membrane irritation. (NTP, 1992)

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including hydrochlorothiazide, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

The Generic Animal Drug and Patent Restoration act requires that each sponsor of an approved animal drug must submit to the FDA certain information regarding patents held for the animal drug or its method of use. The Act requires that this information, as well as a list of all animal drug products approved for safety and effectiveness, be made available to the public. Hydrochlorothiazide is included on this list.

Hydrochlorothiazide. Implantation or injectable dosage form new animal drugs. ... For use in cattle as an aid in the treatment of postparturient udder edema. ... Limitations. Milk taken from dairy animals during treatment and for 72 hours (6 milkings) after the latest treatment must not be used for food. Federal law restricts this drug to use by or on the order of a licensed veterinarian.

Deppeler HP; analytical profiles of drug substances. Hydrochlorothiazide. Anal Profiles Drug Subst 10: 405 (1981) A review on the determination, preparation and metabolism of hydrochlorothiazide.

Welling PG; Pharmacokinetics of the Thiazide Diuretics. Biopharm Drug Dispos 7 (Nov-Dec): 501-35 (1986). The chemical and physical properties of the thiazide diuretics are briefly discussed, and a review of their pharmacokinetics is presented, with emphasis on chlorothiazide, hydrochlorothiazide, bendroflumethiazide, hydroflumethiazide, bemetizide, trichlormethiazide, polythiazide, benzthiazide and cyclopenthiazide.

Sullivan TJ; Cross-reactions Among Furosemide, Hydrochlorothiazide, and Sulfonamides. JAMA 265 (Jan 2): 120-1 (1991). Immunologic data regarding cross-reactions among furosemide Lasix, hydrochlorothiazide, and sulfonamides are discussed.

Kavaru MS et al; Hydrochlorothiazide-Induced Acute Pulmonary Edema. Cleve Clin J Med 57 (2): 181-4 (1990). Hydrochlorothiazide induced acute pulmonary edema has been reported rarely. A case report and review the 16 previously described cases is presented.

PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped & will resist attack from the carcinogen. Both bottle & the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies & airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary & secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen & is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container & the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest & most secure form of transport & notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop.；SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment.；INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. If symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop, call a physician and be prepared to transport the victim to a hospital. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing.；INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. (NTP, 1992)

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary.

PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen & date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/

Keep container tightly closed in a dry and well-ventilated place.

Hydrochlorothiazide tablets and capsules should be stored in tightly closed containers at a controlled room temperature of 15-30 °C and protected from light, moisture, and freezing. Hydrochlorothiazide oral solution should be stored in well-closed containers at a temperature less than 40 °C, preferably at 15-30 °C. Freezing of the oral solution should be avoided.

PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured & the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed & labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Avoid breathing dust. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.

SMALL SPILLS AND LEAKAGE: Should a spill occur while you are handling this chemical, you should dampen the solid spill material with acetone, then transfer the dampened material to a suitable container. Use absorbent paper dampened with acetone to pick up any remaining material. Seal the absorbent paper, and any of your clothes, which may be contaminated, in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with acetone followed by washing with a strong soap and water solution. Do not reenter the contaminate area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned.；STORAGE PRECAUTIONS: You should store this material in a refrigerator. (NTP, 1992)

SRP: Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in air, soil or water; effects on animal, aquatic and plant life; and conformance with environmental and public health regulations. If it is possible or reasonable use an alternative chemical product with less inherent propensity for occupational harm/injury/toxicity or environmental contamination.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber; Contaminated packaging: Dispose of as unused product.

PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds & specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods & recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous & organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/

For more Disposal Methods (Complete) data for Hydrochlorothiazide (7 total), please visit the HSDB record page.

PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food & beverage containers or utensils, & the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, & rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes & wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth & purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care & vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... & when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, & contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) & label fixed to it, giving date of test & avg air-flow measured. This test should be repeated periodically & after any structural changes. /Chemical Carcinogens/

For more Preventive Measures (Complete) data for Hydrochlorothiazide (14 total), please visit the HSDB record page.

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)

Eye/face protection: Safety glasses with side-shields conforming to EN166. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).

Skin protection: Handle with gloves.

Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.

Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator. For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/

Table: Potential Drug Interactions with Hydrochlorothiazide Tablet [Table#4429]

Lithium: Generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such preparations with hydrochlorothiazide.

In some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when hydrochlorothiazide and non-steroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.

The primary object of this fundamental research was to survey the synergistic cardiovascular effects of iptakalim, a novel ATP-sensitive potassium channel (K(ATP)) opener, and clinical first-line antihypertensive drugs, such as calcium antagonists, thiazide diuretics and beta receptor blockers by a 2 x 2 factorial-design experiment. It would provide a theoretical basis for the development of new combined antihypertensive therapy program after iptakalim is applied to the clinic. Amlodipine besylate, hydrochlorothiazide and propranolol were chosen as clinical first-line antihypertensive drugs. Blood pressure, heart rate (HR) and cardiac functions were observed in anesthetized normal rats by an eight-channel physiological recorder. The results showed that iptakalim monotherapy in a low dose could produce significant antihypertensive effect. There was no interaction between iptakalim and amlodipine on the maximal changes of systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial blood pressure (MABP), the left ventricular systolic pressure (LVSP), and the left ventricular end-diastolic pressure (LVEDP) (P > 0.05). However, the effects of combination iptakalim/amlodipine on the maximal changes of SBP, DBP, MABP, LVSP and LVEDP were more obvious than those of iptakalim or amlodipine monotherapy. And there was strong positive interaction between iptakalim and amlodipine on the maximal changes of HR (P>0.05). According to the maximal changes of DBP, MABP, LVSP and LVEDP (P < 0.05) of combination iptakalim with hydrochlorothiazide, there was strong positive interaction between them. But there was no interaction between iptakalim and hydrochlorothiazide on the maximal drop of SBP and HR (P > 0.05). According to the maximal drops of DBP, MABP of combination iptakalim with propranolol, there was strong positive interaction between them (P < 0.05). But there was no interaction between iptakalim and propranolol on the maximal changes of SBP, LVSP, LVEDP and H

For more Interactions (Complete) data for Hydrochlorothiazide (12 total), please visit the HSDB record page.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 12(SRC), determined from a structure estimation method(2), indicates that hydrochlorothiazide is expected to have very high mobility in soil(SRC). The pKa values of hydrochlorothiazide are 7.9 and 9.2(3), indicating that this compound will exist as a zwitterion in the environment and zwitterion absorption is greatly influenced by substrate pH(4). Volatilization of hydrochlorothiazide from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 4.4X10-12 atm-cu m/mole(SRC), developed using a fragment constant estimation method(3). Hydrochlorothiazide is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.8X10-10 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Hydrochlorothiazide has been classified as not readily biodegradable(5).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 12(SRC), determined from a structure estimation method(2), indicates that hydrochlorothiazide is not expected to adsorb to suspended solids and sediment(SRC). Reported pKa values of 7.9 and 9.2(3) indicate hydrochlorothiazide will exist as a zwitterion at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process as hydrochlorothiazole will exist as a neutral compound under environmental conditions (pH 5 to 9)(4). According to a classification scheme(5), an estimated BCF of 3(SRC), from its log Kow of -0.07(6) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Hydrochlorothiazide has been classified as not readily biodegradable(8).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), hydrochlorothiazide, which has an estimated vapor pressure of 1.8X10-10 mm Hg at 25 °C((SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase hydrochlorothiazide may be removed from the air by wet and dry deposition(SRC). Hydrochlorothiazide absorbs UV light at wavelengths >310 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Hydrochlorothiazide is generally well tolerated at low to moderate doses; however, adverse effects are dose-dependent and occur more frequently when daily doses exceed 25 mg.；Electrolyte Derangements；Hypokalemia, hyponatremia, hypomagnesemia, hypercalcemia, and hyperchloremic alkalosis may result from hydrochlorothiazide blocking the sodium-chloride cotransporter in the DCTs, as described earlier. Hyponatremia may be particularly pronounced in older adults, individuals with low solute intake, or those receiving concomitant diuretics. Electrolyte abnormalities are more common with higher doses or combination diuretic therapy.；Hyperglycemia；Hydrochlorothiazide has been associated with mild elevations in fasting plasma glucose. Although the mechanism is not fully elucidated, hypokalemia may impair pancreatic β-cell insulin secretion, contributing to dysglycemia. The effect is generally modest and appears to be dose-related, necessitating monitoring in patients with diabetes mellitus or impaired glucose tolerance.；Hyperuricemia and Gout；Hydrochlorothiazide can increase serum uric acid levels and precipitate gout flares, particularly in predisposed individuals. The mechanism involves volume contraction and enhanced proximal tubular urate reabsorption. Hyperuricemia typically develops within the first weeks of therapy initiation and is dose-dependent.；Dyslipidemia；Thiazide therapy has been associated with modest, dose-related increases in total cholesterol and triglyceride levels. These changes are generally small and may attenuate with long-term therapy.；Sulfa Allergy；Hydrochlorothiazide contains a sulfonamide moiety. Severe hypersensitivity reactions, including rash, urticaria, Stevens-Johnson syndrome, toxic epidermal necrolysis, and anaphylaxis, are rare but reported adverse effects. Although cross-reactivity between sulfonamide antibiotics and nonantibiotic sulfonamides, such as hydrochlorothiazide, is considered low, caution is advised in patients with a history of severe sulfonamide reactions. The absolute contraindication is generally limited to patients with a prior serious hypersensitivity to hydrochlorothiazide itself.；Ocular Disturbance；Rare cases of acute myopia and secondary angle-closure glaucoma have been reported, typically within days of therapy initiation. These events are thought to be related to idiosyncratic sulfonamide-associated choroidal effusion leading to anterior displacement of the lens–iris diaphragm. Immediate drug discontinuation is required if ocular symptoms develop.；Special Considerations；In patients with advanced liver disease, hydrochlorothiazide may precipitate severe hyponatremia, hypokalemia, or hepatic encephalopathy due to fluid and electrolyte shifts. Careful monitoring is required in this population.；Clinicians should also exercise caution during the perioperative period, as diuretic-induced volume depletion may increase the risk of intraoperative hypotension or postoperative acute kidney injury.；Drug-Drug Interactions；* Antidiabetic drugs: When hydrochlorothiazide is administered with antidiabetic drugs, including oral agents and insulin, dosage adjustment of the antidiabetic therapy may be required.；* Alcohol or narcotics: Concomitant use of alcohol, barbiturates, or narcotics with hydrochlorothiazide may potentiate orthostatic hypotension.；* Cholestyramine and colestipol resins: Cholestyramine or colestipol binds hydrochlorothiazide in the gastrointestinal tract, reducing its systemic absorption.

IDENTIFICATION AND USE: Hydrochlorothiazide is a white or almost white crystalline odorless powder. Hydrochlorothiazide tablets are indicated as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy, as well as in the management of hypertension either as the sole therapeutic agent or to enhance the effectiveness of other antihypertensive drugs in the more severe forms of hypertension. They have also been found useful in edema due to various forms of renal dysfunction such as nephrotic syndrome, acute glomerulonephritis, and chronic renal failure. HUMAN STUDIES: Clinical toxicity is relatively infrequent and may result from overdosage, adverse reactions or unexpected hypersensitivity. It may cause electrolytes imbalances that may lead to cardiac arrhythmias and orthostatic hypotension, and metabolic disturbances, such as hyperglycemia and hyperuricemia. In addition it may cause aggravation of hepatic and/or renal insufficiency, hypersensitivity reactions, blood dyscrasias, acute noncardiogenic pulmonary edema, as well as gastrointestinal irritability and CNS manifestations. In general the exposure to diuretics was not associated with teratogenicity. A slight association with respiratory malformation was suggested. Other risks include fetal or neonatal jaundice, and thrombocytopenia. After two weeks of abrupt suspension of hydrochlorothiazide, 8 patients developed an intense edema. In patients, positive associations were observed for squamous cell carcinoma of the skin and lip. ANIMAL STUDIES: Available animal toxicity information comes from National Toxicology Program studies. In rats, no teratogenic, embryotoxic or fetotoxic effect was observed. Toxicology and carcinogenesis studies were conducted by feeding diets containing hydrochlorothiazide to rats and mice of each sex. The incidence of hepatocellular neoplasms was increased in high dose male mice. Changes associated with or secondary to

Signs and Symptoms of Overdose；The most common signs and symptoms observed are hypovolemia and hypotension. Patients may have electrolyte depletion, hypokalemia, hypochloremia, hyponatremia, and excessive diuresis. A rare case of non-cardiogenic pulmonary edema induced by hydrochlorothiazide has been described.；Management of Overdose；In the event of hydrochlorothiazide overdose, symptomatic and supportive measures should be implemented. Airway patency, respiration, and circulation should be maintained. Dehydration, electrolyte disturbances, and hypotension should be corrected as clinically indicated. The extent of hydrochlorothiazide removal by hemodialysis has not been established.

Hydrochlorothiazide, a thiazide diuretic, inhibits water reabsorption in the nephron by inhibiting the sodium-chloride symporter (SLC12A3) in the distal convoluted tubule, which is responsible for 5% of total sodium reabsorption. Normally, the sodium-chloride symporter transports sodium and chloride from the lumen into the epithelial cell lining the distal convoluted tubule. The energy for this is provided by a sodium gradient established by sodium-potassium ATPases on the basolateral membrane. Once sodium has entered the cell, it is transported out into the basolateral interstitium via the sodium-potassium ATPase, causing an increase in the osmolarity of the interstitium, thereby establishing an osmotic gradient for water reabsorption. By blocking the sodium-chloride symporter, hydrochlorothiazide effectively reduces the osmotic gradient and water reabsorption throughout the nephron.

The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.

The following link will take the user to the National Toxicology Program (NTP) Test Status of Agents Search page, which tabulates the results and current status of tests such as "Short-Term Toxicity Studies", "Long-term Carcinogenicity Studies", "Developmental Studies", "Genetic Toxicology Studies", etc., performed with this chemical. Testing status for hydrochlorothiazide is available.[Available from, as of February 1, 2019: https://ntpsearch.niehs.nih.gov/?e=True&ContentType=Testing+Status]

EPA has released the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays/[USEPA; ICSS Dashboard Application; Available from, as of February 4, 2019: http://actor.epa.gov/dashboard/]

Hydrochlorothiazide was reported at a concentration range of 55 to 745 mg/day/1000 inhabitants (median 415 mg/day/1000 inhabitants) in effluents from six sewage treatment plants located in Caliari, Varese, Cuneo, Latina and Naples, Italy. Sampling was conducted in winter, 2004(1). The compound was not detected in influent or effluent samples from three conventional wastewater treatment plants in the Catalonia region, Spain; it was however present in associated sludges. Sampling was conducted between July 2007 and March 2009(2).

PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/

Using a structure estimation method based on molecular connectivity indices(1), the Koc of hydrochlorothiazide can be estimated to be 12(SRC). According to a classification scheme(2), this estimated Koc value suggests that hydrochlorothiazide is expected to have very high mobility in soil(SRC). The pKa values of hydrochlorothiazide are 7.90 and 9.2(3) indicating that this compound will exist as a zwitterion in the environment and zwitterion absorption is greatly influenced by substrate pH(4). Hydrochlorothiazide exhibited 36, 22, 21 and 18% relative attenuation to sediments of the Grundlach, Fyris, Ronne and Viskan Rivers, Sweden, respectively, surveyed in summer, 2014. Samples were taken downstream of waste water treatment plant discharges(5).

Hazard Traits - Carcinogenicity；Authoritative List - IARC Carcinogens - 1；Report - regardless of intended function of ingredient in the product

Hydrochlorothiazide: Does not have an individual approval but may be used under an appropriate group standard

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including hydrochlorothiazide, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

The Generic Animal Drug and Patent Restoration act requires that each sponsor of an approved animal drug must submit to the FDA certain information regarding patents held for the animal drug or its method of use. The Act requires that this information, as well as a list of all animal drug products approved for safety and effectiveness, be made available to the public. Hydrochlorothiazide is included on this list.

Hydrochlorothiazide. Implantation or injectable dosage form new animal drugs. ... For use in cattle as an aid in the treatment of postparturient udder edema. ... Limitations. Milk taken from dairy animals during treatment and for 72 hours (6 milkings) after the latest treatment must not be used for food. Federal law restricts this drug to use by or on the order of a licensed veterinarian.

C03AA03

C09DX03

C - Cardiovascular system；C03 - Diuretics；C03A - Low-ceiling diuretics, thiazides；C03AA - Thiazides, plain；C03AA03 - Hydrochlorothiazide

QC - Cardiovascular system；QC03 - Diuretics；QC03A - Low-ceiling diuretics, thiazides；QC03AA - Thiazides, plain；QC03AA03 - Hydrochlorothiazide

C03AA03

Hydrochlorothiazide prevents the reabsorption of sodium and water from the distal convoluted tubule, allowing for the increased elimination of water in the urine. Hydrochlorothiazide has a wide therapeutic window as dosing is individualized and can range from 25-100mg. Hydrochlorothiazide should be used with caution in patients with reduced kidney or liver function.

Hydrochlorothiazide is transported from the circulation into epithelial cells of the distal convoluted tubule by the organic anion transporters OAT1, OAT3, and OAT4. From these cells, hydrochlorothiazide is transported to the lumen of the tubule by multidrug resistance associated protein 4 (MRP4). Normally, sodium is reabsorbed into epithelial cells of the distal convoluted tubule and pumped into the basolateral interstitium by a sodium-potassium ATPase, creating a concentration gradient between the epithelial cell and the distal convoluted tubule that promotes the reabsorption of water. Hydrochlorothiazide acts on the proximal region of the distal convoluted tubule, inhibiting reabsorption by the sodium-chloride symporter, also known as Solute Carrier Family 12 Member 3 (SLC12A3). Inhibition of SLC12A3 reduces the magnitude of the concentration gradient between the epithelial cell and distal convoluted tubule, reducing the reabsorption of water.

The plasma half life of hydrochlorothiazide is 5.6-14.8h.

Based on determination of plasma drug concentrations over a period of at least 24 hours, the plasma half-life of hydrochlorothiazide reportedly ranges from 5.6-15 hours.

The bioavailability of hydrochlorothiazide from 50-mg oral tablet doses was examined in healthy male volunteers under fasting and nonfasting conditions. ... The pharmacokinetics of hydrochlorothiazide in plasma could be described in terms of a triexponential function, and the mean half-life determined from the 3 exponents were 1.0, 2.2, and 9.0 hr.

The radioactivity in /human/ plasma during the first 10 hr after oral administration /of hydrochlorothiazide (hct)/ declined with a fast phase but the levels of label thereafter suggested a slow phase. The existence of such a phase was verified in 1 subject given 75 mg hct orally. His plasma levels of hct (determined with gas-liquid chromatography) declined according to a 2-compartment model, the half-lives of the alpha-and beta-phases being 1.7 and 13.1 hr, respectively.

Hydrochlorothiazide is not metabolized.

Hydrochlorothiazide is not metabolized. Route of Elimination: Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk. Half Life: 5.6 and 14.8 hours

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HYDROCHLOROTHIAZIDE

Physiologic Effects [PE] - Increased Diuresis

Established Pharmacologic Class [EPC] - Thiazide Diuretic

Chemical Structure [CS] - Thiazides

Hydrochlorothiazide is a Thiazide Diuretic. The physiologic effect of hydrochlorothiazide is by means of Increased Diuresis.

Drugs used in the treatment of acute or chronic vascular HYPERTENSION regardless of pharmacological mechanism. Among the antihypertensive agents are DIURETICS; (especially DIURETICS, THIAZIDE); ADRENERGIC BETA-ANTAGONISTS; ADRENERGIC ALPHA-ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; CALCIUM CHANNEL BLOCKERS; GANGLIONIC BLOCKERS; and VASODILATOR AGENTS.

Agents that promote the excretion of urine through their effects on kidney function.

Agents that inhibit SODIUM CHLORIDE SYMPORTERS. They act as DIURETICS. Excess use is associated with HYPOKALEMIA.

An oral dose of hydrochlorothiazide is 65-75% bioavailable, with a Tmax of 1-5 hours, and a Cmax of 70-490ng/mL following doses of 12.5-100mg. When taken with a meal, bioavailability is 10% lower, Cmax is 20% lower, and Tmax increases from 1.6 to 2.9 hours.

Hydrochlorothiazide is eliminated in the urine as unchanged hydrochlorothiazide.

The volume of distribution varies widely from one study to another with values of 0.83-4.19L/kg.

The renal clearance of hydrochlorothiazide in patients with normal renal function is 285mL/min. Patients with a creatinine clearance of 31-80mL/min have an average hydroxychlorothiazide renal clearance of 75mL/min, and patients with a creatinine clearance of ≤30mL/min have an average hydroxychlorothiazide renal clearance of 17mL/min.

Hydrochlorothiazide is well absorbed from the GI tract, with an oral bioavailability of approximately 65-75%. Although the rate and extent of absorption have been reported to vary depending on the formulation administered, no studies have been performed to determine the clinical importance (if any) of variations in absorption in patients receiving chronic hydrochlorothiazide therapy. Following oral administration of hydrochlorothiazide at doses of 12.5-100 mg, peak plasma concentrations of 70-490 ng/mL are observed within 1-5 hours of dosing. Food decreases the rate and extent of absorption of hydrochlorothiazide capsules (Microzide). Bioavailability and peak plasma concentrations of the drug were decreased by about 10 and 20%, respectively, when hydrochlorothiazide capsules (Microzide) were administered with food. Times to peak plasma concentration for such capsules were delayed by 1.3 hours (from 1.6 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. Hydrochlorothiazide exhibits linear pharmacokinetics. Based on determination of plasma drug concentrations over a period of at least 24 hours, the plasma half-life of hydrochlorothiazide reportedly ranges from 5.6-15 hours. Hydrochlorothiazide apparently is not metabolized and is excreted unchanged in urine. At least 61% of the drug is reportedly eliminated from the body within 24 hours. Increased hydrochlorothiazide plasma concentrations and a prolonged elimination half-life have been reported in patients with renal impairment. The effect of hemodialysis on the elimination of the drug has not been determined.

Thiazides cross the placental barrier and appear in cord blood. /Thiazides/

MEDICATION (VET)

Antihypertensive Agents; Diuretics; Sodium Chloride Symporter Inhibitors

MEDICATION

Use (kg) in Switzerland (2009): >1000；Use (kg; approx.) in Germany (2009): >50000；Use (kg; exact) in Germany (2009): 50914；Use (kg) in USA (2002): 82500；Consumption (g per capita) in Switzerland (2009): 0.13；Consumption (g per capita; approx.) in Germany (2009): 0.61；Consumption (g per capita; exact) in Germany (2009): 0.62；Consumption (g per capita) in the USA (2002): 0.29；Excretion rate: 1；Calculated removal (%): 8.8

For the treatment of high blood pressure and management of edema.

(1976) 1.93X10+7 GRAMS (PRINCPL CUSTMS DISTS)

(1978) 3.65X10+7 GRAMS (PRINCPL CUSTMS DISTS)

(1976) PROBABLY GREATER THAN 1.36X10+6 GRAMS

(1978) PROBABLY GREATER THAN 1.82X10+6 GRAMS

Hydrochlorothiazide is synthesized by either the reaction of para-formaldehyde with 5-chloro-2,4-disulfamoylaniline in nonaqueous media, or the reaction of formaldehyde with 6-chloro-7-sulfamoyl-2H-1,2,4-benzothiadiazine-1,1-dioxide in aqueous alkaline solution.

Chlorothiazide can be reduced electrolytically or with sodium borohydride or catalytically. ... 3-Chloro-4,6-disulfamoylaniline can be cyclized with formaldehyde to give hydrochlorothiazide.

Preparation: ... Jones, Novello, United States of America patent 3025292 (1962 to Merck & Co); de Stevens, Werner, United States of America patent 3163645 (1964 to Ciba); Klosa, German patent 1163332 (1964); J. S. Irons, T. M. Cook, United States of America patent 3164588 (1965 to Merck & Co).

Table: Hydrochlorothiazide Preparations [Table#4419]

Table: Amiloride Hydrochloride and Hydrochlorothiazide Preparations [Table#4420]

Table: Captopril and Hydrochlorothiazide Preparations [Table#4421]

Table: Enalapril Maleate and Hydrochlorothiazide Preparations [Table#4422]

For more Formulations/Preparations (Complete) data for Hydrochlorothiazide (10 total), please visit the HSDB record page.

Pharmaceuticals -> Cardiovascular system -> Diuretics -> Low-ceiling diuretics, thiazides -> Thiazides, plain

Pharmaceuticals -> Animal Drugs -> Approved in Taiwan

2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-, 1,1-dioxide: ACTIVE

Hydrochlorothiazide decomposes upon irradiation with near-UV light (lambda greater than 310 nm) both in methanol and aqueous solutions. In the photolysis the chlorine substituent is removed to be replaced by either--H or--OR from the solvent ROH. Hydrolysis of the thiadiazine ring is superimposed upon the dechlorination. The presence of oxygen inhibits the decomposition. The mechanism of the photolysis is suggested to involve cation radical formation which facilitates the hydrolysis step. 5-Chloro-2,4-disulphonamido-aniline, the normal hydrolysis product from hydrochlorothiazide, is also susceptible to photolytic dechlorination by a similar mechanism.