アセタゾラミド

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Antiepileptics

Pharmaceuticals -> Used in Switzerland

Pharmaceuticals

Log P= -0.45

-0.26

-0.25

CRYSTALS FROM WATER

WHITE TO FAINTLY YELLOWISH WHITE, CRYSTALLINE, POWDER

less than 1 mg/mL at 72 °F (NTP, 1992)

SPARINGLY SOL IN COLD WATER

SLIGHTLY SOL IN ALCOHOL

INSOL IN CHLOROFORM, DIETHYL ETHER, CARBON TETRACHLORIDE; SLIGHTLY SOL IN ACETONE

Readily soluble in 1 N sodium carbonate solution.

Breast Feeding; Lactation; Milk, Human; Anticonvulsants; Antiglaucoma Agents; Carbonic Anhydrase Inhibitors; Diuretics

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Pharmaceuticals

Ophthalmological preparations > Miotics and antiglaucoma medicines

496 to 498 °F (effervescence) (NTP, 1992)

258-259 °C (EFFERVESCENCE)

260.5 °C

Acetazolamide appears as white to yellowish-white fine crystalline powder. No odor or taste. (NTP, 1992)

Solid

7.2

PKA: 7.2

137.8 Ų [M-H]- [CCS Type: DT; Buffer gas: N2; Ionization: ESI-; Dataset: TOXCAST; Source Identifier: DTXSID7022544]

151.05 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

140.7 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

This chemical does not meet GHS hazard criteria for 0.7% (1 of 153) of reports.

Warning

H315 (90.2%): Causes skin irritation [Warning Skin corrosion/irritation]

P203, P264, P264+P265, P280, P302+P352, P305+P351+P338, P318, P321, P332+P317, P337+P317, P362+P364, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 153 reports by companies from 13 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Danger

Hazard Traits - Developmental Toxicity

Acetamide, N-5-(aminosulfonyl)-1,3,4-thiadiazol-2-yl-: Does not have an individual approval but may be used as a component in a product covered by a group standard. It is not approved for use as a chemical in its own right.

SYMPTOMS: Symptoms of exposure to this compound may include paresthesias, "tingling" feeling in the extremities, some loss of appetite, polyuria, occasional drowsiness, confusion and photosensitivity. Other symptoms may include papular or erythematous skin eruptions, nausea, acidosis and blood dyscrasias. In addition it can cause acute transient myopia, malaise syndrome, which includes fatigue, anorexia, loss of weight, depression and loss of libido; gastrointestinal distress, elevated blood urate, acute gouty arthritis skin rashes and hair loss or excess growth of hair.

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

A weak acid and a diazo derivative. Azo, diazo, azido compounds can detonate. This applies in particular to organic azides that have been sensitized by the addition of metal salts or strong acids. Toxic gases are formed by mixing materials of this class with acids, aldehydes, amides, carbamates, cyanides, inorganic fluorides, halogenated organics, isocyanates, ketones, metals, nitrides, peroxides, phenols, epoxides, acyl halides, and strong oxidizing or reducing agents. Flammable gases are formed by mixing materials in this group with alkali metals. Explosive combination can occur with strong oxidizing agents, metal salts, peroxides, and sulfides.

Skin Irrit. 2 (90.2%)

Reproductive toxicity - Category 1B

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.

SMALL SPILLS AND LEAKAGE: If you spill this chemical, dampen the solid spill material with 5% ammonium hydroxide, then transfer the dampened material to a suitable container. Use absorbent paper dampened with 5% ammonium hydroxide to pick up any remaining material. Your contaminated clothing and the absorbent paper should be sealed in a vapor-tight plastic bag for eventual disposal. Wash all contaminated surfaces with 5% ammonium hydroxide followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned.

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

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)

/ACETAZOLAMIDE/ POTENTIATES MERCURIAL DIURETICS /IN ANIMALS/.

Concurrent use /of glucocorticoid corticosteroids, especially with significant mineralocorticoid activity; mineralocorticoid corticosteroids; parenteral amphotericin; corticotropin, especially prolonged therapeutic use/ with carbonic anhydrase inhibitors may result in severe hypokalemia and should be undertaken with caution; serum potassium concentrations and cardiac function should be monitored during concurrent use. /Carbonic anhydrase inhibitors/

Concurrent use of corticosteroids or corticotropin with acetazolamide sodium may increase the risk of hypernatremia and/or edema because these medications cause sodium and fluid retention; the risk with corticosteroids or corticotropin may depend on the patients's sodium requirement as determined by the condition being treated. /Acetazolamide sodium/

The possibility should be considered that concurrent chronic use of corticosteroids or corticotropin with carbonic anhydrase inhibitors may increase the risk of hypocalcemia and osteoporosis because these medications increase calcium excretion. /Carbonic anhydrase inhibitors/

For more Interactions (Complete) data for ACETAZOLAMIDE (16 total), please visit the HSDB record page.

There is a broad range of general and specific adverse effects that acetazolamide use can induce. Fatigue, nausea, vomiting, abdominal pain, and diarrhea are common in patients. Other patients will experience paresthesia, black stools, decreased libido, tinnitus, and taste alteration. There are also reports of patients developing depression while using acetazolamide or developing a bitter or metallic taste. Less commonly, there is a risk of developing metabolic acidosis, hyponatremia, and hypokalemia. Kidney stones can also be seen but are uncommon. Occasionally, patients develop Stevens-Johnson syndrome, aplastic anemia, agranulocytosis, toxic epidermal necrolysis, or fulminant hepatic necrosis.

IDENTIFICATION: Acetazolamide is of synthetic origin. Acetazolamide exists as a white to faintly yellowish-white, odorless crystalline powder. Acetazolamide is very slightly soluble in water and only slightly soluble in ethanol (approx 750 g/l); it is practically insoluble in ether and chloroform. Uses: Preoperative management of closed-angle glaucoma, or as an adjunct in the treatment of open-angle glaucoma. Abnormal retention of fluid: drug-induced edema, obesity, and congestive cardiac failure. Epilepsy Metabolic alkalemia. Periodic paralysis HUMAN EXPOSURE: Patients with either acute or chronic overdosage with acetazolamide may show signs of dehydration with thirst, lethargy, confusion, poor skin turgor, and prolonged capillary refill time, but may have a paradoxical continued diuresis. Electrolyte abnormalities include hyponatremia, hypokalemia, and a non-anion gap hyperchloremic metabolic acidosis in the more than mild ingestion which may lead to further deterioration in mental status, production of seizures, electrocardiographic abnormalities, and arrhythmias. Prior renal insufficiency will lead to increased toxicity at a given dose. There are idiosyncratic reactions producing bone marrow suppression with hepatic and renal insufficiency. Acetazolamide may also precipitate in the renal tubules producing calculi with renal colic. Hypokalemia may lead to muscular weakness, hyporeflexia, and hypochloremic metabolic alkalosis. In geriatric patients, a chronic metabolic acidosis may lead to a chronic compensatory hyperventilation which increases pulmonary vascular resistance and decreases left ventricular function. This can be especially significant in patients on concurrent beta-blocker or calcium channel blocker therapy. The ventricular fibrillation threshold may then be reduced. Cardiac arrhythmias may occur due to potassium deficiency. Abuse or overdose may result in pancreatitis. Hyperglycemia, hyperuricemia, and hyperlipidemia may occur with acute overdose or in chronic use or abuse. Hypersensitivity reactions such as rash, photosensitivity, thrombocytopenia, and pancreatitis are rare. Contraindications: Renal hyperchloremic acidosis. Addison's disease and all types of suprarenal gland failure. Conditions where there is known depletion of sodium and potassium (at least until this is treated). Long-term administration is contraindicated in patients with chronic closed angle-closure glaucoma. Known sensitivity to sulfonamides. Acetazolamide should not be used to alkalinize urine following salicylate overdose since it may worsen metabolic acidosis. Acetazolamide is well absorbed from the gastrointestinal tract. Acetazolamide is distributed throughout body tissues; it concentrates principally in erythrocytes, plasma and kidneys and to a lesser extent in liver, muscles, eyes and the central nervous system. Acetazolamide does not accumulate in tissues. The drug crosses the placenta in unknown quantities. Acetazolamide is tightly bound to carbonic anhydrase and high concentrations are present in tissues containing this enzyme such as erythrocytes and the renal cortex. There is a small amount of irreversible binding to red cells. It is 70 to 90% bound to plasma protein. Acetazolamide is not metabolized. Acetazolamide is excreted unchanged by the kidneys via tubular secretion and passive reabsorption. There is no evidence of enterohepatic circulation although small amounts of unchanged drug are eliminated in the bile. Acetazolamide is a carbonic anhydrase inhibitor. Acetazolamide reduces the formation of hydrogen and bicarbonate ions from carbon dioxide and water by noncompetitive, reversible inhibition of the enzyme carbonic anhydrase, thereby reducing the availability of these ions for active transport into secretions. One patient died of cholestatic jaundice after taking 13 g of acetazolamide in 26 days. In one patient, fatal bone marrow depression with leukopenia, thrombocytopenia, and anemia occurred after therapy with 500 mg of acetazolamide twice daily for 14 weeks. One case of renal failure (anuria) occurred in a patient after taking 500 mg of acetazolamide twice daily for 2 weeks. There have been no reports of congenital defects despite past widespread use though one women on 750 mg per day for glaucoma during the 1st and 2nd trimester had a baby with a sacrococcygeal teratoma but no causal link could be made. Teratogenicity tests in rats and mice showed the absence of fourth and fifth digits from the right forelimb in the offspring of rats and mice. There were no apparent lessions in the newborn of rabbits and monkeys. The drug crosses the placenta in unknown quantities. Potentially hazardous interactions: The effects of folic acid antagonists, oral hypoglycaemic agents and oral anticoagulants may be increased by acetazolamide. The urinary antiseptic effect of methenamine may be prevented by acetazolamide by keeping the urine alkaline. The alkalinization of the urine by acetazolamide can reduce the urinary excretion of many weak bases (including amphetamine, quinine, quinidine, and diethylcarbamazine) and thus enhance their pharmacological effects. In one patient taking phenytoin and acetazolamide drug-induced osteomalacia was reported. The more serious effects include blood disorders, skin toxicity and renal stone formation. Stevens-Johnson syndrome has not been reported. Symptomatic adverse effects: Flushing, thirst, headache, drowsiness, dizziness, fatigue, irritability, excitement, paresthesias, ataxia, hyperpnoa and gastrointestinal disturbances have all been reported (Dollery). Oral ingestion is the usual means of exposure. There is no appreciable dermal absorption. There is no significant absorption or local irritation. ANIMAL/PLANT STUDIES: Numerous animal studies have demonstrated that the toxicity of acetazolamide was very low in the species studied (mouse, dog, rat, monkey).

There have been reports of central nervous system (CNS) toxicity with coma. In addition, hyperchloremic metabolic acidosis and electrolyte disturbances are usually seen in acetazolamide overdose. Therefore, clinicians should rapidly obtain serum electrolyte levels (especially serum potassium) and arterial blood gas analysis. According to product labeling, there is no specific antidote to acetazolamide; hence treatment is usually supportive. Bicarbonate administration can usually correct metabolic acidosis. Despite its plasma protein binding and high RBC distribution, acetazolamide may be dialyzable. Dialysis may be especially valuable in managing acetazolamide overdosage complicated with acute kidney injury.

Serious toxic reactions to carbonic anhydrase inhibitors are infrequent; however, these drugs are sulfonamide derivatives and, like other sulfonamides, may cause bone marrow depression, skin toxicity, and sulfonamide-like renal lesions and may cause allergic reactions in patients hypersensitive to sulfonamides. /Carbonic Anhydrase Inhibitors/

Bone marrow depression manifested by aplastic anemia, thrombocytopenia or thrombocytopenic purpura, leukopenia, agranulocytosis, and hemolytic anemia has been reported with carbonic anhydrase inhibitors. Fatalities resulting from aplastic anemia have been reported following therapy with acetazolamide or methazolamide. In one patient, fatal bone marrow depression with leukopenia, thrombocytopenia, and anemia occurred after therapy with 500 mg of acetazolamide twice daily for 14 weeks.

Hypersensitivity reactions common to all sulfonamide derivatives occur rarely in patients receiving carbonic anhydrase inhibitors. One patient died of cholestatic jaundice after taking 13 g of acetazolamide in 26 days. The jaundice was attributed to drug-induced hypersensitivity and hepatitis. Other hypersensitivity reactions which may occur include fever, rash and skin eruptions including exfoliative dermatitis and urticaria, and pruritus.

One case of renal failure (anuria) occurred in a patient after taking 500 mg of acetazolamide twice daily for 2 weeks. The patient recovered after treatment of sodium bicarbonate (4 g orally initially, followed by 2 g every 6 hours) and forced fluids.

For more Human Toxicity Excerpts (Complete) data for ACETAZOLAMIDE (7 total), please visit the HSDB record page.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Acetazolamide

vMost-DILI-concern

8

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

IV INFUSION OF ACETAZOLAMIDE INTO DOGS DECR GLOMERULAR FILTRATION RATE @ ALL DOSE LEVELS.

IV ADMIN OF ACETAZOLAMIDE 25 MG/KG INDUCED INCR OF CORTICAL OXYGEN TENSION IN RABBITS, ALSO ELEVATION OF LOCAL BLOOD FLOW IN CEREBRAL CORTEX. LENGTHENED SURVIVAL TIME OF MICE SUBMITTED TO ATMOSPHERIC DECOMPRESSION. NOT PROTECTIVE IN RATS UNDER ASPHYXIA.

IN RHESUS MONKEYS, ACETAZOLAMIDE PRODUCED AN IMMEDIATE & SIGNIFICANT INCR IN CEREBRAL BLOOD FLOW, INCR IN ARTERIAL CO2 TENSION, & A DECR IN CEREBRAL OXYGEN CONSUMPTION.

... Post-axial forelimb defects in mice and rats by feeding a diet containing 0.6% acetazolamide. The defect was specifically localized to the forelimb and the light side more often involved. Symmetric forelimb defects have been produced in the hamster. In monkeys, administration of 600 mg/kg for 3 to 6 embryonic days gave negative results.

For more Non-Human Toxicity Excerpts (Complete) data for ACETAZOLAMIDE (6 total), please visit the HSDB record page.

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

S01EC01

S - Sensory organs

QS - Sensory organs

S01EC01

Acetazolamide is a potent carbonic anhydrase inhibitor, effective in the control of fluid secretion, in the treatment of certain convulsive disorders and in the promotion of diuresis in instances of abnormal fluid retention. Acetazolamide is not a mercurial diuretic. Rather, it is a nonbacteriostatic sulfonamide possessing a chemical structure and pharmacological activity distinctly different from the bacteriostatic sulfonamides.

The anticonvulsant activity of Acetazolamide may depend on a direct inhibition of carbonic anhydrase in the CNS, which decreases carbon dioxide tension in the pulmonary alveoli, thus increasing arterial oxygen tension. The diuretic effect depends on the inhibition of carbonic anhydrase, causing a reduction in the availability of hydrogen ions for active transport in the renal tubule lumen. This leads to alkaline urine and an increase in the excretion of bicarbonate, sodium, potassium, and water.

Carbonic anhydrase inhibitors potently inhibit (IC50 for acetazolamide is 10 nM) both the membrane bound and cytoplasmic forms of carbonic anhydrase, resulting in nearly complete abolition of NaHCO3 reabsorption in the proximal tubule. /Carbonic Anhydrase Inhibitors/

Although the proximal tubule is the major site of action of carbonic anhydrase inhibitors, carbonic anhydrase also is involved in secretion of titratable acid in the collecting duct system (a process which involves a proton pump), and therefore the collecting duct system is a secondary site of action for this class of drugs. /Carbonic Anhydrase Inhibitors/

Acetazolamide frequently causes paresthesias and somnolence, suggesting an action of carbonic anhydrase inhibitors in the CNS. The efficacy of acetazolamide in epilepsy is in part due to the production of metabolic acidosis; however, direct actions of acetazolamide in the CNS also contribute to its anticonvulsant action.

... Inhibition of carbonic anhydrase decreases the rate of formation of aqueous humor and consequently reduce intraocular pressure. /Carbonic Anhydrase Inhibitors/

For more Mechanism of Action (Complete) data for ACETAZOLAMIDE (6 total), please visit the HSDB record page.

3 to 9 hours

Plasma half-life: 6-9 hours /From table/

O3FX965V0I

ACETAZOLAMIDE

Established Pharmacologic Class [EPC] - Carbonic Anhydrase Inhibitor

Mechanisms of Action [MoA] - Carbonic Anhydrase Inhibitors

Chemical Structure [CS] - Sulfonamides

Acetazolamide is a Carbonic Anhydrase Inhibitor. The mechanism of action of acetazolamide is as a Carbonic Anhydrase Inhibitor.

Drugs used to prevent SEIZURES or reduce their severity.

A class of compounds that reduces the secretion of H+ ions by the proximal kidney tubule through inhibition of CARBONIC ANHYDRASES.

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

Carbonic anhydrase inhibitors are avidly bound by carbonic anhydrase and, accordingly, tissues rich in this enzyme will have higher concentrations of carbonic anhydrase inhibitors following systemic administration. /Carbonic Anhydrase Inhibitors/

Inhibitors of Carbonic Anhydrase. Drug: acetazolamide; Oral Absorption: nearly complete; Plasma Half-Life: 6-9 hours; and Route of Elimination: renal excretion of intact drug. /From table/

ACETAZOLAMIDE RELATED TO RESPONSE IN RABBIT; KIDNEY RESPONSE, MEASURED BY MONITORING URINE FLOW & NA ELIMINATION, URINE FLOW & NA ELIMINATION OCCUR IMMEDIATELY AFTER INJECTION CORRELATED WITH LOG DOSE.

IV BOLUS INJECTIONS OF (14)C-LABELED, ACETAZOLAMIDE WERE MADE IN RABBITS. PLASMA, URINE, & WASHED RED BLOOD CELL CONCN WERE MEASURED, THE LATTER INDICATING BOUND DRUG.

For more Absorption, Distribution and Excretion (Complete) data for ACETAZOLAMIDE (6 total), please visit the HSDB record page.

MEDICATION (VET)

MEDICATION

Use (kg) in Switzerland (2009): >250

(1977) PROBABLY GREATER THAN 4.54X10+5 GRAMS

(1979) PROBABLY GREATER THAN 4.54X10+5 GRAMS

REACTION OF HYDRAZINE HYDRATE WITH AMMONIUM THIOCYANATE, TO PRODUCE 5-AMINO-2-MERCAPTO-1,3,4-THIADIAZOLE, WHICH IS ACETYLATED AND OXIDIZED, THEN AMIDATED WITH AMMONIA

Hydrazine + ammonium thiocyanate + acetic anhydride + ammonia (thiocyanate addition/cyclization/acetylation/oxidation/sulfonamide formation)

Oxidative chlorination of 2-acetyl-amino-5-mercapto-1,3,4-thiadiazole or its S-benzyl or S-acyl derivatives to the corresponding sulfonyl chlorides followed by reaction with ammonia has proved to be an optimal method for the synthesis of acetazolamide.

Acetamide, N-[5-(aminosulfonyl)-1,3,4-thiadiazol-2-yl]-: ACTIVE

WARNING: DO NOT SLAUGHTER ANIMALS OR USE MILK FOR FOOD WITHIN 72 HR AFTER LAST TREATMENT.