What Is Acetazolamide?

Acetazolamide, Chinese Pharmacopoeia, Acetazolamide, Trade Name Diamox, Scientific Name N- (5-Sulfamoyl-1,3,4-thiadiazole-2- ) Acetamide. Acetazolamide is a diuretic. Carbonic anhydrase inhibitors, which inhibit carbonic anhydrase in renal tubular epithelial cells after taking it, reduce the formation of H ₂ CO ₃ and reduce the production of H ⁺ . Therefore, the exchange of H ⁺ and Na ⁺ is greatly slowed, and as a result, HCO ₃ , Na ⁺ , K ⁺ excretion increases, and urine output increases. The product can still inhibit the secretion of aqueous humor and reduce intraocular pressure. It is used to treat glaucoma and mild cardiac edema.

Drug type: Essential medicines
Drug name: Acetazolamide

English name: Acetazolamide
Chinese alias: Acetazolamide; acetazolamide; acetazamide
English alias: Oedemin; Ledamox; Inidrase

Brief introduction of acetazolamide compounds

Acetazolamide Basic Information

Chinese name: acetazolamide

Chinese alias: 2-acetylamino-1,3,4-thiadiazole-5-sulfonamide; ACET azoamide; N- [5- (aminosulfonyl) -1,3,4-thiadiazole-2 -Yl] acetamide; acyclovir impurity A; acetazolamide; acetazolamide; acetazolamide; acetazolamide; dammus; acetazosam;

English name: acetazolamide

English alias: Cidamex; 5-acetamido-1,3,4-thiadiazole-2-sulphonamide; Diamox; Acetamide, N- [5- (aminosulfonyl) -1,3,4-thiadiazol-2-yl]-; DIACARB; Acetazolamidum; Diamox

CAS number: 59-66-5

Molecular formula: C ₄ H ₆ N ₄ O ₃ S ₂

Molecular structure formula:

Molecular weight: 222.24500

Exact mass: 221.98800

PSA: 151.66000

LogP: 0.99800

Acetazolamide physical and chemical properties

Appearance and properties: white to off-white crystalline powder, odorless and tasteless. Soluble in ammonia solution, slightly soluble in boiling water, very slightly soluble in water and ethanol, almost insoluble in chloroform and ether.

Density: 1.744 g / cm ³

Melting point: 256-261 ° C

Stability: Photosensitive

Storage conditions: storeroom ventilated, low temperature and dry

Acetazolamide Safety Information

Symbol: GHS07

Signal Word: Warning

Hazard statement: H315; H319

Cautionary statement: P305 + P351 + P338

Packing level: III

Danger category: 6.1

Customs Code: 29350009090

Dangerous Goods Transport Code: 2811

Danger category code: R36 / 38

Safety instructions: S26

RTECS number: AC8225000

Dangerous goods mark: Xi ^[1]

Production method of acetazolamide

1. Chlorinated and oxidized 2-acetylamino-5-mercapto-1,3,4-thiadiazole was added to a mixture of glacial acetic acid and water, cooled to -2 ° C and passed through chlorine, and the final temperature did not exceed 5 ° C. When the temperature of the material drops significantly, a large amount of foam appears on the liquid surface, and the chlorine is stopped when the liquid chlorine is consumed to the specified amount, and the filter cake is washed with ice water to a pH of 4, to obtain the chlorine oxide (2-acetylchloro-5 -Sulfonyl chloride-1,3,4-thiadiazole).

2. Ammonia Mix ammonia water with crushed ice and lower the temperature to below 5 . Chlorine oxide was added, and after completion, the reaction was held for half an hour. Adjust the pH to 5-6 with hydrochloric acid, filter, wash the filter cake to pH 7, and dry to obtain the crude acetazolamide. The crude product, water, activated carbon and sodium metabisulfite were heated to 95 ° C, decolorized for 1-1.5 h, filtered while hot, the filtrate was cooled to crystallize, filtered, washed, and dried to obtain acetazolamide ^[1] .

Acetazolamide uses

Acetazolamide is a diuretic. A carbonic anhydrase inhibitor, which inhibits carbonic anhydrase in renal tubular epithelial cells after taking, reduces the formation of H2CO3, and the production of H + decreases accordingly. Therefore, the exchange of H + and Na + is greatly slowed, with the result that HCO3-, Na +, K + excretion increases and urine output increases. The product can still inhibit the secretion of aqueous humor and reduce intraocular pressure. It is used to treat glaucoma, mild cardiac edema, etc. ^[1] .

Acetazolamide Pharmacopoeia Standard

[Source (name), content (potency)]

This product is N- (5-sulfamoyl-1,3,4-thiadiazol-2-yl) acetamide. Calculated based on dry products, C4H6N4O3S2 should be 98.0% to 102.0%.

[Character]

This product is white needle-like crystal or crystalline powder; odorless and slightly bitter.

This product is slightly soluble in boiling water, very slightly soluble in water or ethanol, almost insoluble in chloroform or ether; easily soluble in ammonia solution.

[Identification] (1) Take about 0.1g of this product, add sodium hydroxide test solution to dissolve, add 10ml of water, add 1 drop of phenolphthalein indicator solution, add dilute hydrochloric acid until the pink color disappears, add a few drops of mercury nitrate test solution, A white precipitate was formed. (2) Take about 0.2g of this product, put in a test tube, add 1ml each of ethanol and sulfuric acid, and heat to produce the aroma of ethyl acetate. (3) The infrared absorption spectrum of this product should be consistent with the control spectrum (spectrum set 9).

an examination

acidity

Take 1.0g of this product, heat 50ml of water, shake, let cool, and measure according to law (Appendix VI H), the pH value should be 4.0 ~ 6.0.

Clarity of alkaline solution

Take 1.0g of this product, add 5ml of 10% sodium hydroxide solution to dissolve, the solution should be clear.

chloride

Take 2.0g of this product, add 100ml of water, heat and dissolve, quickly cool, filter, take 25ml of the filtrate, check according to law (Appendix A), compared with the control solution made of 7.0ml of standard sodium chloride solution, it must not be more concentrated (0.014%).

Sulfate

Take 25ml of the remaining filtrate under the above chloride and check it according to law (Appendix B). It must not be more concentrated (0.04%) than the control solution made from 2.0ml of standard potassium sulfate solution.

relative substance

Take 50mg of this product, put it in a 100ml measuring bottle, add 80ml of water, heat it in a water bath at 80 ° C for 5 minutes, shake to dissolve the acetazolamide, let it cool, dilute with water to the mark, shake well, as the test solution; Take 1ml, put it into a 100ml volumetric flask, add water to dilute to the mark, shake well, and use it as a control solution. Measured according to high performance liquid chromatography (Appendix VD), using octadecylsilane bonded silica as a filler, 0.43% anhydrous sodium acetate solution-methanol-acetonitrile (95: 2: 3, pH adjusted with glacial acetic acid) The value is 4.0 ± 0.05) is the mobile phase, the detection wavelength is 265nm, and the theoretical number of plates should not be less than 5000 calculated from the acetazolamide peak. Take 20l of the control solution, inject it into the liquid chromatograph, adjust the detection sensitivity so that the peak height of the main component chromatographic peak is about 20% of the full range, and then accurately measure 20l each of the two solutions, and inject them into the liquid chromatograph and record The chromatogram has twice the retention time of the main component peak. If the chromatogram of the test solution shows impurity peaks, the peak area of a single impurity peak must not be greater than 0.5 times (0.5%) the peak area of the main peak of the control solution, and the sum of the peak areas of each impurity peak must not be greater than the peak area of the main peak of the control solution (1.0 %).

Silver reduction

Take 5.0g of this product, moisten it with 5ml of absolute ethanol, add 125ml of water and 10ml of nitric acid, add 5ml of silver nitrate titration solution (0.1mol / L) precisely, shake it, and leave it in the dark for 30 minutes, and filter through a fused glass funnel Wash the container and the funnel with 10 ml of water, combine the filtrate and the washing solution, add 5 ml of ammonium ferric sulfate indicator solution, titrate with the ammonium thiocyanate titration solution (0.1 mol / L) to the end point, and consume the ammonium thiocyanate titration solution (0.1 mol / L) shall not be less than 4.8ml.

Loss on drying

Take this product and dry it at 105 to constant weight, and the weight loss shall not exceed 0.5% (Appendix L).

Residue on ignition

Must not exceed 0.1% (Appendix N).

Heavy metal

Take 0.50g of this product and check it according to law (Appendix H Third Method), the content of heavy metals must not exceed 20 parts per million.

[Content determination]

Take about 0.2g of this product, accurately weigh, add 400ml of boiling water, stir to dissolve, let cool, transfer to a 1000ml measuring flask, add water to the mark, and shake well; take 5ml precisely, place it in a 100ml measuring bottle, add 1mol / 10ml L hydrochloric acid solution, diluted with water to the mark, shake well, measure the absorbance at 265nm according to the UV-visible spectrophotometry (Appendix IV A), and press the absorption coefficient (E1 of C ₄ H ₆ N ₄ O ₃ S ₂ % 1cm) is calculated as 474.

[Category] Carbonic anhydrase inhibitor.

Acetazolamide Drug Description

Acetazolamide classification

Circulatory Drugs> Antihypertensive Drugs> Diuretic Antihypertensive Drugs

Acetazolamide dosage form

1. Tablets: 250mg each;

2. Injection (powder): 500mg.

Acetazolamide pharmacological action

1. Reduce intraocular pressure. Carbonic anhydrase is present in all tissues of the eye (such as the retina, uveal membrane, and crystals), with the largest amount of the ciliary body. In glaucoma, the activity of carbonic anhydrase in the ciliary body epithelium is increased, thereby generating excessive sodium bicarbonate, which increases the osmotic pressure in the aqueous humor, increases the production of aqueous humor, and increases the intraocular pressure. Acetazolamide can inhibit the activity of carbonic anhydrase in the ciliary body, thereby reducing the production of aqueous humor (50% to 60%) and reducing the intraocular pressure in glaucoma patients. It is also believed that the ocular hypotensive effect of acetazolamide is due to its decrease in HCO3 concentration in plasma and increase in plasma chloride concentration, which leads to metabolic acidosis and decreases in blood alkali reserve.

2. Cardiogenic edema. Acetazolamide can be used for cardiogenic edema, but it is not effective for renal and liver edema. Acetazolamide can inhibit carbonic anhydrase in renal tubular epithelial cells, reduce the production of H and the reabsorption of Na, and increase the excretion of Na, water, and bicarbonate, thereby producing a diuretic effect. However, acetazolamide does not have a strong diuretic effect (good diuretic and antihypertensive effect for eclampsia patients with edema), and long-term use can produce drug resistance, so it is rarely used alone for diuretics. When combined with mercury diuretics, they can correct the acid-base balance imbalance caused by each other.

3. Others: Acetazolamide can also reduce the production of cerebrospinal fluid and inhibit gastric acid secretion. The mechanism may also be related to the inhibition of carbonic anhydrase. The mechanism of acetazolamide against epilepsy is not very clear.

Acetazolamide pharmacokinetics

It is easily absorbed by mouth and has a high protein binding rate. After oral administration of 500mg, intraocular pressure began to decrease from 1 to 1.5 hours, and the blood concentration reached a peak of 2 to 27 g / ml in 2 to 4 hours. The effect could be maintained for 4 to 6 hours, and the half-life was 24 to 5.8 hours. Oral sustained-release capsules started at 2 hours after 500 mg It plays a role in reducing intraocular pressure, with a peak time of 8-12 hours, a peak serum concentration of 6 g / ml, and the effect lasts 18 to 24 hours. After intravenous injection of 500 mg, the effect of reducing intraocular pressure begins 2 minutes later, and the peak blood concentration is reached within 15 minutes. . Whether acetazolamide is administered orally or intravenously, 90% to 100% of the dose is excreted by the kidneys in the original form within 24 hours, but the sustained release capsules only excrete 47% within 24 hours.

Acetazolamide indications

1. Treatment of various types of glaucoma and reduction of intraocular pressure before anti-glaucoma and certain internal eye surgery, is an effective auxiliary drug for lowering intraocular pressure for short-term control of various types of glaucoma.

2. For cardiogenic edema. It is also used for cerebral edema, which can reduce the production of cerebrospinal fluid.

3. Treat peptic ulcer, can inhibit gastric acid secretion.

4. Try for large and small seizures.

5. Can also be used to treat acute mountain sickness and juvenile myoclonic epilepsy.

6. Hypochloric alkalemia and hypokalemia periodic paralysis during heart failure.

Acetazolamide contraindications

1. Allergy to acetazolamide or other carbonic anhydrase inhibitors, sulfa drugs, thiazide diuretics.

2. Adrenal failure and adrenal insufficiency.

3. Hyponatremia and hypokalemia.

4. Severe liver and kidney dysfunction.

5. Perchloric acidosis.

6. Heart failure.

7. Have a history of urinary stones.

8. Patients with chronic non-congestive angle-closure glaucoma.

Acetazolamide precautions

1. (1) Diabetes; (2) Pulmonary infarction or emphysema.

2. The effects of drugs on the elderly: Elderly patients are more likely to develop drug resistance after long-term use, and are likely to cause metabolic acidosis and hypokalemia.

3. The effects of drugs on pregnancy: Animal experiments have confirmed that giving rodents 10 times the normal dose of acetazolamide in adults has a higher teratogenicity, so pregnant women should not use acetazolamide, especially in the first 3 of pregnancy. Months.

4. The influence of the drug on the test value or diagnosis: (1) It can interfere with the absorption of the Glenn-Nelson method, which can cause a false positive result of the urine 17-hydroxysteroid measurement; Bromphenol blue test, etc.) false positive results; (3) can increase blood ammonia concentration, serum bilirubin, urobilinogen concentration; (4) can increase blood glucose concentration, urine glucose concentration, but non-diabetics are not affected; (5) The concentration of plasma chloride can be increased, and the concentration of serum potassium can be reduced.

5. Check or monitor before, during and after medication: For glaucoma patients: (1) IOP should be measured daily during acute episodes, IOP should be measured regularly during chronic periods, and vision and visual field should be checked regularly; (2) After IOP control According to the type of glaucoma, iris corneal angle changes, etc., adjust the dosage and choose appropriate anti-glaucoma surgery; (3) the use of pupil shrinkage or timolol eye drops combined with acetazolamide to control the intraocular pressure is still not ideal in the late stage In patients with open-angle glaucoma, congenital glaucoma, and patients who need to postpone anti-glaucoma surgery, in addition to taking potassium salts, they need to have a 24-hour IOP curve, vision, visual field, blood pressure, blood, and urine routine records before treatment. In order to evaluate the efficacy and find possible adverse reactions during the treatment process.

6. Patients who cannot tolerate sulfa drugs or other sulfa derivative diuretics cannot tolerate acetazolamide.

7. For angle-closure glaucoma, after using acetazolamide in the acute phase, in principle, appropriate anti-glaucoma surgery should be selected according to the iris corneal angle and tonography, otherwise the reduction in intraocular pressure will give people the illusion of safety, thus Corner adhesions develop further, delaying the timing of surgery.

8. Some patients who are intolerant of acetazolamide adverse reactions or long-term ineffective acetazolamide can use other carbonic anhydrase inhibitors (such as diclofenamide).

9. In order to prevent the occurrence of renal complications, in addition to the general precautionary principles of sulfa drugs, potassium salts and magnesium salts should be added. Patients with high calcium urine should enter a low calcium diet.

10. For patients with kidney stones (mainly containing calcium), acetazolamide can induce or aggravate the condition. If abdominal colic and hematuria occur, the drug should be stopped immediately.

11. Drink plenty of water during the taking period. For long-term taking, you should take potassium salt. It should not be combined with calcium, iodine and broad-spectrum antibiotics.

12. Pulmonary heart disease, heart failure, Addison's syndrome, liver failure, metabolic acidemia and edema with hypokalemia should not be used. It is not suitable for patients with chronic non-congestive angle-closure glaucoma.

13. Acetazolamide can cause myopia, loss of eye conditioning, forward lens displacement, retinal edema, etc., and should be discontinued in time.

Acetazolamide adverse reactions

Acetazolamide rarely has serious adverse reactions during short-term and intermittent use in ophthalmology. Some adverse reactions are common to sulfa derivatives, and some adverse reactions are dose-dependent.

1. Common numbness and tingling in extremities, nausea, lack of appetite, drowsiness, weight loss, depression, metal taste, diarrhea and polyuria.

2. Occasional hearing loss and temporary myopia and sulfa-like rash after the first medication.

3. Rare exfoliative dermatitis, neutropenia, or aplastic anemia.

4. Long-term medication can aggravate symptoms such as hypokalemia, hyponatremia, electrolyte disturbances, and metabolic acidosis, as well as renal complications (such as renal colic, calculi, sulfa urine crystals, nephrotic syndrome, etc.) Long-term use can cause paresthesia, gastrointestinal disorders, anorexia, lethargy, fatigue, and temporary myopia. Long-term use can easily cause hypokalemia, and potassium salts should be added in time. The drug can reduce uric acid excretion, and exacerbations of gout have been reported during treatment. For diabetic patients with pre-existing kidney disease, renal function can be rapidly reduced. Long-term use of urine is alkaline, calcium phosphate crystals are easy to precipitate, and kidney stones occur, and sometimes acute renal failure can occur. Adverse reactions of sulfa may also occur, such as rash, crystalline urine, agranulocytosis, aplastic anemia, and platelet deficiency.

Acetazolamide dosage

1. Oral administration: (1) open-angle glaucoma: the first dose of 250 mg, 1 to 4 times a day. The maintenance dose should be determined according to the patient's response to the drug. Try to use smaller doses to control the intraocular pressure, generally 250mg each time, twice daily to keep the intraocular pressure in the normal range; (2) secondary glaucoma and IOP reduction before surgery: 250mg each time, 2 times a day; (3) Acute cases: double the initial dose to 500mg, and then switch to a maintenance amount of 125-250mg, once every 4 hours; (4) treatment of cardiogenic edema : 250 ~ 500mg each time, once a day, the best effect after taking breakfast; (5) Treatment of cerebral edema: 250mg each time, 2 to 3 times a day; (6) Treatment of peptic ulcer: 500mg each time, 3 times a day 3 weeks is a course of treatment, and the pain disappears in 7-9 days. During the medication period, 2 g of sodium bicarbonate, 1 g of sodium citrate, 1 g of potassium bicarbonate, 1.5 g of magnesium oxide, and 1500 to 2000 ml of water can be used in combination to prevent water and electrolyte disorders. Prevent familial periodic palsy: Adults take 250 to 750 mg per day in 2 to 3 doses.

2. Intravenous injection: For the rescue of acute glaucoma and some patients with nausea and vomiting that prevent oral administration, acetazolamide 500mg can be injected intravenously or intramuscularly, or 250mg intravenously and 250mg intramuscularly can be used alternately. For some acute-onset glaucoma patients, the above dose can be repeated within 2 to 4 hours, but the continuous treatment should be changed to oral dosage according to the condition of the patient.

3. Intramuscular injection: same as intravenous injection.

4. Children: (1) Oral administration: anti-glaucoma, orally administered 5 to 10 mg / kg or 300 to 900 mg / m orally daily in divided doses. (2) Intravenous injection: anti-acute glaucoma, often intravenously according to body weight, 5 to 10 mg / kg each time, once every 6 hours. (3) Intramuscular injection: see intravenous injection.

Acetazolamide drug interactions

1. Combined with corticotropin, glucocorticoid, mineralocorticoid, can cause severe hypokalemia and cause osteoporosis. When combined with the above drugs, attention should be paid to monitoring the concentration of blood potassium and cardiac function.

2. When combined with amphetamine, anti-M-choline drugs (especially atropine), quinidine, etc., it can form alkaline urine, thereby reducing excretion of acetazolamide and aggravating the adverse reactions of acetazolamide.

3. Since acetazolamide can cause hyperglycemia and urine sugar, the dosage of antidiabetic drugs should be adjusted when combined with antidiabetic drugs (such as insulin).

4. Combined with phenobarbital, carbamazepine, or phenytoin sodium can cause an increase in the incidence of osteomalacia.

5. Combined with digitalis, it can increase the toxicity of digitalis and hypokalemia.

6. Combined with mannitol or urea, it can increase the amount of urine while enhancing the effect of reducing intraocular pressure.

Acetazolamide poisoning

Acetazolamide (acetazolamide, acetazamide) is a carbonic anhydrase inhibitor. Inhibiting carbonic anhydrase in renal tubular epithelial cells, reducing the formation of H and HC03, slowing the exchange of Na and H, reducing the reabsorption of Na, increasing the excretion of Na, K, H2O and HC03, resulting in diuretic effects. Sometimes used to treat brain edema and mild cardiogenic edema.

This medicine inhibits the carbonic anhydrase in the ciliary body cells, reduces the production of aqueous humor, and reduces the intraocular pressure, so it is mainly used to treat glaucoma. It is also used as an antiepileptic drug. Oral LD50> 1.0g / kg in mice, and LD50> 2g / kg in dogs. The drug is completely excreted by the kidneys within 24 hours without accumulation. Oral glaucoma and cerebral edema are usually taken 0.25 g each time, 1 to 2 / d. Mainly damage the central nervous system, blood system, liver and kidney.

Clinical manifestation

Adverse reactions are as follows:

Central nervous system

Occasionally numbness of the face and limbs, tingling sensation, lethargy, fatigue, weakness, dizziness, loss of orientation, depression, muscle weakness, retarded paralysis, ataxia, etc.

2. Digestive system

Anorexia, nausea, vomiting, dry mouth, thirst, diarrhea, etc .; may have gastric ulcer gastrointestinal bleeding, cholestatic jaundice; patients with liver cirrhosis can induce hepatic encephalopathy.

3. Blood system

Bone marrow suppression, granulocytopenia, leukopenia, thrombocytopenic purpura, bleeding, megaloblastic anemia, aplastic anemia, etc. are produced.

4. Urinary system

Frequent urination, polyuria, urine sugar, anuria, hematuria, crystalline urine and urinary stones, kidney stones, renal colic.

5. Other

Slow heart rate, hyperglycemia, hyperuricemia exacerbates gout, abnormal liver function, deafness, temporary myopia, and increased serum bilirubin, increased excretion of calcium, potassium, magnesium, and sodium, while increased concentrations of chlorine produce low potassium Anemia, hyperchloric acidosis.

treatment

The main points of treatment for acetazolamide poisoning are:

1. Stop the medicine immediately.

2. Rehydration, potassium supplementation, correction of dehydration and acidosis, maintaining water and electrolyte balance.

3. If bone marrow suppression appears, glucocorticoids, vitamin B6, inosine, nucleotide tablets, etc. are given, and a small amount of fresh blood is transfused if necessary.

4. If an allergic reaction occurs, give anti-allergic treatment.

5. Other symptomatic and supportive treatments ^[2] .

Acetazolamide Expert Reviews

Acetazolamide is a carbonic anhydrase inhibitor and is a sulfa derivative. By inhibiting carbonic anhydrase in the cells of the ciliary body of the eye, the formation of carbonic acid is reduced, HCO3 is reduced, and the production of aqueous humor is reduced due to osmotic pressure, thereby reducing intraocular pressure. It is often used clinically in combination with a miotic agent or other intraocular pressure-lowering drugs. Commonly used in all types of glaucoma and intraocular surgery before hypotension and delayed anterior chamber formation.

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