What Factors Affect a Sufficient Bumetanide Dose?

Bumetanide, also known as butylamine furosemide, bupropion acid, is a white or off-white chemical powder chemical. Chemical name 5-n-butylamino-4-phenoxy-3-aminosulfonylbenzoic acid, molecular formula is C ₁₇ H ₂₀ N ₂ O ₅ S, molecular weight 361.41600, insoluble in water, soluble in ethanol and acetone, slightly soluble In dichloromethane. Bumetanib is a powerful fast-acting diuretic. It is mainly used in the treatment of heart failure, liver disease, kidney disease edema, including various refractory edema and acute pulmonary edema. It is especially suitable for patients with acute and chronic renal failure.

Chinese name: Bumetani
Foreign name: Bumetanide

CAS number: 28395-03-1
Molecular formula: C17H20N2O5S
Molecular weight: 361.41600

Basic information

Chinese name

Chinese alias: powerful fast-acting diuretic; 5-n-butylamino-4-phenoxy-3-aminosulfonylbenzoic acid; 3- (aminosulfonyl) -5- (butylamino) -4-phenoxybenzene Formic acid; 3-n-butylamino-4phenoxy-5-aminosulfonylbenzoic acid;

English name: bumetanide

English alias: Fordiuran; Bumetanide; 3- (Aminosulfonyl) -5- (butylamino) -4-phenoxybenzoic acid; 3- (butylamino) -4-phenoxy-5-sulfamoylbenzoic acid; Bumetanida;

CAS number: 28395-03-1

Molecular formula: C ₁₇ H ₂₀ N ₂ O ₅ S

Chemical structure:

Molecular weight: 361.41600

Exact mass: 361.10900

PSA: 127.10000

LogP: 1.89060 ^[1]

Physical properties of bumetanide

Appearance and properties: crystalline solid

Density: 1.347g / cm ³

Melting point: 230-231 ° C

Boiling point: 571.2ºC at 760mmHg

Flash point: 299.3ºC

Refractive index: 1.612

Stability: Stable at normal temperatures and pressures.

Storage conditions: storeroom ventilated, low temperature and dry

Vapor pressure: 6.89E-14mmHg at 25 ° C ^[1]

Bumetani calculation chemical data

1. Hydrophobic parameter calculation reference value (XlogP): 2.8

2.Number of hydrogen-bonded donors: 3

3.Number of hydrogen bond acceptors: 7

4.Number of rotatable chemical bonds: 8

5.Number of tautomers: none

6. Topological molecular polar surface area 127

7.Number of heavy atoms: 25

8.Surface charge: 0

9.Complexity: 528

10.Number of isotope atoms: 0

11. Determine the number of atomic stereocenters: 0

12. Uncertain number of atomic stereocenters: 0

13. Determine the number of chemical bond stereocenters: 0

14. Uncertain number of chemical bond stereocenters: 0

15. Number of covalent bond units: 1 ^[2]

Bumetani production method

O-Chloro-m-carboxybenzenesulfonyl chloride is synthesized by the reaction of p-chlorobenzoic acid and chlorosulfonic acid. Nitrification with mixed acid produces 2-chloro-3-nitro-5-carboxybenzenesulfonyl chloride. Sulfonyl chloride was aminated with ammonium hydroxide to give 2-chloro-3nitro-5-hydroxy-benzimidamide. Reduction of the nitro group with sodium bisulfite produces ethyl-chloro-3-amino-5-carboxybenzenesulfonamide. Then it reacts with butanol to form ethyl-chloro-3-butylamino-5-carboxylic acid butylbenzenesulfonamide. Hydrolysis with sodium hydroxide to form ethyl-chloro-3-butylamino-5-hydroxy-benzenesulfonamide. Finally, it reacts with phenol to form butyroxy acid.

Bumetanide Bumetanide Drug Analysis

1 Bumetani 1. Identification

(1) Take about 1mg of this product, add 2ml of absolute ethanol to dissolve it, and inspect under ultraviolet light (365nm), showing purple fluorescence.

(2) Take about 5mg of this product, add 1 drop of sodium formate alkaline solution (take 5g of sodium formate and 6g of sodium hydroxide, add water to dissolve to 100ml), slowly heat to dry, continue to heat until it is gray and slightly carbonized, and let cool. Add 0.5ml of sulfuric acid solution (1 2) to acidify, add 0.5ml of water, filter, place the filtrate on the drip reaction plate, add 1 drop of potassium ferricyanide test solution, it will be green, and a blue precipitate will gradually form.

(3) The infrared light absorption spectrum of this product should be consistent with the control spectrum ("Infrared Spectra of Drugs" 86).

2 Bumetani 2, check

2.1 Clarity and color of alkaline solution

Take 50mg of this product, add 1ml of potassium hydroxide test solution and 9ml of water to dissolve, the solution should be clear and colorless; if it is turbid, compare with No. 1 turbidity standard solution (Appendix B of Part Two of the Pharmacopoeia of 2010 Edition), it must not be more concentrated ; If the color is developed, it must not be deeper compared with the orange yellow standard colorimetric solution No. 1 (Appendix A of the 2010 edition of the Pharmacopoeia, Section II A).

2.2 Chloride

Take 0.25g of this product, place it in a 50ml conical flask, add 25ml of water, shake it for about 10 minutes, and filter. The filter residue and the conical flask are washed with a small amount of water, filtered, and the washing solution and the filtrate are combined, and checked according to law. (Appendix A of Part Two of the 2010 Pharmacopoeia), compared with a control solution made of 5.0 ml of a standard sodium chloride solution, it must not be more concentrated (0.02%).

2.3 Aromatic primary amines

Take 40mg of this product, place it in a 10ml volumetric flask, add ethanol to dissolve and dilute to the mark, shake well, take 1ml accurately, place in a 10ml volumetric flask, add 3ml of hydrochloric acid solution (9 100) and 4% sodium nitrite solution 0.5 ml, shake well, let stand for 2 minutes, add 1 ml of 10% ammonium sulfamate solution, shake well, let stand for 5 minutes, add 2 ml of dilute ethanol solution of 2% naphthyl ethylenediamine dihydrochloride, shake well, let stand for 2 minutes, Dilute with water to the mark, shake well, and measure the absorbance at a wavelength of 518nm according to the UV-Vis spectrophotometry (Appendix IV A of Part Two of the Pharmacopoeia 2010), which should not be greater than 0.19.

2.4 Related substances

Take about 12.5mg of this product, weigh it accurately, place it in a 50ml measuring bottle, add mobile phase to dissolve and dilute to the mark, shake well, as the test solution; take an appropriate amount of precise amount, add mobile phase to quantitatively dilute it into each 1ml A solution containing 0.5 g was used as a control solution. According to high-performance liquid chromatography (2010 edition Pharmacopoeia Part II Appendix V D) test. Octadecylsilane-bonded silica gel was used as the filler, methanol-0.1% trifluoroacetic acid solution (58:42) was used as the mobile phase, and the detection wavelength was 220 nm. The number of theoretical plates is not less than 3,000 based on the calculation of the bumetanide peak, and the resolution of the bumetanib peak and the adjacent impurity peaks should meet the requirements. Take 20l of the control solution and 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 test solution and the control solution, and inject them into the liquid chromatograph Record the retention time of the chromatogram to the peak of the main component 3 times. If there is an impurity peak in the chromatogram of the test solution, the area of the single impurity peak must not be larger than the area of the main peak of the control solution (0.2%), and the sum of the area of each impurity peak must not be larger than the control Double the area of the main peak of the solution (0.4%).

2.5 Loss on drying

Take this product and dry it to constant weight at 105 ° C, and the weight loss shall not exceed 0.5% (Appendix L of Pharmacopoeia Part II of 2010 Edition).

2.6 Ignition residue

Take 1.0g of this product and check it according to law (Appendix N of Part Two of the 2010 Pharmacopoeia). The residual residue shall not exceed 0.1%.

2.7 Heavy metals

Take the residue left under the burning residue and inspect it according to law (Appendix H of the 2010 edition of the Pharmacopoeia, the second method). The heavy metal must not exceed 10 parts per million.

2.8 Arsenic salts

Take 1.0g of this product, add 1.0g of calcium hydroxide, add a small amount of water, stir well. After drying, first carbonize with a small fire, then burn to an off-white at 500 600 , let cool, add 8ml of hydrochloric acid and 20ml of water After dissolving, check according to law (Appendix J First Law of Pharmacopoeia Part II of the 2010 edition), and it should meet the requirements (0.0002%).

3 Bumetani 3, content determination

Take about 0.5g of this product, accurately weigh, add 60ml of neutral ethanol (p-cresol red indicator solution is neutral), add 5 drops of cresol red indicator solution, and use sodium hydroxide titration solution (0.1mol / L ) Titrate until the solution is red. Each 1ml of sodium hydroxide titration solution (0.1mol / L) is equivalent to 36.44mg of C17H20N2O5S.

4 Bumetani 4, category

Diuretics.

5 Bumetani 5, storage

Shaded and sealed.

6 Bumetani 6, preparations

(1) Bumetanib tablets (2) Bumetanib injection

7 Bumetani 7, version

The 2010 Edition of the Pharmacopoeia of the People's Republic of China ^[3]

Related information for Bumetane

1 Bumetani 1, drug instructions

1.1 Drug name

Bumetani

1.2 English name

Bumetanide

1.3 Bumetani's alias

Butylamine furosemide; Butyric acid; Buturamine; Buturamine; Buturic acid; Bumex

1.4 Classification

Circulatory Drugs> Antihypertensive Drugs> Diuretic Antihypertensive Drugs

1.5 dosage form

1. Injection: 0.5mg each;

2. Tablet: 1mg.

1.6 Pharmacological effects of bumetanide

It is a derivative of m-aminobenzenesulfonamide and is a potent diuretic. The diuretic mechanism is related to the inhibition of Na-K-ATPase activity. It mainly affects the process of urine concentration and dilution by inhibiting the active reabsorption of Cl- and the passive reabsorption of Na by the thick segment of the ascending branch of the myelinary ridge. It also acts on proximal tubules, and also has a certain renal vasodilator effect. During the initial stage of diuresis, the excretion of Cl- increased by 20 times, and the excretion of Na + increased by 13 times. When the medication was continued, there was no more Cl- in urine than Na. Bumetanide inhibits carbonic anhydrase less than furosemide, so its potassium loss is also lighter than furosemide. 1 mg of bumetanide is equivalent to 40 mg of furosemide.

1.7 Pharmacokinetics of Bumestanib

After oral administration, 95% was rapidly absorbed by the gastrointestinal tract, with a bioavailability of 95% and a protein binding rate of 95%. Diuretic effect occurred within 30 minutes after taking the drug. The plasma concentration reached a peak of 1 to 2 hours, and the effect lasted for 4 to 6 hours. The diuretic effect occurred after intravenous injection for 5 minutes, peaked at 30 minutes, and the effect was maintained for 2 to 3 hours. About 45% of the oral dose is excreted as it is. Elimination half-life is 1 to 1.5 hours, prolonged renal failure.

1.8 Indications for Bumetani

For the treatment of heart failure, liver disease, kidney disease and edema. Mainly used for various refractory edema and acute pulmonary edema. It is especially suitable for patients with acute and chronic renal failure.

1.9 Contraindications for Bumetani

Those who are allergic to sulfa, hepatic encephalopathy, hypovolemia, and urethral obstruction are contraindicated, and pregnant women are contraindicated.

1.10 Notes

1). Monitor blood sodium, potassium, and renal function, especially in patients at risk for such symptoms. Hypokalemia should be supplemented with potassium or potassium diuretics.

2). Blood glucose and urine glucose should be monitored in patients with diabetes and gout.

3). When patients with renal insufficiency use large doses, skin, mucous membranes and myalgia may occur; most of them disappear on their own after lasting 1 to 3 hours. If pain is severe or lasts longer, the drug should be discontinued.

4). The effect of antihypertensive drugs can be strengthened. Therefore, the amount of antihypertensive drugs should be reduced when treating edema in patients with hypertension.

5). It is not advisable to add this product to an acidic infusion for intravenous drip to avoid precipitation.

1.11 Adverse Reactions of Bumetanib

1). Adverse effects of this drug are similar to furosemide, but its toxicity is low and its side effects are few.

2). Adverse reactions are the same as furanilide, such as causing low salt syndrome, hypochloremia, hypokalemia, hyperuricemia and hyperglycemia. However, the incidence of hypokalemia is lower than that of thiazide diuretics and furanilic acid. Those who apply this product for a long time or a large amount should regularly check the electrolyte.

3). A few people may have transient neutropenia and thrombocytopenia; occasional nausea, vomiting, male breast development, rash and other adverse reactions.

1.12 Dosage of Bumetanib

1). Adults take 0.5 2mg each time, preferably in the morning. If necessary, the interval is 4 to 5 hours, and the second and third times can be given. The maximum daily dose is 10mg.

2). Intravenous injection: 0.5 ~ 1mg each time, the second and third times can be given every 2 ~ 3h, but the daily dosage should not exceed 10mg. Should not be compatible with acidic liquids to avoid precipitation.

1.13 Interactions of Bumestanib with Other Drugs

Furosemide

1.14 Drug Evaluation

See furosemide. ^[4]

2 Bumetani 2, Pometani poisoning

Bumetanide (butyric acid, buturamine) is a myelin diuretic, and its mechanism of action and characteristics are similar to furosemide. It is mainly used to treat various refractory edema and acute pulmonary edema, especially suitable for patients with acute and chronic renal failure. The drug is absorbed quickly and completely by oral administration, and is excreted mainly in the form of the kidney. It can excrete 65% of the dosage within 24 hours. Plasma half-life is 1.5h, oral LD50 of mice is 1.62 to 1.67g / kg, intraperitoneal injection and intravenous injection> 50mg / kg; rat LD50 is 6.0g / kg orally, intraperitoneal injection> 30mg / kg, intravenous injection> 25mg / kg. The usual amount is 0.5 to 1 mg orally, 1 to 3 / d; the intravenous injection is 0.5 to 1 mg / time. Mainly affect water and salt metabolism, leading to hypochloremia and hypokalemia.

2.1 Clinical manifestations

Adverse reactions are as follows:

1). Abnormal metabolism can cause hypokalemia, hypochloremia, hyponatremia, hyperuricemia and hyperglycemia.

2). Others have fatigue, diarrhea, muscle cramps, vomiting, etc., transient myalgia or arthralgia, nausea, vomiting, and dizziness at high doses; a few patients may have temporary granulocytopenia or thrombocytopenia, rash, urticaria , Itching and so on. Occasional male breast development.

2.2 Treatment

The main points for the treatment of Bumetani poisoning are:

1. Rehydration and potassium supplementation to correct water and electrolyte imbalances.

2. Symptomatic treatment. ^[5]

Bumetani drug analysis

Method name: Bumestanib APIDetermination of BumestanilNeutralization Titration

Scope of application: This method uses titration to determine the content of bumetanide in the drug substance.

This method is applicable to Bumestanib drug substance.

Principle of the method: After the test sample is dissolved with neutral ethanol, a cresol red indicator liquid is added, and then titrated with a sodium hydroxide titration solution. The content of bumetanide is calculated according to the amount of the titration solution used.

Reagent: 1. Neutral ethanol

2. Cresol Red Indicator Solution

3. Sodium hydroxide titration solution (0.1mol / L)

4. Phenolphthalein indicator liquid

5. Reference potassium phthalate

equipment:

Sample preparation: 1. Cresol red indicator liquid

Take 0.1g of cresol red, dissolve by adding 5.3mL of 0.05mol / L sodium hydroxide solution, and dilute to 100mL with water.

2. Sodium hydroxide titration solution (0.1mol / L)

Preparation: Take an appropriate amount of sodium hydroxide, add water and shake to dissolve it into a saturated solution. After cooling, place it in a polyethylene plastic bottle and let it stand for several days. Take 5.6mL of a clear saturated sodium hydroxide solution, add freshly boiled cold water to 1000mL, and shake well.

Calibration: Take about 0.6g of standard potassium hydrogen phthalate dried to constant weight at 105 ° C, weigh it accurately, add 50mL of freshly boiled cold water, shake it to dissolve it as much as possible, add 2 drops of phenolphthalein indicator solution, When this solution is titrated, when the end point is reached, potassium hydrogen phthalate should be completely dissolved and titrated until the solution becomes pink. Each 1mL of sodium hydroxide titration solution (0.1mol / L) is equivalent to 20.42mg of potassium hydrogen phthalate. Calculate the concentration of this solution based on the consumption of this solution and the amount of potassium hydrogen phthalate taken.

Storage: Put it in a polyethylene plastic bottle and keep it in a sealed container. There are 2 holes in the plug. One glass tube is inserted into the hole. One tube is connected to the soda lime tube. One tube is used to suck out the liquid.

Sodium hydroxide titration solution (0.01mol / L or 0.05mol / L) can be prepared by diluting sodium hydroxide titration solution (0.1mol / L) with fresh boiling cold water.

3. Phenolphthalein indicator liquid

Take 1 g of phenolphthalein and add 100 mL of ethanol to dissolve.

Operation steps: Precisely weigh about 0.1g of the test sample, add 25mL of neutral ethanol (p-cresol red indicator solution is neutral), add 3-4 drops of cresol red indicator solution, and use sodium hydroxide titration solution ( 0.01mol / L) Titrate until the solution becomes red. Each 1mL of sodium hydroxide titration solution (0.01mol / L) is equivalent to 3.644mg of C17H20N2O5S.

Note: "Precision weighing" means that the weighed weight should be accurate to one thousandth of the weighed weight. "Precision measurement" means that the accuracy of measuring the volume should meet the accuracy requirements of the volume pipette in national standards. ^[6]

Bumetani clinical study

Indications of Bumetanide

1. Edema diseases include congestive heart failure, liver cirrhosis, kidney disease (nephritis, nephropathy, and acute and chronic renal failure caused by various reasons), especially when other diuretics are not effective, the use of this class of drugs is still possible effective. Combined with other drugs to treat acute pulmonary edema and acute brain edema.

2. Hypertension is not the drug of choice for the treatment of essential hypertension in the ladder therapy of hypertension, but when thiazide drugs are not effective, especially when accompanied by renal insufficiency or hypertension crisis Especially applicable.

3 Prevention of acute renal failure is used for various reasons leading to insufficient renal blood perfusion, such as dehydration, shock, poisoning, accidental anesthesia, and circulatory insufficiency. It can be applied in a timely manner while correcting insufficient blood volume to reduce the incidence of acute tubular necrosis opportunity.

4 Hyperkalemia and hypercalcemia.

5. Dilute hyponatremia, especially when the blood sodium concentration is below 120 mmol / L.

6. Antidiuretic hormone hypersecretion (SIADH).

7. Acute drug poisoning, such as barbiturate poisoning.

8. It may still be effective for some cases of furosemide.

Bumetani chemical composition

The main ingredients of this product are: Bumetani. Its chemical name is: 5-n-butylamino-4-phenoxy-3-aminosulfonylbenzoic acid.

Molecular formula: C17H20N2O5S

Molecular weight: 364.42

Pharmacological effects of bumetanide

The effect on water and electrolyte excretion is basically the same as furosemide, and its diuretic effect is 20 to 60 times that of furosemide. It mainly inhibits the active reabsorption of NaCl by the thick-walled section of the ascending branch of the renal tubular pulp, and also inhibits Na + reabsorption of the proximal tubule, but has no effect on the distal renal tubule, so the potassium excretion effect is less than furosemide. It can inhibit the activity of prostaglandin degrading enzymes, increase the content of prostaglandin E2, and thus have a vasodilator effect. Dilatation of renal blood vessels, reduction of renal vascular resistance, and increase of renal blood flow, especially deep renal cortex blood flow, have important significance in the diuretic effect of bumetanide, and it is also the theoretical basis for its prevention of acute renal failure. In addition, unlike other diuretics, diuretics do not decrease the glomerular filtration rate while the renal tubular fluid flow increases, which may be related to the reduction of chlorine flowing through dense plaques, which weakens or blocks the bulb-tube balance. Bumetanide can expand the volume of the veins in the lungs, reduce pulmonary capillary permeability, and its diuretic effect can reduce the amount of return to the heart and reduce the left ventricular end-diastolic pressure, which is helpful for the treatment of acute left heart failure. Because bumetanide can reduce pulmonary capillary permeability, it provides a theoretical basis for the treatment of adult respiratory distress syndrome.

Bumetani drug interactions

1 Adrenal glucose, mineralocorticoids, adrenocorticotropic hormones and estrogen can reduce the diuretic effect of this drug and increase the chance of electrolyte disturbances, especially hypokalemia.

2 Non-steroidal anti-inflammatory analgesics can reduce the diuretic effect of this drug, and the chance of kidney damage is also increased, which is related to the former inhibiting prostaglandin synthesis and reducing renal blood flow.

3 In combination with sympathomimetic drugs and anticonvulsants, diuretic effect is weakened.

4 When used in combination with clobetin (amtox), the effects of both drugs are enhanced, and muscle soreness and rigidity can occur.

5 In combination with dopamine, the diuretic effect is strengthened.

6 Drinking and alcohol-containing preparations and drugs that can cause blood pressure can enhance the diuretic and hypotensive effects of this drug; combined with barbiturates and anesthetics, it can easily cause orthostatic hypotension.

7 This medicine can reduce the excretion of uric acid and increase the blood uric acid. Therefore, when it is used in combination with drugs for treating gout, the dosage of the latter should be adjusted appropriately.

8 The efficacy of hypoglycemic agents.

9 The effect of reducing anticoagulant drugs and antifibrinolytic drugs is mainly related to the decrease in blood volume after diuresis, the increase of blood coagulation factor concentration, and the improvement of liver blood supply and increased synthesis of coagulation factors in the liver by diuresis.

10 This medicine strengthens the effect of non-depolarizing muscle relaxants, which is related to the decrease of blood potassium.

11 Combined with antibiotics such as amphotericin, cephalosporin, and aminoglycosides, renal toxicity and ototoxicity increase, especially when the original kidney is damaged.

12 When combined with antihistamines, ototoxicity increases, and tinnitus, dizziness, and dizziness are easy to occur.

13 The nephrotoxicity with lithium is significantly increased and should be avoided as much as possible.

14 Intravenous injection of this drug after taking chloral hydrate can cause sweating, flushing, and increased blood pressure. This is related to an increase in thyroxine from a bound state to a free state, which leads to increased catabolism.

15 Increased chance of hypochlorine alkalosis in combination with sodium bicarbonate.