What Is Spironolactone?

Synthetic steroid, a low-efficiency diuretic, has a structure similar to aldosterone and is a competitive inhibitor of aldosterone. Since this medicine only acts on the distal tubules and collecting ducts, it has no effect on other sections of the renal tubules, so the diuretic effect is weak. In addition, the drug also has effects on aldosterone target organs other than renal tubules.

Chinese name: Spironolactone
Chinese alias: Spironone

English name: Spironolactone
Molecular formula: C24H32O4S

Introduction of Spirolactone Compounds

Spirolactone Basic Information

Chinese name: spironolactone

Chinese alias: 17beta-hydroxy-3-oxo-7alpha- (acetylthio) -17alpha-pregn-4-ene-21-carboxylic acid-gamma-lactone; (7, 17) -7- (acetylthiol) -17-Hydroxy-3-oxoprogesterone-4-ene-21-carboxylic acid -lactone; spironolactone; Aldactone; spironolactone; spironosteroid sterol; spironosteroid

English name: Spironolactone

English alias: 7-alpha-Acetylthio-3-oxo-17-alpha-pregn-4-ene-21,17-beta-carbolactone; S- (10,13-dimethyl-3,5'-dioxo-1,2 , 3,4 ', 5', 6,7,8,9,10,11,12,13,14,15,16-hexadecahydro-3'H-spiro [cyclopenta [a] phenanthrene-17,2'- furan] -7-yl) ethanethioate; S-[(7R, 8R, 9S, 10R, 13S, 14S, 17R) -10,13-dimethyl-3,5'-dioxo-1,2,3,4 ', 5 ', 6,7,8,9,10,11,12,13,14,15,16-hexadecahydro-3'H-spiro [cyclopenta [a] phenanthrene-17,2'-furan] -7-yl ] ethanethioate; S-[(7R, 9S, 10R, 13S, 14S, 17R) -10,13-dimethyl-3,5'-dioxo-1,2,3,4 ', 5', 6,7,8 , 9,10,11,12,13,14,15,16-hexadecahydro-3'H-spiro [cyclopenta [a] phenanthrene-17,2'-furan] -7-yl] ethanethioate; spironolactone; Antisterone; ALDACTONE ; Aldonar; Verospiron; spirolang

CAS: 52-01-7

Molecular structure ^[1]

EINECS: 200-133-6

Molecular formula: C ₂₄ H ₃₂ O ₄ S

Molecular weight: 416.5735

Exact mass: 416.20200

PSA: 85.74000

LogP: 4.85230 ^[2]

Spirolactone physicochemical properties

Appearance and properties: white powder with slight thiol odor

Density: 1.24g / cm ³

Melting point: 207-208 ° C (lit.)

Boiling point: 597ºC at 760mmHg

Flash point: 302.3ºC

Refractive index: -36 ° (C = 1, CHCl3)

Solubility: very soluble in chloroform, easily soluble in benzene or ethyl acetate, soluble in ethanol, insoluble in water.

Stability: Stable under normal temperature and pressure.

Storage conditions: storeroom is ventilated, low-temperature and dry, and stored separately from food ingredients ^[2]

Spironolactone Safety Information

Customs code: 2937290090

WGK Germany: 3

Danger category code: R40; R60

Safety instructions: 53-22-36 / 37 / 39-45-36-26

RTECS number: TU4725000

Dangerous goods mark: T ^[2]

Spironolide drug determination

Method name: Determination of spironolactone content-spectrophotometric method.

Application : This method uses spectrophotometry to determine the content of spironolactone. This method is suitable for spironolactone.

Principle of the method : The test product is dissolved and diluted in ethanol and placed in a spectrophotometer. The absorbance is measured at a wavelength of 238 nm. The content is calculated based on the absorption coefficient of C ₂₄ H ₃₂ O ₄ S being 471.

Reagent : absolute ethanol.

Equipment : UV-visible spectrophotometer.

Operating steps : 1. Precise measurement of the test sample Take the above test solution, measure the absorbance at 238nm, and calculate the content according to the absorption coefficient of C ₂₄ H ₃₂ O ₄ S ^[ 471 ^] .

Spironolactone Pharmacopoeia Standard

Spirolactone source content

This product is 17-hydroxy-3-oxo-7- (acetylthio) -17-pregn-4-en-21-carboxylic acid -lactone. Calculated on dry basis, C ₂₄ H ₃₂ O ₄ S should be 97.0% 103.0%.

Spirolactone properties

This product is white or off-white fine crystalline powder; it has a slight mercaptan odor.

This product is extremely soluble in chloroform, easily soluble in benzene or ethyl acetate, soluble in ethanol, and insoluble in water.

5.5.1 Melting point

The melting point of this product (Appendix VIC of Part Two of the 2010 Pharmacopoeia) is 203 to 209 ° C, and it will decompose at the same time when melting.

5.5.2 Specific rotation

Take this product, accurately weigh it, add chloroform to dissolve and quantitatively dilute it to make a solution containing about 10mg per 1ml, and measure it according to law (Appendix VI E of the Pharmacopoeia Part II of the 2010 edition), with a specific rotation of -33 ° to -37 °.

Spirolactone identification

(1) Take 10mg of this product, add 2ml of sulfuric acid, shake well, the solution is orange-yellow, with strong yellow-green fluorescence, slowly heating, the solution will turn deep red, and hydrogen sulfide gas will be generated. In case of wet lead acetate test paper, Dark black; pour this solution into about 10 ml of water to make a yellow-green emulsion.

(2) In the chromatogram recorded under the content determination item, the retention time of the main peak of the test solution should be consistent with the retention time of the main peak of the reference solution.

(3) The infrared light absorption spectrum of this product should be the same as that of the control ("Infrared Spectra of Medicine" 582).

Spironolactone inspection

Crystal fineness

Take an appropriate amount of this product, place 1 drop of water on the slide glass, cover the cover glass and press it properly, place it under the microscope field of view with a micrometer to check, first move up and down, left and right, count in the field of view with uniform crystal distribution, first Count above 10 m, and count below 10 m. As a result of counting, the crystals below 10 m should not be less than 90%.

Mercapto compound

Take 2.0g of this product, add 30ml of water, shake, filter, take 15ml of filtrate, add 2ml of starch indicator solution, titrate with iodine titrant (0.005mol / L), and correct the titration result with blank test. The consumption of iodine titrant (0.005mol / L) shall not exceed 0.10ml.

relative substance

Take about 62.5mg of this product, accurately weigh it, put it in a 25ml measuring bottle, add 2.5ml of tetrahydrofuran to dissolve it, dilute to the mark with mobile phase, shake well, and use it as the test solution; take 1ml of precise quantity and place it in a 100ml measuring bottle , Dilute to the mark with mobile phase, shake well, as the control solution (1); Measure 0.5ml of control solution (1) precisely, place in a 10ml volumetric flask, dilute to the mark with mobile phase, shake well, and use as the control solution (2 ); Take about 25mg of cannidone reference substance, weigh it accurately, place it in a 10ml volumetric flask, add 1.0ml tetrahydrofuran to dissolve it, dilute to the mark with mobile phase, shake well, and use it as the reference solution (1); 1ml of test solution (1), placed in a 100ml volumetric flask, diluted with mobile phase to the mark, shake well, as the reference solution (2); take 1ml each of the test solution and the reference solution (1), and place in a 100ml volumetric bottle Medium, dilute to the mark with mobile phase, shake well, and use it as the system suitability test solution. According to the high performance liquid chromatography (2010 Pharmacopoeia Part II Appendix VD) test, octylsilane-bonded silica gel was used as the filler, acetonitrile-tetrahydrofuran-water (8:18:74) was used as the mobile phase, and the flow rate was per minute. 1.8ml, detection wavelength is 254nm. Take 20l of the system suitability test solution, inject it into the liquid chromatograph, and record the chromatogram. The resolution of the spironolactone peak and the canrenone peak should be greater than 1.4. Precisely measure 20 l each of the test solution, the control solution (1), the control solution (2), and the reference solution (2), and inject them into the liquid chromatograph respectively. Record the chromatogram to the peak retention time of the main component of the test solution. 2 times. The signal-to-noise ratio of the main peak in the chromatogram of the control solution (2) should be greater than 6. If there is an impurity peak in the chromatogram of the test solution, the sum of the areas of the impurity peaks must not be greater than the area of the main peak of the control solution (1), except for the cannidone peak and the chromatographic peak smaller than the area of the main peak of the control solution (2). ); Switch the detection wavelength to 283nm, and accurately measure 20l each of the test solution and the reference solution (2), and inject them into the liquid chromatograph, record the chromatogram. 2) In the chromatogram, the peak with the same retention time of the canlidone peak should not be larger than the reference solution (2) the main peak area (1.0%); the total amount of impurities detected at the wavelengths of 254nm and 283nm should not be greater than 1.0%.

remaining solvent

Methanol, ethanol, acetone, ethyl acetate, tetrahydrofuran, pyridine and dimethylformamide

Take about 1g of this product, weigh it accurately, place it in a 20ml headspace bottle, and add the internal standard solution precisely (take an appropriate amount of n-propanol, weigh it accurately, and dilute with dimethyl sulfoxide to make a solution containing about 1mg per 1ml. 1ml), quantitatively diluted to 10ml with dimethyl sulfoxide, sealed with a lid, shaken to dissolve, as a test solution; take methanol, ethanol, acetone, ethyl acetate, tetrahydrofuran, pyridine and two Methylformamide reference, accurately weighed, and quantitatively diluted with dimethyl sulfoxide to make methanol, ethanol, acetone, and ethyl acetate in about 1mg per 1ml, containing tetrahydrofuran, pyridine, and dimethylformamide, respectively Approximately 0.07mg, 0.02mg, and 0.09mg solutions: precisely measure 5ml, place it in a 20ml headspace bottle, precisely add 1ml of internal standard solution, quantitatively dilute to 10ml with dimethyl sulfoxide, seal with a lid, shake well, As a reference solution. Tested according to the residual solvent determination method (Appendix P of Part Two of the Pharmacopoeia, 2010 Edition). A capillary column with 6% cyanopropylphenyl-94% dimethylpolysiloxane (or similar polarity) as the fixed liquid was used as the column. The column temperature was 40 ° C and maintained for 8 minutes at 45 ° C per minute. The temperature was raised to 200 ° C for 3 minutes; the detector temperature was 250 ° C, the inlet temperature was 200 ° C, the headspace bottle equilibrium temperature was 80 ° C, and the equilibration time was 30 minutes. Precisely measure the headspace of the test solution and the reference solution, and record the chromatogram. Calculate the peak area according to the internal standard method. It contains methanol, ethanol, acetone, ethyl acetate, tetrahydrofuran, pyridine, and dimethylformamide. All should meet the requirements.

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).

Residue on ignition

Must not exceed 0.1% (Appendix N of Part Two of the 2010 Pharmacopoeia).

Determination of spironolactone

It was determined by high performance liquid chromatography (Appendix D, Part Two of the Pharmacopoeia, 2010 Edition).

Chromatographic conditions and system suitability tests

Octadecylsilane-bonded silica gel was used as the filler; acetonitrile-water (50:50) was used as the mobile phase; the detection wavelength was 238 nm. The number of theoretical plates calculated from the spironolactone peak is not less than 3000, and the resolution of the spironolactone peak and the adjacent impurity peaks should meet the requirements.

Assay

Take an appropriate amount of this product, accurately weigh it, add mobile phase to dissolve and quantitatively dilute it to make a solution containing about 25g per 1ml. Precisely measure 20l into the liquid chromatograph and record the chromatogram; take another spironolactone reference substance and measure the same . Calculate the peak area according to the external standard method.

Spirolactone category

Diuretics.

Spironolactone storage

Keep sealed.

Spironolactone

(1) Spironolactone tablets (2) Spironolactone capsules

Spironolactone version

The 2010 Edition of the Pharmacopoeia of the People's Republic of China ^[4]

Spirolactone Drug Description

Spirolactone Classification

Urinary System Drugs> Diuretics> Low-Effective Diuretics

Spironolactone dosage form

1. Tablet: 20mg;

2. Capsule: 20mg.

Spironolactone pharmacological action

Spirolactone is a steroid and is a strong endogenous salt corticosteroid aldosterone. Spironolactone has a similar chemical structure to aldosterone. It competes with aldosterone for binding to aldosterone receptors in the cortical segment epithelium of distal tubules and collecting ducts, thereby inhibiting aldosterone's role in promoting K-Na exchange. Increased Na and Cl excretion, diuretic effect, while K is retained. The drug has a weak diuretic effect, slow and long-lasting. After continuous administration, the diuretic effect gradually weakened. At the same time, it has anti-androgenic activity, which can selectively destroy testicles and adrenal microsomal cytochrome P450, thereby inhibiting the production of androgens by the gonads, and can compete with dihydrotestosterone for receptors at target tissues, reducing the stimulation of sebaceous glands by androgens ^5] .

Spironolactone pharmacokinetics

The drug is well absorbed orally, about 65%, bioavailability is greater than 90%, plasma protein binding rate is more than 90%, and 80% is rapidly metabolized by the liver into active canrenone after entering the body. Oral 1 It takes effect around the day and reaches its peak on 2 to 3 days. The effect can be maintained for 2 to 3 days after stopping the drug. The half-life varies according to the method of taking the medicine, with an average of 19 hours (13 to 24 hours) when taken once or twice a day, and shortened to 12.5 hours (9 to 16 hours) when taken four times a day. Inactive metabolites are excreted from the kidney and biliary tract, and about 10% are excreted from the kidney in their original form.

Spironolactone indications

1. Edema disease is used in combination with other diuretics to treat edema diseases such as congestive edema, ascites due to cirrhosis of the liver, and renal edema. The purpose is to correct the increase in secondary aldosterone secretion associated with the above diseases, and to combat the excretion of other diuretics. Potassium effect. Also used for the treatment of idiopathic edema.

2. Hypertension is an adjuvant drug for the treatment of hypertension.

3 Primary aldosteronism can be used for the diagnosis and treatment of this disease.

4 Hypokalemia prevention is combined with thiazide diuretics to enhance the diuretic effect and prevent hypokalemia.

It is clinically used to treat refractory edema related to elevated aldosterone, so it is more effective in patients with liver cirrhosis and nephrotic syndrome, and in patients with congestive heart failure unless the secondary aldosterone increases due to sodium deficiency, the effect Both are poor.

Spironolactone dosage

1. adult

For the treatment of edema disease, take 40 to 120 mg daily, divided into 2 to 4 times, for at least 5 days. Adjust the dose later as appropriate.

For the treatment of hypertension, start with 40 to 80 mg per day in divided doses for at least 2 weeks, and adjust the dose as appropriate afterwards. It should not be combined with angiotensin-converting enzyme inhibitors to avoid increasing the chance of developing hyperkalemia.

For the treatment of primary aldosteronism, the daily dosage of patients before surgery is 100 to 400 mg, divided into 2 to 4 times. Patients who are not suitable for surgery, choose a smaller dose to maintain.

diagnosis of primary aldosteronism. Long-term test, 400mg daily, divided into 2 to 4 times for 3 to 4 weeks. Short-term test, 400 mg daily, divided into 2 to 4 times for 4 consecutive days. The elderly are more sensitive to this medicine, and the starting dose should be small.

2. To treat edema disease in children, start daily by 1-3mg / kg of body weight or 30-90mg / m2 of body surface area in single or divided doses of 2-4 times, and adjust the dosage as appropriate after 5 days. The maximum dose is 3-9 mg / kg or 90-270 mg / kg daily.

Spironolactone is forbidden to use with caution

(1) The drug can pass through the placenta, but the effect on the fetus is unclear. Pregnant women should take medication under the guidance of a physician, and the duration of medication should be as short as possible.

(2) Hyperkalemia and excessive diuresis are more likely to occur in the elderly.

(3) disabled patients with hyperkalemia.

(4) Use with caution when:

no urine;

Renal insufficiency;

Hepatic insufficiency, electrolyte disturbance caused by this drug can induce liver coma;

Hyponatremia;

Acidosis, on the one hand, acidosis can aggravate or promote hyperkalemia caused by this drug; on the other hand, this drug can aggravate acidosis;

breast enlargement or menstrual disorders.

Renal failure and high blood potassium are contraindicated. In elderly patients, daily doses of more than 200 mg, combined with potassium-sparing diuretics or potassium supplements, may cause renal failure and liver function abnormalities, and blood potassium concentrations must be monitored regularly.

Spironolactone adverse reactions

(1) Common are:

Hyperkalemia is most common, especially when taken alone, with a high-potassium diet, with potassium or potassium-containing drugs such as penicillin potassium, and when there is renal impairment, oliguria, or anuria; even with thiazide diuretics Combined use, the incidence of hyperkalemia can still reach 8.6% to 26%, and arrhythmia is the first manifestation. Therefore, potassium and ECG must be closely followed during the medication;

gastrointestinal reactions, such as nausea, vomiting, stomach cramps and diarrhea; peptic ulcers have been reported.

(2) Rarely:

Hyponatremia is rare when applied alone, and the incidence is increased when combined with other diuretics;

Anti-androgen-like effects or effects on other endocrine systems. Long-term use of this drug can cause male breast development, impotence, and low sexual function in men. In women, it can cause breast tenderness, thickening of the voice, increased hair, and menstrual disorders. 2. Decreased sexual performance;

Central nervous system manifestations, long-term or large doses of this drug can cause walking discomfort, headache and so on.

(3) Rarely:

Allergic reactions, rashes and even breathing difficulties;

Temporary elevated plasma creatinine and urea nitrogen are mainly related to excessive diuresis, insufficient effective blood volume, and decreased glomerular filtration rate;

Mild hyperchloric acidosis;

Tumor, breast cancer was reported in 5 patients who took the drug and hydrochlorothiazide for a long time.

Spirolactone precautions

Single application can cause hyponatremia and hyperkalemia, so long-term medication should be regularly measured potassium and sodium ions.

(1) Administration should be individualized and used from the minimum effective dose to reduce the occurrence of side effects such as electrolyte disturbance.

(2) If you take the medicine once a day, you should take it in the morning to avoid increasing the number of urination at night.

(3) The blood potassium concentration of the patient should be known before medication, but in some cases the blood potassium concentration does not represent the potassium content in the body. For example, when potassium is transferred from the cell to the outside of the cell during acidosis, hyperkalemia and acidosis are prone to occur. After correction, blood potassium can drop.

(4) This medicine has a slower effect and a longer maintenance time, so the first day dose can be increased to 2 to 3 times the conventional dose, and the dose can be adjusted later as appropriate. When combined with other diuretics, it can be taken 2 to 3 days before other diuretics. When other diuretics have been applied and this drug is added, the dose of other diuretics can be reduced by 50% in the first 2 to 3 days, and the dose can be adjusted later as appropriate. When discontinued, the drug should be discontinued 2 to 3 days before other diuretics.

(5) If hyperkalemia occurs during medication, the medication should be stopped immediately.

(6) Medication should be taken during or after meals to reduce gastrointestinal reactions and possibly increase the bioavailability of this medicine.

(7) Interference to diagnosis:

Increase the concentration of plasma cortisol by fluorescence method. Therefore, this drug should be discontinued or another measurement method should be used 4-7 days before blood collection.

Increase the following measured values, plasma creatinine and urea nitrogen (especially when the original renal function is impaired), plasma renin, serum magnesium, and potassium; urinary calcium excretion may increase while urinary sodium excretion decreases.

Spironolactone drug interactions

(1) Adrenal corticosteroids, especially those with strong mineralocorticoid effects, can reduce the diuretic effect of this drug, and antagonize the potassium-killer effect of this drug.

(2) Estrogen can cause water and sodium retention, thereby weakening the diuretic effect of the drug.

(3) Non-steroidal anti-inflammatory analgesics, especially indomethacin, can reduce the diuretic effect of this drug and increase renal toxicity when combined.

(4) Sympathomimetic drugs reduce the hypotensive effect of this drug.

(5) Dopamine strengthens the diuretic effect of this drug.

(6) Combined with drugs that cause blood pressure drop, the diuretic and antihypertensive effects are enhanced.

(7) When combined with the following drugs, the chance of developing hyperkalemia increases, such as potassium-containing drugs, stock blood (30mmol / L potassium, such as 65mmol / L potassium for more than 10 days), angiotensin converting enzyme Inhibitor, cyclosporine A.

(8) Combined with glucose insulin solution, alkaline agent, sodium type potassium reduction exchange resin, the chance of developing hyperkalemia is reduced.

(9) This medicine prolongs the half-life of digoxin.

(10) The combination with ammonium chloride is prone to metabolic acidosis.

(11) In combination with nephrotoxic drugs, nephrotoxicity increases.

(12) Sodium glycyrrhizinate and licorice preparations have aldosterone-like effects, which can reduce the diuretic effect of the drug. This product has a weak enzymatic induction effect, accelerates the metabolic degradation of amphibrine and digoxin, and increases the steady-state blood concentration of digoxin by about 30%. Aspirin can block the secretion of Canrenone, the main metabolite of spironolactone, in the renal tubules, and its diuretic effect is weakened. This product can reduce the anticoagulant effect of warfarin by about 25%, counteracting the antiulcer effect of progesterone.

Spirolactone poisoning

Spironolactone (antisol) competes for aldosterone receptors in the epithelial cells of the renal tubules and collecting ducts, reduces the exchange of K + and Na +, and promotes the excretion of Na and Cl to produce diuretics. Due to reduced K excretion, it is a diuretic to protect K. It is mainly used to treat refractory edema related to elevated aldosterone, such as cirrhosis, ascites, nephrotic syndrome, and refractory heart failure. Oral LD50 in mice was> 1.0g / kg, and intraperitoneal injection of LD50 in rats was 0.277g / kg. The usual amount is 20 to 40 mg each time, 3 / d. Mainly affect water and salt metabolism, causing hyponatremia and hyperkalemia

Clinical manifestation

Adverse reactions are as follows:

Central nervous system

Headache, dizziness, weakness, lethargy, insanity and ataxia.

2. Digestive system

Anorexia, nausea, vomiting, stomach cramps, abdominal pain, diarrhea, etc.

3. Endocrine system

Gynecomastia, hyposexuality, impotence, oligospermia; breast enlargement and pain in women, hirsutism in women, irregular menstruation or amenorrhea, induration of the breast, and occasional reports of breast cancer

4. Metabolic abnormalities

Hyponatremia, hyperkalemia, hyperuricemia, elevated blood urea nitrogen, and mild acidosis.

5. Other

Rash, urticaria, fever, eosinophilia, granulocytopenia, lupus erythematosus-like syndrome, etc

treatment

The main points of treatment of spironolactone poisoning are:

1. Those who ingest large doses of poisoning should immediately induce vomiting and gastric lavage.

2. Rehydration, correct hyponatremia, hyperkalemia, and maintain water and electrolyte balance.

3. Other: symptomatic treatment ^[6] .

Spironolide Expert Reviews

Potassium diuretics combined with potassium loss diuretics have an additive effect, while offsetting their respective adverse reactions. In particular, spironolactone has a significant effect on severe CHF by antagonizing the effect of aldosterone. The effective rate of spironolactone in the treatment of acne is 50% to 100%. Combination with other conventional therapies can improve the efficacy. For hirsutism, continuous medication is required for 2 to 12 months. Long-term application should pay attention to its adverse reactions ^[5] .

Spirolactone Clinical Study

Spironolactone is the third drug to reduce mortality in patients with chronic heart failure (CHF) after angiotensin-converting enzyme inhibitors (ACEI) and beta-blockers (BRB). Aldosterone antagonists are recommended as strong indications for heart failure and myocardial infarction. Spironolactone plays an important role in the treatment of heart failure. Studies have found that in patients who have not been treated with digoxin or ACEI, spironolactone has a beneficial trend, but there is no statistical difference. Patients without beta-blockers can benefit from treatment with spironolactone, while patients who use both beta-blockers and spironolactone benefit more. Other studies have found that spironolactone can improve vascular endothelial function and increase endothelial nitric oxide synthesis in patients with heart failure. The incidence of spironolactone in male breast hyperplasia and breast pain is 10%. Spirolactone should not be used when serum creatinine is greater than 2.5 mg and serum potassium is greater than 5.0 mmol / l. In patients with serum creatinine greater than 1.6 mg / dL, serum potassium concentration greater than 4.2 mmol / L, use of high-dose ACEI preparations, or use of non-steroidal painkillers, the use of spironolactone may cause severe hyperkalemia and worsened renal function Should closely monitor blood potassium and renal function, and timely treatment and adjustment of treatment options.