What Is Enalapril?

This product is an angiotensin converting enzyme inhibitor (ACEI). It is hydrolyzed into enalapril in the body after oral administration, which strongly inhibits angiotensin converting enzyme, reduces the content of angiotensin , causes systemic vasodilation and decreases blood pressure, and is used to treat hypertension.

Chinese name: Enalapril
English name: Enalapril
nickname: Phenylpropionate
Chemical formula: C20H28N2O5

Molecular weight: 492.51900
CAS Registry Number: 75847-73-3
Boiling point: 582.4 ° C at 760 mmHg
Density: 1.204g / cm3
Flash point: 306 ° C

About Enalapril Compounds

Enalapril Basic Information

Chinese name:

Chinese alias: (S) -1- (N- (1- (ethoxycarbonyl) -3-phenylpropyl) -L-alanyl) -L-proline; phenylbutyric acid; Ennap Lee; Phenylproproate; Intraoral; Inver; Yue Ningding; Phenylproline; Elapiride maleate; Enalapril maleate

English name: enalapril

English alias: Amprace; Vaseretic; Vasotec; Relpax; [3H] -Eletriptan; Enalapril; N-[(S) -1- (ethoxycarbonyl) -3-phenylpropyl] -L-alanyl-L-proline; Eletriptan [INN: BAN ]; Renitec; Innovace; Inovoril; Invoril; Mkozl; Vascare; ENAM; Xanef; MK-421

CAS number: 75847-73-3

Molecular formula: C ₂₄ H ₃₂ N ₂ O ₉

Structural formula:

Molecular weight: 492.51900

Exact mass: 492.21100

PSA: 170.54000

LogP: 1.64520

InChI: InChI = 1 / C20H28N2O5 / c1-3-27-20 (26) 16 (12-11-15-8-5-4-6-9-15) 21-14 (2) 18 (23) 22- 13-7-10-17 (22) 19 (24) 25 / h4-6,8-9,14,16-17,21H, 3,7,10-13H2,1-2H3, (H, 24,25 ) / t14-, 16-, 17- / m0 / s1

Physical properties of enalapril

Density: 1.204g / cm ³

Melting point: 143-144.5ºC

Boiling point: 582.4ºC at 760 mmHg

Flash point: 306ºC

Refractive index: 1.549

Vapor pressure: 2.1E-14mmHg at 25 ° C

Storage conditions: Keep in a cool, dry and dark place in a sealed container. Keep away from fire. Security and labeling area.

Enalapril safety information

Symbol: GHS07 GHS08

Signal Word: Warning

Hazard statement: H317; H361

Cautionary Statement: P280

Safety instructions: S22-S24 / 25 ^[1]

Enalapril production method

Method 1: Ethyl -oxophenylbutyrate and L-alanyl-L-proline dipeptide are condensed under the action of a 4A molecular sieve to form Schiff's base. If further salted with maleic acid, enalapril maleate can be obtained.

Method 2: Ethyl -bromophenylbutyrate and L-alanyl-L-proline dipeptide can also be condensed in dimethylformamide solution under the action of triethylamine. Puli.

Method 3: The above methods all require phenylbutyric acid derivatives. When the raw materials are limited, the following methods can be used. The benzene was acylated with butadiene anhydride to form benzoylacrylic acid with a yield of 90.1%. -benzoylacrylic acid, absolute ethanol, benzene and concentrated sulfuric acid are separated under reflux. Neutralize with sodium hydroxide solution, wash with saturated sodium chloride and water, dry, and filter. The filtrate was concentrated under reduced pressure, and a fraction of 148 to 150 ° C / 133 Pa was collected by distillation to obtain -benzoyl acrylate, with a yield of 97.3%. -Ethyl benzoyl acrylate, benzyl alanine p-toluenesulfonate, anhydrous ethanol and triethylamine were mixed and stirred at room temperature. The solid was filtered and dried to obtain compound (I) in a yield of 75%. Compound (I), sulfuric acid, glacial acetic acid, and a 10% palladium-carbon catalyst were passed through hydrogen. It was filtered, and the filtrate was concentrated to dryness under reduced pressure, and washed after alkali treatment. Recrystallization from ethyl acetate gave compound (II) in a yield of 52.6%. Compound (II) and N-hydroxysuccinimide were dissolved in dimethylformamide, and dicyclohexylcarbodiimide (DCC) was added in portions under ice-cooling, and stirred at room temperature. Add L-proline tetramethylammonium dimethylformamide solution under ice-cooling, and react. The solid was filtered off, treated with acid and alkali, and extracted with ethyl acetate. The extract was dried and concentrated under reduced pressure. The residual liquid was dissolved in acetonitrile, and a solution of maleic acid in acetonitrile was added, and the mixture was left to stir overnight. The solid was obtained by filtration and recrystallized from acetonitrile to obtain enalapril maleate in white needle crystals with a yield of 46.7%. The above compound (11) is directly condensed with proline tert-butyl ester in the presence of DCC, and then hydrolyzed to remove tert-butanol to obtain enalapril ^[1] .

Enalapril use

Angiotensin-converting enzyme inhibitor (ACE-I) is the second ACE-I on the market after Captopril. The effect of treating hypertension is similar to captopril, but it is stronger than captopril, and the effect is slow and long-lasting. Like captopril, a diuretic dihydrochlorothiazide compound (trade name Vaseretic, marketed in 1988) can generally improve the efficacy by 15% -30%. It is used for primary, renal hypertension, renal vascular hypertension, malignant hypertension, etc.It is also suitable for congestive heart failure, especially hypertensive patients with high renin and hypercalcemia requiring long-term medication, digitalis and diuretics Patients with congestive heart failure who are not treated with drugs can also be used in patients who cannot tolerate captopril ^[1] .

Enalapril drug description

Enalapril classification

Circulatory System Drugs> Cardiovascular Dilation Drugs> Angiotensin Converting Enzyme Inhibitors

Enalapril dosage form

Tablet: 2.5mg, 5mg, 10mg, 20mg.

Enalapril Pharmacodynamics

Antihypertensive, this product hydrolyzes to enalapril in the liver, becoming a competitive vascular tight

Enalapril Intensin converting enzyme inhibitor prevents angiotensin from converting to angiotensin , resulting in increased plasma renin activity, decreased aldosterone secretion, and decreased vascular resistance. Enalapril also interferes with the degradation of bradykinin, which also reduces vascular resistance. Although this product is believed to reduce blood pressure mainly by inhibiting the renin-angiotensin-aldosterone system, it is also effective for hypertension with low renin activity.

Reduce the heart load. This product dilates arteries and veins during heart failure, reduces peripheral vascular resistance or afterload, reduces pulmonary capillary entrapment or preload, and reduces pulmonary vascular resistance, thereby improving cardiac output and exercise tolerance time Extend ^[2] .

Enalapril pharmacokinetics

After oral administration, the product absorbs about 60%, and the absorption is not affected by food in the gastrointestinal tract. This product absorbs

Enalapril Enalapril dicarboxylate, which is produced after hydrolysis in the liver, has a stronger inhibitory effect on angiotensin-converting enzyme than this product, but oral enalapril has extremely poor absorption. After taking this product orally, the blood concentration reaches a peak about 1 hour, while the peak blood concentration of enalapril is 3 to 4 hours. The majority of Enalapril has an effective half-life of 11 hours after giving this product. After oral administration of one dose of this product, the antihypertensive effect begins at 1 hour and reaches a peak in 4 to 6 hours. When administered at the recommended dosage, the antihypertensive effect can be maintained for more than 24 hours. Excreted by the kidney, about 94% of the oral dose is present in the urine and feces with this product or enalapril, without other metabolites. When the glomerular filtration rate is reduced to less than 30 ml per minute, the peak time and steady state time are delayed. Enalapril is cleared by dialysis at a rate of 62 ml per minute. This product does not easily cross the blood-brain barrier, and enalapril does not enter the brain ^[2] .

Enalapril pharmacological action

This product is an angiotensin-converting enzyme inhibitor. It is hydrolyzed into enalapril in the liver after oral administration.

Enalapril And make a difference. The latter has an inhibitory effect on angiotensin-converting enzyme more than 8 times that of captopril. The antihypertensive action mechanism is the same as that of captopril, but the action time is long. This product lowers blood pressure while maintaining myocardial contractility without affecting cardiac output. In patients with congestive heart failure, the peripheral vascular resistance and pulmonary capillary wedge pressure can be reduced, thereby reducing the pre- and post-load of the heart and improving cardiac function. This product can increase renal blood flow without significant effects on blood glucose, uric acid and cholesterol metabolism.

Enalapril indication

For the treatment of hypertension, it can be used alone or in combination with other antihypertensive drugs such as diuretics.

Enalapril

For the treatment of heart failure, it can be used alone or in combination with diuretics.

This product is suitable for the treatment of patients with various degrees of hypertension, renal vascular hypertension and diabetes with hypertension; it can also be used for the treatment of chronic congestive heart failure, especially those who are difficult to control with digitalis or diuretics. Can delay the clinical progress of congestive heart failure symptoms and reduce the need for hospitalization. Because the effect of this product is better than captopril, and the adverse reactions are relatively light, it is increasingly used, and it is the first choice for the treatment of hypertension.

Enalapril dosage

Commonly used amount for adults: Hypertensive, oral 5mg once a day, once a day, and then adjusted with blood pressure response

Enalapril Take the whole dose to 10-40mg daily, taking 2-3 times. If the effect is still not satisfactory, diuretics can be added. When the renal function is impaired, the initial dose is 5mg when the creatinine clearance is 30-80ml per minute. For example, if the creatinine clearance is <30ml per minute, the initial dose is 2.5mg. In dialysis patients, the daily dialysis dose is 2.5mg.

For the treatment of heart failure, the starting dose is 2.5mg once a day or 1-2 times a day. Pay attention to blood pressure within 2-3 hours after administration, especially those who use diuretics to prevent hypotension. The general daily dosage is 5-20mg, divided into two oral doses.

Enalapril is prohibited with caution

(1) This product can pass through the placenta. Inadequate research in humans, but in pregnancy

Enalapril The late use of this product has reported neonatal hypotension, renal failure, cranial dysplasia, or death, and oligohydramnios also occurs. Therefore, the use of this product during pregnancy must be weighed against the pros and cons.

(2) This product can be drained into breast milk, so the use of this product by lactating women must be weighed against the pros and cons.

(3) The application research of this product in children is not enough.

(4) The elderly are more sensitive to the antihypertensive effect, and the dosage of this product must be reduced accordingly.

(5) Use this product with caution:

Use of this product when renal function declines may cause oliguria and progressive azotemia, and most of them can recover after stopping this product;

The blood potassium is too high, there is a danger of exacerbation with this product;

Insufficient blood supply to the cerebral arteries or coronary arteries. In severe cases, this product may increase ischemia due to lower blood pressure;

Aortic valve stenosis may reduce coronary perfusion after using this product. May cause teratogenicity, be used with caution by lactating women. Those who are allergic to this product and bilateral renal artery stenosis should not use it; pregnant women, lactating women and children, and those with severe liver and kidney dysfunction should be used with caution.

Enalapril dosing instructions

The dosage should be adjusted according to the individual effect according to the principle of individualization.

The antihypertensive effect of this product is the same in the standing position and the supine position, and there is no orthostatic hypotensive response.

It is recommended to stop using other antihypertensive drugs for 1 week before starting treatment with this product.

For patients with malignant hypertension or severe hypertension who cannot stop taking antihypertensive drugs for a long time, the minimum dose of this product is given immediately after stopping the drug, and the dose is increased every 24 hours under close observation until the effect is sufficient or the maximum dose is reached.

During surgery or anesthesia, if hypotension occurs in patients taking this product, it can be corrected by dilatation.

Enalapril Patients with poor renal function should take a small dose or reduce the number of doses or increase the interval between doses, and slowly increase; if you need to use diuretics at the same time, it is recommended to use furosemide instead of thiazines. Reduce the amount of this product or stop using diuretics.

If proteinuria is getting worse, consider suspending or reducing the dosage.

In renal insufficiency, diabetes, and those who use potassium-sparing diuretics, pay attention to produce high blood potassium.

The use of this product for the treatment of heart failure has the advantages of no fluid retention and no increase in blood aldosterone levels, but attention must be paid to the hypotensive response.

If the white blood cell count decreases when using this product, it can be recovered after stopping the medicine.

Follow-up inspection during the use of this product:

Urine protein test, once a month.

Patients with kidney disease or collagenous vascular disease regularly check the white blood cell count. Regular white blood cell count and renal function tests. Renal hypofunction can be removed by dialysis when drug accumulation occurs.

Enalapril adverse reactions

(1) The more common ones are: dizziness, headache, fatigue, and cough, all of which are mild and transient.

(2) Less common: muscle spasms, nausea, fatigue, upright discomfort, impotence, and diarrhea.

Enalapril

(3) Rare: syncope, orthostatic hypotension, palpitations, tachycardia; vomiting, indigestion, dry mouth, constipation, insomnia, nervousness, paresthesia; rash, itching; rare neurovascular edema, if it occurs It can be fatal in the throat. This product should be discontinued immediately after the occurrence of angioedema, and treated quickly. Subcutaneous injection of 1: 1000 adrenaline injection 0.3-0.5ml.

Dizziness, headache, also burnout, fatigue, hypotension and orthostatic hypotension, syncope, nausea, diarrhea, myalgia spasm, rash and cough. Can cause renal failure, symptoms disappear (return to normal) after withdrawal. Can cause angioedema, peripheral nerve paralysis, purpura. Mainly rash, taste disorders, dizziness, headache, cough, drowsiness, dry mouth, epigastric discomfort, nausea, chest tightness or chest pain, proteinuria, fatigue, fatigue, low blood pressure, etc., can generally be tolerated or only need to be symptomatic deal with. Occasionally urea urea, creatinine or alanine aminotransferase, aspartate aminotransferase increased slightly. If leukopenia or angioedema (especially in the throat) occurs, the drug should be stopped immediately.

Enalapril drug interactions

1. The antihypertensive effect is strengthened when used with other antihypertensive drugs. Among them, the antihypertensive effect is greater when used with drugs that cause renin release or affect sympathetic activity. The same use with -blocker drugs does not enhance its effect. Buck effect.

2. With the use of diuretics, the antihypertensive effect is enhanced, which can cause severe hypotension. Before starting treatment, diuretics should be discontinued or reduced. The starting dose of enalapril should be small, and then gradually adjusted according to blood pressure.

3. The same use with potassium-releasing diuretics can reduce potassium loss, but the same use with potassium-sparing diuretics, potassium supplements and potassium salt preparations can cause significant increase in blood potassium. Patients with heart failure treated with enalapril should generally not use potassium-sparing diuretics.

4. With the use of lithium can cause lithium poisoning, toxic reactions can disappear after withdrawal.

5. Captopril and allopurinol can cause hypersensitivity reactions. Care should also be taken when using enalapril.

6. Combination of azathioprine and angiotensin-converting enzyme inhibitors can increase bone marrow suppression.

7. Captopril combined with bupivacaine can cause severe bradycardia, hypotension, and even loss of consciousness due to the inhibition of the renin-angiotensin system. Enalapril should also be used with bupivacaine.

8. Enalapril has been reported to increase the toxicity of clomipramine.

9. Trimethoprim and ACE inhibitors can cause significant hyperkalemia. Therefore, patients who use enalapril should add trimethoprim or compound sulfamethoxazole to methamidazole. Monitor closely or avoid co-use.

10. Combined with cyclosporine can reduce kidney function.

11. It has been reported that patients with non-insulin-dependent diabetes mellitus with hypertension and renal insufficiency caused high potassium lactic acidosis after using enalapril and metformin simultaneously.

12. Rifampicin can reduce the efficacy of enalapril.

13. Non-steroidal anti-inflammatory drugs, especially indomethacin, can inhibit the synthesis of renal prostaglandins, causing water and sodium retention, thereby reducing the antihypertensive effect of enalapril. Aspirin can also significantly reduce the antihypertensive effect of enalapril, which should be paid attention to when used together.

14. Ephedra contains ephedrine and pseudoephedrine, which can reduce the efficacy of antihypertensive drugs. Patients with hypertension treated with enalapril should avoid using ephedra-containing preparations.

15. Enalapril has no obvious interaction with digoxin, mibediril, sevelamer, tamsulosin, etc. ^[3] .

Enalapril poisoning

Enalapril (phenyl propionate, enalapril, phenbutyl proline, Yue Ning Ding, MK-421) is a potent angiotensin-converting enzyme inhibitor that does not contain thiol groups. Puliqiang 10 times, slow and long-lasting antihypertensive effect, can be used to treat hypertension and congestive heart failure. About 60% was absorbed orally, peaked at 3.5-4.5h, and half-life was llh. Oral 10mg, 1 / d. Increase the daily dose to 40 mg according to the patient's condition. The oral LD50 of the mice was 3696 mg / kg, and the intravenous LD50 was 859 mg / kg.

Clinical manifestation

Adverse reaction

Headache, dizziness, fatigue, nausea, diarrhea, skin flushing, muscle cramps; dry cough, dry throat, and itching.

2. Poisoning performance

(1) The first dose can cause severe hypotension, increased potassium, and arrhythmia.

(2) Impaired liver and kidney function.

(3) Nerve-like edema of the face, extremities, lips, tongue, glottis and or laryngeal blood vessels can occur. If accompanied by laryngeal edema, it can cause suffocation and death.

treatment

The main points of treatment of enalapril poisoning are:

1. In case of a large number of accidental ingestion, prompt vomiting, gastric lavage, and infusion to accelerate drug excretion.

2. Hypotension, patient lying supine, volume expansion and pressure medication. Angioedema, the application of antihistamine drugs, such as edema occurred in the tongue, glottis or throat can cause airway obstruction, should be given subcutaneously 1: 1000 epinephrine (0.3 ~ 0.5ml), if necessary, sugar Corticosteroids.

3. Dry cough, inhalable sodium cromoglycate and application of cough suppressant.

4. Hyperkalemia patients can apply potassium-releasing diuretics, such as furosemide, dihydroketrazia, orally or intravenously, and intravenous drip of 10% glucose ^[4] .

Enalapril expert review

Enalapril controls blood pressure by dilating blood vessels, is safe and effective for mild and moderate hypertension, and is listed as a first-line treatment. Its advantages are that it also has anti-congestive heart failure and can eliminate the original left ventricular hypertrophy. Slow down the development of renal failure. Captopril is preferred when hypertension is associated with congestive heart failure and left ventricular hypertrophy ^[3] .