What Is Esmolol?

The chemical name of Esmolol is methyl 4- (3-isopropylamino-2-hydroxypropoxy) phenylpropanoate, the molecular formula is C16H25NO4, the molecular weight is 295.37400, the density is 1.026, the melting point is 48-50ºC, The boiling point is 430.2ºC at 760 mmHg, the flash point is 214ºC, and the vapor pressure is 3.62E-08mmHg at 25 ° C.

Chinese name: Esmolol
Foreign name: Esmolol

CAS number: 81147-92-4
Molecular formula: C16H25NO4

Introduction to esmolol compounds

Basic information of esmolol

Chinese name

English name: Esmolol

English alias: methyl 3- <4- <2-hydroxy-3- (isopropylamino) propoxy> phenyl> propionate; 5-Isothiazolecarboxylic acid, 3- (2-methyl-4-thiazolyl)-, methyl ester; methyl3- <4 -(2-methylthiazolyl)> isothiazole-5-carboxylate; methyl 4- [2-hydroxy-3-[(1-methylethyl) amino] -propoxy] benzenepropanoate;

CAS number: 81147-92-4

Molecular formula: C ₁₆ H ₂₅ NO ₄

Molecular weight: 295.37400

Structural formula:

Exact mass: 295.17800

PSA: 67.79000

LogP: 1.92080 ^[1]

Esmolol molecular structure data

1. Molar refractive index: 81.73

2. Molar volume (cm / mol): 272.3

3. Isotonic specific volume (90.2K): 683.2

4. Surface tension (dyne / cm): 39.5

5. Polarizability (10-24cm3): 32.40 ^[2]

Esmolol physical and chemical properties

Density: 1.026

Melting point: 48-50ºC

Boiling point: 430.2ºC at 760 mmHg

Flash point: 214ºC

Vapor pressure: 3.62E-08mmHg at 25 ° C ^[1]

production method

1. P-hydroxybenzaldehyde and malonic acid are dissolved in toluene. In the presence of an organic base, reflux and condensation decarboxylation yield p-hydroxybenzene acrylic acid. Hydrogenated p-hydroxyphenyl acrylic acid in a mixed solvent of dioxane and water was catalyzed by 10% palladium-carbon to obtain p-hydroxyphenylpropionic acid. Esterification of p-hydroxyphenylpropionic acid and methanol under sulfuric acid catalyzed by reflux to obtain methyl p-hydroxyphenylpropionate, then in an alkaline solution in the presence of cetyltrimethylammonium bromide (CTAB), and epoxy Chloropropane was refluxed to obtain methyl 3 [4 (2,3-glycidoxy) phenyl] propanoate. Finally, it was refluxed with isopropylamine in methanol to obtain esmolol. Saturated hydrogen chloride in ether was added dropwise in methanol to obtain esmolol hydrochloride as a white solid. Or use p-methoxybenzaldehyde as a raw material, and condense with ethyl acetate in the presence of sodium to generate ethyl 3-p-methoxyphenyl acrylate, which is hydrogenated and reduced to ethyl 3-p-methoxyphenylpropionate, and hydrolyzed It produces 3-p-hydroxyphenylpropionic acid, which is methylated, reacts with epichlorohydrin, and finally reacts with isopropylamine to produce esmolol.
2.Using p-methoxybenzaldehyde as raw material, it is condensed with ethyl acetate in the presence of sodium to form ethyl 3-p-methoxyphenyl acrylate, which is hydrogenated and reduced to ethyl 3-p-methoxyphenylpropionate, It is hydrolyzed to produce 3-p-hydroxyphenylpropionic acid, then methylated, and then reacted with epichlorohydrin, and then reacted with isopropylamine to form espart ^[1]

use

Ultrashort-acting -adrenergic blockers. It is easy to be hydrolyzed by esterase to carboxylic acid with almost no -blocking activity in the metabolism in the body. It has fast onset and short duration, with accurate curative effect and small side effects. It selectively blocks 1-receptors, so it has little effect on the bronchus and is beneficial to patients with chronic obstructive pulmonary disease. It is an ideal medicine for the treatment of supraventricular tachyarrhythmias, acute myocardial ischemia, and postoperative hypertension. For patients undergoing coronary artery surgery, the prophylactic use of this product can significantly reduce hypertension, tachycardia and arrhythmia caused by intubation and surgical stimulation. ^[1]

Esmolol compound related drugs

Esmolol drug name:

[General name] Esmolol Hydrochloride Injection

[English name] Esmolol Hydrochloride Injection

[Chinese Pinyin] Yan Suan Ai Si Luo Er Zhu She Ye ^[3]

Esmolol Ingredients:

The main ingredient is esmolol hydrochloride, chemical name: 4- (3-isopropylamino-2-hydroxypropoxy) phenylpropanoic acid methyl ester hydrochloride.
Molecular formula: C ₁₆ H ₂₅ NO ₄ · HCl
Molecular weight: 331.84
The auxiliary materials of this product are: sodium acetate, glacial acetic acid and propylene glycol ^[3]

Esmolol category:

Chemicals & Biological Products >> Circulatory System Drugs >> Antiarrhythmic Drugs >> Antitachycardia Drugs

Traits:

This product is colorless or slightly yellowish clear liquid. ^[3]

Indications for esmolol :

For atrial fibrillation and atrial flutter to control ventricular rate; perioperative hypertension; sinus tachycardia. ^[3]

Isilol specifications:

(1) 1ml: 0.1g
(2) 2ml: 0.2g ^[3]

Esmolol Usage and Dosage:

1. Control ventricular rate during atrial fibrillation and atrial flutter. Adult intravenous load first: 0.5mg / kg / min, about 1 minute, and then intravenous drip maintenance: from 0.05mg / kg / min, if the effect is satisfactory after 4 minutes, continue to maintain, if the effect is not good, repeat administration Load the amount and increase the maintenance amount in the range of 0.05 mg / kg / min. The maintenance amount can be increased up to 0.3 mg / kg / min, but doses above 0.2 mg / kg / min have not been shown to bring significant benefits.
2. Perioperative hypertension or tachycardia (1) Immediately controlled dose: 1mg / kg intravenous injection within 30 seconds, continue to 0.15mg / kg / min static point, the maximum maintenance amount is 0.3mg / kg / min.
(2) Gradually control the dose and treat supraventricular tachycardia.
(3) The amount of hypertension is usually larger than that of arrhythmia. ^[3]

Esmolol adverse reactions:

Most adverse reactions were mild and transient. The most important adverse reaction is hypotension. Deaths have been reported using esmolol alone to control ventricular rate.
1. Adverse reactions with incidence> 1%: hypotension (63%) during injection, persistent hypotension (80%) after stopping medication, asymptomatic hypotension (25%), symptomatic hypotension (sweating, dizziness) ) (12%), sweating with hypotension (10%), injection site reactions include inflammation and intolerance (8%), nausea (7%), dizziness (3%), and lethargy (3%).
2. 1% of adverse reactions: peripheral ischemia, unconsciousness, headache, irritability, fatigue, and vomiting.
3. Adverse reactions with incidence <1%: hemiplegia, weakness, depression, abnormal thinking, anxiety, lack of appetite, mild headache, seizures, trachea spasm, snoring, dyspnea, nasal congestion, dry rales, wet rales , Indigestion, constipation, dry mouth, abdominal discomfort, perverted taste, edema, erythema, skin discoloration, burning sensation at the injection site, thrombophlebitis and extravasated skin necrosis, urinary retention, speech impairment, visual abnormality, middle scapula Pain, chills, fever. ^[3]

Esmolol contraindications:

1. Bronchial asthma or a history of bronchial asthma.
2. Severe chronic obstructive pulmonary disease.
3. Sinus bradycardia.
4. Second to third degree AV block.
5. Refractory cardiac insufficiency.
6. Cardiogenic shock.
7. People who are allergic to this product ^[3]

Note on esmolol :

1. High concentration administration (> 10mg / ml) will cause severe venous reactions, including thrombophlebitis. A concentration of 20mg / ml outside the blood vessels can cause serious local reactions and even necrosis. medicine.
2. The acidic metabolites of this product are eliminated by the kidney, and the half-life (t _1/2 ) is about 3.7 hours. Patients with renal disease are about 10 times normal. Therefore, patients with renal failure should pay attention to monitoring this product.
3. Care should be taken in the application of diabetic patients, as this product can mask the hypoglycemic response.
4. Bronchial asthma patients should be used with caution.
5. Monitor blood pressure, heart rate, and cardiac function during medication.
6. Use with caution by athletes. ^[3]

Esmolol medication for pregnant and lactating women:

The teratogenicity of this product in rats has been studied. It was administered intravenously at a dose of 3mg / kg / min for 30 minutes a day. No toxicity and teratogenic effects on pregnant and fetal rats were found. However, a dose of 10 mg / kg / min was toxic to pregnant rats and fatal. Teratogenicity studies on rabbits found that intravenous drips given at a dose of 1 mg / kg / min lasted 30 minutes a day, and no toxicity and teratogenic effects on pregnant and fetal rabbits were found. However, the dose of 2.5 mg / kg / min was toxic to pregnant rabbits and caused an increase in fetal rabbit mortality. There is no suitable human research on this issue. It is unknown whether this product is secreted by breast milk, and should be used with caution by lactating women. ^[3]

Esmolol for children:

The application of this product in children has not been fully studied. ^[3]

Esmolol elderly medication:

The application of this product in the elderly has not been fully studied. However, the elderly are sensitive to the effects of lowering blood pressure and heart rate, and their renal function is poor, so caution should be taken when using this product. ^[3]

Esmolol drug interactions:

1. Combined with sympathetic ganglion blockers, there will be a synergistic effect, and hypotension, bradycardia, and syncope should be prevented.
2. When used in combination with warfarin, the blood concentration of this product seems to increase, but it has little clinical significance.
3. When combined with digoxin, the blood concentration of digoxin can increase by 10% -20%.
4. When combined with morphine, the steady-state blood concentration of this product will increase by 46%.
5. Combined with succincholine can prolong the neuromuscular block effect of succincholine for 5-8 minutes.
6. This product will reduce the efficacy of adrenaline.
7. The combination of this product and verapamil for cardiac dysfunction can cause cardiac arrest. ^[3]

Esmolol overdose:

It can be fatal in a single dose of 12-50mg / kg. Cardiac arrest, bradycardia, hypotension, electromechanical separation, and loss of consciousness occur when the drug is overdose. This product has a short half-life, so it should be stopped immediately to observe the clinical effect. Atropine can be given for bradycardia; 2 receptor agonists or theophylline can be used for asthma; diuretics and digitalis can be used for patients with cardiac insufficiency; dopamine, dobutamine, isobutyramine can be given to shock patients Adrenaline, amrinone and other treatments. ^[3]

Esmolol pharmacology and toxicology:

1. Pharmacological effect Esmolol hydrochloride injection is a selective ₁ adrenergic blocker with a rapid onset of action and a short duration of action. It mainly acts on the ₁ epinephrine receptor of the myocardium, and also blocks the ₂ epinephrine receptor of trachea and vascular smooth muscle at high doses. There was no intrinsic sympathomimetic or membrane stabilization at the therapeutic dose. It can reduce the heart rate of normal people during exercise and resting, and counteract the increase of heart rate caused by isoproterenol. Its hypotensive effect is related to the degree of -adrenergic blockade. The blocking effect of -adrenergic receptors disappeared 10-20 minutes after the intravenous injection was stopped.
Electrophysiological studies suggest that esmolol hydrochloride injection has a typical -adrenergic blocker effect: reducing heart rate, reducing sinus node self-regulation, extending sinus node recovery time, prolonging sinus rhythm and atrial rhythm The AH interval at this time extends the forward cyclic transmission period.
Radionuclide cardiopulmonary angiography indicates that at a dose of 0.2mg / kg / min, this product can reduce resting heart rate, systolic blood pressure, heart rate blood pressure product, left and right ventricular ejection fraction, and heart index. Propranolol (propranolol) is similar. In exercise state, esmolol hydrochloride injection is similar to propranolol, which can slow the heart rate, lower the heart rate blood pressure product and the cardiac index, but it has a more significant effect on reducing systolic blood pressure. Cardiovascular angiography: at a dose of 0.3mg / kg / min, in addition to the above effects, this product can also cause a slight increase in left ventricular end-diastolic pressure and pulmonary wedge pressure. Hemodynamic parameters 30 minutes after withdrawal That is fully restored.
2. Carcinogenicity, mutagenicity and reproductive toxicity Due to the ultra-short-term use of esmolol hydrochloride injection, there have been no research results on its carcinogenicity, mutagenicity and affecting reproduction. ^[3]

Esmolol pharmacokinetics:

This product is rapidly metabolized in the body and is mainly metabolized by the esterase in the cytoplasm of red blood cells, which hydrolyzes its ester bonds. Its total clearance in the human body is about 20L / kg / hr, which is greater than the cardiac output, so the metabolism of this product is not affected by the blood flow of metabolic tissues (such as liver and kidney). The distribution half-life (t _1/2 ) of this product is about 2 minutes, and the elimination half-life (t _1/2 ) is about 9 minutes. After an appropriate loading, followed by a static dose of 0.05-0.3mg / kg / min, the product can reach a steady-state blood concentration within 5 minutes (if no loading is required, it takes 30 minutes to reach a steady-state blood drug concentration). Beyond the above-mentioned doses, the steady-state blood drug levels increased linearly, but clearance was independent of doses. This product has a short half-life. The steady-state blood drug concentration can be maintained by continuous intravenous drip, and the blood drug concentration can be changed quickly by changing the intravenous drip rate.
This product is metabolized into acidic metabolites and methanol in vivo, and its acid metabolites have only 1/1500 of the original drug's activity in the body, so there is no beta adrenergic blockade in normal humans. Within 24 hours after administration, about 73-88% of the drug is excreted from the urine as acidic metabolites, and only 2% is excreted from the urine in its original form. The elimination half-life of acidic metabolites (t _1/2 ) is about 3.7 hours, and in patients with kidney disease, it is about 10 times normal. About 55% of this product binds to plasma proteins, and its acidic metabolites bind to 10% of plasma proteins. ^[3]

Clinical evaluation of esmolol

[Clinical evaluation] The clinic is composed of Union Medical College Hospital and Fuwai Hospital of Chinese Academy of Medical Sciences, Zhongshan Hospital of Shanghai Medical University, First and Third Hospitals of Beijing Medical University, Friendship Hospital of Capital Medical University, Shandong Provincial Hospital, and Affiliated Hospital of Shandong Medical University The multi-center collaboration group observed a total of 225 cases of supraventricular arrhythmia treated with esmolol intravenously, with a total effective rate of 74.6%, of which 49 cases (sinus that occurred during the perioperative period, especially during induction of anesthesia and trachea Patients with tachycardia) were randomized and compared with imported esmolol, a total of 49 pairs. Results The total effective rate of the domestic esmolol group was 87.8%, and the imported group was 93.9%, P> 0.05; another 35 patients were randomized. Comparing the group with domestic metoprolol, a total of 35 pairs, the results of the esmolol treatment group were significantly effective in 15 cases, effective in 11 cases, and ineffective in 9 cases. The metoprolol group was 20, 9, and 6 cases, respectively. Efficiency is similar. Clinical results show that esmolol is effective in treating supraventricular arrhythmias, and most patients are well tolerated, and the incidence of adverse reactions is 6.2%. Nausea, chest tightness, sweating, and palpitations occurred in some cases. The incidence of hypotension is 40%.

Shanghai Central Hospital selected 104 patients with elective thoracic and hepatic surgery with ASA grade cardiopulmonary function. They were randomly divided into the intravenous infusion of esmolol (1mg / kg) and the control group. Observation of tracheal intubation after induction of general anesthesia Changes in heart rate and mean arterial pressure immediately, 1, 3, and 5 minutes. Results: The heart rate and mean arterial pressure were significantly different between the treatment group and the control group. Perioperative sinus tachycardia was found in 24 patients with HR> 120bpm for 10 minutes. After intravenous injection with esmolol, the effect was significant in 14 minutes. 14 %, 85.7% in 3 minutes and 100% in 5 minutes. Nine of the 24 patients had a 10-minute increase in heart rate after medication, and retreated with 0.5 mg / kg esmolol.