(+-)-1-(Isopropylamino)-3-[4-(2-methoxyethyl)phenoxy]-2-propanol tartrate
(+-)metoprolol-(+)tartrate
CAS: 56392-17-7
Molecular Formula: 2C15H25NO3.C4H6O6
(+-)-1-(Isopropylamino)-3-[4-(2-methoxyethyl)phenoxy]-2-propanol tartrate - Names and Identifiers
| Name | (+-)metoprolol-(+)tartrate |
| Synonyms | Metoprolol tar METOPROLOE TARTRATE Metoproloe Tartrate Metoprolol Tartrate METOPROLOLTARTRATE,USP (+-)metoprolol-(+)tartrate Metoprolol tartrate solution (+-)-1-(Isopropylamino)-3-[4-(2-methoxyethyl)phenoxy]-2-propanol tartrate (±)1-(isopropylamino)-3-[p-(β-methoxyethyl)phenoxy]-2-propanol tartrate salt |
| CAS | 56392-17-7 |
| EINECS | 260-148-9 |
| InChI | InChI=1/2C15H25NO3.C4H6O6/c2*1-12(2)16-10-14(17)11-19-15-6-4-13(5-7-15)8-9-18-3;5-1(3(7)8)2(6)4(9)10/h2*4-7,12,14,16-17H,8-11H2,1-3H3;1-2,5-6H,(H,7,8)(H,9,10)/t;;1-,2-/m..1/s1 |
(+-)-1-(Isopropylamino)-3-[4-(2-methoxyethyl)phenoxy]-2-propanol tartrate - Physico-chemical Properties
| Molecular Formula | 2C15H25NO3.C4H6O6 |
| Molar Mass | 684.82 |
| Density | 1.1946 (rough estimate) |
| Melting Point | 120℃ |
| Boling Point | 695.37°C (rough estimate) |
| Flash Point | 9℃ |
| Water Solubility | Soluble in water (>1000 mg/ml), methanol (>500 mg/ml), chloroform (496 mg/ml), ethanol (31 mg/ml at 25°C), and DMSO (100 mg/ml at 25°C). |
| Solubility | H2O: soluble50mg/mL |
| Appearance | powder |
| Color | white to off-white |
| Maximum wavelength(λmax) | ['223nm(H2O)(lit.)'] |
| Merck | 14,6151 |
| Storage Condition | 2-8°C |
| Stability | Stable. Incompatible with strong oxidizing agents. |
| Refractive Index | 1.5300 (estimate) |
| Use | For the treatment of hypertension |
(+-)-1-(Isopropylamino)-3-[4-(2-methoxyethyl)phenoxy]-2-propanol tartrate - Risk and Safety
| Risk Codes | R11 - Highly Flammable R23/24/25 - Toxic by inhalation, in contact with skin and if swallowed. R39/23/24/25 - |
| Safety Description | S7 - Keep container tightly closed. S16 - Keep away from sources of ignition. S36/37 - Wear suitable protective clothing and gloves. S45 - In case of accident or if you feel unwell, seek medical advice immediately (show the label whenever possible.) S24/25 - Avoid contact with skin and eyes. |
| UN IDs | UN1230 - class 3 - PG 2 - Methanol, solution |
| WGK Germany | 3 |
| RTECS | UB7450100 |
| HS Code | 29225090 |
| Toxicity | LD50 in female mice, male rats (mg/kg): 118, ~90 i.v.; 2090, 3090 orally (Bodin) |
(+-)-1-(Isopropylamino)-3-[4-(2-methoxyethyl)phenoxy]-2-propanol tartrate - Reference Information
| background | due to the negative inotropic effect of β-blockers and the risk of aggravating hemodynamic disorders, it has been contraindicated in patients with CHF. The pathophysiological concept and mechanism of heart failure have made great progress in recent years. It is believed that chronic congestive heart failure reduces arterial and renal blood flow, sympathetic nerve excitement, abnormal neurohumoral regulation, renal-angiotensin-aldosterone system (RAAS) is activated, β-blockers can inhibit sympathetic nerve activity, prevent the toxic effects of catecholamines on myocardium and blood vessels, block the activation of neuroendocrine system, inhibit RAAS, reduce the load before and after the heart, reduce myocardial oxygen consumption, improve myocardial electrical stability, and up-regulate β1 receptor density, restore β1 receptor function and improve diastolic and systolic function. Metoprolol tartrate is a cardioselective β1 receptor blocker that does not have endogenous sympathomimetic activity. It is used in the treatment of patients with heart failure. It blocks the β1 receptor of the glomerular cells and inhibits the over-activated renin-angiotensin-aldosterone system, dilates peripheral blood vessels, reduces sodium retention, reduces the anterior and posterior load of the heart and prevents ventricular remodeling. Metoprolol tartrate reduces the excitability of the excessively elevated sympathetic nervous system, regulates the abnormal changes of myocardial β receptors, and through the improvement of left ventricular diastolic function, it slows the heart rate and improves the diastolic function of the heart. Prevent or reverse ventricular remodeling, so that heart function can be improved. Metoprolol tartrate has weak membrane stability and no intrinsic sympathomimetic activity. Compared with the similar drug propranolol commonly used in clinical practice, in addition to its pharmacodynamic advantages of β1 receptor blockers, It also has its pharmacokinetic advantages, such as weaker first pass effect than propranolol, simple metabolic pathway in vivo, and most metabolites without pharmacological activity. |
| β1 receptor blocker | metoprolol tartrate (metoprolol, metoprolol, metoprolol) is a selective adrenergic β1 receptor blocker, which is rapidly and completely absorbed by mouth. it can be used for the treatment of hypertension, angina pectoris, myocardial infarction, hypertrophic cardiomyopathy, aortic dissection, arrhythmia, hyperthyroidism, cardiac neurosis and other diseases. in recent years, it has also been used for the treatment of heart failure, can reduce mortality. The role of metoprolol is clearly defined in the American Heart Association's guidelines for the control of unstable/non-ST-segment elevated myocardial infarction and acute myocardial infarction. In the past, there were too many concerns about hypotension caused by β-blocker treatment. It was also considered that Oriental people may have racial differences with Westerners in the use of β-blockers. Therefore, β-blockers are used in China. There are fewer patients and the amount of β-blockers used is also lower. Metoprolol tartrate has weak membrane stability and no intrinsic sympathomimetic activity. Compared with the similar drug propranolol commonly used in clinical practice, in addition to its pharmacodynamic advantages of β1 receptor blockers, it also has Its pharmacokinetic advantages, such as weaker first-pass effect than propranolol, simple metabolic pathways in the body, and most metabolites have no pharmacological activity. |
| Pharmacological effects | Metoprolol is a selective β1 receptor blocker, which means that the dose required for metoprolol to affect the β1 receptor of the heart is lower than the dose required for it to affect the β2 receptor in the peripheral blood vessels and bronchus. However, when metoprolol dose increases, its selectivity to β1 receptor will decrease. metoprolol has no β receptor agonist and almost no membrane stabilizing effect. Beta blockers have negative inotropic and negative time-varying effects. Metoprolol treatment weakens the effect of catecholamines, reduces physical and psychological load, thereby reducing heart rate, cardiac output and blood pressure. Under stress conditions accompanied by increased adrenaline secretion, metoprolol does not hinder normal physiological vasodilation. The therapeutic dose of metoprolol has a weaker effect on the contraction of the bronchial muscle system than non-selective β-blockers. This makes it possible for metoprolol to be used in combination with β2 receptor agonists for the treatment of patients with bronchial asthma or other chronic obstructive pulmonary diseases. Metoprolol has less effect on insulin release and carbohydrate metabolism than non-selective β-blockers, so it can also be used in diabetic patients. Metoprolol has less effect on cardiovascular responses (such as tachycardia) during hypoglycemia, and the rate of blood glucose level returning to normal is faster than that of non-selective β-blockers. In acute myocardial infarction, intravenous metoprolol can relieve chest pain and reduce the incidence of atrial fibrillation and atrial flutter. Early treatment (within 24 hours after the onset of symptoms) helps to limit the size and progression of myocardial infarction. The earlier the treatment starts, the greater the benefit. metoprolol can reduce ventricular rate in patients with paroxysmal supraventricular tachycardia, atrial fibrillation and atrial flutter. |
| Synthesis route | Synthesis route 1: Phenols react with epoxidation reagents under the action of organic bases to form intermediates with epoxy groups, and then The intermediate reacts with the amination reagent to form the target product, which forms a salt to obtain its tartrate. The specific reaction equation is: synthetic route 2: p-nitrobenzene and phenylethanol are used to obtain tartrate after etherification reaction, nitration reaction, reduction reaction, diazotization hydrolysis reaction, condensation reaction, amination reaction, salt formation and other reaction steps. The specific reaction equation is: |
| Pharmacokinetics | The fat solubility of metoprolol is between PP and. Oral absorption is rapid and complete, the absorption rate is greater than 90%, but the liver metabolism rate is 95%, and the first pass effect is 25 ~ 60%, so the bioavailability is only 40 ~ 75%, which is similar to. The peak time of oral plasma concentration is generally 1.5 hours, and the maximum action time is 1~2 hours. The decrease of blood pressure is not parallel to the blood drug concentration, while the decrease of heart rate is linearly related to the blood drug concentration. It is mainly metabolized to hydroxymetoprolol in the liver, and its metabolism in the body is affected by genetic factors. 90% is fast metabolic type in Caucasians, t1/2 is 3~4 hours; 10% is slow metabolic type, t1/2 can reach 7.55 hours. The individual difference of plasma peak concentration can reach 20 times. There is no obvious change in renal insufficiency. Metabolism in the liver, excreted by the kidney, mainly metabolites in the urine, only a small amount (<5%) of the prototype. It cannot be drained through dialysis. The peak concentration of sustained-release tablets was significantly reduced, the peak time was prolonged, and the peak change was small. The effective blood concentration is reached after 1~2 hours of oral administration, and the steady state is reached after 3~4 days, and the bioavailability is the 96% of ordinary tablets. Similar to PP, food can increase the blood concentration of this product by twice when it is taken orally on an empty stomach. The body volume is 5.6L/kg, and the plasma protein binding rate is about 12%. It can penetrate the blood-cerebrospinal fluid barrier and placenta, and can also be secreted from milk. Metoprolol oral 200mg/day, the brain concentration is 1.5 β g/g, slightly lower than PP, 10 times higher than. Only 3 ~ 10% are excreted through the kidneys in their original form. |
| indications | this product is used to treat hypertension, angina pectoris, myocardial infarction, hypertrophic cardiomyopathy, aortic dissection, arrhythmia, hyperthyroidism, cardiac neurosis, variant angina pectoris, etc. In recent years, it is still used for the treatment of heart failure. At this time, it should be used under the guidance of experienced doctors. |
| specification | 50mg: Chinese medicine standard H32025390 25mg: Chinese medicine standard H32025391 100mg: Chinese medicine standard H32025392 |
| usage and dosage | 1. treatment of hypertension: 100~200mg/time, twice a day, immediately after hemodynamic stabilization. 2. Acute myocardial infarction: It is recommended to use it in the early stage, that is, in the first few hours, because immediate use can reduce the infarct area and reduce the short-term (15-day) mortality in patients who fail to thrombolytic therapy (This effect occurs 24 hours after medication). 3. The rate of reinfarction and reischemia can be reduced in patients who have been thrombolytic, and the mortality can also be reduced if the drug is used within 2 hours. General usage: metoprolol can be injected intravenously at 2.5~5mg/time (within 2 minutes) once every 5 minutes for 3 times of 10~15mg. After 15 minutes, 25~50mg was taken orally once every 6~12 hours for a total of 24~48 hours, and then 50~100mg/time was taken orally twice a day. 4. Unstable angina: It is also recommended to use early, and the usage and dosage can refer to acute myocardial infarction. 5. If there is no contraindication for atrial fibrillation in acute myocardial infarction, intravenous metoprolol can be used, and the method is the same as above. 6. If there is no contraindication after myocardial infarction, it should be used for a long time, because it has been proved to reduce cardiac mortality, including sudden death. Generally 50~100mg/time, twice a day. 7. In the treatment of hypertension, angina pectoris, arrhythmia, hypertrophic cardiomyopathy, hyperthyroidism and other diseases, generally 25~50mg/time, 2~3 times a day, or 100mg/time, 2 times a day. 8. Heart failure: This drug should be used on the basis of anti-heart failure treatment such as digitalis and/or diuretics. At first, 6.25mg/time, 2-3 times a day, and later, depending on the clinical situation, 6.25-12.5mg/time, 2-3 times a day, the maximum dose can be 50-100mg/time, 2 times a day. The maximum dose should not exceed 300~400mg/day. |
| Drug interaction | Metoprolol is a substrate for CYP2D6. Drugs that inhibit CYP2D6 can affect the plasma concentration of metoprolol. Drugs that inhibit CYP2D6 such as quinidine, terbinafine, paroxetine, fluoxetine, sertraline, celecoxib, propafenone and diphenhydramine. For patients taking this product, the dose of this product should be reduced at the beginning of the treatment of the above drugs. 1. this product should be avoided in combination with the following drugs: (1) barbiturates: barbiturates (studied on pentobarbital) can increase the metabolism of metoprolol through enzyme induction. (2) propafenone: in 4 patients who have already used metoprolol, the plasma concentration of metoprolol increased 2-5 times after administration of propafenone, and 2 of them had side effects related to metoprolol. This interaction was confirmed in 8 healthy volunteers. A possible explanation for this interaction is that propafenone is similar to quinidine and can inhibit the metabolism of metoprolol through the cytochrome P4502D6 pathway. Since propafenone also has a β-receptor blocking effect, its combined use with metoprolol is difficult to master. (3) verapamil: when verapamil is combined with β-blockers (it has been reported that it is combined with atenolol, silonalol and indolol), it may cause bradycardia and blood pressure drop. Verapamil and β-blockers have an additive inhibitory effect on atrioventricular conduction and sinoatrial node function. 2. the dosage of this product may need to be adjusted when used in combination with the following drugs: (1) amiodarone: a case report shows that obvious sinus bradycardia may occur when amiodarone and metoprolol are used simultaneously. Amiodarone has a long half-life (about 50 days), which means that the interaction of the two drugs may still occur with metoprolol for a longer period of time after amiodarone treatment is stopped. (2) class I antiarrhythmic drugs: class 1 antiarrhythmic drugs and β receptor blockers have additive negative inotropic effects, so in patients with impaired left ventricular function, it may cause serious hemodynamic side effects. Patients with sick sinus syndrome and pathological atrioventricular block should also avoid simultaneous use of metoprolol and class I antiarrhythmic drugs. The interaction between disopyramide and metoprolol has been clearly documented. (3) non-steroidal anti-inflammatory/antirheumatic drugs (NSAID): NSAID anti-inflammatory analgesics have been found to counteract the antihypertensive effects of beta-blockers. In this regard, the drug studied is mainly indomethacin. It is likely that beta blockers do not interact with sulindac. In a study of diclofenac, no interaction was found between beta blockers and diclofenac. (4) diphenhydramine: in people with rapid hydroxylation metabolism, diphenhydramine reduces the clearance of metoprolol metabolized into α-hydroxymetoprolol by 2.5 times through CYP2D6 conversion. The effect of metoprolol is thus enhanced. Diphenhydramine may inhibit the metabolism of other CYP2D6 substrates. (5) diltiazem: calcium antagonists and β-blockers have additive inhibitory effects on atrioventricular conduction and sinus node function. There have been case reports of marked bradycardia when β-blockers are used in combination with diltiazem. (6) Adrenaline: About 10 cases have been reported to show that patients treated with non-selective receptor blockers (including indolol and propranolol) have obvious hypertension and bradycardia after administration of epinephrine. These clinical observations have been confirmed in studies of healthy volunteers. Epinephrine in local anesthetics may cause this reaction when administered intravascular. According to speculation, the risk of this reaction is low when using heart-selective β-blockers. (7) phenylpropanolamine: the single dose of phenylpropanolamine 50mg can increase the diastolic blood pressure of healthy volunteers to the pathological level. Propranolol usually antagonizes this increased blood pressure caused by phenylpropanolamine, but in patients treated with high doses of phenylpropanolamine, β-blockers can paradoxically cause hypertensive reactions. Hypertensive reactions have also been reported during treatment with phenylpropanolamine alone. (8) quinidine: quinidine can inhibit the metabolism of metoprolol in the so-called "rapid hydroxylators" (this type is more than 90% in Sweden), resulting in a significant increase in the plasma concentration of the latter and an enhanced β-receptor blockade. Other β-blockers metabolized by the same enzymatic hydrolysis pathway (cytochrome P450 2D6) may also interact with quinidine in the same way. (9) clonidine: beta blockers may aggravate the rebound hypertension that occurs when clonidine is suddenly stopped. If you want to terminate the combination therapy with clonidine, you should stop the beta blocker several days before stopping clonidine. (10) Rifampicin: Rifampicin can induce the metabolism of metoprolol, resulting in a decrease in the blood concentration of the latter. (11) Patients receiving other beta blockers (eg, eye drops) or monoamine oxidase (MAO) inhibitors should be closely monitored. Inhalation anesthesia increases cardiac inhibition in patients treated with beta-blockers. (12) Patients receiving beta blockers should readjust the dosage of oral hypoglycemic agents. If combined with cimetidine or hydralazine, the plasma concentration of metoprolol will increase. |
| overdose | overdose can lead to significant hypotension and bradycardia. at this time, 1~2mg atropine can be injected intravenously before metahydroxylamine or norepinephrine is given. If intravenous injection of β-blockers causes serious side effects such as atrioventricular block, severe bradycardia or hypotension, it can be quickly corrected by β-receptor agonist isoproterenol 1~5 μg/min. |
| adverse reactions | the incidence of adverse reactions is about 10%, usually related to dose. 1. common (>1/100) (1) general side effects: fatigue, headache, dizziness (2) circulatory system: limb chills, bradycardia, palpitations (3) gastrointestinal system: abdominal pain, nausea, vomiting, diarrhea and constipation 2. rare (1) general side effects: chest pain, weight gain (2) circulatory system: temporary deterioration of heart failure (3) nervous system: sleep disorder, paresthesia (4) respiratory system: shortness of breath, bronchial asthma or asthma symptoms can occur bronchospasm 3. rare (<1/1000) (1) general side effects: hyperhidrosis, alopecia, taste changes, reversible sexual dysfunction (2) Blood system: thrombocytopenia (3) Circulatory system: prolonged atrioventricular conduction time, arrhythmia, edema, syncope (4) Nervous system: nightmare, depression, Memory impairment, confusion, nervousness, anxiety, hallucinations (5) Skin: skin allergic reaction, aggravation of psoriasis, photosensitivity (6) Liver: elevated transaminase (7) eye: visual impairment, dry eye and/or eye irritation (8) ear: tinnitus occasional arthralgia, hepatitis, muscle pain spasm, dry mouth, conjunctivitis-like symptoms, rhinitis and attention impairment, and gangrene in patients with vascular diseases. |
| taboo | 1. cardiogenic shock. 2. Sick sinus syndrome. 3. degree II, III atrioventricular block. 4. Patients with unstable, decompensated heart failure (pulmonary edema, hypoperfusion, or hypotension) who receive positive beta-agonist therapy continuously or intermittently. 5. Symptomatic bradycardia or hypotension. 6. this product should not be given to patients with suspected acute myocardial infarction with heart rate <45 beats/minute, P-Q interval> 0.24 seconds or systolic blood pressure <100mmHg. 7. patients with severe peripheral vascular diseases accompanied by gangrene risk. 8. people who are allergic to any ingredients or other beta blockers in this product. |
| precautions | 1. renal function damage: renal function has no obvious effect on the clearance rate of this product, so patients with renal function damage do not need to adjust the dose. 2. Liver function damage: usually the dose of metoprolol used in patients with liver cirrhosis is the same as that in patients with normal liver function. Dose reduction should only be considered when liver function is very severely impaired (such as bypass surgery patients). Patients receiving beta-blocker therapy should not be given verapamil intravenously. 3. metoprolol may aggravate the symptoms of peripheral vascular circulatory disorders such as intermittent claudication. You must be cautious about severe renal damage, severe emergencies with metabolic acidosis, and joint use of yellow. In the absence of concomitant treatment, this product cannot be used in patients with potential or symptomatic cardiac insufficiency. Patients with variant (Prinzmetal's) angina pectoris may increase the frequency and degree of angina pectoris attacks due to α receptor-mediated coronary vasoconstriction after using β-blockers. Therefore, non-selective β-blockers cannot be used in such patients. Selective β1 receptor blockers must also be used with caution. For patients with bronchial asthma or other chronic obstructive pulmonary disease, adequate bronchodilator therapy should be given at the same time, and the dose of β2 receptor agonists may need to be increased. 4. The effect of metoprolol treatment on glucose metabolism or the risk of masking hypoglycemia is lower than that of non-selective β-blockers. 5. In rare cases, the original moderate atrioventricular conduction abnormality may aggravate (may lead to atrioventricular block). β-blocker therapy may hinder the treatment of allergic reactions, and conventional adrenergic therapy does not always get the expected effect. If patients with pheochromocytoma use this product, combined use of alpha blockers should be considered. 6. this product should be withdrawn gradually as much as possible. the whole withdrawal process should take at least 2 weeks, and the dose should be gradually reduced until it is finally reduced to 25 mg (half of 50 mg tablets). During this period, especially patients with known ischemic heart disease should be closely monitored. During the withdrawal of beta blockers, the risk of coronary events, including sudden cardiac death, may increase. 7. Before the operation, the anesthesiologist should be informed that the patient is taking this product. Beta-blockers are not recommended for patients undergoing surgery. 8. Impact on driving cars and operating machinery: dizziness and fatigue may occur during the treatment with this product, so it should be used with caution when you need to concentrate, such as driving and operating machinery. Athletes use it with caution. |
| main reference materials | [1] Zhang Taoli et al. Observation on therapeutic effect of metoprolol tartrate on elderly patients with chronic heart failure. Chinese medical records, 2010,11 (11):23-24 [2] Wang Jing. Study on human bioavailability and bioequivalence of metoprolol tartrate tablets. Chinese clinical pharmacology and therapeutics, 2006; 11 ( 9) : 1043-1047 [3] Xu Jianan et al. Pharmacokinetics of metoprolol tartrate tablets in healthy volunteers in China. Chinese Journal of Clinical Pharmacology, 2005;21(2):136-139 [4] The Food and Drug Administration announced the seventh batch of chemical drug instructions. http://db.yaozh.com/instruct/53812.html. [5] Tian Jianwen et al. The latest progress in metoprolol synthesis. Jiangxi Chemical, 2003,1:4-6. [6] http://drugs.dxy.cn/drug/88381.htm |
| use | hypertension medication. β1-adrenoceptor antagonist (β1-adrenoceptor antagonist). |
| Production method | 4-(2-methoxyethyl) phenol reacts with chlorinated propylene oxide to obtain the product and isopropylamine in isopropanol, Heat 12g at about 100°C to obtain metoprolol. The tartrate is obtained by salt. |
| category | toxic substances |
| toxicity classification | poisoning |
| acute toxicity | oral-rat LD50: 5500 mg/kg; Oral-mouse LD50: 1500 mg/kg |
| flammability hazard characteristics | flammability; fire scene decomposition of toxic nitrogen oxide gas |
| storage and transportation characteristics | warehouse low temperature, ventilation, drying |
| fire extinguishing agent | water, carbon dioxide, dry powder, sand |
Last Update：2024-04-09 21:04:16
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