Approval date: November 04, 2006
Modification date: November 30, 2007
Revision date: 01 October 2010
Modification date: 01/25/2011
Modification date: December 01, 2015
Modification date: 03/18/2016
Propranolol hydrochloride tablets instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Propranolol Hydrochloride Tablets English name: Propranolol Hydrochloride Tablets Chinese pinyin: Yansuan Punailuo’er Pian
Ingredients
The main ingredient of this product is propranolol hydrochloride.
Chemical name: 1-isopropylamino-3-(1-naphthoxy)-2-propanol hydrochloride. Chemical structure formula.
Molecular Formula: C16H21NO2-HCl Molecular Weight: 295.81
Properties】This product is a white tablet.
Specification】10mg
Indications
1. As secondary prevention, to reduce the mortality of myocardial infarction.
2. Hypertension (alone or in combination with other anti-hypertensive drugs).
3. Exertional angina pectoris.
4. Control of supraventricular tachyarrhythmias, ventricular arrhythmias, especially those related to catecholamines or digitalis-induced arrhythmias. It can be used for the control of atrial flutter and ventricular rate of atrial fibrillation where digitalis is not effective, and also can be used for intractable pre-term contractions to improve patients’ symptoms.
5. Reduce the pressure difference of outflow tract in hypertrophic cardiomyopathy and alleviate the symptoms of angina pectoris, palpitations and syncope.
6. Used in conjunction with alpha-blockers to control tachycardia in patients with pheochromocytoma.
7. Used to control tachycardia in hyperthyroidism, also used to treat thyroid crisis.
Dosage and Administration
1 Hypertension: Take orally at an initial dose of 10mg 3-4 times daily, either alone or in combination with diuretics. The dose should be gradually increased to a maximum daily dose of 200mg.
2 Angina pectoris: 5-10mg at the beginning, 3-4 times daily; every 3 days can be increased by 10-20mg, can be gradually increased to 200mg daily, divided into doses.
3 Arrhythmia: 10-30mg daily, take 3-4 times daily. Take before meals and bedtime.
4 Myocardial infarction: 30-240mg daily, take 2-3 times daily.
5 Hypertrophic cardiomyopathy: 10-20mg, 3-4 times daily. Adjust the dose according to the need and tolerance level.
6 Pheochromocytoma: 10-20mg (1-2 tablets), 3-4 times daily. For three days before surgery, alpha-blockers should generally be used first, and propranolol should be added after the effect of the drug has stabilized.
[Adverse reactions].
In a population of 11,303 hypertensive patients, 403 (3.6%) adverse reactions were reported. The major adverse reactions included circulatory adverse reactions of 1.4% (156 cases), including bradycardia of 0.8% (87 cases), and psychoneurological adverse reactions including vertigo of 1.3% (142 cases).
(1) Serious adverse reactions
(1) Congestive heart failure (or deterioration), bradycardia, peripheral ischemia (Raynaud’s-like symptoms, etc.), atrioventricular block (0.1-5%); upright hypotension with delirium (<0.1%): reduce or discontinue the drug when such symptoms occur and give appropriate treatment.
(②Granulocyte deficiency, thrombocytopenia, purpura (<0.1%): when such symptoms occur, the dose should be reduced or discontinued and appropriate treatment should be given.
(③) Bronchospasm (0.1 to <5%); dyspnea, wheezing (<0.1%): When such symptoms occur, the dose should be reduced or discontinued, and appropriate treatment such as β2 agonists can be given as needed.
(2) Other adverse reactions
0.1~＜5%＜0.1% allergyNote 1 rash circulatory system hypotension chest tightness, shortness of breath during activity, chest discomfort and uneasiness psychoneurological system headache, dizziness, feeling of uncertainty, sleepiness, insomnia, hallucinations, depression, nightmares, confusion, paralysis and other mood swings, mental weakness eyeNote 2 abnormal vision, foggy vision, reduced tear secretion digestive system thirst, nausea, vomiting, loss of appetite, epigastric discomfort abdominal cramps, constipation, diarrhea, etc. Liver Liver function abnormalities [AST (GOT), ALT (GPT), elevated Al-P, etc.] Other extremity weakness, fatigue, muscle pain, reversible hair loss Elevated LDH, elevated blood urea levels, decreased blood glucose, dry ringworm-like rash, aggravation of dry ringworm, positive antinuclear antibodies, myasthenia gravis-like symptoms, aggravation of myasthenia gravis Note 1: The presence of such Note 1: Discontinue administration of the drug when these symptoms occur.
Note 2: Discontinue administration when such symptoms occur (to prevent serious complications such as corneal ulceration).
Contraindication】 1.
1. Hypersensitivity to any of the ingredients of this product. 2.
2. Patients with bronchial asthma or at risk of bronchospasm (the product can constrict the bronchial tubes, which may trigger or aggravate asthma symptoms).
3. Patients with diabetic ketoacidosis, metabolic acidosis (may enhance myocardial contractility depression caused by acidosis).
4. Patients with severe or symptomatic bradycardia, atrioventricular block (degree II or III), sinus atrioventricular block, sick sinus node syndrome (may exacerbate these symptoms).
5. Patients with cardiogenic shock (this product has cardiac function depressant effects and may aggravate symptoms)
6. Patients with right heart insufficiency due to pulmonary hypertension (this product has cardiac function depressant effects and may aggravate symptoms)
7. Patients with congestive heart failure (this product has cardiac function inhibitory effects and may aggravate symptoms).
8. Patients with hypotension (this product has a cardiac function inhibitory effect and may aggravate symptoms).
9. Patients in a prolonged fasting state (it is likely to cause hypoglycemic symptoms and may mask this symptom, leading to delayed detection)
10. Patients with severe peripheral circulatory failure (gangrene, etc.) (may aggravate symptoms)
11. Patients with untreated pheochromocytoma (see “Precautions Regarding Dosage”).
12. Patients with variant angina pectoris (may aggravate symptoms).
13. Patients who have been administered rizatriptan benzoate (see “Interactions”).
Precautions
Warning: Cases of worsening of symptoms and myocardial infarction have been reported in patients with angina pectoris using this product who suddenly stop taking it. Therefore, when discontinuation is required, the dose must be gradually reduced, and the discontinuation period should normally be more than 1 week with adequate observation. In addition, patients should be cautioned not to stop taking the drug without medical advice. Patients with conditions other than angina pectoris, such as cardiac arrhythmia, especially the elderly, should also be aware of the above.
1. Use this product with caution in the following cases.
(1) Patients who are at risk of congestive heart failure (Because cardiac function may be suppressed and congestive heart failure may occur, close observation and caution are necessary. In addition, beta-blockers do not counteract the positive inotropic effects of drugs such as digitalis). If congestive heart failure occurs, it can be corrected with digitalis glycosides and/or diuretics, and the dose should be gradually reduced and finally discontinued.
(2) Patients with thyrotoxicosis (which may mask the symptoms of toxicity) and hypothyroidism.
(3) Patients with idiopathic hypoglycemia, poorly controlled diabetes mellitus, and fasting state (perioperative period, etc.) (blood glucose values should be noted because they are prone to hypoglycemic symptoms and tend to mask their symptoms).
(4) Patients with severe hepatic or renal impairment (drug metabolism and excretion may be affected).
(5) Patients with non-severe peripheral circulatory failure (Raynaud’s syndrome, intermittent claudication, etc.) (symptoms may be exacerbated).
(6) Patients with bradycardia (see “Contraindications”) (may aggravate bradycardia).
(7) Patients with atrioventricular block (degree I) (may aggravate symptoms by prolonging atrioventricular conduction time).
(8) Elderly (see “Important Precautions” and “Drugs for the Elderly”).
(9) Children (may cause severe hypoglycemia with seizures and drowsiness).
2. Other precautions.
(1) The tolerated amount of β-blockers varies greatly among individuals, so the dosage must be individualized. The dosage should be individualized. The administration should start from a low dose. The pulse rate, blood pressure, ECG, X-ray and cardiac function should be monitored regularly during long-term administration. When bradycardia occurs and causes hypotension, the dosage should be reduced or stopped, and atropine should be used as needed. In addition, attention should be paid to liver function, kidney function and blood routine, etc.
(2) Except for use in pheochromocytoma surgery, it is best not to use this product 24 hours before surgery.
(3) Since vertigo and dizziness may occur, patients who are taking this product (especially at the beginning of administration) should be warned to take care when driving a car or other dangerous mechanical operations.
(4) This product can be taken orally on an empty stomach or with food, as the latter can slow down intrahepatic metabolism and improve bioavailability.
(5) Hyperthyroidism patients should not stop using this product suddenly, otherwise the symptoms of hyperthyroidism will be aggravated.
(6) Interference with diagnosis: When taking this product, the measurement of blood urea nitrogen, lipoprotein, creatinine, potassium, triglyceride and uric acid may be increased, while blood sugar is decreased. However, it is sometimes increased in diabetic patients. In renal insufficiency, metabolites of this product may accumulate in the blood and interfere with the determination of diazo reaction of serum bilirubin, resulting in false positives.
(7) Use with caution in athletes.
Pregnant women and nursing mothers
1. Delayed development, decreased blood glucose and respiratory depression in newborns have been reported during pregnancy. In addition, animal experiments have shown that propranolol has a prolonged beta-blocking effect on fetuses. Therefore, it is not recommended for use in pregnant women or women who may be in pregnancy, except when administration is necessary in an emergency.
2. Since diffusion into breast milk has been reported, breast-feeding should be avoided during administration.
Pediatric Use]
The safety and efficacy of this product in the pediatric population has not been established.
Geriatric use]
The following points should be noted when administering medication to the elderly and starting with a low dose, as well as observing the patient’s status to administer the medication carefully.
1. Among the elderly, excessive lowering of blood pressure should not be done (it may cause cerebral infarction, etc.).
2. When it is necessary to stop the drug, the dosage should be gradually reduced. (Refer to “Important Precautions”)
Drug Interactions]
The metabolism of propranolol involves multiple pathways of cytochrome P450 (CYP2D6, 1A2, 2C19) and therefore interacts with substrates, inhibitors, or inducers of cytochrome P450 enzymes, and may lead to clinically relevant drug interactions when combined with drugs metabolized by these pathways or with drugs that affect the activity of one or more metabolic pathways.
CYP2D6 enzyme substrates or inhibitors
Combination with CYP2D6 enzyme substrates or inhibitors, such as amiodarone, cimetidine, delavirdine, fluoxetine, paroxetine, quinidine, and ritonavir, may increase blood concentrations and/or toxicity of propranolol. No interactions were observed with ranitidine or lansoprazole.
CYP1A2 enzyme substrates or inhibitors
Combination with CYP1A2 enzyme substrates or inhibitors, such as promethazine, cimetidine, ciprofloxacin, vincristine, isoniazid, ritonavir, theophylline, zileuton, zolmitriptan, and rizatriptan, may increase blood concentrations and/or toxicity of propranolol.
CYP2C19 enzyme substrates or inhibitors
Combination with CYP2C19 enzyme substrates or inhibitors, such as fluconazole, cimetidine, fluoxetine, fluvoxamine, teridoside, and toluenosulfonylurea, can increase blood concentrations and/or toxicity of propranolol. No interaction with omeprazole has been observed.
Hepatic Inducers
Increased blood levels and/or toxicity of propranolol when combined with inducers such as rifampin, ethanol, phenytoin, and phenobarbital. Smoking also induces hepatic metabolism and increases propranolol clearance by up to 77%, resulting in lower plasma concentrations.
Cardiovascular Drugs
Antiarrhythmics
In combination with propranolol, the AUC of propafenone is increased by more than 200%.
In combination with quinidine, the metabolism of propranolol is reduced, resulting in a 2-3 fold increase in blood concentrations, to a greater extent than when combined with beta inhibitors.
In combination with propranolol, the metabolism of lidocaine is inhibited, resulting in a 25% increase in lidocaine concentrations.
Calcium channel blockers
In combination with nicardipine, the mean Cmax and AUC of propranolol increased by 50% and 30%, respectively, and in combination with nisoldipine, by 80% and 47%.
In combination with propranolol, the mean Cmax and AUC of nifedipine increased by 64% and 79%, respectively.
Propranolol did not affect the pharmacokinetics of verapamil and desmethyl verapamil. Verapamil did not affect the pharmacokinetics of propranolol.
Migraine Drugs
In combination with propranolol, AUC increased by 56% and Cmax increased by 37% for zolmitriptan, and AUC and Cmax increased by 67% and 75%, respectively, for rizatriptan.
Theophylline
In combination with propranolol, clearance after oral administration of theophylline was reduced by 30% to 52%.
Benzodiazepines
Propranolol inhibits the metabolism of diazepam, resulting in increased concentrations of diazepam and its metabolites. Diazepam does not alter the pharmacokinetics of propranolol.
The pharmacokinetics of oxazepam, triazolam, lorazepam, and alprazolam are not affected by the combination of propranolol.
Psychiatric drugs
Administration of long-acting propranolol at doses greater than 160 mg/day resulted in increases in thioridazine plasma concentrations of 55% to 369% and thioridazine metabolite (metazolam) concentrations of 33% to 209%.
In combination with chlorpromazine, plasma levels of propranolol were increased by 70%.
Anti-ulcer drugs
In combination with cimetidine, a non-specific CYP450 inhibitor, increased propranolol AUC and Cmax by 46% and 35%. Combination with aluminum hydroxide gel (1200 mg) resulted in a decrease in propranolol concentrations.
Combination of metoclopramide with long-acting propranolol had no significant effect on the pharmacokinetics of propranolol.
Lipid-lowering drugs
Combination with metoclopramide or colestipol reduced propranolol concentrations by up to 50%.
Combination with propranolol reduced the AUC of lovastatin and pravastatin by 18% to 23%, but did not alter their pharmacodynamics. Propranolol had no effect on the pharmacokinetics of fluvastatin.
Warfarin
In combination with propranolol, the bioavailability of warfarin was increased and the prothrombin time was prolonged.
Alcohol
Use of alcohol during dosing may increase plasma levels of propranolol.
Clinical symptoms, mechanisms and risk factors for the combination of propranolol with the following drugs are detailed in the following table.
Drug Name Clinical Symptoms and Management Mechanisms and Risk Factors Other Sympathetic Nervous System Depressants
Risperdal, beta-blockers (including eye drops such as timolol), etc. should be disposed of such as dose reduction because they can cause excessive inhibition of the sympathetic nervous system (bradycardia, cardiac failure, etc.). Synergistic effects (sympathetic nervous system inhibition) are enhanced. Glucose-lowering drugs
The hypoglycemic effect of insulin, toluenesulfonylurea, and vinblastine may be enhanced. In addition, attention should be paid to the blood glucose value because it can mask the symptoms of hypoglycemia (tachycardia, etc.). When blood sugar drops, catechol will be secreted from the adrenal glands to promote the breakdown of glycogen in the liver, thus increasing the blood sugar value.
At this time, when hepatic beta receptors are blocked, the effect of elevated blood glucose caused by catechol will be inhibited, thus potentially enhancing the hypoglycemic effect.
In addition, symptoms of hypoglycemia such as catecholamine-induced tachycardia may be masked. Calcium antagonists
Verapamil, diltiazem, nifedipine, etc. should be reduced with caution because hypotension, bradycardia, conduction disturbances such as atrioventricular block, and heart failure may occur with the use of verapamil and diltiazem, etc. In addition, in dihydropyridines, care should be taken because hypotension and cardiac failure may also occur.
If the product is to be replaced by an intravenous calcium antagonist, an interval of more than 48 hours should be observed. Synergistic effects (inhibition of cardiac contractility and stimulation of conduction system, hypotensive effects, etc.)
Although the mechanism of pharmacokinetic interactions is not known, it is generally believed that the metabolism of this product is affected by changes in hepatic blood flow. Colistin may enhance the rebound phenomenon (increased blood pressure, headache, nausea, etc.) after Colistin discontinuation. When stopping Colistin, the product should be discontinued, followed by several days of observation before stopping Colistin. In addition, when changing treatment from colistin to this product, this product should be given several days after colistin has been discontinued. Discontinuation of colistin in patients on colistin administration causes an increase in blood catecholamines and an increase in blood pressure. β-blocker administration is associated with a predominance of catecholamine-induced stimulation of α receptors, which further enhances vasoconstriction. class I antiarrhythmic agents
Propiamine, procainamide, arymaline, etc.
Class III antiarrhythmic agents
Amiodarone, etc. should be disposed of by dose reduction because excessive cardiac depression (bradycardia, cardiac arrest, etc.) can occur. Anti-arrhythmics have negative force-change and negative time-change effects. β-blockers can also inhibit cardiac function through catecholamine blockade, so their combined use can cause excessive cardiac depression. Sympathomimetic drugs
Antagonistic effects such as adrenaline. In addition, care should be taken because they can cause vasoconstriction and increase blood pressure. When sympathetic agonists such as epinephrine are used in a state where beta receptors in the peripheral vasculature are blocked due to non-selective beta blockers, only alpha receptor-mediated vasoconstriction may occur. In addition, bradycardia is the result of a reflex of the parasympathetic nervous system. Narcotics
Reflex tachycardia such as sevoflurane is attenuated and the risk of hypotension is increased.
Choose anesthetics with low negative variability effects. In addition, avoid coadministration of anesthetics with myocardial depressant effects whenever possible. When hypotension is induced by anesthetics, reflex tachycardia is induced. When beta-blockers are used in combination, reflex tachycardia may be diminished and hypotension may be enhanced.
In addition, the effects are mutually enhanced in anesthetics that have a negative force-modifying effect. Lidocaine should be avoided because it delays the metabolism of lidocaine, which in turn increases its blood concentration. The metabolism of lidocaine is delayed because it reduces hepatic blood flow and inhibits hepatic drug metabolizing enzymes. Attention should be paid to digitalis preparations because they may cause prolonged atrioventricular conduction time, bradycardia and AV block. Digitalis and beta-blockers can prolong AV node conduction time. Special attention should be paid when digitalis is poisoned. Cimetidine should be noted because it may increase the blood concentration of this product and enhance its effect. Cimetidine decreases hepatic blood flow, and in addition, by inhibiting drug metabolizing enzymes in the liver, the breakdown of this product in the liver decreases, resulting in increased blood levels. The effects of chlorpromazine are enhanced by this product and chlorpromazine, respectively. This product has a competitive binding effect with drug metabolizing enzymes with chlorpromazine, thus the blood concentration of both this product and chlorpromazine will be increased. Attention should be paid to hydrazinepyridazine because of the increased blood levels and enhanced effects of this product. The cause of increased hepatic blood flow by hydrazinepyridazine. Ergot alkaloids
Ergotamine and others should be noted because pain, chills, and cyanosis in the lower extremities are seen. Ergot alkaloids and beta-blockers synergistically decrease peripheral perfusion. Non-steroidal anti-inflammatory drugs
Indomethacin and others can reduce the hypotensive effect of this product. Non-steroidal anti-inflammatory drugs can inhibit the synthesis of prostaglandins that have vasodilatory effects. Alcohol can reduce or enhance the effect of this product due to changes in blood concentration, so care should be taken. Alcohol may cause changes in absorption and metabolism of this drug. Rifampicin should be noted because it may decrease the blood concentration of this product and weaken its effect. Rifampin can induce hepatic enzymes, thus promoting the metabolism and elimination of this product. Quinidine and propafenone should be noted because they may increase the blood concentration of this product and enhance its effect. This product is metabolized through cytochrome P450. Therefore, in drugs that receive metabolism via cytochrome P450, there may be an effect on blood concentrations. Warfarin should be noted because elevated blood concentrations and enhanced effects of warfarin may occur. Although the mechanism of the interaction is not known, it should be due to the inhibition of hepatic metabolism of warfarin by this product. Fingolimod has been found to have severe bradycardia and cardiac conduction block when combined with this product at the start of fingolimod administration. Both may cause bradycardia and cardiac conduction block. Combination of drugs is prohibited.
Drug Name Clinical Symptoms and Management Mechanisms and Risk Factors Rizatriptan Benzoate (Maxalt®) Rizatriptan has a prolonged elimination half-life and an increased AUC, and thus the effect may be enhanced.
Rizatriptan should not be given to patients during or within 24 hours after cessation of this drug administration. Although the mechanism of interaction is not clear, it is implied that this product has the potential to inhibit rizatriptan. [Drug overdose].
In general, in case of overdose, the stomach contents should be emptied as soon as possible and aspiration pneumonia should be prevented.
When significant bradycardia occurs, first administer atropine sulfate hydrate (1 to 2 mg) intravenously, then dobutamine, a beta1 receptor stimulant (2.5 to 10 μg/kg per minute, intravenously), as needed. Glucagon (10 mg, intravenous) has also been reported to be effective.
In bronchospasm, symptoms can also be made to disappear by high-dose β2 agonists (intravenous and inhalation, increasing or decreasing the dose of the drug according to the patient’s response). Aminophylline hydrate (intravenous) and ipratropium bromide (inhalation) can also be considered.
Glucagon (1 to 2 mg, intravenous) has been reported to induce bronchodilation. In severe cases, oxygen or artificial ventilation needs to be given.
Dialysis cannot discharge this product.
Pharmacology and Toxicology
Pharmacological effects
Propranolol is a non-selective β-adrenoceptor blocker that competitively binds both β1 and β2 subtypes of the adrenoceptor. In hypertension, propranolol exerts hypotensive effects by decreasing cardiac output, inhibiting renin release and reducing sympathetic excitation in the vasodilatory center. For angina pectoris, propranolol reduces catecholamines or exercise-induced increases in heart rate, systolic blood pressure, and degree of myocardial contraction, and decreases myocardial oxygen consumption. For arrhythmias, propranolol exerts a membrane stabilizing effect and affects myocardial action potential. The mechanism of action of propranolol in migraine and atrial fibrillation is unclear.
Toxicological studies
Genotoxicity
Propranolol hydrochloride has shown suspicious results in the Ames test in the S. typhimurium strain TA 1538 system.
Reproductive toxicity
Propranolol hydrochloride was given orally to rats during gestation and lactation at 150 mg/kg/day, which is 6 times the maximum recommended human dose (MRHD) of 240 mg based on body surface area (adult body weight at 60 kg), and embryotoxicity such as reduced litter size, increased fetal absorption and neonatal mortality were observed. The results showed embryotoxicity such as reduced litter size, increased fetal absorption and neonatal mortality. In rabbits, propranolol hydrochloride was given orally at 150 mg/kg/day during gestation and lactation, which is 12 times the MRHD based on body surface area, and no effect on embryos or newborn rabbits was observed.
Propranolol hydrochloride was administered to rats by adulteration at a concentration of 0.05% (a dose approximately equivalent to MRHD) for a period beginning 60 days prior to mating, including gestation and lactation, and no effects on fertility were observed.
Carcinogenicity
In an 18-month carcinogenicity test in mice and rats, propranolol hydrochloride was administered at doses up to 150 mg/kg/day, equivalent to 3 or 6 times the MRHD, converted to body surface area, and no administration-related tumorigenesis was observed.
[Pharmacokinetics].
Absorption
Propranolol is highly lipid soluble and is almost completely absorbed after oral administration. It has a high hepatic first-pass metabolism, and about 25%-30% of propranolol reaches the body circulation. The plasma concentration peaks about 1~4 hours after oral administration.
A high-protein diet increases the bioavailability of propranolol by about 50%, with no effect on peak concentration, plasma protein binding, half-life, or the amount of prodrug in the urine.
Distribution
Plasma protein (albumin and α1 acidic glycoprotein) binding is approximately 90% and is enantiomerically selective. the S(-)-isomer is primarily bound to α1 glycoprotein and the R(+)-isomer is primarily bound to albumin. The volume of distribution of propranolol is about 4 L/kg.
Propranolol crosses the blood-brain barrier and the placenta and is secreted into breast milk.
Metabolism and elimination
Propranolol is extensively metabolized by three main pathways: aromatic hydroxylation (mainly 4-hydroxylation), further side chain oxidation after N-dealkylation and direct glucuronidation, which account for approximately 42%, 41% and 17% of total metabolism, with large inter-individual variability. The main metabolites were propranolol glucosinolate, naphthoxylactate and glucuronide, and 4-hydroxy sulfate conjugate, respectively
In vitro studies have shown that aromatic hydroxylated propranolol is mainly mediated by CYP2D6 enzymes; side chain oxidation is mainly mediated by CYP1A2 and to some extent by CYP2D6; 4-hydroxypropranolol is a weak inhibitor of CYP2D6.
Propranolol is also a substrate for CYP2C19 and the efflux protein p-glycoprotein (p-gp). Studies have shown that there is no dose-limiting effect of p-gp on the intestinal absorption of propranolol within the therapeutic dose range.
In healthy subjects, no differences were observed in clearance and elimination half-life after oral administration in the CYP2D6 extensively metabolized population (EMs) and the weakly metabolized population (PMs). Clearance of 4-hydroxypropranolol was significantly higher than that of naphthoxyacetic acid in the extensive metabolizer population, while partial clearance of naphthoxyacetic acid was significantly lower than that of the weak metabolizer population.
The half-life of propranolol is approximately 3-6 h, and most metabolites can be detected in urine.
Enantiomeric isomers
Propranolol is a racemic mixture of two enantiomers, R(+) and S(-). the S(-)-isomer blocks β-adrenergic receptors approximately 100 times more potently than the R(+)-isomer. When racemic propranolol is administered orally to healthy subjects, the S(-)-enantiomer concentration exceeds the R(+)-isomer concentration by 40% to 90% due to stereoselective hepatic metabolism. The clearance of the S(-)-isomer was lower than that of the R(+)-isomer after intravenous and oral administration.
Special Populations
Elderly subjects
A study including 12 elderly subjects (62-79 years old) and 12 younger (25-33 years old) healthy subjects showed reduced clearance of the S(-)-isomer of propranolol in the elderly. In addition, the half-lives of both R(+)- and S(-)-isomers were increased in older compared to younger subjects (11 hours and
5 h).
The clearance of propranolol decreases with age due to decreased oxidative capacity (epoxidation and side chain oxidation). Conjugation capacity remained unchanged. In a study using 32 patients aged 30 to 84 years, a single administration of 20 mg of propranolol showed a negative correlation between age and metabolic clearance of 4-hydroxypropranolol (4OHP-epoxidation) and naphthoxylactide (NLA-side chain oxidation), and no correlation with metabolic clearance of glucuronide (PPLG-conjugation).
Gender
In a study including 9 healthy women and 12 healthy men, neither the administration of testosterone nor the menstrual cycle affected the plasma binding of the enantiomeric isomers of propranolol. In contrast, administration of ethinyl estradiol resulted in a significant decrease in plasma binding of propranolol diastereoselectively. In another study, administration of testosterone cypionate showed hormonal stimulation of propranolol metabolism and concluded that propranolol clearance in men was dependent on plasma concentrations of testosterone. In women, propranolol clearance was not significantly correlated with either estradiol or testosterone. There were some differences in the results of the two studies.
Ethnic differences
Studies of 12 Caucasian and 13 African-American male subjects taking propranolol showed that at steady state, African-Americans had 76% and 53% higher clearance of R(+)- and S(-)-propranolol, respectively, than Caucasians.
The proportion of unbound propranolol in plasma was higher in Chinese subjects compared to Caucasians (approximately 18% to 45% higher), which was associated with lower concentrations of α1 acidic glycoprotein in plasma.
Renal insufficiency
Results of a study conducted in five patients with chronic renal failure, six patients on conventional dialysis and five healthy subjects showed that a single oral dose of 40 mg propranolol resulted in a 2- to 3-fold higher Cmax in the group of patients with chronic renal failure (161 ± 41 ng/mL) than in dialysis patients (47 ± 9 ng / mL) and healthy subjects (26 ± 1 ng / mL). Plasma clearance of propranolol was reduced in patients with chronic renal failure. Studies have shown that patients with varying degrees of renal failure have a delayed rate of propranolol absorption and a shortened half-life. Despite the shortened plasma half-life in patients with renal failure compared to subjects with normal renal function, peak plasma concentrations of propranolol were 3-4 times higher and total plasma metabolite levels were increased 3-fold.
The reduced drug metabolism in patients with chronic renal failure is associated with lower “first-pass” clearance due to downregulation of hepatic cytochrome P450 enzyme activity. Propranolol is not cleared by dialysis.
Hepatic insufficiency
Propranolol is extensively metabolized by the liver. Results of a study in seven patients with cirrhosis and nine healthy subjects showed a three-fold increase in the concentration of unbound propranolol at steady state in patients with cirrhosis when 80 mg of propranolol was administered orally every 8 hours for seven doses.
In patients with cirrhosis, the half-life increased from 4 to 11 hours (see Precautions).
Storage】Store under shade and seal.
Package】Packaged in high-density polyethylene bottles for oral solid dosage, 100 tablets/bottle.
Expiration date】24 months
【Execution standard
Approval number】State Drug Administration H42022488
【Drug marketing license holder】 【Emplementation standard
Company Name: Huazhong Pharmaceutical Co.
Registered Address: No. 118, Dangshan Road, Xiangyang City, Hubei Province, China
Postal Code: 441000
Contact: (0710)3150944 (0710)3150386
Fax: (0710)3150921
Web address: www.huazhong-pharma.com
【Manufacturer】
Company name: Huazhong Pharmaceutical Co.
Address: No. 118, Dangshan Road, Xiangyang City, Hubei Province, China
Postal Code: 441000
Contact：(0710)3150944 (0710)3150386
Fax: (0710)3150921
Web address: www.huazhong-pharma.com