Propranolol hydrochloride preparations should be protected from light and storedat room temperature (approximately 25 °C). The manufacturer recommends that propranolol hydrochloride extended-release capsules be stored in tight, light resistant containers and be protected from moisture, freezing, and excessive heat. USP recommends that propranolol hydrochloride preparations be stored in well closed containers. Solutions of the drug have maximum stability at pH 3 and decompose rapidly at alkaline pH. Decomposition in aqueous solution is accompanied by a lowered pH and discoloration. Propranolol hydrochloride injection is reportedly compatible with 0.9% sodium chloride injection; however, specialized references should be consulted for specific compatibility information.
分解：
When heated to decomposition it emits toxic fumes of oxides of nitrogen.
Besides ... 4-hydroxypropranolol and naphthoxylacetic acid, 6 new urinary metabolites have... been identified... /which are/ n-deisopropylpropranolol; 1-(alpha-naphthoxy)-2,3-propyleneglycol; ring hydroxylated 1-(alpha-naphthoxy)-2,3-propyleneglycol; alpha-naphthoxyacetic acid; alpha-naphthol and 1,4-dihydroxynaphthalene.
Isopropylamine and hexadeuteriated isopropylamine have been identified as urinary metabolites of propranolol and hexadeuteriated propranolol, respectively; this is believed to be 1st recorded example of single-step oxidative deamination of n-isopropylamine compound.
During initial oral therapy (but not during iv or chronic oral therapy), an active metabolite, 4-hydroxypropranolol, is formed. 4-Hydroxypropranolol has about the same beta-adrenergic blocking potency as does propranolol and may be present in plasma in amounts about equal to propranolol. This metabolite is eliminated more rapidly than propranolol and is virtually absent from the plasma 6 hr after oral administration of the drug. Results of one study indicate that after iv administration or chronic oral administration of propranolol, 4-hydroxypropranolol is not formed to a substantial extent, and beta-adrenergic blocking activity is more closely reflected by propranolol concentrations. Individual variations in ability to hydroxylate propranolol to the active metabolite may also exist. In addition, some other metabolites of propranolol may possess antiarrhythmic activity without beta-adrenergic blocking activity.
Propranolol is almost completely metabolized in the liver and at least 8 metabolites have been identified in urine. Only 1-4% of an oral or iv dose of the drug appears in feces as unchanged drug and metabolites.
IDENTIFICATION: Propranolol is a class II antiarrhthmic drug which be longs to the beta-andrenergic blocking agents. Propranol hydrochloride is a white, odorless white crystalline powder. It is soluble in alcohol; slightly soluble in chloroform; practically insoluble in ether. Cardiovascular diseases: Propranolol, a non cardioselective beta-blocker, is mostly used in the treatment of hypertension, angina, for the prevention of re-infarction in patients who have suffered from myocardial infarction. It is also used to control symptoms of anxiety and in the treatment of supraventricular tachycardia, hypertrophic obstructive and cardiomyopathy. Endocrine disorders: In hyperthyroidism and thyrotoxic crisis; together with alpha-blocking agents in the preoperative treatment of pheochromocytoma. Hepatic diseases: Prevention of hemorrhage in portal hypertension Neurological disorders: Propranolol has also been used in the treatment of extrapyramidal disorders and in the prophylaxis of migraine headache. Anxiety disorders: Propranolol may be used in acute stress reactions, somatic anxiety and panic reactions, but its value is questioned. HUMAN EXPOSURE: Main risks and target organs: Beta-blockers compete with endogenous and/or exogenous beta-adrenergic agonists. Propranolol is not cardioselective and it has no intrinsic sympathomimetic activity. It has membrane stabilizing properties and is highly lipid soluble. At toxic doses, propranolol has a pronounced negative chronotropic and inotropic effect and also a quinidine like effect on the heart. The cardiovascular system is the main target organ. Propranolol decreases sinus rate, atrio-ventricular conduction, intraventricular conduction and cardiac contractility. Central nervous system toxicity (coma and convulsions) may also occur because of its high liposolubility.Summary of clinical effects: Toxicity occurs within 1 to 2 hours following ingestion but the delay in onset may vary according to the formulation. Symptoms may include: Cardiovascular disturbances: bradycardia, atrioventricular block of varying degrees, intraventricular block, hypotension, cardiogenic shock and pulmonary edema. Neurological symptoms: coma and convulsions. Respiratory depression and apnea. Cardiovascular collapse and apnea may occur suddenly. Patients with underlying cardiovascular disease are predisposed to the adverse cardiac effects of propranolol. Propranolol may induce bronchospasm in asthmatic patients. Contraindications: Absolute: asthma, congestive cardiac failure, atrio-ventricular block, bradycardia and treatment with amiodarone. Relative: Raynaud's disease, diabetes mellitus. Routes of entry: Oral: Ingestion is the most frequent cause of poisoning Inhalation: no case has been reported. The effect of 10 mg propranolol given by nasal route is rapid and equivalent to the intravenous route. Parenteral: No case of overdoses has been reported. Cardiovascular symptoms have been reported after therapeutic administration. Absorption by route of exposure: After oral administration, propranolol is almost completely and rapidly absorbed from the gastrointestinal tract. However, because of the high first-pass metabolism and hepatic tissue binding, the absolute bioavailability is only about 30% and varies greatly between individuals. Peak plasma concentration occurs one to two hours after administration. After administration of the sustained release formulation, the peak plasma concentration occurs 7 hours after absorption. Distribution by route of exposure: About 90 to 95 % of the drug is bound to plasma proteins. Propranolol is highly lipophilic: it crosses the blood-brain barrier and the placenta. Biological half-life by route of exposure: After oral administration, propranolol undergoes saturable kinetics. The plasma half-life is 3 to 6 hours and is about 12 hours with the sustained release forms. The total body clearance is 800 mL/minute/1.73 m2. After overdose, the plasma half-life is prolonged. One study reported a half-life of 16 hours. In two cases reported, the half-life was 13.8 and 8.3 hours. In five cases, the mean plasma half-life was 10.5 hours (range: 5.1 to 17). Metabolism: Propranolol is extensively metabolized by the liver. At least one of the metabolites, the 4-hydroxypropranolol, is biologically active. The hepatic metabolism is saturable and bioavailability may be increased in overdoses. Elimination by route of exposure: After a single oral dose, propranolol is completely eliminated in 48 hours, mainly by hepatic metabolism. Less than 0.5 % is excreted unchanged in urine. The renal clearance is 12 mL/kg/minute. About 20% of the dose is eliminated in urine mainly as glucuronide conjugates. Propranolol is excreted in breast milk at a concentration of 50% that of blood. Mode of action Toxicodynamics: Propranolol is a non cardioselective beta-blocker with no intrinsic sympathomimetic action. It has membrane stabilizing activity and is highly lipid soluble. At toxic doses, propranolol has a pronounced negative chronotropic and inotropic effect and a quinidine-like effect on the heart: the result is a reduction of the heart rate, a decrease of the sino-atrial and atrioventricular conduction, a prolongation of the intraventricular conduction and a decrease of cardiac output. Blockade of beta-2 receptors may cause bronchospasm and hypoglycemia. Given its high lipid solubility, propranolol crosses the blood-brain barrier and may cause coma and convulsions. Pharmacodynamics: Beta-blocking agents compete with endogenous and/or exogenous beta-adrenergic agonists. Their specific effects depend on their selectivity for beta-1 receptors (located in the heart) or beta-2 receptors (located in bronchi, blood vessels, stomach, gut, uterus). Beta-blockers are classified according to their cardioselectivity, membrane stabilizing effect, intrinsic sympathomimetic effect and lipid solubility. At therapeutic doses, propranolol slightly decreases heart rate (15%), supraventricular conduction and cardiac output (15 to 20%). Cardiac work and oxygen consumption are also decreased. Propranolol decreases the secretion of renin. The pharmaceutical form of propranolol is a racemate: the dextrorotary isomer accounts for most of the beta-blocking effect, whereas the levorotary isomer has a predominantly membrane stabilizing effect. Toxicity: Human data: Adults: Propranolol toxicity shows individual variations which may be due to an underlying cardiac disease, to the ingestion of other cardiotoxic drugs and to variations in first-pass metabolism. Children: Ingestion of 70 mg by a 2 year old child produced drowsiness, second degree atrioventricular block and hypoglycemia. Ingestion of 100 mg by a 5-year-old child produced drowsiness, delirium and hallucinations. Interactions: Decreased bioavailability: Antacids decrease the gastric absorption of propranolol. Barbiturates, phenytoïn and rifampicin increase the first-pass clearance of propranolol by hepatic enzyme induction. Increased bioavailability: Plasma propranolol concentrations may be increased up to 50% by histamine H2 antagonists and oral contraceptives, which decrease hepatic metabolism by enzyme inhibition. Diminished pharmacodynamic effects: Non-steroidal anti-inflammatory drugs decrease the antihypertensive effect of propranolol. Nifedipine might exacerbate the symptoms of beta-blocker withdrawal. Enhanced pharmacodynamic effects: Digitalis, amiodarone, verapamil and diltiazem may increase bradycardia due to propranolol. Verapamil, prenylamine, flecainide and disopyramide enhance the negative inotropic effect of propranolol. Main adverse effects: Numerous adverse effects during propranolol treatment have been reported. Cardiovascular: sinus bradycardia, atrioventricular block, hypotension, increase of left ventricular failure, cardiogenic shock, intermittent claudication. Respiratory: bronchospasm, exacerbation of asthmatic symptoms in known asthmatics, pulmonary edema. Central nervous system: depression, psychosis, convulsions, hallucinations. Musculoskeletal: muscle weakness, aggravation of myasthenia gravis, peripheral neuropathy. Gastrointestinal: vomiting, diarrhea, dry mouth. Endocrine and metabolic: hypoglycemia, hyperkalemia, hypothyroidism, sexual dysfunction (impotence). Dermatological: urticaria, exfoliative dermatitis. Hematological: agranulocytosis (immunologic reaction), thrombocytopenia. Teratogenicity: a case of tracheoesophageal fistula in a newborn of a mother treated with propranolol during the pregnancy has been reported. However, a teratogenic effect of propranolol has not been confirmed. Pregnancy: hypoglycemia and lethargy have been reported in newborn from mothers treated with propranolol before delivery. Others: propranolol treatment may potentiate anaphylactic shock. Clinical effects: Acute poisoning: Ingestion: The severity of propranolol poisoning is due to its cardiotoxicity and depends on the dose ingested, the presence of underlying cardiac disease and concomitant ingestion of other cardiotoxic drugs. Symptoms and signs appear within one to two hours and may include the following: Cardiovascular effects: bradycardia, hypotension, cardiogenic shock. The ECG may show nodal rhythm, atrioventricular block and QRS widening. CNS effects: lethargy, coma and convulsions and mydriasis. Hypoventilation resulting from severe shock. Parenteral exposure: Cardiovascular effects: bradycardia, hypotension, cardiogenic shock. The ECG may show nodal rhythm, atrioventricular block and QRS widening CNS effects: lethargy, coma and convulsions, mydriasis Hypoventilation resulting from severe shock. Course, prognosis, cause of death: Patients who survive 48 hours after acute poisoning or who have not developed cardiac arrest before admission are likely to recover. Death may occur from cardiac asystole which is noted by hypoxemia. The prognosis depends on the dose ingested and is worse in patients with an underlying cardiac disease and in those who have ingested other cardiotoxic drugs. Systematic description of clinical effects: Cardiovascular: Acute: Cardiovascular symptoms are the major features of propranolol poisoning. Bradycardia is the commonest symptom (present in 60 to 90% of cases) and occurs soon after ingestion. Hypotension is observed in about 50 to 70% of the cases. Hypotension and shock are due to decreased cardiac output and vasodilatation. Cardiac arrest may occur within 1 to 2 hours of ingestion. Cardiac arrest has been reported to occur in 45 minutes following an over dose propranolol by a 60 year old man. ECG changes are always present in symptomatic poisoning: sinus or nodal bradycardia, atrioventricular block (1st to 3rd degree) are the most common. Widening of the QRS interval, bundle branch block or increased QT interval are less frequently observed. Respiratory: Acute: Respiratory depression and apnea is mostly associated with severe shock and is due to cerebral hypoxia. Pulmonary edema may occur, especially in patients with a previous compromised cardiac function. Bronchospasm may occur in susceptible patients. Neurological: CNS: Acute: Lethargy, drowsiness, agitation, delirium, hallucinations and mydriasis may be observed. Coma is usually only seen in patients with cardiovascular collapse. Convulsions have been reported after ingestion of large doses. Convulsions may be due to hypotension or to a direct effect of propranolol (membrane stabilizing effect). Chronic: Fatigue, CNS depression, hallucinations and psychosis have been reported. Autonomic nervous system: Acute: Effects of beta-receptor blockade. Chronic: Effects of beta-receptor blockade. Skeletal and smooth muscle: Chronic: Muscular fatigue may be observed. Gastrointestinal: Acute: vomiting, nausea may be seen; spasm of the lower oesophageal sphincter has been reported in two cases. A case of mesenteric ischemia following propranolol overdose has been reported. Eye, ear, nose, throat: local effects: Acute: Mydriasis and diplopia may be noted. Metabolic: Acid-base disturbances: Metabolic acidosis may occur in severe poisoning with shock. Fluid and electrolyte disturbances: Hypokalemia or a hyperkalaemia have been reported rarely. Others: Hypoglycemia was reported in two cases of poisoning in children.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
相互作用
普萘洛尔拮抗心脏刺激，可能会限制肼屈嗪的效果，而联合使用已被证明比单独使用任何一种药物都更有效。
Propranolol antagonizes cardiac stimulation that may limit effectiveness of hydralazine, and combination has been shown to be more effective than either drug alone.
Neuromuscular blockade produced by tubocurarine was prolonged in 2 thyrotoxic patients receiving high doses (120 mg/day for 14 days) of propranolol. ...Decamethonium and succinylcholine have been shown to interact with propranolol in similar manner... in animals.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
相互作用
心得安增加了醚、己巴比妥、吗啡和尿烷对小鼠的急性中枢神经系统毒性。
Propranolol increased acute CNS toxicity of ether, hexobarbital, morphine and urethane in mice.
Stimulatory effect of epinephrine on heart is blocked by propranolol. If epinephrine is administered to patient receiving propranolol, reflex tachycardia may result, /SRP: due to fall in blood pressure because of beta blockade on blood vessels/.
Studies in man and experimental animals indicate that rapid hepatic clearance is responsible for appearance of only trace amount of unmetabolized propranolol in blood after small oral doses. With larger doses, blood levels are linearly related to dose, suggesting saturation of hepatic metabolic system.
Propranolol is almost completely absorbed from the GI tract; however, plasma concentrations attained are quite variable among individuals. There is no difference in the rate of absorption of the 2 isomers of propranolol. Propranolol appears in the plasma within 30 min, and peak plasma concentrations are reached about 60-90 min after oral administration of the conventional tablets. The time when peak plasma concentrations are reached may be delayed, but concentrations are not necessarily lowered, when the drug is administered with food. Oral bioavailability of the drug may be increased in children with Down's syndrome; higher than expected plasma propranolol concentrations have been observed in such children. Bioavailability of a single 40-mg oral dose of propranolol hydrochloride as a conventional tablet or oral solution reportedly is equivalent in adults.
Propranolol hydrochloride is slowly absorbed following administration of the drug as extended release capsules, and peak blood concentrations are reached about 6 hr after administration. When measured at steady state over a 24 hr period, the area under the plasma concentration time curve for the extended release capsules is about 60-65% of the plasma concentration time curve for a comparable divided daily dose of the conventional tablets. The lower plasma concentration time curve is probably caused by the slower rate of absorption of the drug from the extended release capsules with resultant greater hepatic metabolism. After administration of a single dose of propranolol as the extended release capsules, blood concentrations are fairly constant for about 12 hr and then decline exponentially during the following 12 hr.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
静脉注射普罗帕酮后，其作用几乎立即开始。动物研究表明，普罗帕酮在肌内注射后能迅速吸收。
Following iv administration of propranolol, the onset of action is almost immediate. Animal studies indicate that propranolol is rapidly absorbed after im administration.
The present invention relates to compounds of formula I
wherein R
1
to R
4
and G are as defined in the description and claims and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors.
The present invention relates to compounds of formula I
wherein A and R
1
to R
4
are as defined in the description and claims, and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors.
BENZOFURAN AND BENZOTHIOPHENE-2-CARBOXYLIC ACID AMIDE DERIVATIVES
申请人：Mohr Peter
公开号：US20090029976A1
公开（公告）日：2009-01-29
The present invention relates to compounds of formula I
wherein X, A and R
1
to R
4
are as defined in the description and claims, and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors.
[EN] NITROGEN RING CONTAINING COMPOUNDS FOR TREATMENT OF INFLAMMATORY DISORDERS<br/>[FR] COMPOSÉS CONTENANT UN CYCLE AZOTÉ POUR LE TRAITEMENT DE TROUBLES INFLAMMATOIRES
申请人：WEINGARTEN M DAVID
公开号：WO2012135669A1
公开（公告）日：2012-10-04
The invention provides compounds, pharmaceutical compositions and methods of treatment of inflammatory disorders including a compound of Formula I, or its pharmaceutically acceptable salt, ester, pharmaceutically acceptable derivative or prodrug wherein R1, R2, R3, R4, X, Y, W, Z and Q are as defined herein.
A dibenzylamine compound represented by the formula (1)
wherein R
1
and R
2
are each a C
1-6
alkyl group optionally substituted by halogen atoms and the like; R
3
, R
4
and R
5
are each a hydrogen atom, a halogen atom and the like, or R
3
and R
4
may form, together with carbon atoms bonded thereto, a homocyclic or heterocyclic ring optionally having substituent(s); A is
—N(R
7
) (R
8
) and the like; ring B is an aryl group or a heterocyclic residue; R
6
is a hydrogen atom, a halogen atom, a nitro group, a C
1-6
alkyl group and the like; n is an integer of 1 to 3, a prodrug thereof and a pharmaceutically acceptable salt thereof show selective and potent CETP inhibitory activity, and therefore, they can be provided as therapeutic or prophylactic agents for hyperlipidemia or arteriosclerosis and the like.
