Amitriptylin

Amitriptylin · amitriptilina · Amitryptiline · Amitryptyline · Elavil · 5-(3-dimethylaminopropylidene)-10,11-dihyro-5h-dibenzo(a,d)cycloheptene · 5-(3-Dimethylaminopropylidene)-10,11-dihydro-5H-dibenzo(a,d)cycloheptatriene · n750

https://huagongshe.com/de/chemical/2160

Identifikatoren & physikalische Daten

CAS No.	50-48-6
Summenformel	C20H23N
Durchschnittliche Molmasse	277,4 g/mol
Monoisotopische Masse	277,18304974 g/mol
SMILES	CN(C)CCC=C1c2ccccc2CCc2ccccc21
InChIKey	KRMDCWKBEZIMAB-UHFFFAOYSA-N
PubChem CID	2160
ChEMBL	CHEMBL629
ChEBI	CHEBI:2666
EC No.	200-041-6
DTXSID	DTXSID7022594
Lokaler Name	Amitriptylin

Chemische & physikalische Eigenschaften

XLogP	5
Polarare Oberfläche (TPSA)	3,2
H-Brücken-Donoren	0
H-Brücken-Akzeptoren	1
Frei drehbare Bindungen	3
Schwere Atome	21
Formalladung	0
Komplexität	331
Stoffklassen	Pharmaceutical
Arzneimittel	DEA NFLIS-Drug Category -> AntidepressantsPharmaceuticals -> Used in SwitzerlandPharmaceuticals -> Listed in ZINC15Pharmaceuticals -> Antipsychotics
LogP (Verteilungskoeffizient)	log Kow = 4.925.04
Color/Form	Crystals
Löslichkeit	freely soluble in waterIn water, 9.71 mg/L at 24 °C4.50e-03 g/L9.7 mg/mL
Human Drugs	Antidepressants -> Tricyclic antidepressants (TCA)Breast FeedingLactationMilk, HumanAntidepressive AgentsAntidepressive Agents, TricyclicPharmaceuticalsMedicines for depressive disorders
Endocrine Disruptors	Potential endocrine disrupting compound
Siedepunkt	410.26°C (rough estimate)
Decomposition	When heated to decomposition it emits toxic fumes of /nitrogen oxides/
Schmelzpunkt	196-197196 - 197 °C196-197°C
Physical Description	Solid
Stability/Shelf Life	Following the date of manufacture, amitriptyline hydrochloride preparations have expiration dates of 3-5 years depending on the manufacturer and dosage form.Stable under recommended storage conditions. /Amitriptyline hydrochloride/
Dichte	0.9415 (rough estimate)
Brechungsindex	1.7500 (estimate)
Lagerbedingungen	Store at -20°C
Aggregatzustand	Liquid
pKa (Säurekonstante)	9.4(at 25℃)
Farbe	Colorless to light yellow
Stabilität	Light Sensitive
CAS Datenbank	50-48-6(CAS DataBase Reference)
NIST chemische Informationen	Amitriptyline(50-48-6)
EPA chemische Informationen	Amitriptyline (50-48-6)

Sicherheit & Vorschriften

GHS-Einstufung	DangerH301+H311+H331 (44.3%): Toxic if swallowed, in contact with skin or if inhaled [Danger Acute toxicity, oralacute toxicity, dermalacute toxicity, inhalation]P203, P261, P262, P264, P264+P265, P270, P271, P273, P280, P301+P316, P301+P317, P302+P352, P304+P340, P305+P354+P338, P316, P317, P318, P321, P330, P361+P364, P391, P403+P233, P405, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 70 reports by companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.H301: Toxic if swallowed [Danger Acute toxicity, oral]
Regulatorische Informationen	Status: Active Update: 11-10-2018 https://echa.europa.eu/registration-dossier/-/registered-dossier/18939Amitriptyline: Does not have an individual approval but may be used as a component in a product covered by a group standard. It is not approved for use as a chemical in its own right.
FDA-Anforderungen	The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including amitriptyline hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Amitriptyline hydrochloride/
Special Reports	Sarris J et alAdjunctive Nutraceuticals for Depression: A Systematic Review and Meta-Analyses. Am J Psychiatry 173 (6): 575-87 (2016)
Toxic Combustion Products	Special hazards arising from the substance or mixture: Carbon oxides, nitrogen oxides (NOx), Hydrogen chloride gas /Amitriptyline hydrochloride/
Hazard Classes and Categories	Acute Tox. 3 (44.3%)
Hazardous Reactivities and Incompatibilities	Incompatible materials: Strong oxidizing agents /Amitriptyline hydrochloride/
Brandbekämpfungsverfahren	Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. /Amitriptyline hydrochloride/Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary. /Amitriptyline hydrochloride/
Lagerbedingungen	Keep container tightly closed in a dry and well-ventilated place. Recommended storage temperature: 2 - 8 °C. Keep in a dry place. /Amitriptyline hydrochloride/Amitriptyline hydrochloride tablets should be stored in well-closed containers at a temperature preferably between 15-30 °Cexposure to temperatures exceeding 30 °C should be avoided.
Reinigungsverfahren	ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dustEnvironmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Discharge into the environment must be avoidedMethods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal. /Amitriptyline hydrochloride/
Entsorgungsverfahren	SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubberContaminated packaging: Dispose of as unused product. /Amitriptyline hydrochloride/
Preventive Measures	Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed. /Amitriptyline hydrochloride/Appropriate engineering controls: Avoid contact with skin, eyes and clothing. Wash hands before breaks and immediately after handling the product. /Amitriptyline hydrochloride/Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. /Amitriptyline hydrochloride/SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.
Personal Protective Equipment (PPE)	Eye/face protection: Face shield and safety glasses. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /Amitriptyline hydrochloride/Skin protection: Handle with gloves. /Amitriptyline hydrochloride/Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace. /Amitriptyline hydrochloride/Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face particle respirator type N99 (US) or type P2 (EN 143) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /Amitriptyline hydrochloride/
Körperbelastung	Amitriptyline and its active metabolite, nortriptyline, are distributed into milk. Amitriptyline and nortriptyline concentrations in milk appear to be similar to or slightly greater than those present in maternal serum. It is estimated that a nursing infant would ingest less than 1% of the daily maternal dose of amitriptyline ... .Amitriptyline is extensively excreted in sweat (0.78-0.2 mg/L) after cases of severe poisoning(1).2% Amitriptyline is excreted unchanged(1).
Treatment	Consider gastric lavage only if within one hour of a potentially fatal overdose. Give 50 grams of charcoal if within one hour of ingestion. Prolonged resuscitation may be successful in case of cardiac arrest. Give sodium bicarbonate in case of arrhythmias. (A311)
Wechselwirkungen	The teratogenic potential of a combination of chlordiazepoxide (Cdz) and amitriptyline (Amt) was examined with regard to both internal and external anomalies. Timed pregnant golden hamsters were given a single intraperitoneal injection on day 8 of gestation of one of the following: chlordiazepoxide hydrochloride (28.5 mg/kg), amitriptyline hydrochloride (70.3 mg/kg), Cdz-Amt combination (28.5 mg/kg Cdz + 70.3 mg/kg Amt, in order to retain the 1:2.5 dose ratio utilized in a clinically-used preparation of these agents), or saline vehicle (control). Fetuses were recovered on gestation day 15 following maternal sacrifice. Cranial malformations were analyzed in Bouin's-fixed fetuses by making 1-mm coronal sections through each head, whereas visceral anomalies were examined following general dissection of each body. Amt alone produced a significant (P less than 0.05) incidence of bent tail and encephalocele, whereas Cdz significantly (P less than 0.05) altered the male:female ratio of surviving fetuses when compared with saline-injected controls. The Cdz-Amt combination caused significant increases in cranial malformations, open eye, bent tail, abnormal lung, and urogenital anomalies. The teratogenic effects of potentiation between the components of this combination are discussed in terms of external and internal malformations.Caution is advised if patients receive large doses of ethchlorvynol concurrently. Transient delirium has been reported in patients who were treated with one gram of ethchlorvynol and 75 to 150 mg of amitriptyline hydrochloride.The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the caucasian population (about 7 to 10% of Caucasians are so called "poor metabolizers")reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8 fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidinecimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the coadministration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be coadministered with another drug known to be an inhibitor of P450 2D6. /Tricyclic antidepressants/The combination (ethanol and amitriptyline) produced greater impairment of 3 psychomotor functions in animals than did either drug alone. Ethanol pretreatment also produced A 2.23% increase in the total tricyclic antidepressant brain concentration.For more Interactions (Complete) data for AMITRIPTYLINE (33 total), please visit the HSDB record page.
Gesundheitliche Auswirkungen	Some rare side effects include tinnitus, hypotension, mania, psychosis, heart block, arrhythmias, lip and mouth ulcers, extrapyramidal symptoms, depression, and hepatic toxicity.Amitriptyline exhibits strong anticholinergic activity, cardiovascular effects including orthostatic hypotension, changes in heart rhythm and conduction, and a lowering of the seizure threshold (A308, L1032).
Hepatotoxicity	Liver test abnormalities have been reported to occur in 10% to 12% of patients on amitriptyline, but elevations are uncommonly above 3 times the upper limit of normal. The aminotransferase abnormalities are usually mild, asymptomatic and transient, reversing even with continuation of medication. Rare instances of clinically apparent acute liver injury have been reported in patients on amitriptyline. The latency to onset is quite variable, ranging from 1 to 14 months of starting the medication. The reported pattern of serum enzyme elevations has varied from hepatocellular to cholestatic. An acute hepatitis-like syndrome with acute liver failure has been reported, as well as acute cholestatic hepatitis and prolonged jaundice compatible with vanishing bile duct syndrome. Signs or symptoms of hypersensitivity (rash, fever and eosinophilia) are frequent, but are usually mild and transient. Autoantibody formation is rare.
Ökotoxizitätswerte	EC50Species: Daphnia magna (Water Flea) age <24 hr neonateConditions: freshwater, static, 21 °C, pH 7.6Concentration: 0.00415 mM for 24 hrEffect: intoxication, immobilizationSpecies: Daphnia pulex (Water Flea) age <24 hrConditions: freshwater, static, 20 °C, pH 7.6Concentration: 0.00373 mM for 24 hrEffect: intoxication, immobilization /formulation/
Umweltverhalten	TERRESTRIAL FATE: Based on a classification scheme(1), a measured Koc value of 3530(2) indicates that amitriptyline is expected to have slight mobility in soil(SRC). The estimated pKa of amitriptyline is 9.76(3), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization from moist soil is not expected because the compound exists as an cation and cations do not volatilize. Amitriptyline is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.6X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(5). Utilizing the various loam soils, half-lives of 34-85 days were observed with the formation of degradation products over 80 days(6) indicating that biodegradation is an environmental fate process in soil, with rate dependent on conditions(SRC).AQUATIC FATE: Based on a classification scheme(1), a meaured Koc value of 3530(2) indicates that amitriptyline is expected to adsorb to suspended solids and sediment(SRC). An estimated pKa of 9.76(3) indicates amitriptyline will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process(SRC). According to a classification scheme(4), an estimated BCF of 820(SRC), from its log Kow of 4.92(5) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is high(SRC). Utilizing the various loam soils, half-lives of 34-85 days were observed with the formation of degradation products over 80 days(6) indicating that biodegradation is an environmental fate process in water, with rate dependent on conditions(SRC).ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), amitriptyline, which has an estimated vapor pressure of 3.6X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase amitriptyline is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC)the half-life for this reaction in air is estimated to be 0.72 hours(SRC), calculated from its rate constant of 1.8X10-10 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase amitriptyline may be removed from the air by wet and dry deposition(SRC). Amitriptyline contains chromophores that absorb at wavelengths >290 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).
Unerwünschte Wirkungen	The most commonly encountered side effects of amitriptyline include weight gain and gastrointestinal symptoms like constipation, xerostomia, dizziness, headache, and somnolence.
Expositionspfade	Oral (A308) Rapidly and well absorbed following oral administration (bioavailability is 30-60% due to first pass metabolism). Peak plasma concentrations occur 2-12 hours following oral or intramuscular administration.
Milk Concentrations	Amitriptyline and its active metabolite, nortriptyline, are distributed into milk. Amitriptyline and nortriptyline concentrations in milk appear to be similar to or slightly greater than those present in maternal serum. It is estimated that a nursing infant would ingest less than 1% of the daily maternal dose of amitriptyline ... .
Toxizitätsübersicht	IDENTIFICATION AND USE: Amitriptyline is in the form of crystals. It is a tricyclic antidepressant. HUMAN EXPOSURE AND TOXICITY: Symptoms of overdose/poisoning may include the following: hypothermia, respiratory depression, seizures, abnormal tendon reflexes, disorientation, agitation, myoclonic jerks, coma, pyramidal signs, arrhythmias, bundle branch block, cardiac arrest, hypotension, circulatory collapse, mydriasis, blurred vision, tachycardia, vasodilation, urinary retention, decreased gastrointestinal motility, decreased bronchial secretions, and dry mucous membranes and skin. A study on children showed that initial symptoms and signs of acute amitriptyline intoxication appeared severe, but they disappeared with only supportive care required in most children except for cases that ingested high doses of drug within a few days. However, antidepressants have been shown to increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. An experiment with amitriptyline demonstrated that antidepressants reduce the release of non-neuronal acetylcholine in the human placenta, but only at concentrations roughly 30-fold above the therapeutic range. Antidepressant therapy of pregnant women should still be done with caution. Amitriptyline HCl was evaluated for its genotoxicity. The evaluation was performed in somatic (bone marrow) and germ (spermatocytes) cells, as well as the sperm morphology (i.e., head and tail) and count of the resulting sperm. The results showed that the treatment induced structural and numerical chromosome abnormalities in somatic cells (bone marrow) and germ cells (spermatocytes). Moreover, the drug significantly reduced both the mitotic index and meiotic activity after the different treatments used. Amitriptyline was found to increase significantly the incidence of sperm-cell head and tail abnormalities. The sperm-cell count was also significantly decreased. These results showed that the effect of the drug was dose dependent. In another study, amitriptyline was found to be nongenotoxic at plasma levels. However, frequencies of chromosome aberrations and sister chromatid exchanges were significantly increased at concentrations 4 and 40 times the plasma level. ANIMAL STUDIES: Symptoms of exposure in dogs include lethargy, tachycardia, vomiting, and hyperthermia. Symptoms in cats have included mydriasis and/or tachycardia, ataxia, lethargy, disorientation, and vomiting. In mice, amitriptyline produces rapid but reversible clouding of the lens, if the eyes are allowed to remain open and unprotected from evaporation. In a study on dogs, oral doses of 20 and 40 mg/kg/day were tolerated for 6 months without hematologic, biochemical or anatomical evidence of drug toxicity. Oral doses of 80 mg/kg/day were not well tolerated: 2 of 4 dogs died within 3 weeks after exhibiting severe ataxia and sedation. Doses of 100 mg/kg/day or greater were not tolerated for more than a few days. Offspring of amitriptyline-treated rats showed reduced locomotor activity. In rats, an oral dose of 25 mg/kg/day (8 times the maximum recommended human dose) produced delays in ossification of fetal vertebral bodies. In rabbits, an oral dose of 60 mg/kg/day (20 times the maximum recommended human dose) was reported to cause incomplete ossification of cranial bones. Amitriptyline was tested for genotoxicity using the somatic mutation and recombination test (SMART) in wing cells of Drosophila melanogaster. The drug was not genotoxic at concentrations up to 100 mM.Amitriptyline toxicity is measurable by a dose of over 5 mg/kg. The clinical symptoms of amitriptyline toxicity include neurological, cardiac, and anticholinergic adverse reactions. Neurological symptoms include sedation, seizure, and coma. Cardiac symptoms include tachycardia, hypotension, conduction abnormalities, and QTc prolongation. Anticholinergic symptoms include dilated pupils, dry mouth, decreased (or absent) bowel sounds, and urinary retention.Amitriptyline is metabolized to nortriptyline which inhibits the reuptake of norepinephrine and serotonin almost equally. Amitriptyline inhibits the membrane pump mechanism responsible for uptake of norepinephrine and serotonin in adrenergic and serotonergic neurons. Pharmacologically this action may potentiate or prolong neuronal activity since reuptake of these biogenic amines is important physiologically in terminating transmitting activity. This interference with the reuptake of norepinephrine and/or serotonin is believed by some to underlie the antidepressant activity of amitriptyline.
Signs and Symptoms	Symptoms of overdose include abnormally low blood pressure, confusion, convulsions, dilated pupils and other eye problems, disturbed concentration, drowsiness, hallucinations, impaired heart function, rapid or irregular heartbeat, reduced body temperature, stupor, and unresponsiveness or coma. Side effects include: sedation, hypotension, blurred vision, dry mouth, constipation, urinary retention, postural hypotension, tachycardia, hypertension, ECG changes, heart failure, impaired memory and delirium, and precipitation of hypomanic or manic episodes in bipolar depression. Withdrawal symptoms include gastrointestinal disturbances, anxiety, and insomnia.
Gefahrenklasse	IRRITANT
Gefahrstoffdaten	50-48-6(Hazardous Substances Data)

Anwendungen & Verwendung

Verwenden

Amitriptyline is used for anxious-depressive conditions. It is easier to tolerate than imipramine.