Amitriptyline

DEA NFLIS-Drug Category -> Antidepressants

Pharmaceuticals -> Used in Switzerland

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals

Pharmaceuticals -> Antipsychotics

log Kow = 4.92

4.9

5.04

freely soluble in water

In water, 9.71 mg/L at 24 °C

4.50e-03 g/L

Antidepressants -> Tricyclic antidepressants (TCA)

Breast Feeding; Lactation; Milk, Human; Antidepressive Agents; Antidepressive Agents, Tricyclic

Pharmaceuticals

Medicines for depressive disorders

196-197

196 - 197 °C

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/

Danger

H301+H311+H331 (44.3%): Toxic if swallowed, in contact with skin or if inhaled [Danger Acute toxicity, oral; acute toxicity, dermal; acute 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.

Danger

H301: Toxic if swallowed [Danger Acute toxicity, oral]

Status: Active Update: 11-10-2018 https://echa.europa.eu/registration-dossier/-/registered-dossier/18939

Amitriptyline: 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.

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/

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/

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 °C; exposure to temperatures exceeding 30 °C should be avoided.

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 dust; Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Discharge into the environment must be avoided; Methods 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/

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 scrubber; Contaminated packaging: Dispose of as unused product. /Amitriptyline hydrochloride/

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.

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/

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).

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)

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 (quinidine; cimetidine) 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.

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).

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.

EC50; Species: Daphnia magna (Water Flea) age <24 hr neonate; Conditions: freshwater, static, 21 °C, pH 7.6; Concentration: 0.00415 mM for 24 hr; Effect: intoxication, immobilization

EC50; Species: Daphnia pulex (Water Flea) age <24 hr; Conditions: freshwater, static, 20 °C, pH 7.6; Concentration: 0.00373 mM for 24 hr; Effect: intoxication, immobilization /formulation/

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).

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 ... .

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.

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.

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/

N06AA09

N - Nervous system

QN - Nervous system

N06AA09

**Effects in pain and depression** Amitriptyline is a tricyclic antidepressant and an analgesic. It has anticholinergic and sedative properties. Clinical studies have shown that oral amitriptyline achieves, at a minimum, good to moderate response in up to 2/3 of patients diagnosed with post-herpetic neuralgia and 3/4 of patients diagnosed with diabetic neuropathic pain, and neurogenic pain syndromes that are frequently unresponsive to narcotic analgesics. Amitriptyline has also shown efficacy in diverse groups of patients with chronic non-malignant pain. There have also been some studies showing efficacy in managing fibromyalgia (an off-label use of this drug),. **Cardiovascular and Anticholinergic Effects** Amitriptyline has strong anticholinergic properties and may cause ECG changes and quinidine-like effects on the heart. Amitriptyline may inhibit ion channels, which are necessary for cardiac repolarization (hERG channels), in the upper micromolar range of therapeutic plasma concentrations. Therefore, amitriptyline may increase the risk for cardiac arrhythmia. Orthostatic hypotension and tachycardia can be a problem in elderly patients receiving this drug at normal doses for depression. There is evidence in the literature that these effects may occur, rarely, at the lower dosages utilized in the treatment of pain. As with any other tricyclic antidepressant agent, increased glucose levels can occur with amitriptyline. **Effects on seizure threshold** This drug also decreases the convulsive threshold and causes alterations in EEG and sleep patterns.

The mechanism of action of this drug is not fully elucidated. It is suggested that amitriptyline inhibits the membrane pump mechanism responsible for the re-uptake of transmitter amines, such as norepinephrine and serotonin, thereby increasing their concentration at the synaptic clefts of the brain,. These amines are important in regulating mood. The monoamine hypothesis in depression, one of the oldest hypotheses, postulates that deficiencies of serotonin (5-HT) and/or norepinephrine (NE) neurotransmission in the brain lead to depressive effects. This drug counteracts these mechanisms, and this may be the mechanism of amitriptyline in improving depressive symptoms. Whether its analgesic effects are related to its mood-altering activities or attributable to a different, less obvious pharmacological action (or a combination of both) is unknown.

Acute and chronic effects of the antidepressant drugs tranylcypromine, a monoamine oxidase inhibitor, and amitriptyline, a monoamine uptake inhibitor, were studied on beta-adrenergic receptor function in mouse astrocytes in primary cultures. In clinically relevant concentrations, acute administration of either antidepressant drug had a direct inhibitory effect on the binding of the beta-adrenergic ligand dihydroalprenolol and on the isoproterenol-induced accumulation of cyclic AMP. However, in the absence of isoproterenol, these drugs enhanced the formation of cyclic AMP in the astrocytes. Chronic exposure to amitriptyline or tranylcypromine led to a decrease in isoproterenol-induced accumulation of cyclic AMP, and the time course for the development of this phenomenon was similar to that reported for whole brain in vivo. These findings suggest that these antidepressant drugs act as a partial agonists at beta-adrenergic receptors on astrocytes, and that the down-regulation of beta-adrenergic activity that occurs in vivo after chronic administration of antidepressant drugs may, to a large extent, take place in astrocytes and may result from the partial beta-agonist nature of the drugs.

Astrocytes play important roles in guiding the construction of the nervous system, controlling extracellular ions and neurotransmitters, and regulating CNS synaptogenesis. Egr-1 is a transcription factor involved in neuronal differentiation and astrocyte cell proliferation. In this study, we investigated whether the tricyclic antidepressant (TCA) amitriptyline induces Egr-1 expression in astrocytes using rat C6 glioma cells as a model. We found that amitriptyline increased the expression of Egr-1 in a dose- and time-dependent manner. The amitriptyline-induced Egr-1 expression was mediated through serum response elements (SREs) in the Egr-1 promoter. SREs were activated by the Ets-domain transcription factor Elk-1 through the ERK and JNK mitogen-activated protein (MAP) kinase pathways. The inhibition of the ERK and JNK MAP kinase signals attenuated amitriptyline-induced transactivation of Gal4-Elk-1 and Egr-1 promoter activity. Our findings suggest that the induction of Egr-1 expression in astrocytes may be required to attain the therapeutic effects of antidepressant drugs.

Antidepressants such as serotonin-noradrenaline reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs) are frequently used for the management of neuropathic pain. Noradrenaline (NA) and serotonin (5-HT) increase in the spinal cord by reuptake inhibition is considered to be main mechanism of the therapeutic effect of antidepressants in neuropathic pain. In the present study, we examined the analgesic effects of duloxetine (SNRI) and amitriptyline (TCA) in a rat model of neuropathic pain induced by spinal nerve ligation (SNL). Intraperitoneal administration of duloxetine and amitriptyline dose-dependently (3,10 and 30 mg/kg) suppressed hyperalgesia induced by SNL. In vivo microdialysis in the lumbar spinal dorsal horn revealed that NA and 5-HT concentrations increased after intraperitoneal administration of duloxetine and amitriptyline (10 mg/kg, respectively). We further determined NA and 5-HT contents in homogenized samples from the ipsilateral dorsal spinal cord after SNL. Although the NA content in SNL rats 2 weeks after ligation was higher than that in SNL rats 4 weeks after ligation, the analgesic efficacy of duloxetine and amitriptyline was similar between two groups. The present study suggests that NA/5-HT increase in the spinal cord is crucial in the antihyperalgesic effect of duloxetine and amitriptyline. The plastic change of the descending noradrenergic system does not obviously affect the analgesic efficacy of duloxetine and amitriptyline.

Recent studies show that neuronal and glial plasticity are important for the therapeutic action of antidepressants. Here, we demonstrated that amitriptyline, a tricyclic antidepressant, significantly increased GDNF mRNA and GDNF release in C6 cells. Furthermore, different classes of antidepressants increased GDNF release, but non-antidepressant psychotropic drugs did not. The amitriptyline-induced GDNF release was completely inhibited by U0126, a mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor, but was not inhibited by H-89, a protein kinase A inhibitor or calphostin C, a protein kinase C inhibitor. These results suggest that the amitriptyline-induced GDNF release may be regulated through a MEK/MAPK pathway. Next, we examined the effects of monoamines on GDNF release, because antidepressants are known to increase monoamines. 5-HT increased GDNF mRNA and GDNF release, but noradrenaline and dopamine did not. The 5-HT-induced GDNF release was partially, but significantly, blocked by ketanserin, a 5-HT2A receptor antagonist. The 5-HT-induced GDNF release was completely inhibited by U0126, but was not inhibited by H-89 or calphostin C. These results suggest that the 5-HT-induced GDNF release was mediated through a MEK/MAPK pathway and, at least, 5-HT2A receptors. GDNF, as well as other neurotrophic factors, may contribute to explain the therapeutic action of antidepressants and suggest a novel strategy of pharmacological intervention.

For more Mechanism of Action (Complete) data for AMITRIPTYLINE (13 total), please visit the HSDB record page.

The elimination half-life (t1⁄2 β) amitriptyline after peroral administration is about 25 hours (24.65 ± 6.31 hours; range 16.49-40.36 hours).

The plasma half-life of amitriptyline ranges from 10 to 50 hours.

The toxicokinetics of amitriptyline were studied in nine patients admitted to hospital in Matthew-Lawson Coma Scale grade III-IV after an estimated ingestion of 1-5 g amitriptyline. ... The T1/2 alpha and T1/2 beta for amitriptyline were 1.5 - 3.1 and 15 - 43 hr respectively. ...

... The purpose of this pilot study was to describe the individual and population pharmacokinetic parameters of amitriptyline after a single oral dose at 1.5 mg/kg, 4.5 mg/kg, and 9 mg/kg in healthy African grey parrots ( Psittacus erithacus , n = 3) and cockatoos (Cacatua species, n = 3). Three birds received an initial 1.5 mg/kg oral dose, and blood samples were collected for 24 hours at fixed time intervals. Serum concentrations of amitriptyline and its metabolites were determined by polarized immunofluorescence. After determining the initial parameters and a 14-day washout period, 2 African grey parrots and 1 cockatoo received a single oral dose at 4.5 mg/kg, and 3 cockatoos and 1 African grey parrot received a single oral dose at 9 mg/kg. ... Elimination half-life varied from 1.6 to 91.2 hours. ...

In vitro, the metabolism of amitriptyline occurs mainly by demethylation (CYP2C19, CYP3A4) as well as hydroxylation (CYP2D6) followed by conjugation with glucuronic acid. Other isozymes involved in amitriptyline metabolism are CYP1A2 and CYP2C9. The metabolism of this drug is subject to genetic polymorphisms. The main active metabolite is the secondary amine, _nortriptyline_. Nortriptyline is a stronger inhibitor of noradrenaline than of serotonin uptake, while amitriptyline inhibits the uptake of noradrenaline and serotonin with equal efficacy. Other metabolites such as _cis-_ and _trans-10-hydroxyamitriptyline_ and _cis-_ and _trans-10-hydroxynortriptyline_ have the same pharmacologic profile as nortriptyline but are significantly weaker. _Demethylnortriptyline_ and amitriptyline N oxide are only present in plasma in negligible amounts; the latter is mostly inactive.

A method for the determination of amitriptyline and some of its metabolites in serum on a reversed phase system consisting of C-8 bonded phase material as the stationary phase and water-methanol-dichloromethane-propylamine as the mobile phase by liquid chromatography with UV detection at 254 nm is described. ... Serum levels of amitriptyline and its 4 main metabolites (nortriptyline, desmethylnortriptyline, trans-10-hydroxyamitriptyline and trans-10-hydroxynortriptyline) in a patient receiving 150 mg of oral amitriptyline daily are reported.

Amitriptyline is metabolized via the same pathways as are other tricyclic antidepressants; nortriptyline, its N-monodemethylated metabolite, is pharmacologically active.

To investigate the metabolism of amitriptyline and debrisoquine ... 8 healthy Chinese volunteers received a single oral dose of 100 mg amitriptyline and the ratios between the area under the curve (AUC) of amitriptyline and its 3 metabolites were evaluated. Results indicated that large interindividual differences in AUC were observed. In addition, hydroxylation of amitriptyline and debrisoquine may be regulated by similar enzymatic processes.

Biotransformation of amitriptyline to its demethylated product nortriptyline was studied in vitro with human liver microsomes from four different donors, preselected to reflect a range of metabolic rates. Reaction velocity versus substrate concn was consistent with a sigmoid Vmax model. Vmax varied from 0.42 to 3.42 nmol/mg/min, Km from 33 to 89 uM amitriptyline. Ketoconazole was a highly potent inhibitor of N-demethylation, with a mean Ki value of 0.11 + or - 0.013 uM ... whereas quinidine (up to 50 uM), a CYP2D6 inhibitor, and alpha-naphthoflavone (up to 5 uM), a CYP1A2 inhibitor only at low concn, showed no effect. All selective serotonin reuptake inhibitors tested had an inhibitory effect on the formation of nortriptyline, with mean Ki values of 4.37 (+ or - 3.38) uM for sertraline, 5.46 (+ or - 1.95) uM for desmethylsertraline, 9.22 (+ or - 3.69) uM for fluvoxamine, 12.26 (+ or - 5.67) uM for norfluoxetine, 15.76 (+ or - 5.50) uM for paroxetine, and 43.55 (+ or - 18.28) uM for fluoxetine. A polyclonal rabbit antibody against rat liver CYP3A1, in antibody/microsomal protein rations varying from 1:1 to 10:1, inhibited N-demethylation of amitriptyline to an asymptotic max of 60%.

For more Metabolism/Metabolites (Complete) data for AMITRIPTYLINE (8 total), please visit the HSDB record page.

1806D8D52K

AMITRIPTYLINE

Established Pharmacologic Class [EPC] - Tricyclic Antidepressant

Amitriptyline is a Tricyclic Antidepressant.

Substances that contain a fused three-ring moiety and are used in the treatment of depression. These drugs block the uptake of norepinephrine and serotonin into axon terminals and may block some subtypes of serotonin, adrenergic, and histamine receptors. However, the mechanism of their antidepressant effects is not clear because the therapeutic effects usually take weeks to develop and may reflect compensatory changes in the central nervous system.

A subclass of analgesic agents that typically do not bind to OPIOID RECEPTORS and are not addictive. Many non-narcotic analgesics are offered as NONPRESCRIPTION DRUGS.

Drugs that block the transport of adrenergic transmitters into axon terminals or into storage vesicles within terminals. The tricyclic antidepressants (ANTIDEPRESSIVE AGENTS, TRICYCLIC) and amphetamines are among the therapeutically important drugs that may act via inhibition of adrenergic transport. Many of these drugs also block transport of serotonin.

Rapidly absorbed following oral administration (bioavailability is 30-60% due to first pass metabolism). Peak plasma concentrations are reached 2-12 hours after oral or intramuscular administration. Steady-state plasma concentrations vary greatly and this variation may be due to genetic differences.

Amitriptyline and its metabolites are mainly excreted in the urine. Virtually the entire dose is excreted as glucuronide or sulfate conjugate of metabolites, with approximately 2% of unchanged drug appearing in the urine. 25-50% of a single orally administered dose is excreted in urine as inactive metabolites within 24 hours. Small amounts are excreted in feces via biliary elimination.

The apparent volume of distribution (Vd)β estimated after intravenous administration is 1221 L±280 L; range 769-1702 L (16±3 L/kg). It is found widely distributed throughout the body. Amitriptyline and the main metabolite _nortriptyline_ pass across the placental barrier and small amounts are present in breast milk.

The mean systemic clearance (Cls) is 39.24 ± 10.18 L/h (range: 24.53-53.73 L/h). No clear effect of older age on the pharmacokinetics of amitriptyline has been determined, although it is possible that clearance may be decreased.

This study reports the pharmacokinetics of oral amitriptyline and its active metabolite nortriptyline in Greyhound dogs. Five healthy Greyhound dogs were enrolled in a randomized crossover design. A single oral dose of amitriptyline hydrochloride (actual mean dose 8.1 per kg) was administered to fasted or fed dogs. Blood samples were collected at predetermined times from 0 to 24 hr after administration, and plasma drug concentrations were measured by liquid chromatography with mass spectrometry. Noncompartmental pharmacokinetic analyses were performed. Two dogs in the fasted group vomited following amitriptyline administration and were excluded from analysis. The range of amitriptyline CMAX for the remaining fasted dogs (n = 3) was 22.8-64.5 ng/mL compared to 30.6-127 ng/mL for the fed dogs (n = 5). The range of the amitriptyline AUCINF for the three fasted dogs was 167-720 hr ng/mL compared to 287-1146 hr ng/mL for fed dogs. The relative bioavailability of amitriptyline in fasted dogs compared to fed dogs was 69-91% (n = 3). The exposure of the active metabolite nortriptyline was correlated to amitriptyline exposure (R(2) = 0.84). Due to pharmacokinetic variability and the small number of dogs completing this study, further studies are needed assessing the impact of feeding on oral amitriptyline pharmacokinetics. Amitriptyline may be more likely to cause vomiting in fasted dogs.

The inability of a 30-yr-old female with graft-versus-host disease to absorb oral doses of amitriptyline was reported. Only trace plasma levels of the drug were determined following 4 wk therapy with 50 mg daily doses. Additional therapy with 75 mg daily doses for 10 days failed to incr the antidepressant's plasma levels.

MEDICATION

Adrenergic Uptake Inhibitors; Analgesics, Non-Narcotic; Antidepressive Agents, Tricyclic

Use (kg; approx.) in Germany (2009): >7500

For the treatment of depression, chronic pain, irritable bowel syndrome, sleep disorders, diabetic neuropathy, agitation and insomnia, and migraine prophylaxis.

(1977) 5.32X10+6 GRAMS (PRINCPL CUSTMS DISTS)

(1979) 1.00X10+6 GRAMS (PRINCPL CUSTMS DISTS)

(1976) PROBABLY GREATER THAN 4.54X10+5 GRAMS

(1979) PROBABLY GREATER THAN 4.54X10+5 G-HCL

Phthalic anhydride is reacted with phenylacetic acid to form 3-benzylidenephthalide, which is hydrogenated to 2-phenethylbenzoic acid. Conversion to the acid chloride followed by intramolecular dehydrochlorination yields the ketone (5H-dibenzo[a,d]cyclohepten-5-one), which is grignardized with 3-(dimethylamino)propyl chloride. Dehydration of the resulting tertiary carbinol gives amitriptyline, which is dissolved in a suitable solvent and converted to the hydrochloride by a stream of HCl. USA patent 3,205,264.

... Prepared from 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one (well known under the trivial name dibenzosuberone) and 3-dimethylaminopropylmagnesium chloride and subsequent dehydration with HCl in ethanol. ... a versatile alternative process makes use of cyclopropylmagnesium bromide as Grignard reagent.

... Prepared by reaction of 5-oxo-10,11-dihydro-5H-dibenzo(a,d)cycloheptene with the Grignard reagent of 3-dimethylaminopropyl chloride followed by dehydration of the resulting tertiary alcohol in a strongly acidic medium.

Table: Amitriptyline Hydrochloride Preparations [Table#4348]

Table: Chlordiazepoxide and Amitriptyline Hydrochloride Preparations [Table#4349]

Table: Perphenazine and Amitriptyline Preparations [Table#4350]

Adepril; Amineurin; Domical; Elavi; Endep; Euplit; Laroxyl; Lentizol; Miketorin; Redomex; Saroten; Sarotex; Triptizol; Tryptanol; Tryptizol. /Amitriptyline hydrochloride/

Pharmaceuticals -> Antidepressants

Pharmaceuticals