Amitriptyline Stats & Data
CN(C)CCC=C1c2ccccc2CCc2ccccc12KRMDCWKBEZIMAB-UHFFFAOYSA-NPharmacology
DrugBankDescription
Amitriptyline hydrochloride, also known as _Elavil_, is a tricyclic antidepressant (TCA) with analgesic properties, widely used to treat depression and neuropathic pain . It was originally approved by the FDA in 1977 and manufactured by Sandoz .
Mechanism of Action
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 .
Pharmacodynamics
**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.
Metabolism
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 .
Absorption
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 .
Toxicity
**Toxicity Data**: Oral TDLO (child): 4167 μg/kg; Oral TDLO (man): 714 μg/kg/1D (intermittent); Oral TDLO (woman): 10 mg/kg . Ingestion of 750 mg or more by an adult may result in severe toxicity. The effects in overdose are further increased by simultaneous ingestion of alcohol and another psychotropic agent . 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, among others , . **Use in pregnancy** For amitriptyline, only limited clinical data are available regarding its use in pregnancy. Amitriptyline is not recommended during pregnancy unless clearly required and only after careful consideration of both risks and benefits . **Use in breastfeeding** Amitriptyline and its metabolites are excreted into breast milk (corresponding to 0.6 % - 1 % of the maternal dose). A risk to the suckling child must be considered. A decision should be made as to whether it is appropriate to discontinue breastfeeding or to discontinue/abstain from the therapy of this medicinal product, considering the benefit of breastfeeding for the child and the benefit of therapy for the woman. **Effects on fertility** Animal studies have shown reproductive toxicity.
Indication
This drug in indicated for the following conditions : Major depressive disorder in adults Management of neuropathic pain in adults Prophylactic treatment of chronic tension-type headache (CTTH) in adults Prophylactic treatment of migraine in adults Treatment of nocturnal enuresis in children aged 6 years and above when organic pathology, including spina bifida and related disorders, have been excluded and no response has been achieved to all other non-drug and drug treatments, including antispasmodics and vasopressin-related products. This product should only be prescribed by a healthcare professional with expertise in the management of persistent enuresis Off-label uses: irritable bowel syndrome, sleep disorders, diabetic neuropathy, agitation, fibromyalgia, and insomnia
Half-life
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) .
Protein Binding
Very highly protein bound (95%) in plasma and tissues .
Elimination
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 .
Volume of Distribution
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 .
Clearance
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 .
Tolerance & Pharmacokinetics
drugs.wikiTolerance Decay
Experience Report Analysis
ErowidDemographics
Gender Distribution
Age Distribution
Reports Over Time
Effect Analysis
ErowidEffects aggregated from 39 experience reports (39 Erowid)
Effect Sentiment Distribution
Confidence Distribution
Positive Effects 11
Adverse Effects 7
Dose-Response Correlation
How effect frequency changes across dose levels
View data table
| Effect | Common (n=12) |
|---|---|
| Sedation | 58.3% |
| Anxiety Suppression | 33.3% |
| Nausea | 25.0% |
| Auditory Effects | 25.0% |
| Focus Enhancement | 25.0% |
| Stimulation | 25.0% |
| Headache | 16.7% |
| Music Enhancement | 16.7% |
| Euphoria | 16.7% |
| Confusion | 16.7% |
| Muscle Tension | 16.7% |
Dose–Effect Mapping
Experience ReportsHow reported effects shift across dose tiers, based on 39 experience reports.
Limited tier coverage — most reports fall within the Common range. Effects at other dose levels may not be represented.
| Effect | Common (n=12) | |
|---|---|---|
| sedation | ||
| anxiety suppression | ||
| nausea | ||
| auditory effects | ||
| focus enhancement | ||
| stimulation | ||
| headache | ||
| music enhancement | ||
| euphoria | ||
| confusion | ||
| muscle tension |
Dosage Distribution
Dose distribution from experience reports
Real-World Dose Distribution
62K DosesFrom 111 individual dose entries
Oral (n=95)
Form / Preparation
Most common forms and preparations reported
Body-Weight Dosing
Dose relative to body weight from reports with weight data
Redose Patterns
Redosing behavior across 36 reports