General
Preferred name
AMITRIPTYLINE
Synonyms
AMITRIPTYLINE HYDROCHLORIDE ()
Amitriptyline HCl ()
Annoyltin ()
Tryptizol ()
Domical ()
Amitriptyline (HCl) ()
Amitryptiline hydrochloride ()
Amitriptyline-d3 (hydrochloride) ()
Amitriptyline (hydrochloride) ()
MK-230, N-750, Ro41575 ()
Amitriptyline (hydrochloride) (CRM) ()
Amitriptyline-d3 (hydrochloride) (CRM) ()
Novoprotect ()
Elavil ()
Lentizol ()
Saroten Retard ()
NIH 10794 ()
Triptafen-M ()
Amitid ()
Amitriptylini hydrochloridum ()
Tryptizol-75 ()
Saroten ()
Limbitrol 5 ()
Triptafen ()
Cytriptyline ()
Endep ()
Amitril ()
Etravil ()
NSC-104210 ()
Syneudon ()
Damitriptyline ()
Laroxyl ()
Etrafon-Forte ()
Triptanol ()
Proheptadiene ()
Flavyl ()
Limbitrol ()
Etrafon-A ()
Seroten ()
P&D ID
PD010103
CAS
549-18-8
50-48-6
30227-34-0
342611-00-1
Tags
natural product
drug
biased GPCR ligand
nuisance
obsolete probe
available
Approved by
FDA
First approval
1961
Drug indication
Depression
Antidepressant
Drug Status
approved
Max Phase
4.0
Structure
Probe scores
P&D probe-likeness score
[[ v.score ]]%
Structure formats
[[ format ]]
[[ compound[format === 'MOL' ? 'molblock' : format.toLowerCase()] ]]
Description
(extracted from source data)
MOA 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 [FDA label], [A174673]. 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 [A174670]. 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 [A174661].
ROE 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 [FDA Label]. 25-50% of a single orally administered dose is excreted in urine as inactive metabolites within 24 hours [FDA label]. Small amounts are excreted in feces via biliary elimination [F3454].
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 [FDA label]. Steady-state plasma concentrations vary greatly and this variation may be due to genetic differences [F3454].
MOA 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 [FDA label], [A174673]. 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 [A174670]. 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 [A174661].
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_ [FDA label].; ; 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 [FDA label].
DESCRIPTION Amitriptyline is a tricyclic antidepressant (TCA). (GtoPdb)
PHARMACODYNAMICS **Effects in pain and depression** Amitriptyline is a tricyclic antidepressant and an analgesic. It has anticholinergic and sedative properties [FDA label]. 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) [A174658], [A174667]. **Cardiovascular and Anticholinergic Effects** Amitriptyline has strong anticholinergic properties and may cause ECG changes and quinidine-like effects on the heart [F3454]. 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 [FDA label]. 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 [A174661]. **Effects on seizure threshold** This drug also decreases the convulsive threshold and causes alterations in EEG and sleep patterns [F3454].
INDICATION This drug in indicated for the following conditions [FDA label]: 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 [FDA label] Off-label uses: irritable bowel syndrome, sleep disorders, diabetic neuropathy, agitation, fibromyalgia, and insomnia
TOXICITY **Toxicity Data**: Oral TDLO (child): 4167 μg/kg; Oral TDLO (man): 714 μg/kg/1D (intermittent); Oral TDLO (woman): 10 mg/kg [F3454]. 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 [FDA label]. 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 [FDA label], [F3454]. **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 [FDA label]. **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. No data on the effects of amitriptyline on human fertility are available [FDA label]. **Mutagenesis and carcinogenesis** The genotoxic potential of amitriptyline has been investigated in various in vitro and in vivo studies. Although these investigations showed some contradictory results, a potential of amitriptyline to lead to chromosome abnormalities cannot be excluded. Long-term carcinogenicity studies have not been performed to this date [FDA label].
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_ [FDA label]. 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 [FDA label].
PHARMACODYNAMICS **Effects in pain and depression**; ; Amitriptyline is a tricyclic antidepressant and an analgesic. It has anticholinergic and sedative properties [FDA label]. ; 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) [A174658], [A174667].; ; **Cardiovascular and Anticholinergic Effects**; ; Amitriptyline has strong anticholinergic properties and may cause ECG changes and quinidine-like effects on the heart [F3454]. 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 [FDA label]. 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 [A174661]. ; ; **Effects on seizure threshold**; ; This drug also decreases the convulsive threshold and causes alterations in EEG and sleep patterns [F3454].
INDICATION This drug in indicated for the following conditions [FDA label]:; ; 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 [FDA label]; ; Off-label uses: irritable bowel syndrome, sleep disorders, diabetic neuropathy, agitation, fibromyalgia, and insomnia
TOXICITY **Toxicity Data**: Oral TDLO (child): 4167 μg/kg; Oral TDLO (man): 714 μg/kg/1D (intermittent); Oral TDLO (woman): 10 mg/kg [F3454]. ; ; 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 [FDA label]. 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 [FDA label], [F3454]. ; ; **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 [FDA label].; ; **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. No data on the effects of amitriptyline on human fertility are available [FDA label].; ; ; **Mutagenesis and carcinogenesis**; ; The genotoxic potential of amitriptyline has been investigated in various in vitro and in vivo studies. Although these investigations showed; some contradictory results, a potential of amitriptyline to lead to chromosome abnormalities cannot be excluded. Long-term carcinogenicity studies have not been performed to this date [FDA label].
DESCRIPTION Activator of Nrf2 pathway; primary metabolite of DMF (Cat. No. 4512) (Tocris Bioactive Compound Library)
DESCRIPTION Tricyclic antidepressant (LOPAC library)
Cell lines
3
Organisms
5
Compound Sets
32
BiasDB
Amitriptyline
Cayman Chemical Bioactives
15881
19029
19031
19033
ChEMBL Approved Drugs
CHEMBL1200964
CHEMBL629
ChEMBL Drugs
CHEMBL1200964
CHEMBL629
CZ-OPENSCREEN Bioactive Library
Drug Repurposing Hub
DrugBank
DB00321
DrugBank Approved Drugs
DB00321
DrugCentral
180
DrugCentral Approved Drugs
180
DrugMAP
DMK7F9S
DrugMAP Approved Drugs
DMK7F9S
DrugMatrix
Guide to Pharmacology
200
Ki Database
AMITRIPTYLINE
LOPAC library
LSP-MoA library (Laboratory of Systems Pharmacology)
CHEMBL1200964
CHEMBL629
LSP-OptimalKinase library (Laboratory of Systems Pharmacology)
CHEMBL629
MedChem Express Bioactive Compound Library
HY-B0527A
HY-B0527
HY-135096
NCATS Inxight Approved Drugs
1806D8D52K
NIH Clinical Collections (NCC)
Novartis Chemogenetic Library (NIBR MoA Box)
NPC Screening Collection
Nuisance compounds in cellular assays
Obsolete Compounds
amitriptyline
Prestwick Chemical Library
ReFrame library
Selleckchem Bioactive Compound Library
amitriptyline-hydrochloride
amitriptyline
TargetMol Bioactive Compound Library
T0678
The Spectrum Collection
Tocris Bioactive Compound Library
4456
VGSC-DB
NA0009
NA0010
NA0011
NA0012
NA5916
NA5917
External IDs
74
Properties
(calculated by RDKit )
Molecular Weight
277.18
Hydrogen Bond Acceptors
1
Hydrogen Bond Donors
0
Rotatable Bonds
3
Ring Count
3
Aromatic Ring Count
2
cLogP
4.17
TPSA
3.24
Fraction CSP3
0.3
Chiral centers
0.0
Largest ring
7.0
QED
0.81
Structural alerts
3
styrene_A(13)
[#6]-2-[#6]-c:1:c(:c:c:c:c:1)-[#6](-c:3:c:c:c:c:c-2:3)=[#6]-[#6]
PAINS Family C
historic compounds (Chemical Probes.org)
Obsolete
CAD
Nuisance compounds in cellular assays
Related compounds
Custom attributes
(extracted from source data)
Selectivity
Uptake
Pathway
GPCR/G protein
Neuroscience
Immunology/Inflammation
Membrane Transporter/Ion Channel
Neuronal Signaling
Protein Tyrosine Kinase/RTK
Target
5-HT
5-HT2
5-HT4
Norepinephrine receptor
??1
ADRA1A, ADRA1B, ADRA1D, ADRA2A, ADRB1, ADRB2, ADRB3, CHRM1, CHRM2, CHRM3, CHRM4, CHRM5, HRH1, HRH2, HRH4, HTR1A, HTR1B, HTR1D, HTR2A, HTR2C, HTR6, HTR7, KCNA1, KCND2, KCND3, KCNQ2, KCNQ3, NTRK1, NTRK2, OPRD1, OPRK1, OPRM1, SIGMAR1, SLC6A2, SLC6A4
5-HT Receptor
Adrenergic Receptor
Histamine Receptor
mAChR
Serotonin Transporter
Sodium Channel
Trk Receptor
5-HT Receptor,Histamine Receptor,Serotonin Transporter
Primary Target
5-HT Transporters
MOA
Inhibitor
5-HT Reuptake Inhibitors
Nav1.4 (SkM1) Sodium Channel Blockers
Norepinephrine Reuptake Inhibitors
norepinephrine inhibitor, norepinephrine reuptake inhibitor, serotonin receptor antagonist, serotonin–norepinephrine reuptake inhibitor (SNRI)
Member status
member
Indication
depression
Therapeutic Class
Analgesics
VGSC Target
Nav1.2
Nav1.5
Nav1.7
Nav1.9
Source data