PharmGKB: The Pharmacogenomics Knowledge Base

Drug/Small Molecule:
amitriptyline

2D structure

Overview

Generic Names: Amitriprolidine; Amitriptylin; Amitriptyline HCL; Amitriptyline Hydrochloride; Amitryptiline; Amitryptyline; Amytriptiline
IUPAC Name: 3-(10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine
Trade Names: Adepress; Adepril; Amitid; Amitril; Damilan; Damilen; Elanil; Elavil; Endep; Flavyl; Hexathane; Horizon; Lantron; Laroxil; Laroxyl; Lentizol; Proheptadiene; Redomex; Saroten; Sarotex; Seroten; Sylvemid; Triptanol; Triptilin; Triptisol; Tryptanol; Tryptizol; dAmitriptyline
Brand Mixtures: Apo Peram Tab 2-25 (Amitriptyline Hydrochloride + Perphenazine); Apo Peram Tab 3-15 (Amitriptyline Hydrochloride + Perphenazine); Elavil Plus Tab (Amitriptyline Hydrochloride + Perphenazine); Etrafon 2 10 (Amitriptyline Hydrochloride + Perphenazine); Etrafon D Tab (Amitriptyline Hydrochloride + Perphenazine); Etrafon F Tab (Amitriptyline Hydrochloride + Perphenazine); Etrafon a Tab (Amitriptyline Hydrochloride + Perphenazine); Pms-Levazine 2/25 Tab (Amitriptyline Hydrochloride + Perphenazine); Pms-Levazine 3/15 Tab (Amitriptyline Hydrochloride + Perphenazine); Pms-Levazine 4/25 Tab (Amitriptyline Hydrochloride + Perphenazine); Proavil Tab (Amitriptyline Hydrochloride + Perphenazine); Triavil Tab (Amitriptyline Hydrochloride + Perphenazine)
PharmGKB Accession Id: PA448385

Description

Tricyclic antidepressant with anticholinergic and sedative properties. It appears to prevent the re-uptake of norepinephrine and serotonin at nerve terminals, thus potentiating the action of these neurotransmitters. Amitriptyline also appears to antagonize cholinergic and alpha-1 adrenergic responses to bioactive amines. [PubChem]

Indication

For the treatment of anxiety, bipolar disorders, and depression.

ATC Therapeutic Category

  • N06AA:Non-selective monoamine reuptake inhibitors

Pharmacology and Interactions

Mechanism Of Action

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.

Pharmacology

Amitriptyline, a tertiary amine tricyclic antidepressant, is structurally related to both the skeletal muscle relaxant cyclobenzaprine and the thioxanthene antipsychotics such as thiothixene. It is extremely sedating, and thus improvement of sleep patterns can be the first benefit of treatment. Amitriptyline exhibits strong anticholinergic activity, cardiovascular effects including orthostatic hypotension, changes in heart rhythm and conduction, and a lowering of the seizure threshold. As with other antidepressants, several weeks of therapy may be required in order to realize the full clinical benefit of amitriptyline. Although not a labelled indication, amitriptyline is widely used in the management of chronic nonmalignant pain (e.g., post-herpetic neuralgia, fibromyalgia).

Food Interactions

Avoid St.John's Wort. Avoid alcohol. Avoid excessive quantities of coffee or tea (Caffeine). Take with food to reduce irritation.

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

Exclusively hepatic, with first pass effect. Amitriptyline is demethylated in the liver to its primary active metabolite, nortriptyline.

Protein Binding

Very highly protein bound (90% or more) in plasma and tissues

Absorption

Rapidly and well absorbed following oral administration (bioavailability is 30-60% due to first pass metabolism).

Half Life

10 to 50 hours, with an average of 15 hours

Toxicity

LD50=350 mg/kg (in mice). 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.

Chemical Properties

Chemical Formula:

C20H23N

SMILES Code:

CN(C)CCC=C1c2ccccc2CCc3c1cccc3

(Format: OpenEye Isomeric)

Molecular Weight ( average / monoisotopic )

277.4033 / 277.183

Curated Annotations (Curated Annotation)

  1. rs4148740 at chr7:86990039 in ABCB1
    This variant is associated with differences in clinical efficacy of antidepressants, most likely by influencing their access to the brain.
    Related Drugs:
    amitriptyline, citalopram, paroxetine, venlafaxine
    Related Diseases:
    Depression
    Evidence:
    PMID:18215618
  2. rs10280101 at chr7:86991521 in ABCB1
    This variant is associated with differences in clinical efficacy of antidepressants, most likely by influencing their access to the brain.
    Related Drugs:
    amitriptyline, citalopram, paroxetine, venlafaxine
    Related Diseases:
    Depression
    Evidence:
    PMID:18215618
  3. rs7787082 at chr7:86994987 in ABCB1
    This variant is associated with differences in clinical efficacy of antidepressants, most likely by influencing their access to the brain.
    Related Drugs:
    amitriptyline, citalopram, paroxetine, venlafaxine
    Related Diseases:
    Depression
    Evidence:
    PMID:18215618
  4. rs2032583 at chr7:86998497 in ABCB1
    This variant is associated with differences in clinical efficacy of antidepressants, most likely by influencing their access to the brain.
    Related Drugs:
    amitriptyline, citalopram, paroxetine, venlafaxine
    Related Diseases:
    Depression
    Evidence:
    PMID:18215618
  5. rs4148739 at chr7:86998985 in ABCB1
    This variant is associated with differences in clinical efficacy of antidepressants, most likely by influencing their access to the brain.
    Related Drugs:
    amitriptyline, citalopram, paroxetine, venlafaxine
    Related Diseases:
    Depression
    Evidence:
    PMID:18215618
  6. rs11983225 at chr7:86999456 in ABCB1
    This variant is associated with differences in clinical efficacy of antidepressants, most likely by influencing their access to the brain.
    Related Drugs:
    amitriptyline, citalopram, paroxetine, venlafaxine
    Related Diseases:
    Depression
    Evidence:
    PMID:18215618
  7. rs10248420 at chr7:87002922 in ABCB1
    This variant is associated with differences in clinical efficacy of antidepressants, most likely by influencing their access to the brain.
    Related Drugs:
    amitriptyline, citalopram, paroxetine, venlafaxine
    Related Diseases:
    Depression
    Evidence:
    PMID:18215618
  8. rs2235040 at chr7:87003686 in ABCB1
    This variant is associated with differences in clinical efficacy of antidepressants, most likely by influencing their access to the brain.
    Related Drugs:
    amitriptyline, citalopram, paroxetine, venlafaxine
    Related Diseases:
    Depression
    Evidence:
    PMID:18215618
  9. rs12720067 at chr7:87007292 in ABCB1
    This variant is associated with differences in clinical efficacy of antidepressants, most likely by influencing their access to the brain.
    Related Drugs:
    amitriptyline, citalopram, paroxetine, venlafaxine
    Related Diseases:
    Depression
    Evidence:
    PMID:18215618
  10. rs2235015 at chr7:87037500 in ABCB1
    This variant is associated with differences in clinical efficacy of antidepressants, most likely by influencing their access to the brain.
    Related Drugs:
    amitriptyline, citalopram, paroxetine, venlafaxine
    Related Diseases:
    Depression
    Evidence:
    PMID:18215618
  11. rs11188072 at chr10:96509051 in CYP2C19
    This promoter variant is part of CYP2C19*17 haplotype, which causes increased acitivity and increased transcription of CYP2C19. Patients carrying this allele may exhibit a lack of response to commonly prescribed dosages of certain proton pump inhibitors (PPIs) and antidepressants, due to ultrarapid clearance of these drugs. CYP2C19*17 carriers are more likely to benifit from tamoxifen treatment.
    Variant Name:
    CYP2C19: -3402C>T
    Related Drugs:
    amitriptyline, citalopram, clomipramine, escitalopram, omeprazole, proguanil, tamoxifen
    Evidence:
    PMID:16413245
    PMID:17625515
    PMID:18294333
  12. rs12248560 at chr10:96511647 in CYP2C19
    This promoter variant is part of CYP2C19*17 haplotype, which causes increased acitivity and increased transcription of CYP2C19. Patients carrying this allele may exhibit a lack of response to commonly prescribed dosages of certain proton pump inhibitors (PPIs) and antidepressants, due to ultrarapid clearance of these drugs. CYP2C19*17 carriers are more likely to benifit from tamoxifen treatment.
    Variant Name:
    CYP2C19: -806C>T
    Related Drugs:
    amitriptyline, citalopram, clomipramine, escitalopram, omeprazole, proguanil, tamoxifen
    Evidence:
    PMID:16413245
    PMID:18024866
Variant names are different names that have been used in the literature and other resources to refer to the same variant.

Curated Information

The following genes are in curated knowledge about this drug.

  Gene Relationship Evidence
Phenotype data available Genotype Data Available Literature annotations available Has annotations
ABCB1
  •   
  •   
  •   
  • FA
  •   
Publications, Variants
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP2C19
  • CO
  •   
  • PK
  •   
  •   
Publications, Variants
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP2C9
  •   
  •   
  • PK
  •   
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP2D6
  • CO
  •   
  • PK
  •   
  •   
Publications
No phenotype data Genotype Data Available Literature annotations available Not annotated
CYP2E1
  •   
  •   
  • PK
  •   
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
CYP3A
  •   
  •   
  • PK
  •   
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP3A4
  •   
  •   
  • PK
  •   
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP3A5
  •   
  •   
  • PK
  •   
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
SLC6A4
  • CO
  •   
  •   
  •   
  • GN
Publications

Non-Curated Information

A list of non-curated publications that mention this drug along with other genes is available.

Metabolizing Enzymes

Drug Targets

Non-Curated Information

A list of non-curated publications that mention this drug along with other drugs is available.

Drug Interactions

altretamine Risk of severe hypotension
atazanavir Atazanavir increases the effect and toxicity of tricyclics
carbamazepine The tricyclics increases the effect of carbamazepine
cimetidine Cimetidine increases the effect of tricyclic agent
cisapride Increased risk of cardiotoxicity and arrhythmias
clonidine The tricyclic decreases the effect of clonidine
dihydroquinidine barbiturate Quinidine increases the effect of tricyclic agent
dobutamine The tricyclic increases the sympathomimetic effect
donepezil Possible antagonism of action
dopamine The tricyclic increases the sympathomimetic effect
duloxetine Possible increase in the levels of this agent when used with duloxetine
ephedra The tricyclic increases the sympathomimetic effect
ephedrine The tricyclic increases the sympathomimetic effect
epinephrine The tricyclic increases the sympathomimetic effect
fenoterol The tricyclic increases the sympathomimetic effect
fluconazole The imidazole increases the effect and toxicity of the tricyclic
fluoxetine Fluoxetine increases the effect and toxicity of tricyclics
fluvoxamine Fluvoxamine increases the effect and toxicity of tricyclics
galantamine Possible antagonism of action
grepafloxacin Increased risk of cardiotoxicity and arrhythmias
guanethidine The tricyclic decreases the effect of guanethidine
isocarboxazid Possibility of severe adverse effects
isoproterenol The tricyclic increases the sympathomimetic effect
ketoconazole The imidazole increases the effect and toxicity of the tricyclic
mephentermine The tricyclic increases the sympathomimetic effect
mesoridazine Increased risk of cardiotoxicity and arrhythmias
metaraminol The tricyclic increases the sympathomimetic effect
methoxamine The tricyclic increases the sympathomimetic effect
moclobemide Possible severe adverse reaction with this combination
norepinephrine The tricyclic increases the sympathomimetic effect
orciprenaline The tricyclic increases the sympathomimetic effect
phenelzine Possibility of severe adverse effects
phenylephrine The tricyclic increases the sympathomimetic effect
phenylpropanolamine The tricyclic increases the sympathomimetic effect
pirbuterol The tricyclic increases the sympathomimetic effect
procaterol The tricyclic increases the sympathomimetic effect
pseudoephedrine The tricyclic increases the sympathomimetic effect
quinidine Quinidine increases the effect of tricyclic agent
quinidine barbiturate Quinidine increases the effect of tricyclic agent
rasagiline Possibility of severe adverse effects
rifabutin The rifamycin decreases the effect of tricyclics
rifampin The rifamycin decreases the effect of tricyclics
ritonavir Ritonavir increases the effect and toxicity of tricyclics
rivastigmine Possible antagonism of action
salbutamol The tricyclic increases the sympathomimetic effect
sibutramine Increased risk of CNS adverse effects
sparfloxacin Increased risk of cardiotoxicity and arrhythmias
terbutaline The tricyclic increases the sympathomimetic effect
terfenadine Increased risk of cardiotoxicity and arrhythmias
thioridazine Increased risk of cardiotoxicity and arrhythmias
tranylcypromine Possibility of severe adverse effects

Curated Information

The following diseases are in curated knowledge about this drug.

  Disease Relationship Evidence
Phenotype data available No genotype data Literature annotations available Not annotated
Depression
  • CO
  •   
  • PK
  •   
  • GN
Publications, Variants
No phenotype data No genotype data Literature annotations available Not annotated
Depression, Postpartum
  • CO
  •   
  •   
  •   
  • GN
Publications

Non-Curated Information

A list of non-curated publications that mention this drug along with other diseases is available.

Curated Phenotype Datasets

These datasets are sorted alphabetically by title.

  1. Drug-Induced Long QT Intervals
    • Genotype data available
    • Phenotype data available
    • No literature annotations
    • Not annotated
    • PD
    Submitted by Dan Roden, MD involving ADRB1, ADRB2, KCNE1, KCNE2, KCNH2, KCNQ1, SCN5A, almokalant, amiodarone, amitriptyline, bretylium, bupivacaine, cisapride, disopyramide, dofetilide, encainide, fluconazole, haloperidol, hydroquinidine, isoflurane, itraconazole, ketoconazole, lithium, loratadine, metoclopramide, nortriptyline, procainamide, quinidine, sematilide, sotalol, sulfamethoxazole, thioridazine, trimethoprim, , Long QT Syndrome, Proarrhythmia and Torsades de Pointes

Additional Datasets

These datasets are minimally curated and are sorted alphabetically by title.

  1. Genetic Variants in Tricyclic Antidepressant associated Adverse Events
  2. Physicochemical determinants of human renal clearance
  3. The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease

Downloads

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LinkOuts

Web Resource:
Wikipedia
DrugBank:
DB00321
ChEBI ID:
2666
KEGG Compound ID:
C06824
PubChem Compound ID:
2160
PubChem Substance ID:
9042

Common Searches

Search PubMed
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Search PubChem
Search CTD

Non-Curated Publications

A list of non-curated publications that mention this drug is available.

PharmGKB integrates drug information from different sources: DrugBank, Open Eye Scientific Software.
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