Chemical: Drug
protriptyline

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last updated 10/25/2013

1. FDA Label for protriptyline and CYP2D6

Actionable PGx

Summary

Protriptyline hydrochloride is an antidepressant agent and belongs to the class of tricyclic antidepressants. CYP2D6 poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses.

Annotation

Protriptyline hydrochloride is an antidepressant agent. its mechanism of action in man is not known. Protriptyline belongs to the class of tricyclic antidepressants.

Excerpts from the Protriptyline drug label:

The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquine hydroxylase) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so called "poor metabolizers"). Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses.

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).

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Protriptyline drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Full label available at DailyMed

Genes and/or phenotypes found in this label

  • Depression
    • Indications & usage section
    • source: U.S. Food and Drug Administration
  • CYP2D6
    • other, Precautions section
    • source: U.S. Food and Drug Administration

PharmGKB contains no Clinical Variants that meet the highest level of criteria.

Disclaimer: The PharmGKB's clinical annotations reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision-making and to identify questions for further research. New evidence may have emerged since the time an annotation was submitted to the PharmGKB. The annotations are limited in scope and are not applicable to interventions or diseases that are not specifically identified.

The annotations do not account for individual variations among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider to determine the best course of treatment for a patient. Adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made solely by the clinician and the patient. PharmGKB assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the PharmGKB clinical annotations, or for any errors or omissions.

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Overview

Generic Names
  • Protryptyline
Trade Names
  • Amimetilina
  • Anafranil
  • Apo-Amitriptyline
  • Apo-Imipramine
  • Apo-Trimip
  • Asendin
  • Aventyl
  • Impril
  • Levate
  • Norpramin
  • Novo-Doxepin
  • Novo-Tripramine
  • Novopramine
  • Novotriptyn
  • Pertofrane
  • Rhotrimine
  • Sinequan
  • Surmontil
  • Tofranil
  • Triadapin 5
  • Triptil
  • Vivactil
Brand Mixture Names

PharmGKB Accession Id

PA451168

Type(s):

Drug

Description

Protriptyline hydrochloride is a dibenzocycloheptene-derivative tricyclic antidepressant (TCA). TCAs are structurally similar to phenothiazines. They contain a tricyclic ring system with an alkyl amine substituent on the central ring. In non-depressed individuals, protriptyline does not affect mood or arousal, but may cause sedation. In depressed individuals, protriptyline exerts a positive effect on mood. TCAs are potent inhibitors of serotonin and norepinephrine reuptake. In addition, TCAs down-regulate cerebral cortical beta-adrenergic receptors and sensitize post-synaptic serotonergic receptors with chronic use. The antidepressant effects of TCAs are thought to be due to an overall increase in serotonergic neurotransmission. TCAs also block histamine H 1 receptors, alpha 1-adrenergic receptors and muscarinic receptors, which accounts for their sedative, hypotensive and anticholinergic effects (e.g. blurred vision, dry mouth, constipation, urinary retention), respectively. See toxicity section below for a complete listing of side effects. Protriptyline may be used for the treatment of depression.

Source: Drug Bank

Indication

For the treatment of depression.

Source: Drug Bank

Other Vocabularies

Information pulled from DrugBank has not been reviewed by PharmGKB.

Pharmacology, Interactions, and Contraindications

Mechanism of Action

Protriptyline acts by decreasing the reuptake of norepinephrine and serotonin (5-HT).

Source: Drug Bank

Pharmacology

Protriptyline is a tricyclic antidepressant. It was thought that tricyclic antidepressants work by inhibiting the reuptake of the neurotransmitters norepinephrine and serotonin by nerve cells. However, this response occurs immediately, yet mood does not lift for approximately two weeks. It is now thought that changes occur in receptor sensitivity in the cerebral cortex and hippocampus. The hippocampus is part of the limbic system, a part of the brain involved in emotions. Presynaptic receptors are affected: alpha 1 and beta 1 receptors are sensitized, alpha 2 receptors are desensitised (leading to increased noradrenaline production). Tricyclics are also known as effective analgesics for different types of pain, especially neuropathic or neuralgic pain. A precise mechanism for their analgesic action is unknown, but it is thought that they modulate anti-pain opioid systems in the CNS via an indirect serotonergic route. They are also effective in migraine prophylaxis, but not in abortion of acute migraine attack. The mechanism of their anti-migraine action is also thought to be serotonergic.

Source: Drug Bank

Absorption, Distribution, Metabolism, Elimination & Toxicity

Toxicity

Side effects include anxiety, blood disorders, confusion, decreased libido, dizziness, flushing, headache, impotence, insomnia, low blood pressure, nightmares, rapid or irregular heartbeat, rash, seizures, sensitivity to sunlight, stomach and intestinal discomfort, 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.

Source: Drug Bank

Route of Elimination

Cumulative urinary excretion during 16 days accounted for approximately 50% of the drug. The fecal route of excretion did not seem to be important.

Source: Drug Bank

Chemical Properties

Chemical Formula

C19H21N

Source: Drug Bank

Isomeric SMILES

CNCCCC1c2ccccc2C=Cc3c1cccc3

Source: OpenEye

Canonical SMILES

CNCCCC1C2=CC=CC=C2C=CC2=CC=CC=C12

Source: Drug Bank

Average Molecular Weight

263.3767

Source: Drug Bank

Monoisotopic Molecular Weight

263.167399677

Source: Drug Bank

SMILES

CNCCCC1C2=CC=CC=C2C=CC2=CC=CC=C12

Source: Drug Bank

InChI String

InChI=1S/C19H21N/c1-20-14-6-11-19-17-9-4-2-7-15(17)12-13-16-8-3-5-10-18(16)19/h2-5,7-10,12-13,19-20H,6,11,14H2,1H3

Source: Drug Bank

Genes that are associated with this drug in PharmGKB's database based on (1) variant annotations, (2) literature review, (3) pathways or (4) information automatically retrieved from DrugBank, depending on the "evidence" and "source" listed below.

Curated Information ?

Drug Targets

Gene Description
SLC6A2 (source: Drug Bank)
SLC6A4 (source: Drug Bank)

Drug Interactions

Interaction Description
atazanavir - protriptyline Increases the effect and toxicity of tricyclics (source: Drug Bank)
atazanavir - protriptyline Atazanavir may increase the effect and toxicity of the tricyclic antidepressant, protriptyline, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of protriptyline if atazanavir if initiated, discontinued or dose changed. (source: Drug Bank)
cimetidine - protriptyline Increases the effect of tricyclic agent (source: Drug Bank)
cimetidine - protriptyline Cimetidine may increase the effect of tricyclic antidepressant, protriptyline, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of trimipramine if cimetidine is initiated, discontinued or dose changed. (source: Drug Bank)
cisapride - protriptyline Increased risk of cardiotoxicity and arrhythmias (source: Drug Bank)
cisapride - protriptyline Increased risk of cardiotoxicity and arrhythmias (source: Drug Bank)
clonidine - protriptyline The tricyclic decreases the effect of clonidine (source: Drug Bank)
clonidine - protriptyline The tricyclic antidepressant, protriptyline, decreases the effect of clonidine. (source: Drug Bank)
donepezil - protriptyline Possible antagonism of action (source: Drug Bank)
donepezil - protriptyline Possible antagonism of action (source: Drug Bank)
epinephrine - protriptyline The tricyclic increases the sympathomimetic effect (source: Drug Bank)
epinephrine - protriptyline The tricyclic antidepressant, protriptyline, increases the sympathomimetic effect of epinephrine. (source: Drug Bank)
fenoterol - protriptyline The tricyclic increases the sympathomimetic effect (source: Drug Bank)
fenoterol - protriptyline The tricyclic antidepressant, protriptyline, increases the sympathomimetic effect of fenoterol. (source: Drug Bank)
fluoxetine - protriptyline Fluoxetine increases the effect and toxicity of tricyclics (source: Drug Bank)
fluoxetine - protriptyline The SSRI, fluoxetine, may increase the serum concentration of the tricyclic antidepressant, protriptyline, by decreasing its metabolism. Additive modulation of serotonin activity also increases the risk of serotonin syndrome. Monitor for development of serotonin syndrome during concomitant therapy. Monitor for changes in the therapeutic and adverse effects of protriptyline if fluoxetine is initiated, discontinued or dose changed. (source: Drug Bank)
galantamine - protriptyline Possible antagonism of action (source: Drug Bank)
galantamine - protriptyline Possible antagonism of action (source: Drug Bank)
grepafloxacin - protriptyline Increased risk of cardiotoxicity and arrhythmias (source: Drug Bank)
grepafloxacin - protriptyline Increased risk of cardiotoxicity and arrhythmias (source: Drug Bank)
guanethidine - protriptyline The tricyclic decreases the effect of guanethidine (source: Drug Bank)
guanethidine - protriptyline The tricyclic antidepressant, protriptyline, decreases the effect of guanethidine. (source: Drug Bank)
isocarboxazid - protriptyline Possibility of severe adverse effects (source: Drug Bank)
isocarboxazid - protriptyline Possibility of severe adverse effects (source: Drug Bank)
moclobemide - protriptyline Possible severe adverse reaction with this combination (source: Drug Bank)
moclobemide - protriptyline Possible severe adverse reaction with this combination (source: Drug Bank)
orciprenaline - protriptyline The tricyclic increases the sympathomimetic effect (source: Drug Bank)
orciprenaline - protriptyline The tricyclic antidepressant, protriptyline, increases the sympathomimetic effect of orciprenaline. (source: Drug Bank)
phenelzine - protriptyline Possibility of severe adverse effects (source: Drug Bank)
phenelzine - protriptyline Possibility of severe adverse effects (source: Drug Bank)
phenylephrine - protriptyline The tricyclic increases the sympathomimetic effect (source: Drug Bank)
phenylephrine - protriptyline The tricyclic antidepressant, protriptyline, increases the sympathomimetic effect of phenylephrine. (source: Drug Bank)
phenylpropanolamine - protriptyline The tricyclic antidepressant, protriptyline, increases the sympathomimetic effect of phenylpropanolamine. (source: Drug Bank)
pseudoephedrine - protriptyline The tricyclic increases the sympathomimetic effect (source: Drug Bank)
pseudoephedrine - protriptyline The tricyclic antidepressant, protriptyline, increases the sympathomimetic effect of pseudoephedrine. (source: Drug Bank)
quinidine - protriptyline Quinidine increases the effect of the tricyclic agent (source: Drug Bank)
quinidine - protriptyline Additive QTc-prolonging effects may occur. Quinidine may also increase the serum concentration of the tricyclic antidepressant, protriptyline, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of protriptyline if quinidine is initiated, discontinued or dose changed. Monitor for the development of torsades de pointes during concomitant therapy. (source: Drug Bank)
rasagiline - protriptyline Possibility of severe adverse effects (source: Drug Bank)
rifabutin - protriptyline The rifamycin decreases the effect of tricyclics (source: Drug Bank)
rifabutin - protriptyline The rifamycin, rifabutin, may decrease the effect of the tricyclic antidepressant, protriptyline, by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of protriptyline if rifabutin is initiated, discontinued or dose changed. (source: Drug Bank)
rifampin - protriptyline The rifamycin decreases the effect of tricyclics (source: Drug Bank)
rifampin - protriptyline The rifamycin, rifampin, may decrease the effect of the tricyclic antidepressant, protriptyline, by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of protriptyline if rifampin is initiated, discontinued or dose changed. (source: Drug Bank)
tacrine - protriptyline The therapeutic effects of the central acetylcholinesterase inhibitor, Tacrine, and/or the anticholinergic, Protriptyline, may be reduced due to antagonism. The interaction may be beneficial when the anticholinergic action is a side effect. Monitor for decreased efficacy of both agents. (source: Drug Bank)
tacrine - protriptyline The therapeutic effects of the central acetylcholinesterase inhibitor, Tacrine, and/or the anticholinergic, Protriptyline, may be reduced due to antagonism. The interaction may be beneficial when the anticholinergic action is a side effect. Monitor for decreased efficacy of both agents. (source: Drug Bank)
terbutaline - protriptyline The tricyclic increases the sympathomimetic effect (source: Drug Bank)
terbutaline - protriptyline The tricyclic antidepressant, protriptyline, increases the sympathomimetic effect of terbutaline. (source: Drug Bank)
terfenadine - protriptyline Increased risk of cardiotoxicity and arrhythmias (source: Drug Bank)
terfenadine - protriptyline Increased risk of cardiotoxicity and arrhythmias (source: Drug Bank)
thiothixene - protriptyline May cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration. (source: Drug Bank)
thiothixene - protriptyline May cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration. (source: Drug Bank)
toremifene - protriptyline Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Consider alternate therapy. A thorough risk:benefit assessment is required prior to co-administration. (source: Drug Bank)
tramadol - protriptyline Tramadol increases the risk of serotonin syndrome and seizures. (source: Drug Bank)
tranylcypromine - protriptyline Increased risk of serotonin syndrome. Concomitant therapy should be avoided. A significant washout period, dependent on the half-lives of the agents, should be employed between therapies. (source: Drug Bank)
trazodone - protriptyline Increased risk of serotonin syndrome. The 2D6 inhibitor, Trazodone, may also increase the efficacy of Protriptyline by decreasing Protriptyline metabolism and clearance. Monitor for symptoms of serotonin syndrome and changes in Protriptyline efficacy if Trazodone is initiated, discontinued or dose changed. (source: Drug Bank)
trazodone - protriptyline Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. (source: Drug Bank)
trimethobenzamide - protriptyline Trimethobenzamide and Protriptyline, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Monitor for enhanced anticholinergic effects. (source: Drug Bank)
trimipramine - protriptyline Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. Additive QTc-prolongation may also occur, increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution. (source: Drug Bank)
triprolidine - protriptyline Triprolidine and Protriptyline, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Additive CNS depressant effects may also occur. Monitor for enhanced anticholinergic and CNS depressant effects. (source: Drug Bank)
triprolidine - protriptyline Triprolidine and Protriptyline, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Additive CNS depressant effects may also occur. Monitor for enhanced anticholinergic and CNS depressant effects. (source: Drug Bank)
trospium - protriptyline Trospium and Protriptyline, two anticholinergics, may cause additive anticholinergic effects and enhanced adverse/toxic effects. Monitor for enhanced anticholinergic effects. (source: Drug Bank)
venlafaxine - protriptyline Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. (source: Drug Bank)
voriconazole - protriptyline Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP). (source: Drug Bank)
vorinostat - protriptyline Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP). (source: Drug Bank)
ziprasidone - protriptyline Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated. (source: Drug Bank)
zolmitriptan - protriptyline Use of two serotonin modulators, such as zolmitriptan and protriptyline, increases the risk of serotonin syndrome. Consider alternate therapy or monitor for serotonin syndrome during concomitant therapy. (source: Drug Bank)
zuclopenthixol - protriptyline Additive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP). (source: Drug Bank)

Curated Information ?

Relationships from National Drug File - Reference Terminology (NDF-RT)

May Treat
Contraindicated With

Publications related to protriptyline: 11

No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Pharmacogenetic testing: time for clinical practice guidelines. Clinical pharmacology and therapeutics. 2011. Amstutz U, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Systematic review of pharmacoeconomic studies of pharmacogenomic tests. Pharmacogenomics. 2010. Beaulieu Mathieu, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
ADME pharmacogenetics: current practices and future outlook. Expert opinion on drug metabolism & toxicology. 2009. Grossman Iris. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Protriptyline block of the human ether-à-go-go-related gene (HERG) K+ channel. Life sciences. 2008. Jo Su-Hyun, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
The role of noradrenaline and selective noradrenaline reuptake inhibition in depression. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 2002. Brunello N, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Metabolism of tricyclic antidepressants. Cellular and molecular neurobiology. 1999. Rudorfer M V, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Protriptyline, chronic tension-type headaches, and weight loss in women. Headache. 1997. Cohen G L. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
The clinical application of tricyclic antidepressant pharmacokinetics and plasma levels. The American journal of psychiatry. 1980. Amsterdam J, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Protriptyline kinetics. Clinical pharmacology and therapeutics. 1978. Ziegler V E, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Pharmacokinetic aspects of protriptyline plasma levels. European journal of clinical pharmacology. 1977. Moody J P, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Plasma concentrations of protriptyline and clinical effects in depressed women. The British journal of psychiatry : the journal of mental science. 1976. Whyte S F, et al. PubMed

LinkOuts

Web Resource:
Wikipedia
National Drug Code Directory:
0555-0595-02
DrugBank:
DB00344
ChEBI:
8597
KEGG Compound:
C07408
PubChem Compound:
4976
PubChem Substance:
46505128
9612
Drugs Product Database (DPD):
322741
ChemSpider:
4805
Therapeutic Targets Database:
DAP000863
FDA Drug Label at DailyMed:
a6be6521-7179-442f-8c45-69711a2c3290

Clinical Trials

These are trials that mention protriptyline and are related to either pharmacogenetics or pharmacogenomics.

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NURSA Datasets

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No NURSA datasets available.

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