Drug/Small Molecule:

imipramine

Overview

IUPAC Name:	3-(5,6-dihydrobenzo[b][1]benzazepin-11-yl)-N,N-dimethylpropan-1-amine
Trade Names:	Antideprin; Berkomine; Censtim; Censtin; DPID; Declomipramine; Dimipressin; Dyna-Zina; Dynaprin; Estraldine; Eupramin; IM; Imavate; Imidobenzyle; Imipramina; Imipramine Hcl; Imiprin; Imizin; Imizine; Imizinum; Impramine; Intalpram; Iramil; Irmin; Janimine; Melipramin; Melipramine; Nelipramin; Norfranil; Pramine; Prazepine; Presamine; Promiben; Psychoforin; Sk-Pramine; Surplix; Timolet; Tipramine; Tofranil, Base; Tofranil-Pm; Tofraniln A; Trimipramine Maleate
PharmGKB Accession Id:	PA449969

Description

The prototypical tricyclic antidepressant. It has been used in major depression, dysthymia, bipolar depression, attention-deficit disorders, agoraphobia, and panic disorders. It has less sedative effect than some other members of this therapeutic group. [PubChem]

Indication

For the relief of symptoms of depression and as temporary adjunctive therapy in reducing enuresis in children aged 6 years and older.

ATC Therapeutic Category

• N06AA:Non-selective monoamine reuptake inhibitors

Pharmacology and Interactions

Mechanism Of Action

Imipramine works by inhibiting the re-uptake of the neurotransmitters norepinephrine and serotonin by nerve cells. It binds the Sodium-dependent serotonin transporter and Sodium-dependent noradrenaline transporter, preventing or reducing the reuptake of norepinephrine and serotonin by nerve cells. As norepinephrine and serotonin are used to stimulate the synapse, and depression has been linked to a lack of stimulation of the recipient neuron at a synapse, slowing the reuptake of these neurotransmitters allows them to remain in the synaptic gap longer than it normal, increasing the stimulation of the recipient neuron and relieving the symptoms of depression. However, it does not act primarily by stimulation of the central nervous system. The clinical effect is also hypothesized as being due to potentiation of adrenergic synapses by blocking uptake of norepinephrine at nerve endings.

Pharmacology

Imipramine is a tricyclic antidepressant with general pharmacological properties similar to those of structurally related tricyclic antidepressant drugs such as amitriptyline and doxepin. A tertiary amine, imipramine inhibits the reuptake of serotonin more so than most secondary amine tricyclics, meaning that it blocks the reuptake of neurotransmitters serotonin and noradrenaline almost equally. It is also effective in migraine prophylaxis, but not in abortion of acute migraine attack.

Food Interactions

Avoid St.John's Wort. Avoid alcohol. Avoid excessive quantities of coffee or tea (Caffeine). Do not take fibers at the same time. Take with food.

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

Exclusively hepatic. Imipramine is converted in the liver to desipramine and 2-hydroxydesipramine, both active metabolites.

Protein Binding

89–95%

Absorption

Rapidly and well absorbed after oral administration

Half Life

11–25 hours

Toxicity

Oral, rat LD₅₀: 355 to 682 mg/kg. Toxic signs proceed progressively from depression, irregular respiration and ataxia to convulsions and death.

Chemical Properties

Chemical Formula:

C₁₉H₂₄N₂

SMILES Code:

CN(C)CCCN1c2ccccc2CCc3c1cccc3

(Format: OpenEye Isomeric)

Molecular Weight ( average / monoisotopic )

280.4073 / 280.1939

In-Depth Annotations ()

1. rs59421388 at chr22:40853554 in CYP2D6
   This variant is part of the reduced functioning haplotype CYP2D6*29, which is found at an estimated allele frequency of 20% in African Tanzanians.

   Variant Name:

   CYP2D6: 3183G>A; 3271G>A

   Related Drugs:

   citalopram, codeine, desipramine, fluoxetine, fluvoxamine, gefitinib, haloperidol, imipramine, morphine, tramadol

   Related Diseases:

   Cystic Fibrosis, Depression, Hypertension, Neoplasms, Pain, Parkinson Disease, Schizophrenia

   Evidence:

   http://www.pharmgkb.org/.../variant.jsp
   

2. rs61736512 at chr22:40855078 in CYP2D6
   This variant is part of the reduced functioning haplotype CYP2D6*29, which is found at an estimated allele frequency of 20% in African Tanzanians.

   Variant Name:

   CYP2D6: 1659G>A; 1747G>A

   Related Drugs:

   citalopram, codeine, desipramine, fluoxetine, fluvoxamine, gefitinib, haloperidol, imipramine, morphine, tramadol

   Related Diseases:

   Cystic Fibrosis, Depression, Hypertension, Neoplasms, Pain, Parkinson Disease, Schizophrenia

   Evidence:

   http://www.pharmgkb.org/.../variant.jsp
   

Curated Annotations ()

1. rs11188072 at chr10:96509051 in CYP2C19
   Risk or phenotype-associated allele: T Phenotype: The CYP2C19*17 allele was associated with significantly increased metabolism of imipramine. Study size: 178 Study population/ethnicity: Psychiatric patients aged 18-65 with a score of greater than or equal to 17 on the Hamilton Rating Scale for Depression. Significance metric(s): p = 0.035 Type of association: PK

   Variant Name:

   part of CYP2C19*17; CYP2C19:(-3402)C>T; CYP2C19: -3402C>T

   Related Drugs:

   imipramine

   Evidence:

   PMID:19884907
   

2. rs12248560 at chr10:96511647 in CYP2C19
   Risk or phenotype-associated allele: T Phenotype: The CYP2C19*17 allele was associated with significantly increased metabolism of imipramine. Study size: 178 Study population/ethnicity: Psychiatric patients aged 18-65 with a score of greater than or equal to 17 on the Hamilton Rating Scale for Depression. Significance metric(s): p = 0.035 Type of association: PK

   Variant Name:

   part of CYP2C19*17; CYP2C19:(-806)C>T; CYP2C19: -806C>T

   Related Drugs:

   imipramine

   Evidence:

   PMID:19884907
   

3. rs3892097 at chr22:40854891 in CYP2D6
   The variant allele CYP2D6*4 is the main polymorphism resulting in reduced enzyme activity in Caucasians. A number of studies show that poor metabolizer (PMs:*4/*4) reqiure a lower dose of drugs which get metabolized by CYP2D6.

   Variant Name:

   CYP2D6*4

   Related Drugs:

   clomipramine, codeine, desipramine, imipramine, nortriptyline, venlafaxine

   Related Diseases:

   Drug Toxicity

   Evidence:

   PMID:16958828
   PMID:1782973
   PMID:18070221
   

Curated Information

The following genes are in curated knowledge about this drug.

	Gene	Relationship	Evidence
	BDNF	FA	Publications
	CYP1A2	PK	Publications, Pathways
	CYP2C19	CO    PK    GN	Publications, Pathways, Variants
	CYP2D6	CO    PK    GN	Publications, Pathways, Variants
	CYP2E1	PK	Publications
	CYP3A4	PK	Pathways
	FMO1	PK	Publications
	HSPA8	FA	Publications
	ORM1	PK	Publications
	UGT1A4	PK	Publications

Non-Curated Information

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

Metabolizing Enzymes

• CYP1A2
• CYP2C19
• CYP2D6
• UGT1A4
• CYP2C9
• MAOA
• MAOB

Drug Targets

• SLC6A4
• ADORA1
• SLC6A2

PharmGKB Curated Pathways

• Imipramine/Desipramine Pathway (PK)

Non-Curated Information

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

Drug Interactions

Curated Information

The following diseases are in curated knowledge about this drug.

	Disease	Relationship	Evidence
	Attention Deficit Disorder with Hyperactivity	PK	Pathways
	Depression	CO    PK FA GN	Publications, Variants
	Depressive Disorder, Major	PK	Pathways
	Drug Toxicity	PK    GN	Publications, Variants
	Fibromyalgia	PK	Pathways
	Migraine without Aura	PK	Pathways
	neuropathic pain	PK	Pathways
	Poststroke depression	PK	Pathways

Non-Curated Information

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

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

LinkOuts

Common Searches

Search PubMed
Search Medline Plus
Search PubChem
Search CTD

Non-Curated Publications

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