Imipramine

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Imipramine
Imipramine.svg
Imipramine-3D-balls.png
Clinical data
Trade names Tofranil, Tofranil-PM, others
Synonyms Melipramine; G-22355
AHFS/Drugs.com Monograph
MedlinePlus a682389
Pregnancy
category
  • AU: C
  • US: N (Not classified yet)
Routes of
administration
Oral, intramuscular injection
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 94–96%[2]
Protein binding 86%[1]
Metabolism Hepatic (CYP1A2, CYP2C19, CYP2D6)[1]
Metabolites Desipramine (main active metabolite)[1]
Biological half-life 20 hours[1]
Excretion Renal (80%), fecal (20%) (mostly as inactive metabolites)[1]
Identifiers
CAS Number
  • 50-49-7 YesY
PubChem CID
  • 3696
IUPHAR/BPS
  • 357
DrugBank
  • DB00458 YesY
ChemSpider
  • 3568 YesY
UNII
  • OGG85SX4E4
KEGG
  • D08070 YesY
ChEBI
  • CHEBI:47499 YesY
ChEMBL
  • CHEMBL11 YesY
ECHA InfoCard 100.000.039
Chemical and physical data
Formula C19H24N2
Molar mass 280.407 g/mol
3D model (JSmol)
  • Interactive image
  (verify)

Imipramine, sold under the brand name Tofranil among others, is a tricyclic antidepressant (TCA). It is mainly used in the treatment of major depression and enuresis (inability to control urination).

Medical uses

Imipramine is used in the treatment of depression, such as depression associated with agitation or anxiety. It is similar in efficacy to the antidepressant drug moclobemide.[3] It has also been used to treat nocturnal enuresis because of its ability to shorten the time of delta wave stage sleep, where wetting occurs. In veterinary medicine, imipramine is used with xylazine to induce pharmacologic ejaculation in stallions.

Side effects

Those listed in italics below denote common side effects.[4]

Overdose

Pharmacology

Pharmacodynamics

Imipramine (and metabolite)[5]
Site IMI DSI Species Ref
SERT 1.3–1.4 17.6–163 Human [6][7]
NET 20–37 0.63–3.5 Human [6][7]
DAT 8,500 3,190 Human [6]
5-HT1A ≥5,800 ≥6,400 Human [8][9][10]
5-HT2A 80–150 115–350 Human [8][10]
5-HT2C 120 244–748 Human/rat [11][12][9]
5-HT3 970–3,651 ≥2,500 Rodent [9][13]
5-HT6 190–209 ND Rat [14]
5-HT7 >1,000 >1,000 Rat [15]
α1 32 23–130 Human [8][16][7]
α2 3,100 ≥1,379 Human [8][16][7]
β >10,000 ≥1,700 Rat [17][18][19]
D1 >10,000 5,460 Human [9][20]
D2 620–726 3,400 Human [20][9][16]
D3 387 ND Human [9]
H1 7.6–37 60–110 Human [8][16][21]
H2 550 1,550 Human [21]
H3 >100,000 >100,000 Human [21]
H4 24,000 9,550 Human [21]
mACh 46 66–198 Human [8][16]
  M1 42 110 Human [22]
  M2 88 540 Human [22]
  M3 60 210 Human [22]
  M4 112 160 Human [22]
  M5 83 143 Human [22]
α3β4 410–970 ND Human [23]
σ1 332–520 1,990–4,000 Rodent [24][25][26]
σ2 327–2,100 ≥1,611 Rat [5][25][26]
hERG 3,400 ND Human [27]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Imipramine affects numerous neurotransmitter systems known to be involved in the etiology of depression, anxiety, attention-deficit hyperactivity disorder (ADHD), enuresis and numerous other mental and physical conditions. Imipramine is similar in structure to some muscle relaxants, and has a significant analgesic effect and, thus, is very useful in some pain conditions.

The mechanisms of imipramine's actions include, but are not limited to, effects on:

  • Serotonin: very strong reuptake inhibition.
  • Norepinephrine: strong reuptake inhibition. Desipramine has more affinity to norepinephrine transporter than imipramine.
  • Dopamine: imipramine blocks D2 receptors.[28] Imipramine, and its metabolite desipramine, have no appreciable affinity for the dopamine transporter (Ki = 8,500 and >10,000 nM, respectively).[29]
  • Acetylcholine: imipramine is an anticholinergic, specifically an antagonist of the muscarinic acetylcholine receptors. Thus, it is prescribed with caution to the elderly and with extreme caution to those with psychosis, as the general brain activity enhancement in combination with the "dementing" effects of anticholinergics increases the potential of imipramine to cause hallucinations, confusion and delirium in this population.
  • Epinephrine: imipramine antagonizes adrenergic receptors, thus sometimes causing orthostatic hypotension.
  • Sigma receptor: activity on sigma receptors is present, but it is very weak (Ki = 520 nM) and it is about half that of amitriptyline (Ki = 300 nM).[citation needed]
  • Histamine: imipramine is an antagonist of the histamine H1 receptors.
  • BDNF: BDNF is implicated in neurogenesis in the hippocampus, and studies suggest that depressed patients have decreased levels of BDNF and reduced hippocampal neurogenesis. It is not clear how neurogenesis restores mood, as ablation of hippocampal neurogenesis in murine models do not show anxiety related or depression related behaviours. Chronic imipramine administration results in increased histone acetylation (which is associated with transcriptional activation and decondensed chromatin) at the hippocampal BDNF promotor, and also reduced expression of hippocampal HDAC5.[30][31]

Pharmacokinetics

Within the body, imipramine is converted into desipramine (desmethylimipramine) as a metabolite.

Chemistry

Imipramine is a tricyclic compound, specifically a dibenzazepine, and possesses three rings fused together with a side chain attached in its chemical structure.[32] Other dibenzazepine TCAs include desipramine (N-desmethylimipramine), clomipramine (3-chloroimipramine), trimipramine (2'-methylimipramine or β-methylimipramine), and lofepramine (N-(4-chlorobenzoylmethyl)desipramine).[32][33] Imipramine is a tertiary amine TCA, with its side chain-demethylated metabolite desipramine being a secondary amine.[34][35] Other tertiary amine TCAs include amitriptyline, clomipramine, dosulepin (dothiepin), doxepin, and trimipramine.[36][37] The chemical name of imipramine is 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine and its free base form has a chemical formula of C19H2N2 with a molecular weight of 280.407 g/mol.[38] The drug is used commercially mostly as the hydrochloride salt; the embonate (pamoate) salt is used for intramuscular administration and the free base form is not used.[38][39] The CAS Registry Number of the free base is 50-49-7, of the hydrochloride is 113-52-0, and of the embonate is 10075-24-8.[38][39]

History

Imipramine was discovered in 1951.[40] It was initially developed as an antihistamine and major tranquilizer for use in patients with schizophrenia; its antidepressant effects were discovered serendipitously when moods of patients improved.[16][41]

In the late 1950s, imipramine was the first TCA to be developed (by Ciba). At the first international congress of neuro-pharmacology in Rome, September 1958 Dr Freyhan from the University of Pennsylvania discussed as one of the first clinicians the effects of imipramine in a group of 46 patients, most of them diagnosed as "depressive psychosis". The patients were selected for this study based on symptoms such as depressive apathy, kinetic retardation and feelings of hopelessness and despair. In 30% of all patients, he reported optimal results, and in around 20%, failure. The side effects noted were atropine-like, and most patients suffered from dizziness. Imipramine was first tried against psychotic disorders such as schizophrenia, but proved ineffective. As an antidepressant, it did well in clinical studies and it is known to work well in even the most severe cases of depression.[42] It is not surprising, therefore, that imipramine may cause a high rate of manic and hypomanic reactions in hospitalized patients with pre-existing bipolar disorder, with one study showing that up to 25% of such patients maintained on Imipramine switched into mania or hypomania.[43] Such powerful antidepressant properties have made it favorable in the treatment of treatment-resistant depression.

Before the advent of selective serotonin reuptake inhibitors (SSRIs), its sometimes intolerable side-effect profile was considered more tolerable. Therefore, it became extensively used as a standard antidepressant and later served as a prototypical drug for the development of the later-released TCAs. Today it is no longer used as commonly, but is sometimes still prescribed as a second-line treatment for treating major depression . It has also seen limited use in the treatment of migraines, ADHD, and post-concussive syndrome. Imipramine has additional indications for the treatment of panic attacks, chronic pain, and Kleine-Levin syndrome. In pediatric patients, it is relatively frequently used to treat pavor nocturnus and nocturnal enuresis.

Society and culture

Generic names

Imipramine is the English and French generic name of the drug and its INN, BAN, and DCF, while imipramine hydrochloride is its USAN, USP, BANM, and JAN.[38][39][44][45] Its generic name in Spanish and Italian and its DCIT are imipramina, in German is imipramin, and in Latin is imipraminum.[39][45] The embonate salt is known as imipramine pamoate.[39][45]

Brand names

Imipramine is marketed throughout the world mainly under the brand name Tofranil.[39][45] Imipramine pamoate is marketed under the brand name Tofranil-PM for intramuscular injection.[39][45][46]

References

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External links

  • Imipramine – Medicinenet.com
  • Neurotransmitter – Neurotransmitter.net
  • Imipramine bound to proteins in the PDB
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