Imipramine

Imipramine

Systematic (IUPAC) name
3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine
Clinical data
Trade names	Tofranil
AHFS/Drugs.com	monograph
MedlinePlus	a682389
Pregnancy cat.	D (US) Known risk of damage to fetus.
Legal status	Prescription Only (S4) (AU) ℞ Prescription only
Routes	Oral
Pharmacokinetic data
Bioavailability	?
Metabolism	Hepatic Main active metabolite desipramine
Half-life	11-25 hours
Excretion	Renal
Identifiers
CAS number	50-49-7 Y
ATC code	N06AA02
PubChem	CID 3696
IUPHAR ligand	357
DrugBank	DB00458
ChemSpider	3568 Y
UNII	OGG85SX4E4 Y
KEGG	D08070 Y
ChEBI	CHEBI:47499 Y
ChEMBL	CHEMBL11 Y
Chemical data
Formula	C19H24N2
Mol. mass	280.407 g/mol
SMILES c1cc3c(cc1)CCc2c(cccc2)N3CCCN(C)C
InChI InChI=1S/C19H24N2/c1-20(2)14-7-15-21-18-10-5-3-8-16(18)12-13-17-9-4-6-11-19(17)21/h3-6,8-11H,7,12-15H2,1-2H3 Y Key:BCGWQEUPMDMJNV-UHFFFAOYSA-N Y
Y (what is this?)  (verify)

Imipramine (Tofranil), also known as melipramine, is an a tricyclic antidepressant (TCA) of the dibenzazepine group. Imipramine is mainly used in the treatment of major depression and enuresis (inability to control urination).

It has also been evaluated for use in panic disorder.

Therapeutic uses

Imipramine is used in the treatment of depression, such as depression associated with agitation or anxiety and has similar efficacy to the antidepressant drug moclobemide. It has also been used to treat nocturnal enuresis because of its ability to decrease the delta-wave stage of sleep where this occurs.

History

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

At the advent of SSRIs, its sometimes intolerable side-effect profile became 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 tricyclics. It is not as commonly used today, but is sometimes used to treat major depression as a second-line treatment. 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.

Mechanism of action

Imipramine, a tertiary amine, affects numerous neurotransmitter systems known to be involved in the etiology of depression, anxiety, 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 medicinal action include, but are not limited to, effects on:

• Serotonin (5-HT): Very strong reuptake inhibition. Imipramine has the second highest attraction for the serotonin transporter (SERT) in the tricyclic antidepressant class behind clomipramine. This provides a very strong and proportional effect on the blockade of serotonin reuptake. Moderating this effect, however, is imipramine's continual conversion in the body to its metabolite desipramine, which has extremely strong and relatively selective noradrenergic effects. This blend of imipramine and desipramine circulating together within the body provides a powerful one-two punch in simultaneously blockading both serotonin and norepinephrine reuptake.

• Norepinephrine (NE): Strong reuptake inhibition.

• Dopamine (DA): Reuptake and release at D₁ and D₂ receptors. Similar but less potent than psychostimulants, dopamine agonists, and the atypical antidepressant bupropion on dopaminergic mechanisms (increase in release and blockade of reuptake inhibition). While this effect is much less than the primary effects on NE, SER and ACh, it is nonetheless significant and is partially responsible for the therapeutic benefits of treatment with Imipramine. Enhancement of brain dopamine activity has been implicated in Imipramine's ability to stimulate motor activity and prolong time spent in escape in mice. Regarding dopamine uptake, imipramine is far less potent than most other antidepressants (for example, it has only 5% of the potency of amitryptiline or paroxetine, see the table below).^{[citation needed]}

• Acetylcholine (ACh): Imipramine is an anticholinergic. 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. Imipramine is an antagonist at M₂ muscarinic acetylcholine receptors (see external links). The blockade of cholinergic (muscarine) receptors is known to cause euphoria, potentially contributing to the mood lifting effects of Imipramine as well. Antimuscarinic effect is also responsible for rapid heart rate (tachycardia).

• Epinephrine: Imipramine antagonizes adreno-receptors (II), thus sometimes causing increased heart rate (contributed to by other effects as well), orthostatic hypotension, and a general decrease in the responsiveness of the central nervous system (hence, a contribution to its potent anti-anxiety properties).

• σ receptor and Enkephalinase: Activity on σ-receptors is present, but it is very low (Ki of 520 nM on σ-receptors, see references) and it is about half the power of amitryptiline (300 nM).

• Histamine: Imipramine is an antagonist at histamine H₁ receptors. This contributes to the acute sedative effect that it has in most people. In turn, its anti-histaminergic and general calming effects take place immediately, and, thus, Imipramine is sometimes prescribed as a sleep aid in low doses.

• 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.

• μ receptor: Imipramine has been shown to increase the expression of μ-opioid receptors in rat forebrain.

Comparison with other antidepressants

The potency (affinity) of imipramine and other antidepressants on various transporters and receptors are summarized below. Data are from "Pharmacology of antidepressant", Mayo Clin Proc, May 2001, Vol 76.

Potency (affinity) data are expressed as the inverse of equilibrium dissociation constant multiplied by a factor of 10⁻⁷. So, the higher the number, the higher the blocking power.

Drug	SERT	NET	DAT	α1 blockade	D2 blockade	H1 blockade	muscarinic blockade	5HT2 blockade
imipramine	70	2.7	0.012	1.5	0.05	9.1	1.1	1.2
desipramine (also an imipramine metabolite)	5.7	128	0.024	0.77	0.03	0.91	0.5	0.38
amitriptyline	23	2.9	0.023	3.7	0.1	91	5.6	3.4
clomipramine	360	2.7	0.045	2.6	0.53	3.2	2.7	3.7
paroxetine	800	2.5	0.2	0.025	0.003	0.03	0.93	0.005
citalopram	98	0.035	0.0038	0.053	0	0.21	0.045	0.34

Metabolism

Imipramine is converted to desipramine, another TCA, in the body.

Side effects

Those listed in Italic text below denote common side effects. Those listed in bold text denote life-threatening side effects.

• Central Nervous System: Dizziness, drowsiness, confusion, seizures, headache, anxiety, tremors, stimulation, weakness, insomnia, nightmares, extrapyramidal symptoms in geriatric patients, increased psychiatric symptoms, paresthesia

• Cardiovascular: Orthostatic hypotension, ECG changes, tachycardia, hypertension, palpitations, dysrhythmias

• Eyes, Ears, Nose and Throat: Blurred vision, tinnitus, mydriasis

• Gastrointestinal:Dry mouth, nausea, vomiting, paralytic ileus, increased appetite, cramps, epigastric distress, jaundice, hepatitis, stomatitis, constipation, taste change

• Genitourinary: Urinary retention,

• Hematological: Agranulocytosis, thrombocytopenia, eosinophilia, leukopenia

• Skin: Rash, urticaria, diaphoresis, pruritus, photosensitivity

Dosage

Dosage specified below is too high. 5 mg to 10mg per dose is proper 1 to 2 times per day.

• Hospitalized patients: starting with 3 times 25 mg, increasing to 125 mg. Up to 300 mg may be given in resistant cases. After remission dose is often reduced to 50 to 100 mg daily.
• Ambulatory patients: starting with 25 to 75 mg daily, increasing up to a maximum of 200 mg daily, after remission dose is often reduced to 50–100 mg daily.
• Pediatric patients: starting with 10 mg daily the dose is adjusted according to the severity of the symptoms to be treated, the side-effects encountered and the weight of the patient.

Overdose

Main article: Tricyclic antidepressant overdose

The symptoms and the treatment of an imipramine overdose are largely the same as for the other tricyclic antidepressants. Cardinal symptoms are cardiac (tachycardia, widened QRS complex) and neurological disturbances. Any ingestion by children should be considered as serious and potentially fatal.

See also

• Tricyclic antidepressant

External links

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