|Systematic (IUPAC) name|
|Metabolism||Hepatic (CYP1A2, CYP2C19, CYP2D6)
Main active metabolite desipramine
|Biological half-life||20 hours|
|Excretion||Renal (80%), Faecal (20%) (mostly as inactive metabolites)|
|ATC code||N06AA02 (WHO)|
|Molar mass||280.407 g/mol|
Imipramine (G 22355), sold as Tofranil and also known as melipramine, is a tricyclic antidepressant (TCA) of the dibenzazepine group. Imipramine is mainly used in the treatment of major depression and enuresis (inability to control urination).
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. 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.
In the late 1950s, imipramine was 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 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 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 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. Such powerful antidepressant properties have made it favorable in the treatment of treatment-resistant depression.
Before the advent of 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 tricyclics. 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.
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.
- Norepinephrine (NE): strong reuptake inhibition. Desipramine has more affinity to NET than imipramine.
- Dopamine (DA): Imipramine blocks D2 receptors. Imipramine, and its metabolite desipramine, have no appreciable affinity for the dopamine transporter (8,500 and >10,000 KinM respectively).
- 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).
- 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.
- 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
|imipramine||10.4||51.7||8,500||-||3,100 (Human, Brain)||726||11.0||42||60||>10,000||120 (Rat, Cloned)||120 (Rat, Cloned)||190 (Rat, Cloned)||1,000 (Rat, Cloned)|
|desipramine||179||2.27||>10,000||130||1,380 (Human, Brain)||1,560||45.6||110||210||>10,000||114 (Rat, Cloned)||496 (Rat, Cloned)||-||1,000 (Rat, Cloned)|
|amitriptyline||3.13||22.4||4,440||24 (Human, Brain)||690 (Human, Brain)||1,460 (Human, Brain)||0.5||14.7||12.8||450 (Human, Brain)||5.60 (Rat, Cortex)||6.15 (Rat, Cloned)||103||114 (Rat, Cloned)|
|clomipramine||0.21||45.9||2,610||3.2||525||120||31.2||-||-||>10,000||35.5||64.6||53.8 (Rat, Cloned)||127 (Rat, Cloned)|
Those listed in Italic text below denote common 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
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