Molecular mass: 280.407 g/mol PubChem compound: 3696
Imipramine is a tricyclic antidepressant and has several pharmacological actions including alpha-adrenolytic, antihistamine, anticholinergic and 5HT-receptor blocking properties. However, the main therapeutic activity is believed to be inhibition of the neuronal re-uptake of noradrenaline and 5HT. Imipramine is a so-called “mixed” re-uptake blocker, i.e. it inhibits the reuptake of NA and 5HT to about the same extent.
Imipramine is absorbed quickly and completely following oral administration. The intake of food has no effect on its absorption and bioavailability. During its first passage through the liver, orally administered imipramine becomes partly converted to desmethylimipramine, a metabolite that also exhibits antidepressant activity.
During oral administration of 50mg 3 times daily for 10 days, the mean steady-state plasma concentrations of imipramine and desmethylimipramine were 33-85ng/ml and 43-109ng/ml respectively. Owing to lower clearance in the plasma, resulting in increased systemic availability, elderly patients require lower doses of imipramine than patients in intermediate age groups. Renal impairment is not expected to have any influence on the kinetics of unchanged imipramine and its desmethyl metabolite since both are excreted only in small amounts by the kidneys.
About 86% of imipramine binds to plasma proteins. Concentrations of imipramine in the cerebrospinal fluid and the plasma are highly correlated. The mean distribution volume is about 21L/kg.
Imipramine and its metabolite desmethylimipramine both pass into breast milk in concentrations similar to those found in the plasma.
Imipramine is extensively metabolised in the liver. It is cleared mainly by demethylation and to a lesser extent by hydroxylation. Both metabolic pathways are under genetic control.
Imipramine is eliminated from the blood with a mean half-life of about 19 hours. About 80% is excreted in the urine and about 20% in the faeces, mainly in the form of inactive metabolites. Urinary excretion of unchanged imipramine and of the active metabolite desmethylimipramine is about 5% and 6% respectively. Only small quantities of these are excreted in the faeces.
Owing to reduced metabolic clearance, plasma concentrations of imipramine are higher in elderly patients than in younger patients.
In children, the mean clearance and elimination of half-life does not differ significantly from adult controls but the between-patient variability is high.
In patients with severe renal impairment, no change occurs in renal excretion of imipramine and its biologically active unconjugated metabolites. However, steady-state plasma concentrations of the conjugated metabolites, which are considered to be biologically inactive are elevated. The clinical significance of this finding is not known.
Imipramine has no mutagenic or carcinogenic potential. Studies in four species (mouse, rat, rabbit and monkey) led to the conclusion that orally administered imipramine has no teratogenic potential. Experiments with high doses of parenterally administered imipramine resulted mainly in severe maternal and embryotoxic effects, they were thus inconclusive with regard to teratogenic effects.
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