Imipramine, the prototypical tricyclic antidepressant (TCA), is a dibenzazepine-derivative TCA. TCAs are structurally similar to phenothiazines. They contain a tricyclic ring system with an alkyl amine substituent on the central ring. In non-depressed individuals, imipramine does not affect mood or arousal, but may cause sedation. In depressed individuals, imipramine exerts a positive effect on mood. TCAs are potent inhibitors of serotonin and norepinephrine reuptake. Tertiary amine TCAs, such as imipramine and amitriptyline, are more potent inhibitors of serotonin reuptake than secondary amine TCAs, such as nortriptyline and desipramine. TCAs also down-regulate cerebral cortical β-adrenergic receptors and sensitize post-synaptic serotonergic receptors with chronic use. The antidepressant effects of TCAs are thought to be due to an overall increase in serotonergic neurotransmission. TCAs also block histamine H1 receptors, α1-adrenergic receptors and muscarinic receptors, which accounts for their sedative, hypotensive and anticholinergic effects (e.g. blurred vision, dry mouth, constipation, urinary retention), respectively. Imipramine has less sedative and anticholinergic effects than the tertiary amine TCAs, amitriptyline and clomipramine. See toxicity section below for a complete listing of side effects. Imipramine may be used to treat depression and nocturnal enuresis in children. Unlabeled indications include chronic and neuropathic pain (including diabetic neuropathy), panic disorder, attention-deficit/hyperactivity disorder (ADHD), and post-traumatic stress disorder (PTSD).
Indication
For the relief of symptoms of depression and as temporary adjunctive therapy in reducing enuresis in children aged 6 years and older. May also be used to manage panic disorders, with or without agoraphobia, as a second line agent in ADHD, management of eating disorders, for short-term management of acute depressive episodes in bipolar disorder and schizophrenia, and for symptomatic treatment of postherpetic neuralgia.
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. With chronic use, imipramine also down-regulates cerebral cortical β-adrenergic receptors and sensitizes post-synaptic sertonergic receptors, which also contributes to increased serotonergic transmission. It takes approximately 2 - 4 weeks for antidepressants effects to occur. The onset of action may be longer, up to 8 weeks, in some individuals. It is also effective in migraine prophylaxis, but not in abortion of acute migraine attack.
Toxicity
Oral, rat LD50: 355 to 682 mg/kg. Toxic signs proceed progressively from depression, irregular respiration and ataxia to convulsions and death. Antagonism of the histamine H1 and α1 receptors can lead to sedation and hypotension. Antimuscarinic and anticholinergic side effects such as blurred vision, dry mouth, constipation and urine retention may occur. Cardiotoxicity may occur with high doses of imipramine. Cardiovascular side effects in postural hypotension, tachycardia, hypertension, ECG changes and congestive heart failure. Psychotoxic effects include impaired memory and delirium. Induction of hypomanic or manic episodes may occur in patients with a history of bipolar disorder. Withdrawal symptoms include GI disturbances (e.g. nausea, vomiting, abdominal pain, diarrhea), anxiety, insomnia, nervousness, headache and malaise.
Affected Organisms
Humans and other mammals
Biotransformation
Exclusively metabolized by the liver. Imipramine is converted in the liver by various CYP isoenzymes (e.g. CYP1A2, CYP2D6, CYP3A4, CYP2C9) to active metabolites desipramine and 2-hydroxydesipramine.
Absorption
Rapidly and well absorbed after oral administration. Bioavailability is approximately 43%. Peak plasma concentrations usually attained 1 - 2 hours following oral administration. Absorption is unaffected by food.
Half Life
Imipramine - 8-20 hours; Desipramine (active metabolite) - up to 125 hours
Protein Binding
60-95%
Elimination
Approximately 40% of an orally administered dose is eliminated in urine within 24 hours, 70% in 72 hours. Small amounts are eliminated in feces via the biliary elimination.
