Imipramine Hydrochloride

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 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. 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) .

Imipramine is a tricyclic antidepressant indicated for the treatment of depression and to reduce childhood enuresis.

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 off-label to manage panic disorders with or without agoraphobia, as a second line agent for ADHD in children and adolescents, to manage bulimia nervosa, for short-term management of acute depressive episodes in bipolar disorder and schizophrenia, for the treatment of acute stress disorder and posttraumatic stress disorder, and for symptomatic treatment of postherpetic neuralgia and painful diabetic neuropathy .

• Attention Deficit Hyperactivity Disorder (ADHD)
• Bulimia Nervosa
• Enuresis
• Major Depressive Disorder (MDD)
• Neuropathic Pain
• Panic Disorder
• Post Traumatic Stress Disorder (PTSD)

Imipramine is a tricyclic antidepressant with general pharmacological properties similar to those of structurally related tricyclic antidepressant drugs such as amitriptyline and doxepin. While it acts to block both, imipramine displays a much higher affinity for the serotonin reuptake transporter than for the norepinephrine reuptake transporter . Imipramine produces effects similar to other monoamine targeting antidepressants, increasing serotonin- and norepinephrine-based neurotransmission.

This modulation of neurotransmission produces a complex range of changes in brain structure and function along with an improvement in depressive symptoms. The changes include increases in hippocampal neurogenesis and reduced downregulation of this neurogenesis in response to stress . These implicate brain derived neurotrophic factor signalling as a necessary contributor to antidepressant effect although the link to the direct increase in monoamine neurotransmission is unclear.

Serotonin reuptake targeting agents may also produce a down-regulation in β-adrenergic receptors in the brain .

Imipramine works by inhibiting the neuronal reuptake of the neurotransmitters norepinephrine and serotonin . It binds the sodium-dependent serotonin transporter and sodium-dependent norepinephrine transporter reducing the reuptake of norepinephrine and serotonin by neurons. Depression has been linked to a lack of stimulation of the post-synaptic neuron by norepinephrine and serotonin . Slowing the reuptake of these neurotransmitters increases their concentration in the synaptic cleft, producing knock-on effects in protein kinase signalling which is thought to contribute to changes in neurotransmission and brain physiology which relieves symptoms of depression .

Rapidly and well absorbed (>95%) after oral administration . The primary site of absorption is the small intestine as the basic amine groups are ionized in the acidic environment of the stomach, preventing movement across tissues. Bioavailability ranges from 29-77% due to high inter-individual variability. Peak plasma concentration is usually attained 2-6 hours following oral administration. Absorption is unaffected by food.

Imipramine has a high apparent volume of distribution of 10-20 L/kg . The drug is known to accumulate in the brain at concentrations 30-40 times that in systemic circulation.

Imipramine is 60-96% bound to plasma proteins in circulation . It is known to bind albumin, α1-acid glycoprotein, and lipoproteins.

Imipramine is primarily excreted in the urine with less than 5% present as the parent compound

Imipramine has a mean half life of 12 h. Its active metabolite, desipramine has a mean half life of 22.5 h .

Imipramine has a mean clearance of 1 L/h/kg. Its active metabolite, desipramine has a mean clearance of 1.8 L/h/kg .

The anticholinergic actvity of imipramine can produce dry mucous membranes, blurred vision, increased intraocular pressure, hyperthermia, constipation, adynamic ileus, urinary retention, delayed micturition, and dilation of the urinary tract .

Central nervous system and neuromuscular effects include drowsiness, lethargy, fatigue, agitation, excitement, nightmares, restlessness, insomnia, confusion, disturbed concentration, disorientation, delusions, and hallucinations.

Effects on the GI tract include anorexia, nausea and vomiting, diarrhea, abdominal cramps, increases in pancreatic enzymes, epigastric distress, stomatitis, peculiar taste, and black tongue.

Rarely agranulocytosis, thrombocytopenia, eosinophilia, leukopenia, and purpura have occured.

Infants whose mothers were receiving tricyclic antidepressants prior to delivery have experienced cardiac problems, irritability, respiratory distress, muscle spasms, seizures, and urinary retention.

Serotonin syndrome can occur when used in conjunction with other pro-serotonergic drugs.

LD₅₀/> Values

Rat - Oral 250 mg/kg - Intraperitoneal 79mg/kg - Subcutaneous 250 mg/kg - Intravenous 15.9 mg/kg

Mouse - Oral 188 mg/kg - Intraperitoneal 51.6 mg/kg - Subcutaneous 195 μg/kg - Intravenous 21 mg/kg

Human range of toxicity is considered to include single dosages greater than 5 mg/kg.

• Avoid alcohol.
• Avoid St. John's Wort.
• Do not take with bran and high fiber foods.
• Limit caffeine intake.
• Take with food.

• Initially up to 75 mg daily in divided doses increased gradually to 150-200 mg (up to 300 mg in hospital patients)
• Up to 150 mg may be given as a single dose at bedtime
• Elderly initially 10 mg daily, increased gradually to 30-50 mg daily
• Child not recommended for depression

• Child 7-8 years: 25 mg
• 8-11 years: 25-50 mg
• Over 11 years: 50-75 mg at bedtime; max