Imipramine

Indications

• Major depressive disorder
• Anxiety disorders
• Nocturnal enuresis in children

Dosage

Adults: The usual starting dose for adults is 75 mg daily, which may be increased to a maximum of 200 mg daily depending on clinical response and tolerability.

Mechanism of action

Imipramine works by inhibiting the neuronal reuptake of norepinephrine and serotonin. It binds to the sodium-dependent serotonin transporter and sodium-dependent norepinephrine transporter, reducing the reuptake of these neurotransmitters by neurons. This results in increased concentrations of norepinephrine and serotonin in the synaptic cleft, which is thought to contribute to changes in neurotransmission and brain physiology, thereby relieving symptoms of depression.

Pharmacodynamics

Imipramine is a tricyclic antidepressant that displays a higher affinity for the serotonin reuptake transporter compared to the norepinephrine reuptake transporter. It enhances neurotransmission of serotonin and norepinephrine, leading to a complex range of changes in brain structure and function, including increased neurogenesis in the hippocampus and modulation of β-adrenergic receptors. Although its antidepressant effects are linked to monoamine neurotransmission, the exact relationship with neurogenesis and brain-derived neurotrophic factor signaling remains unclear.

Pharmacokinetics

Imipramine is absorbed from the gastrointestinal tract and undergoes extensive first-pass metabolism, resulting in significant variability in plasma concentrations. It is metabolized in the liver primarily by cytochrome P450 enzymes to active metabolites, including desipramine. The drug exhibits a long half-life, allowing for once-daily dosing in some cases. Imipramine is highly protein-bound, which may affect its distribution and interactions with other medications.

Contra-indications

• Hypersensitivity to imipramine or any of its components
• Acute recovery phase following myocardial infarction
• Concurrent use with monoamine oxidase inhibitors (MAOIs)

Adverse effects

• Dry mouth
• Constipation
• Urinary retention
• Drowsiness
• Dizziness
• Weight gain
• Tachycardia
• Hypotension
• Blurred vision
• Increased sweating

Interactions

• Severe interaction with dacomitinib (increases exposure)
• Moderate interaction with fluvoxamine (increases exposure)

Precautions

• Use with caution in patients with a history of seizures
• Caution in patients with cardiovascular diseases
• Monitor for signs of worsening depression or suicidal thoughts
• Use cautiously in the elderly due to increased sensitivity

Pregnancy

Imipramine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is categorized as a pregnancy category C drug.

Breast-feeding

Imipramine is excreted in breast milk. Caution should be exercised when administering to nursing mothers.

Storage

Store at room temperature, away from moisture and light. Keep out of reach of children.

Formulations

• Oral tablets
• Capsules
• Injection (for hospital use)

Indications

• Depressive illness
• Nocturnal enuresis in children

Dosage

Children: For children aged 6-7 years: 25 mg once daily at bedtime. For children aged 8-10 years: 25-50 mg once daily at bedtime. For children aged 11-17 years: 50-75 mg once daily at bedtime.

Adults: Initially, up to 75 mg daily in divided doses, with gradual increases to a maximum of 300 mg daily in divided doses.

Mechanism of action

Imipramine acts by inhibiting the reuptake of norepinephrine and serotonin, which increases their availability in the synaptic cleft. This enhances neurotransmission and contributes to its antidepressant effects. Additionally, it has anticholinergic properties that may lead to sedation and other side effects.

Pharmacodynamics

As a TCA, imipramine exhibits a dual action on serotonin and norepinephrine reuptake transporters. The increased levels of these neurotransmitters in the brain are associated with improved mood and decreased symptoms of depression. Its sedative effects can be beneficial in patients with insomnia related to depressive disorders.

Pharmacokinetics

Imipramine is well absorbed after oral administration, with peak plasma concentrations occurring approximately 2 to 6 hours post-dose. It undergoes extensive hepatic metabolism, primarily by the cytochrome P450 system, resulting in several active metabolites. The elimination half-life of imipramine ranges from 10 to 20 hours, and it is excreted mainly in urine. The presence of food can affect its absorption, and caution is advised in patients with hepatic impairment due to altered metabolism.

Contra-indications

• Acute porphyrias
• Heart block
• Arrhythmias during manic phase of bipolar disorder

Adverse effects

• Dry mouth
• Coma of varying degree
• Hypotension
• Hypothermia
• Hyperreflexia
• Extensor plantar responses
• Convulsions
• Respiratory failure
• Cardiac conduction defects
• Arrhythmias
• Dilated pupils
• Urinary retention
• Drowsiness
• Confusion
• Delirium
• Depression
• Dizziness
• Headache
• Hepatic disorders
• Hallucinations
• Anxiety
• Decreased appetite
• Asthenia

Interactions

• Alcohol may enhance drowsiness
• Other CNS depressants may increase sedative effects
• Anticholinergic drugs may increase the risk of side effects

Precautions

• Use with caution in elderly patients due to susceptibility to side effects
• Monitor closely for psychiatric and cardiac side effects
• Hepatic impairment may require dose adjustment
• Gradual withdrawal is recommended to avoid withdrawal symptoms

Pregnancy

Use with caution due to limited information available.

Breast-feeding

The amount secreted into breast milk is too small to be harmful, but accumulation of metabolite may cause sedation and respiratory depression in neonates.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Oral suspension
• Oral capsules
• Oral solution

Mechanism of action

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. MANNER IN WHICH IMIPRAMINE RELIEVES...DEPRESSION IS NOT CLEAR. ITS EFFECT HAS BEEN DESCRIBED AS DULLING OF DEPRESSIVE IDEATION... HOWEVER, REPORTS OF MANIC EXCITEMENT AS WELL AS EUPHORIA & INSOMNIA INDICATE THAT IMIPRAMINE DOES HAVE STIMULANT ACTION UNDER CERTAIN CIRCUMSTANCES. TRICYCLIC ANTIDEPRESSANTS HAVE THREE PRIMARY PHARMACOLOGIC ACTIONS, INCLUDING ANTICHOLINERGIC EFFECTS, REUPTAKE BLOCKADE OF CATECHOLAMINES AT THE ADRENERGIC NEURONAL SITE AND QUINIDINE-LIKE EFFECTS ON THE CARDIAC TISSUE. /TRICYCLIC ANTIDEPRESSANTS/

Pharmacodynamics

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.