Molecule

Drug Groups

approved

Description

Desipramine hydrochloride is a dibenzazepine-derivative tricyclic antidepressant (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, desipramine does not affect mood or arousal, but may cause sedation. In depressed individuals, desipramine exerts a positive effect on mood. TCAs are potent inhibitors of serotonin and norepinephrine reuptake. Secondary amine TCAs, such as desipramine and nortriptyline, are more potent inhibitors of norepinephrine reuptake than tertiary amine TCAs, such as amitriptyline and doxepine. 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. See toxicity section below for a complete listing of side effects. Desipramine exerts less anticholinergic and sedative side effects compared to tertiary amine TCAs, such as amitriptyline and clomipramine. Desipramine may be used to treat depression, neuropathic pain (unlabeled use), agitation and insomnia (unlabeled use) and attention-deficit hyperactivity disorder (unlabeled use).

Indication

For relief of symptoms in various depressive syndromes, especially endogenous depression. It has also been used to manage chronic peripheral neuropathic pain, as a second line agent for the management of anxiety disorders (e.g. panic disorder, generalized anxiety disorder), and as a second or third line agent in the ADHD management.

Pharmacology

Desipramine, a secondary amine tricyclic antidepressant, is structurally related to both the skeletal muscle relaxant cyclobenzaprine and the thioxanthene antipsychotics such as thiothixene. It is the active metabolite of imipramine, a tertiary amine TCA. The acute effects of desipramine include inhibition of noradrenaline re-uptake at noradrenergic nerve endings and inhibition of serotonin (5-hydroxy tryptamine, 5HT) re-uptake at the serotoninergic nerve endings in the central nervous system. Desipramine exhibits greater noradrenergic re-uptake inhibition compared to the tertiary amine TCA imipramine. In addition to inhibiting neurotransmitter re-uptake, desipramine down-regulates beta-adrenergic receptors in the cerebral cortex and sensitizes serotonergic receptors with chronic use. The overall effect is increased serotonergic transmission. Antidepressant effects are typically observed 2 - 4 weeks following the onset of therapy though some patients may require up to 8 weeks of therapy prior to symptom improvement. Patients experiencing more severe depressive episodes may respond quicker than those with mild depressive symptoms.

Toxicity

Male mice: LD50 = 290 mg/kg, female rats: LD50 = 320 mg/kg. Antagonism of the histamine H₁ and α₁ receptors can lead to sedation and hypotension. Antimuscarinic activity confers anticholinergic side effects such as blurred vision, dry mouth, constipation and urine retention may occur. Cardiotoxicity may occur with high doses of desipramine. 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

Biotransformation

Desipramine is extensively metabolized in the liver by CYP2D6 (major) and CYP1A2 (minor) to 2-hydroxydesipramine, an active metabolite. 2-hydroxydesipramine is thought to retain some amine reuptake inhibition and may possess cardiac depressant activity. The 2-hydroxylation metabolic pathway of desipramine is under genetic control.

Absorption

Desipramine hydrochloride is rapidly and almost completely absorbed from the gastrointestinal tract. It undergoes extensive first-pass metabolism. Peak plasma concentrations are attained 4 - 6 hours following oral administration.

Half Life

7-60+ hours; 70% eliminated renally

Protein Binding

73-92% bound to plasma proteins

Elimination

Desipramine is metabolized in the liver, and approximately 70% is excreted in the urine.

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