Trimipramine

Trimipramine (Surmontil, Rhotrimine, Stangyl) is a tricyclic antidepressant (TCA) with antipsychotic and sedative properties.

Medical uses

Trimipramine's primary use in medicine is in the treatment of major depressive disorder, especially where sedation is required due to its prominent sedative effects. Trimipramine also has some weak antipsychotic effects which are less pronounced than with the phenothiazine antipsychotic perazine.

Trimipramine is the only effective drug against insomnia known so far that does not alter the normal sleep architecture (there is evidence in medical journals that refute this last statement). In particular, it does not suppress REM sleep, and dreams are said to brighten during treatment.

Adverse effects

Common adverse effects include:

Note: Bolded adverse effects are serious ones.

whereas adverse effects with an unknown incidence includes:

• Confusion
• Nausea
• Vomiting
• Extrapyramidal side effects (e.g. parkinsonism, dystonia, etc.)
• Tinnitus
• Paraesthesia
• ECG changes
• Increased liver function tests

and rare adverse effects include:

• Seizures
• Syndrome of inappropriate secretion of antidiuretic hormone (SIADH)
• Blood dyscrasias including:

- Agranulocytosis

- Thrombocytopenia

- Eosinophilia

- Leukopaenia

• Myocardial infarction
• Heart block
• QTc interval prolongation
• Sudden cardiac death
• Depression worsening
• Suicidal ideation

Contraindications

Contraindications include:

• Recent myocardial infarction
• Any degree of heart block or other cardiac arrhythmias
• Mania
• Severe liver disease
• During breast feeding
• Hypersensitivity to trimipramine maleate or to any of the excipients

Interactions

Trimipramine should not be given with sympathomimetic agents such as adrenaline, ephedrine, isoprenaline, noradrenaline, phenylephrine and phenylpropanolamine.

Barbiturates may increase the rate of metabolism. Trimipramine should be administered with care in patients receiving therapy for hyperthyrodism.

Overdose

Compared to other tricyclic antidepressants trimipramine is relatively safe in overdose, although it is more dangerous than the selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) but less dangerous than bupropion in cases of overdose.

Mechanism of action

Trimipramine's mechanism of action differs from other TCAs. It is a weak to moderate reuptake inhibitor of serotonin, and an extremely weak inhibitor of norepinephrine and dopamine reuptake. Its main effects are due to considerable receptor antagonism as follows:

• Very strong: H₁
• Strong: 5-HT_2A, α₁-adrenergic
• Moderate: D₂, mACh
• Weak: 5-HT_2C, D₁, α₂-adrenergic

Pharmacokinetics

Trimipramine is a racemic compound with two enantiomers.^[1] CYP2C19 is responsible for the demethylation of (D)- and (L)-trimipramine to (D)- (L)-desmethyltrimipramine, respectively, and CYP2D6 is responsible for the 2-hydroxylation of (D)- and (L)-desmethyltrimipramine to (D)- and (L)-2-hydroxydesmethyltrimipramine, respectively. CYP2D6 also metabolizes (L)-trimipramine into (L)-2-hydroxytrimipramine.

Synthesis

Trimipramine is synthesised by treatment of 10,11,dihydro-5H-dibenz[b,f]azepine and with 3-N,N-dimethylamino-2-methylpropylchloride in a nucleophilic substition in present of sodium amide. Trimipramin was applied as his racemate.

History

Trimipramine maleate (as Surmontil) oral capsules were first approved by the Food and Drug Administration prior to January 1, 1982 in 25 mg and 50 mg formulations, with the 100 mg formulation having been approved on September 15, 1982. A generic version of all three formulations was given FDA approval on August 2, 2006.

See also

• Iprindole

References