TRIMIPRAMINE

Absorption

Rapid absorption

Toxicity

Side effects include agitation, coma, confusion, convulsions, dilated pupils, disturbed concentration, drowsiness, hallucinations, high fever, irregular heart rate, low body temperature, muscle rigidity, overactive reflexes, severely low blood pressure, stupor, vomiting

Originator

Surmontil Wyeth-Ayerst,Laboratories

The Uses of TRIMIPRAMINE

Antidepressant.

Background

Tricyclic antidepressant similar to imipramine, but with more antihistaminic and sedative properties.

Indications

For the treatment of depression and depression accompanied by anxiety, agitation or sleep disturbance

Definition

ChEBI: A dibenzoazepine that is 10,11-dihydro-5H-dibenzo[b,f]azepine substituted by a 3-(dimethylamino)-2-methylpropyl group at the nitrogen atom. It is used as an antidepressant.

Manufacturing Process

Bis(3-dimethylamino-2-methylpropyl)-5-iminodibenzylyl carboxylic acid at 185-250°C up to discontinue a separation of oxyde carbonique. The product was dissolved in ether, then washed with the hydrochloric acid. Then this solution was extracted with ether. The solvent was evaporated under vacuum, to give pure oil bis(3-dimethylamino-2-methyl-1-propyl)-5-iminodibenzyle with boiling point 153-154°C at 0.4 mm. Maleate of bis(3-dimethylamino-2-methyl- 1-propyl)-5-iminodibenzyle have melting point 145-146°C.

brand name

Surmontil (Wyeth-Ayerst);Apo-trimip;Herphonal;No-tripramine;Novo-tripramine;Rhotromine;Sapilant;Stangyl;Surmantil;Tydamine.

Therapeutic Function

Antidepressant

World Health Organization (WHO)

Trimipramine, a tricyclic antidepressant was introduced in 1961 for the management of endogenous depression. Much of the adverse effects are caused by its antimuscarinic actions. These include dry mouth, cardiac arrhythmias, central nervous system disturbances, blood disorders and risk of suicide. The risk of suicide and dangers related to overdosage led Norwegian Medicines Control Authority to put the higher strength formulation under prescribing restriction in 1992. The risk of death following overdosage is apparently higher for products containing tricyclic compounds as compared with nontricyclic products.

Pharmacokinetics

Trimipramine is a tricyclic antidepressant. It was thought that tricyclic antidepressants work by inhibiting the re-uptake of the neurotransmitters norepinephrine and serotonin by nerve cells. However, this response occurs immediately, yet mood does not lift for around two weeks. It is now thought that changes occur in receptor sensitivity in the cerebral cortex and hippocampus. The hippocampus is part of the limbic system, a part of the brain involved in emotions. Presynaptic receptors are affected: a1 and b1 receptors are sensitized, a2 receptors are desensitised (leading to increased noradrenaline production). Tricyclics are also known as effective analgesics for different types of pain, especially neuropathic or neuralgic pain. A precise mechanism for their analgesic action is unknown, but it is thought that they modulate anti-pain opioid systems in the CNS via an indirect serotonergic route. They are also effective in migraine prophylaxis, but not in abortion of acute migraine attack. The mechanism of their anti-migraine action is also thought to be serotonergic.

Pharmacokinetics

Trimipramine is one of the antidepressants with the most pronounced differences in pharmacokinetics caused by the CYP2D6 genetic polymorphism. Its bioavailability and systemic clearance depended significantly on the CYP2D6 isoform with a linear dose relationship. Its mean bioavailability was 44% in individuals without CYP2D6 (poor metabolizers) but 16 and 12% in those individuals with two and three active genes of CYP2D6 (fast and ultrafast metabolizers), respectively. Consequently, the mean total clearances of the oral dose were 27, 151, and 253 L/hour in poor, extensive, and ultrarapid metabolizers, respectively. The 44% bioavailability combined with low systemic clearance of trimipramine in poor metabolizers of CYP2D6 substrates results in a very high exposure to trimipramine with the risk of adverse drug reactions. On the other hand, the presystemic elimination may result in subtherapeutic drug concentrations in carriers of CYP2D6 gene duplications with a high risk of poor therapeutic response

Clinical Use

Although trimipramine has the weakest binding affinity for the monoamine transporters, it shares the pharmacological and toxicity actions of the other TCAs and is used primarily in the treatment of depression.

Drug interactions

Potentially hazardous interactions with other drugs
Alcohol: increased sedative effect.
Analgesics: increased risk of CNS toxicity with tramadol; possibly increased risk of side effects with nefopam; possibly increased sedative effects with opioids.
Anti-arrhythmics: increased risk of ventricular arrhythmias with amiodarone - avoid; increased risk of ventricular arrhythmias with disopyramide, flecainide or propafenone; avoid with dronedarone.
Antibacterials: increased risk of ventricular arrhythmias with delamanid and moxifloxacin and possibly telithromycin - avoid with delamanid and moxifloxacin.
Anticoagulants: may alter anticoagulant effect of coumarins.
Antidepressants: enhanced CNS excitation and hypertension with MAOIs and moclobemide - avoid; concentration possibly increased with SSRIs; risk of ventricular arrhythmias with citalopram and escitalopram - avoid; possible increased risk of convulsions with vortioxetine.
Antiepileptics: convulsive threshold lowered; concentration reduced by carbamazepine, phenobarbital and possibly fosphenytoin, phenytoin and primidone.
Antimalarials: avoid with artemether/lumefantrine and piperaquine with artenimol.
Antipsychotics: increased risk of ventricular arrhythmias especially with droperidol, fluphenazine, haloperidol, pimozide, sulpiride and zuclopenthixol - avoid; increased risk of ventricular arrhythmias with risperidone; increased antimuscarinic effects with clozapine and phenothiazines; concentration increased by antipsychotics.
Antivirals: increased risk of ventricular arrhythmias with saquinavir - avoid; concentration possibly increased with ritonavir.
Atomoxetine: increased risk of ventricular arrhythmias and possibly convulsions.
Beta-blockers: increased risk of ventricular arrhythmias with sotalol.
Clonidine: tricyclics antagonise hypotensive effect; increased risk of hypertension on clonidine withdrawal.
Dapoxetine: possibly increased risk of serotonergic effects - avoid.
Dopaminergics: avoid use with entacapone; CNS toxicity reported with selegiline and rasagiline.
Pentamidine: increased risk of ventricular arrhythmias.
Sympathomimetics: increased risk of hypertension and arrhythmias with adrenaline and noradrenaline; metabolism possibly inhibited by methylphenidate.

Metabolism

Hepatic

Metabolism

Trimipramine is metabolised in the liver to its major metabolite desmethyltrimipramine, which is active. Trimipramine is excreted in the urine mainly in the form of its metabolites.