Opipramol, sold under the brand name Insidon among others, is an anxiolytic and antidepressant which is used throughout Europe. Although it is a member of the tricyclic antidepressants, opipramol is atypical among TCAs and its primary mechanism of action is much different in comparison. Most TCAs act as monoamine reuptake inhibitors, but opipramol does not, and instead acts primarily as a sigma receptor agonist. It is a dibenzazepinederivative. Opipramol was developed by Schindler and Blattner in 1961.
Symptoms of intoxication from overdose include drowsiness, insomnia, stupor, agitation, coma, transient confusion, increased anxiety, ataxia, convulsions, oliguria, anuria, tachycardia or bradycardia, arrhythmia, AV block, hypotension, shock, respiratory depression, and, rarely, cardiac arrest. As therapy of intoxication, specific antidote is not available, removal of the drug by vomiting or gastric lavage should be done. Continuous cardiovascular monitoring for at least 48 hours should be done. In case of respiratory failure due to overdose, intubation and artificial respiration should be done. During severe hypotension due to overdose, corresponding recumbent positioning, plasma expander, dopamine or dobutamine as drops-infusion should be initiated. In heart rhythm disturbances, individualized treatment should be done where appropriate pacemaker and compensation in low potassium levels and possible acidosis should be done. While in convulsions due to overdose, administration of intravenous diazepam or another anticonvulsant agent such as phenobarbital or paraldehyde should be done though intensification of existing respiratory insufficiency, hypotension, or coma may happen.
Interactions
The therapy with opipramol indicates an additional therapy with antipsychotics, hypnotics, and other anxiolytics. Therefore, some specific reactions, particularly central nervous system depressant effects, could be intensified and an intensification of common side effects may occur. If necessary the dosage may be reduced. Co-administration with alcohol can cause stupor. MAOIs should be discontinued at least 14 days before the treatment with opipramol. Concomitant use of opipramol with beta blockers, antiarrhythmics, as well as drugs from the TCA group and preparations which influence the microsomal enzyme system, can lead to changes in plasma concentrations of these drugs. Co-administration of antipsychotics can increase the plasma concentration of opipramol. Barbiturates and anticonvulsants can reduce the plasma concentration of opipramol and thereby weaken the therapeutic effect.
Pharmacology
Pharmacodynamics
Opipramol acts as a high affinitysigma receptoragonist, primarily of the σ1 subtype, but also of the σ2 subtype with lower affinity. In one study of σ1 receptor ligands that also included haloperidol, pentazocine, -3-PPP, ditolylguanidine, dextromethorphan, SKF-10,047, ifenprodil, progesterone, and others, opipramol showed the highest affinity for the guinea pig σ1 receptor of all the tested ligands except haloperidol, which it was approximately equipotent with. The sigma receptor agonism of opipramol is thought to be responsible for its therapeutic benefits against anxiety and depression. Unlike other TCAs, opipramol does not inhibit the reuptake of serotonin or norepinephrine. However, it does act as a high affinity antagonist of the histamine H1 receptor and as a low to moderate affinity antagonist of the dopamine D2, serotonin 5-HT2, and α1-adrenergic receptors. H1 receptor antagonism accounts for its antihistamine effects and associated sedative side effects. In contrast to other TCAs, opipramol has very low affinity for the muscarinic acetylcholine receptors and virtually no anticholinergic effects. Sigma receptors are a set of proteins located in the endoplasmic reticulum. σ1 receptors play key role in potentiating intracellular calcium mobilization thereby acting as sensor or modulator of calcium signaling. Occupancy of σ1 receptors by agonists causes translocation of the receptor from endoplasmic reticulum to peripheral areas where the σ1 receptors cause neurotransmitter release. Opipramol is said to have a biphasic action, with prompt initial improvement of tension, anxiety, and insomnia followed by improved mood later. Hence, it is an anxiolytic with an antidepressant component. After sub-chronic treatment with opipramol, σ2 receptors are significantly downregulated but σ1 receptors are not.
Pharmacokinetics
Opipramol is rapidly and completely absorbed by the gastrointestinal tract. The bioavailability of opipramol amounts to 94%. After single oral administration of 50 mg, the peak plasma concentration of the drug is reached after 3.3 hours and amounts to 15.6 ng/mL. After single oral administration of 100 mg the maximum plasma concentration is reached after 3 hours and amounts to 33.2 ng/mL. Therapeutic concentrations of opipramol range from 140 to 550 nmol/L. The plasma protein binding amounts to approximately 91% and the volume of distribution is approximately 10 L/kg. Opipramol is partially metabolized in the liver to deshydroxyethylopipramol. Metabolism occurs through the CYP2D6isoenzyme. Its terminal half-life in plasma is 6–11 hours. About 70% is eliminated in urine with 10% unaltered. The remaining portion is eliminated through feces.
History
Opipramol was developed by Geigy. It first appeared in the literature in 1952 and was patented in 1961. The drug was first introduced for use in medicine in 1961. Opipramol was one of the first TCAs to be introduced, with imipramine marketed in the 1950s and amitriptyline marketed in 1961.
Society and culture
Generic names
Opipramol is the English, German, French, and Spanishgeneric name of the drug and its,, and, while opipramol hydrochloride is its,, and. Its generic name in Italian and its is opipramolo and in Latin is opipramolum.
Brand names
Opipramol is marketed under the brand names Deprenil, Dinsidon, Ensidon, Insidon, Insomin, Inzeton, Nisidana, Opipram, Opramol, Oprimol, Pramolan, and Sympramol among others.