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| Trade names | Insidon, Pramolan, others |
| Other names | G-33040; RP-8307[1] |
| AHFS/Drugs.com | International Drug Names |
| Routes of administration | By mouth |
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| Pharmacokinetic data | |
| Bioavailability | 94%[3] |
| Protein binding | 91%[3] |
| Metabolism | CYP2D6-mediated[3] |
| Eliminationhalf-life | 6–11 hours[3] |
| Excretion | Urine (70%),feces (10%)[3] |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.005.687 |
| Chemical and physical data | |
| Formula | C23H29N3O |
| Molar mass | 363.505 g·mol−1 |
| 3D model (JSmol) | |
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Opipramol, sold under the brand nameInsidon among others, is ananxiolytic andtricyclic antidepressant that is used throughoutEurope.[1][4][5][6][7] Despite chemically being a tricyclicdibenzazepine (iminostilbene) derivative similar toimipramine, opipramol is not amonoamine reuptake inhibitor like most other tricyclic antidepressants, and instead acts primarily as asigma-1 receptoragonist.[7] It was developed by Schindler and Blattner in 1961.[8]
Opipramol is typically used in the treatment ofgeneralized anxiety disorder (GAD) andsomatoform disorders.[3][6] Preliminary studies suggest that opipramol shows potential clinical significance in the treatment of severesleep bruxism.[9]
Experimental animal studies did not indicate injurious effects of opipramol on theembryonic development orfertility. Opipramol should only be prescribed during pregnancy, particularly in the first trimester, for compelling indication.It should not be used duringlactation andbreastfeeding, since it passes intobreast milk in small quantities.
Frequently (≥1% to <10%) reported adverse reactions with opipramol, especially at the beginning of the treatment, includefatigue,dry mouth, blocked nose,hypotension, and orthostatic dysregulation.
Adverse reactions reported occasionally (≥0.1% to <1%) includedizziness,stupor,micturition disturbances,vigilance,accommodation disturbances,tremor,weight gain,[10] thirst, allergic skin reactions (rash, urticaria), abnormalejaculation,erectile impotence,constipation, transient increases in liver enzymes,tachycardia, andpalpitations.[11][12][13][3]
Rarely (≥0.01% to <0.1%) reported adverse reactions include excitation, headache,paresthesia especially in elderly patients,restlessness,sweating,sleep disturbances,edema,galactorrhea, urine blockage,nausea andvomiting,fever,[14] collapse conditions, stimulation conducting disturbances, intensification of present heart insufficiency, blood profile changes particularlyleukopenia,confusion,delirium, stomach complaints, taste disturbance, andparalytic ileus especially with sudden discontinuation of a longer-term high-dose therapy.[3]
Very rarely (<0.01%) reported adverse reactions includeseizures,motor disorders (akathisia,dyskinesia,ataxia),polyneuropathy,glaucoma,anxiety,hair loss,agranulocytosis, severe liver dysfunction after long-term treatment,jaundice, and chronic liver damage.[13][3][15]
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Symptoms of intoxication fromoverdose 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.
While opipramol is not a monoamine reuptake inhibitor, any irreversible MAOIs should still be discontinued at least 14 days before treatment. Opipramol can compete with other tricyclic antidepressants,beta blockers,antiarrhythmics (ofclass 1c), and other drugs formicrosomal enzymes, which can lead to slower metabolism and higher plasma concentrations of these drugs. Co-administration ofantipsychotics (e.g.,haloperidol,risperidone) can increase the plasma concentration of opipramol.Barbiturates andanticonvulsants can reduce the plasma concentration of opipramol and thereby weaken its therapeutic effect.[3]
| Site | Ki (nM) | Species | Ref |
|---|---|---|---|
| σ1 | 0.2–50 | Rodent | [17][18][19] |
| σ2 | 110 | ND | [20] |
| SERTTooltip Serotonin transporter | ≥2,200 | Rat/? | [21][22][23] |
| NETTooltip Norepinephrine transporter | ≥700 | Rat/? | [21][22][23] |
| DATTooltip Dopamine transporter | ≥3,000 | Rat/? | [21][22][23] |
| 5-HT1A | >10,000 | ? | [23] |
| 5-HT2A | 120 | ? | [23] |
| 5-HT2C | ND | ND | ND |
| α1 | 200 | ? | [23] |
| α2 | 6,100 | ? | [23] |
| D1 | 900 | Rat | [19] |
| D2 | 120–300 | Rat | [23][19] |
| H1 | 6.03 | Human | [24] |
| H2 | 4,470 | Human | [24] |
| H3 | 61,700 | Human | [24] |
| H4 | >100,000 | Human | [24] |
| mAChTooltip Muscarinic acetylcholine receptor | 3,300 | ? | [23] |
| NMDA/PCP | >30,000 | Rat | [19] |
| Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site. | |||
Opipramol acts as a highaffinitysigma receptoragonist, primarily of theσ1 subtype, but also of theσ2 subtype with lower affinity.[6][3] In one study of σ1 receptorligands that also includedhaloperidol,pentazocine,(+)-3-PPP,ditolylguanidine,dextromethorphan,SKF-10,047 ((±)-alazocine),ifenprodil,progesterone, and others, opipramol showed the highest affinity (Ki = 0.2–0.3) for theguinea pig σ1 receptor of all the tested ligands except haloperidol, which it was approximatelyequipotent with.[17] The sigma receptor agonism of opipramol is thought to be responsible for its therapeutic benefits against anxiety and depression.[7][3]
Unlike other TCAs, opipramol does notinhibit thereuptake ofserotonin ornorepinephrine.[3] However, it does act as a high affinityantagonist of thehistamineH1 receptor[24] and is a low to moderate affinity antagonist of thedopamineD2,serotonin5-HT2, andα1-adrenergic receptors.[3][23] H1 receptor antagonism accounts for itsantihistamine effects and associatedsedative side effects.[6][3] In contrast to other TCAs, opipramol has very low affinity for themuscarinic acetylcholine receptors and virtually noanticholinergic effects.[23][25]
Sigma receptors are a set ofproteins located in theendoplasmic reticulum.[3] σ1 receptors play key role in potentiating intracellular calcium mobilization thereby acting as sensor or modulator of calcium signaling.[3] Occupancy of σ1 receptors by agonists causes translocation of the receptor from endoplasmic reticulum to peripheral areas (membranes) where the σ1 receptors causeneurotransmitter release.[3] Opipramol is said to have a biphasic action, with prompt initial improvement of tension, anxiety, and insomnia followed by improved mood later.[3] Hence, it is an anxiolytic with an antidepressant component.[3] After sub-chronic treatment with opipramol, σ2 receptors are significantlydownregulated but σ1 receptors are not.[3]
Opipramol is rapidly and completelyabsorbed by thegastrointestinal tract.[3] Thebioavailability of opipramol amounts to 94%.[3] After singleoral administration of 50 mg, thepeak plasma concentration of the drug is reached after 3.3 hours and amounts to 15.6 ng/mL.[3] After single oral administration of 100 mg the maximum plasma concentration is reached after 3 hours and amounts to 33.2 ng/mL.[3] Therapeutic concentrations of opipramol range from 140 to 550 nmol/L.[26] Theplasma protein binding amounts to approximately 91% and thevolume of distribution is approximately 10 L/kg.[3] Opipramol is partiallymetabolized in theliver to deshydroxyethylopipramol.[3] Metabolism occurs through theCYP2D6isoenzyme.[3] Itsterminal half-life in plasma is 6–11 hours.[3] About 70% iseliminated inurine with 10% unaltered.[3] The remaining portion is eliminated throughfeces.[3]
Opipramol was developed byGeigy.[27] It first appeared in the literature in 1952 and was patented in 1961.[27] The drug was first introduced for use in medicine in 1961.[27] Opipramol was one of the first TCAs to be introduced, withimipramine marketed in the 1950s andamitriptyline marketed in 1961.[27]
Opipramol is theEnglish,German,French, andSpanishgeneric name of the drug and itsINNTooltip International Nonproprietary Name,BANTooltip British Approved Name, andDCFTooltip Dénomination Commune Française, whileopipramol hydrochloride is itsUSANTooltip United States Adopted Name,BANMTooltip British Approved Name, andJANTooltip Japanese Accepted Name.[1][4][28][5] Its generic name inItalian and itsDCITTooltip Denominazione Comune Italiana isopipramolo and inLatin isopipramolum.[4][5]
Opipramol is marketed under the brand names Deprenil, Dinsidon, Ensidon, Insidon, Insomin, Inzeton, Nisidana, Opipram, Opramol, Oprimol, Pramolan, and Sympramol among others.[1][4][5]