Opipramol

Opipramol, sold under the brand name Insidon among others, is an anxiolytic and antidepressant that is used throughout Europe.[1][3][4][5][6] Despite chemically being a tricyclic dibenzazepine (iminostilbene) derivative similar to imipramine, opipramol is not a monoamine reuptake inhibitor like most other tricyclic antidepressants, and instead, uniquely among antidepressants, acts primarily as a sigma receptor agonist.[6] It was developed by Schindler and Blattner in 1961.[7]

Opipramol
Clinical data
Trade namesInsidon, others
Other namesG-33040; RP-8307[1]
AHFS/Drugs.comInternational Drug Names
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability94%[2]
Protein binding91%[2]
MetabolismCYP2D6-mediated[2]
Elimination half-life6–11 hours[2]
ExcretionUrine (70%), feces (10%)[2]
Identifiers
IUPAC name
  • 4-[3-(5H-dibenz[b,f]azepin- 5-yl)propyl]-1-piperazinethanol
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.005.687
Chemical and physical data
FormulaC23H29N3O
Molar mass363.505 g·mol−1
3D model (JSmol)
SMILES
  • OCCN1CCN(CC1)CCCN4c2ccccc2\C=C/c3ccccc34
InChI
  • InChI=1S/C23H29N3O/c27-19-18-25-16-14-24(15-17-25)12-5-13-26-22-8-3-1-6-20(22)10-11-21-7-2-4-9-23(21)26/h1-4,6-11,27H,5,12-19H2 Y
  • Key:YNZFUWZUGRBMHL-UHFFFAOYSA-N Y
 NY (what is this?)  (verify)

Medical uses

Opipramol is typically used in the treatment of generalized anxiety disorder (GAD) and somatoform disorders.[2][5] Preliminary studies suggest that opipramol shows potential clinical significance in the treatment of severe sleep bruxism.[8]

Contraindications

Pregnancy and lactation

Experimental animal studies did not indicate injurious effects of opipramol on the embryonic development or fertility. Opipramol should only be prescribed during pregnancy, particularly in the first trimester, for compelling indication. It should not be used during lactation and breastfeeding, since it passes into breast milk in small quantities.

Side effects

Frequently (≥1% to <10%) reported adverse reactions with opipramol, especially at the beginning of the treatment, include fatigue, dry mouth, blocked nose, hypotension, and orthostatic dysregulation.

Adverse reactions reported occasionally (≥0.1% to <1%) include dizziness, stupor, micturition disturbances, vigilance, accommodation disturbances, tremor, weight gain,[9] thirst, allergic skin reactions (rash, urticaria), abnormal ejaculation, erectile impotence, constipation, transient increases in liver enzymes, tachycardia, and palpitations.[10][11][12][2]

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 and vomiting, fever,[13] collapse conditions, stimulation conducting disturbances, intensification of present heart insufficiency, blood profile changes particularly leukopenia, confusion, delirium, stomach complaints, taste disturbance, and paralytic ileus especially with sudden discontinuation of a longer-term high-dose therapy.[2]

Very rarely (<0.01%) reported adverse reactions include seizures, motor disorders (akathisia, dyskinesia, ataxia), polyneuropathy, glaucoma, anxiety, hair loss, agranulocytosis, severe liver dysfunction after long-term treatment, jaundice, and chronic liver damage.[12][2][14]

Overdose
Main article: Tricyclic antidepressant overdose

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.

Since no antidote for tricyclic antidepressant overdose is known, its treatment remains largely supportive. Removal of the drug should be facilitated by vomiting or gastric lavage. Cardiovascular function should be monitored continuously for at least 48 hours. Arrhythmias should be treated on a case-by-case basis with an appropriate pacemaker and correction of metabolic irregularities, particularly electrolyte imbalances. Respiratory failure should be managed by intubation and artificial respiration. Convulsions should be managed with anticonvulsants (typically diazepam), while monitoring for any worsening in CNS depression. Hypotension can be treated by assuming the corresponding recovery position, by increasing plasma volume with saline infusions, or by pressors, such as adrenaline or dobutamine.

Interactions

Opipramol can be co-prescribed with other psychiatric drugs, such as antidepressants, anxiolytics and antipsychotics, in which case it can interact with them. Most problematic interactions are generally additive or synergistic, such that, when drugs are combined, their effects intensify, which usually manifests as an increase in side effects, but can also be dangerous, depending on the drugs involved.

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 TCAs, beta blockers, antiarrhythmics (of class 1c) and other drugs for microsomal enzymes, which can lead to slower metabolism and higher plasma concentrations of these drugs. Co-administration of antipsychotics (e.g., haloperidol, risperidone) can increase the plasma concentration of opipramol. Barbiturates and anticonvulsants, on the other hand, can reduce the plasma concentration of opipramol and thereby weaken its therapeutic effect.[2]

Pharmacology

Pharmacodynamics
See also: Pharmacology of antidepressants and Tricyclic antidepressant § Binding profiles
Opipramol[15]
SiteKi (nM)SpeciesRef
σ10.2–50Rodent[16][17][18]
σ2110ND[19]
SERT≥2,200Rat/?[20][21][22]
NET≥700Rat/?[20][21][22]
DAT≥3,000Rat/?[20][21][22]
5-HT1A>10,000 ?[22]
5-HT2A120 ?[22]
5-HT2CNDNDND
α1200 ?[22]
α26,100 ?[22]
D1900Rat[18]
D2120–300Rat[22][18]
H16.03Human[23]
H24,470Human[23]
H361,700Human[23]
H4>100,000Human[23]
mACh3,300 ?[22]
NMDA/PCP>30,000Rat[18]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Opipramol acts as a high affinity sigma receptor agonist, primarily of the σ1 subtype, but also of the σ2 subtype with lower affinity.[5][2] In one study of σ1 receptor ligands that also included haloperidol, pentazocine, (+)-3-PPP, ditolylguanidine, dextromethorphan, SKF-10,047 ((±)-alazocine), ifenprodil, progesterone, and others, opipramol showed the highest affinity (Ki = 0.2–0.3) for the guinea pig σ1 receptor of all the tested ligands except haloperidol, which it was approximately equipotent with.[16] The sigma receptor agonism of opipramol is thought to be responsible for its therapeutic benefits against anxiety and depression.[6][2]

Unlike other TCAs, opipramol does not inhibit the reuptake of serotonin or norepinephrine.[2] However, it does act as a high affinity antagonist of the histamine H1 receptor[23] and is a low to moderate affinity antagonist of the dopamine D2, serotonin 5-HT2, and α1-adrenergic receptors.[2][22] H1 receptor antagonism accounts for its antihistamine effects and associated sedative side effects.[5][2] In contrast to other TCAs, opipramol has very low affinity for the muscarinic acetylcholine receptors and virtually no anticholinergic effects.[22][24]

Sigma receptors are a set of proteins located in the endoplasmic reticulum.[2] σ1 receptors play key role in potentiating intracellular calcium mobilization thereby acting as sensor or modulator of calcium signaling.[2] Occupancy of σ1 receptors by agonists causes translocation of the receptor from endoplasmic reticulum to peripheral areas (membranes) where the σ1 receptors cause neurotransmitter release.[2] Opipramol is said to have a biphasic action, with prompt initial improvement of tension, anxiety, and insomnia followed by improved mood later.[2] Hence, it is an anxiolytic with an antidepressant component.[2] After sub-chronic treatment with opipramol, σ2 receptors are significantly downregulated but σ1 receptors are not.[2]

Pharmacokinetics

Opipramol is rapidly and completely absorbed by the gastrointestinal tract.[2] The bioavailability of opipramol amounts to 94%.[2] 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.[2] After single oral administration of 100 mg the maximum plasma concentration is reached after 3 hours and amounts to 33.2 ng/mL.[2] Therapeutic concentrations of opipramol range from 140 to 550 nmol/L.[25] The plasma protein binding amounts to approximately 91% and the volume of distribution is approximately 10 L/kg.[2] Opipramol is partially metabolized in the liver to deshydroxyethylopipramol.[2] Metabolism occurs through the CYP2D6 isoenzyme.[2] Its terminal half-life in plasma is 6–11 hours.[2] About 70% is eliminated in urine with 10% unaltered.[2] The remaining portion is eliminated through feces.[2]

History

Opipramol was developed by Geigy.[26] It first appeared in the literature in 1952 and was patented in 1961.[26] The drug was first introduced for use in medicine in 1961.[26] Opipramol was one of the first TCAs to be introduced, with imipramine marketed in the 1950s and amitriptyline marketed in 1961.[26]

Society and culture
Opipramol as Insidon and Pramolan 50 mg tablets.

Generic names

Opipramol is the English, German, French, and Spanish generic name of the drug and its INN, BAN, and DCF, while opipramol hydrochloride is its USAN, BANM, and JAN.[1][3][27][4] Its generic name in Italian and its DCIT is opipramolo and in Latin is opipramolum.[3][4]

Brand names

Opipramol is marketed under the brand names Deprenil, Dinsidon, Ensidon, Insidon, Insomin, Inzeton, Nisidana, Opipram, Opramol, Oprimol, Pramolan, and Sympramol among others.[1][3][4]

References
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  2. Mohapatra S, Rath NM, Agrawal A, Verma J (October 2013). "Opipramol: A Novel Drug" (PDF). Delhi Psychiatry Journal. 16 (2): 409–411.
  3. Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 760–761. ISBN 978-3-88763-075-1.
  4. "Opipramol".
  5. Möller HJ, Volz HP, Reimann IW, Stoll KD (February 2001). "Opipramol for the treatment of generalized anxiety disorder: a placebo-controlled trial including an alprazolam-treated group". Journal of Clinical Psychopharmacology. 21 (1): 59–65. doi:10.1097/00004714-200102000-00011. PMID 11199949. S2CID 27014778.
  6. Müller WE, Siebert B, Holoubek G, Gentsch C (November 2004). "Neuropharmacology of the anxiolytic drug opipramol, a sigma site ligand". Pharmacopsychiatry. 37 (Suppl 3): S189–S197. doi:10.1055/s-2004-832677. PMID 15547785.
  7. Grosser HH, Ryan E (February 1965). "Drug Treatment of Anxiety: A Controlled Study of Opipramol and Chlordiazepoxide". The British Journal of Psychiatry. 111 (471): 134–141. doi:10.1192/bjp.111.471.134. PMID 14270525. S2CID 40241272.
  8. Wieckiewicz M, Martynowicz H, Wieczorek T, Wojakowska A, Sluzalec-Wieckiewicz K, Gac P, et al. (January 2021). "Consecutive Controlled Case Series on Effectiveness of Opipramol in Severe Sleep Bruxism Management-Preliminary Study on New Therapeutic Path". Brain Sciences. 11 (2): 146. doi:10.3390/brainsci11020146. PMC 7911172. PMID 33499332.
  9. Carpéné C, Les F, Mercader J, Gomez-Zorita S, Grolleau JL, Boulet N, et al. (March 2020). "Opipramol Inhibits Lipolysis in Human Adipocytes without Altering Glucose Uptake and Differently from Antipsychotic and Antidepressant Drugs with Adverse Effects on Body Weight Control". Pharmaceuticals. 13 (3): 41. doi:10.3390/ph13030041. PMC 7151722. PMID 32151075.
  10. Jepson K, Beaumont G (March 1973). "A Comparative Trial of Opipramol and Chlordiazepoxide in the Treatment of Anxiety". Journal of International Medical Research. 1 (3): 145–150. doi:10.1177/030006057300100301. ISSN 0300-0605. S2CID 74130809.
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  14. Braun JS, Geiger R, Wehner H, Schäffer S, Berger M (July 1998). "Hepatitis caused by antidepressive therapy with maprotiline and opipramol". Pharmacopsychiatry. 31 (4): 152–155. doi:10.1055/s-2007-979319. PMID 9754852.
  15. Roth BL, Driscol J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
  16. Hanner M, Moebius FF, Flandorfer A, Knaus HG, Striessnig J, Kempner E, Glossmann H (July 1996). "Purification, molecular cloning, and expression of the mammalian sigma1-binding site". Proceedings of the National Academy of Sciences of the United States of America. 93 (15): 8072–8077. Bibcode:1996PNAS...93.8072H. doi:10.1073/pnas.93.15.8072. PMC 38877. PMID 8755605.
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  22. Holoubek G, Müller WE (October 2003). "Specific modulation of sigma binding sites by the anxiolytic drug opipramol". Journal of Neural Transmission. 110 (10): 1169–1179. doi:10.1007/s00702-003-0019-5. PMID 14523629. S2CID 5832198.
  23. Appl H, Holzammer T, Dove S, Haen E, Strasser A, Seifert R (February 2012). "Interactions of recombinant human histamine H1R, H2R, H3R, and H4R receptors with 34 antidepressants and antipsychotics". Naunyn-Schmiedeberg's Archives of Pharmacology. 385 (2): 145–170. doi:10.1007/s00210-011-0704-0. PMID 22033803. S2CID 14274150.
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