Trimipramine

Structural formula
	1: 1 mixture ( racemate ) of ( R ) form (left) ; and ( S ) form (right)
General
Non-proprietary name	Trimipramine
other names	( RS ) -3- (10,11-dihydro-5 H -dibenzo [ b , f ] azepin-5-yl) - N , N , 2-trimethylpropan-1-amine ( IUPAC ); (±) -3- (10,11-dihydro-5 H -dibenzo [ b , f ] azepin-5-yl) - N , N , 2-trimethylpropan-1-amine; rac -3- (10,11-dihydro-5 H -dibenzo [ b , f ] azepin-5-yl) - N , N , 2-trimethylpropan-1-amine; DL -3- (10,11-dihydro-5 H -dibenzo [ b , f ] azepin-5-yl) - N , N , 2-trimethylpropan-1-amine;
Molecular formula	C 20 H 26 N 2
External identifiers / databases
EC number	212-008-3
ECHA InfoCard	100.010.917
PubChem	5584
ChemSpider	5382
DrugBank	DB00726
Wikidata	Q423498
Drug information
ATC code	N06 AA06
Drug class	Tricyclic antidepressant , anxiolytic
Mechanism of action	Blocks serotonin , dopamine and α-adrenoceptors
properties
Molar mass	294.43 g mol −1
Physical state	firmly
Melting point	45 ° C
safety instructions
	Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
H and P phrases	H: 302-315-319-335-361
	P: 261-281-305 + 351 + 338
Toxicological data	250 mg kg −1 ( LD 50 , mouse , oral ) ; 42 mg kg −1 ( LD 50 , mouse , iv ) ; 425 mg kg −1 ( LD 50 , mouse , oral , maleate) ; 40 mg kg −1 ( LD 50 , mouse , iv , maleate) ; 800 mg kg −1 ( LD 50 , rat , oral , maleate) ; 38 mg kg −1 ( LD 50 , rat , iv , maleate) ;
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Trimipramine is a dibenzazepine that is used as a drug from the group of tricyclic antidepressants . Its effect is strongly dampening and anxiety-relieving .

effect

Trimipramine blocks various serotonin , dopamine and α-adrenoceptors in the central nervous system . The uptake of monoamine from the synaptic gap into the presynaptic vesicle is only slightly delayed. Thus, the antidepressant mechanism of action is different from that of other tricyclic antidepressants. Trimipramine also has an anticholinergic and antihistaminergic effect ; consequently, it also has the characteristic accompanying and side effects of the other tricyclic antidepressants . Trimipramine also acts as a FIASMA (functional inhibitor of acid sphingomyelinase ).

Due to the comparatively lower influence of serotonin and noradrenaline, the antidepressant effects are less pronounced. Therefore, it is mainly used in anxious-agitated depression with restlessness, anxiety, sleep-wake rhythm disorders, but also for the treatment of monosymptomatic sleep disorders. The sedative effects can be very strong; for this reason, the daily dose is mainly taken in the evening. Daytime sleepiness almost always occurs, especially when you start taking it.

The half-life of trimipramine in the human body is 24 hours.

Indications

Trimipramine is approved for the treatment of depression , especially when anxiety and sleep disorders as symptoms are in the foreground.

In a low dose , it can also be used adjuvantly for the treatment of chronic pain .

Its use as a hypnotic is popular. But since there is no usable proof of efficacy even after years of off-label use and the alleged tolerability advantages over Doxepin and similar a. could never be proven, there is still no approval as a sleep-promoting agent.

Contraindications

Trimipramine should not be taken:

in acute alcohol, hypnotics, analgesics and psychotropic drugs,
in acute delirium,
with untreated angle-closure glaucoma,
for urinary evacuation disorders such as urinary retention or prostatic hyperplasia with residual urine formation,
with pyloric stenosis ,
with paralytic ileus,
with simultaneous use of irreversible MAO inhibitors,
during pregnancy and breastfeeding.

unwanted effects

Trimipramine can have vegetative side effects (dry mouth, hypotension , tachycardia , mydriasis and accommodation disorders , gastrointestinal problems, micturition disorders , etc.) due to the anticholinergic effects that are also typical of other tricyclic antidepressants .

In addition, u. a. Changes in the blood count ( leukopenia , agranulocytosis ) occur, as well as weight gain (mainly due to water retention) and mood swings.

Weaning problem

After prolonged treatment, abrupt discontinuation can lead to nausea , headache and malaise. Sleep disorders, anxiety, restlessness and increased irritability can also occur. The treatment should be stopped gradually .

Dosage forms

Trimipramine is offered in the form of tablets , dragees or as a solution.

Use in pregnancy

Trimipramine must not be used during pregnancy and breastfeeding, as there is insufficient experience and limited animal studies have shown evidence of damage to the offspring (increased mortality rate and malformations).

Genotoxic potential

In experiments on Drosophila , trimipramine led to genetic damage. According to one study, taking trimipramine may increase the risk of breast cancer.

Manufacturing and stereochemistry

The synthesis takes place starting from 10,11, dihydro-5 H -dibenzo [ b, f ] azepine by its deprotonation with sodium amide and a subsequent nucleophilic substitution with racemic 3- N , N -dimethylamino-2-methylpropyl chloride.

Trimipramine contains a stereocenter, the drug is used as a racemate .

Trade names

Monopreparations

Herphonal (D), Stangyl (D), Surmontil (CH), numerous generics (D, CH)

Individual evidence

↑ Entry on trimipramine in the ChemIDplus database of the United States National Library of Medicine (NLM) .
↑ ^a ^b Data sheet Trimipramine maleate salt from Sigma-Aldrich , accessed on April 24, 2011 ( PDF ).
↑ ^a ^b ^c ^d ^e ^f ^g A. Kleemann , J. Engel, B. Kutscher, D. Reichert: Pharmaceutical Substances - Synthesis, Patents, Applications , 4th edition (2000), Thieme-Verlag Stuttgart, ISBN 978-1- 58890-031-9 .
↑ Roth, BL; Driscol, J (January 12, 2011). "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 November 30, 2013.
↑ Kornhuber J, Muehlbacher M, Trapp S, Pechmann S, Friedl A, Reichel M, Mühle C, Terfloth L, Groemer T, Spitzer G, Liedl K, Gulbins E, Tripal P: Identification of novel functional inhibitors of acid sphingomyelinase . In: PLoS ONE . 6, No. 8, 2011, p. E23852. doi : 10.1371 / journal.pone.0023852 .
^ Frank Block: Compendium of neurological pharmacotherapy , Springer Verlag, Heidelberg 2008, ISBN 978-3-540-31348-9 , p. 436 ( limited preview in the Google book search).
↑ ^a ^b German specialist information: Stangyl; Status: March 2006.
^ Specialist information from the Swiss Medicines Compendium: Trimin, as of November 2003.
↑ German specialized information "Stangyl"; Status: June 2008.
↑ CR Sharpe, JP Collet, E. Belzile, JA Hanley, JF Boivin: The effects of tricyclic antidepressants on breast cancer risk. In: British Journal of Cancer . Volume 86, Number 1, January 2002, pp. 92-97, doi : 10.1038 / sj.bjc.6600013 , PMID 11857018 , PMC 2746543 (free full text).
↑ EJ Ariëns: Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology , European Journal of Clinical Pharmacology 26 (1984) pp. 663-668; doi : 10.1007 / BF00541922 .

[ChemIDplus-1] Entry on trimipramine in the ChemIDplus database of the United States National Library of Medicine (NLM) .

[Sigma-2] Data sheet Trimipramine maleate salt from Sigma-Aldrich , accessed on April 24, 2011 ( PDF ).

[Kleemann-3] ↑ ^a ^b ^c ^d ^e ^f ^g A. Kleemann , J. Engel, B. Kutscher, D. Reichert: Pharmaceutical Substances - Synthesis, Patents, Applications , 4th edition (2000), Thieme-Verlag Stuttgart, ISBN 978-1- 58890-031-9 .

[4] Roth, BL; Driscol, J (January 12, 2011). "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 November 30, 2013.

[pmid18504571-5] Kornhuber J, Muehlbacher M, Trapp S, Pechmann S, Friedl A, Reichel M, Mühle C, Terfloth L, Groemer T, Spitzer G, Liedl K, Gulbins E, Tripal P: Identification of novel functional inhibitors of acid sphingomyelinase . In: PLoS ONE . 6, No. 8, 2011, p. E23852. doi : 10.1371 / journal.pone.0023852 .

[6] Frank Block: Compendium of neurological pharmacotherapy , Springer Verlag, Heidelberg 2008, ISBN 978-3-540-31348-9 , p. 436 ( limited preview in the Google book search).

[Deutsche_Fachinformation_2006-7] German specialist information: Stangyl; Status: March 2006.

[8] Specialist information from the Swiss Medicines Compendium: Trimin, as of November 2003.

[9] German specialized information "Stangyl"; Status: June 2008.

[10] CR Sharpe, JP Collet, E. Belzile, JA Hanley, JF Boivin: The effects of tricyclic antidepressants on breast cancer risk. In: British Journal of Cancer . Volume 86, Number 1, January 2002, pp. 92-97, doi : 10.1038 / sj.bjc.6600013 , PMID 11857018 , PMC 2746543 (free full text).

[ARIENS-11] EJ Ariëns: Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology , European Journal of Clinical Pharmacology 26 (1984) pp. 663-668; doi : 10.1007 / BF00541922 .