Quetiapine

from Wikipedia, the free encyclopedia
Structural formula
Structure of quetiapine
General
Non-proprietary name Quetiapine
other names
  • Seroquel
  • IUPAC : 2- {2- [4- (Dibenzo [ b, f ] [1,4] thiazepin-11-yl) -piperazin-1-yl] ethoxy} ethanol
  • Latin : Quetiapinum
Molecular formula
  • C 21 H 25 N 3 O 2 S (quetiapine)
  • (C 21 H 25 N 3 O 2 S) 2 C 4 H 4 O 4 (quetiapine hemi fumarate )
Brief description

white crystalline powder

External identifiers / databases
CAS number
  • 111974-69-7 (quetiapine)
  • 111974-72-2 (quetiapine hemifumarate)
  • 111997-26-3 (quetiapine hydrochloride)
EC number 601-143-7
ECHA InfoCard 100.131.193
PubChem 5002
ChemSpider 4827
DrugBank DB01224
Wikidata Q408535
Drug information
ATC code

N05 AH04

Drug class
Mechanism of action
  • D 2 receptor antagonist
  • 5-HT 1A receptor partial agonist
  • 5-HT 2A receptor antagonist
  • 5-HT 2C receptor antagonist
  • H 1 receptor antagonist
  • Norepinephrine reuptake inhibitor (NAT) (norquetiapine)
properties
Molar mass
  • 383.51 g · mol -1 (quetiapine)
  • 883.09 g · mol -1 (· quetiapine hemifumarate)
Melting point
  • 172–173 ° C (quetiapine hemifumarate)
  • 218–219 ° C (hydrochloride)
pK s value

6.83 in phosphate buffer at 22 ° C (quetiapine hemifumarate)

solubility
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
05 - Corrosive

danger

H and P phrases H: 302-318-335-412
P: ?
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Quetiapine is a drug that is used to treat mental disorders. The substance from the group of atypical neuroleptics is indicated for the treatment of schizophrenia as well as manic and depressive episodes that occur in bipolar illness .

The preparation Seroquel, which contains the active ingredient quetiapine, is one of the so-called blockbuster drugs (sales over 2 billion dollars in 2013).

Chemical properties

Quetiapine is a white, crystalline substance that is not very soluble in water. The dibenzothiazepine derivative is structurally similar to clozapine , olanzapine and zotepine . The much more water-soluble salt of fumaric acid , fumarate , is used pharmaceutically .

pharmacology

Quetiapine influences biochemical signaling processes in the nervous system.

Mode of action

As an antagonist, quetiapine blocks several receptors that have been associated with its atypical antipsychotic efficacy, in particular serotonin 5 HT 2 receptors and dopamine D 2 receptors . By blocking the former, dopamine is released in increased amounts. The blockade of the dopamine D 2 receptors in turn prevents their inhibitory effect on the nerve cells.

The release of dopamine is inhibited by the agonist serotonin at 5-HT 2A receptors ; negative affective and cognitive symptoms of schizophrenia are considered an indication of a dopamine deficiency in the prefrontal cortex . At the same serotonin to the 5-HT 2A - receptor in the dorsolateral prefrontal cortex responsible for depression be and fears.

The 5-HT 2A receptor antagonism of quetiapine thus releases dopamine; In the prefrontal cortex there are comparatively few D 2 receptors and many D 1 receptors, which are thereby stimulated. In the limbic system, on the other hand, serotonin 2A regulation is said to play only a subordinate role in dopamine release, so that in this brain region there is only a slightly increased D 2 receptor occupancy by released dopamine, which is compensated by the D 2 antagonistic effect of quetiapine becomes.

The blockade of D 2 receptors in nigrostriatal structures is so-called loose binding , similar to clozapine, ie the complex antipsychotic D 2 low (low- affinity dopamine 2 receptor) is easily made by the physiological ligand (Dopamine) dissolved, which postulates a very low EPMS -inducing potential for quetiapine (like clozapine) ; Quetiapine appears to have the second lowest EPMS potential of all atypicals after clozapine. Quetiapine also has a σ-receptor antagonistic effect, the meaning of which has not yet been clarified.

The active metabolite norquetiapine ( N- desalkylquetiapine) inhibits the reuptake of noradrenaline by binding to the noradrenaline transporter (NAT) ; it also shows weak partial agonistic effects on 5-HT 1A receptors and antagonistic effects on 5-HT 2C receptors. The agonistic effects at 5-HT 1A receptors are considered to be one reason for the improved cognitive and affective abilities, as they contribute to the release of dopamine in the prefrontal cortex.

Since quetiapine blocks histamine H 1 receptors even in low doses, temporary somnolence during the day and an improvement in the disturbed day-night rhythm can occur.

Dismantling

Quetiapine is mainly broken down in the liver via cytochrome P-450 3A4 (CYP3A4), which is mainly responsible for the metabolism of quetiapine. This creates the active metabolite N- desalkylquetiapine (norquetiapine), which has a half-life of around twelve hours. N-Desalkylquetiapine has a moderate to high affinity for several muscarinic receptor subtypes.

The pharmacokinetics of quetiapine was after co-administration of the antidepressants imipramine (which acts as CYP2D6 is known inhibitor) or fluoxetine (which is known as CYP3A4 and CYP2D6 inhibitor) is not significantly altered. The same applies to the administration of the antipsychotics risperidone or haloperidol with quetiapine. Inhibitors of this enzyme system such as B. ciprofloxacin , erythromycin , ketoconazole , cimetidine and grapefruit juice can sometimes significantly slow down the breakdown of quetiapine.

In contrast, the simultaneous use of quetiapine and thioridazine increased the quetiapine clearance by approximately 70%. This leads to side effects based on anticholinergic effects. Quetiapine should therefore be used with caution in patients receiving medicinal products with anticholinergic (muscarinic) effects.

Quetiapine itself has a half-life of around seven hours. This is also confirmed by data from a PET study , which showed that quetiapine binds to 5HT2 and D2 receptors for up to twelve hours.

Side effects

The most common side effects are drowsiness, dizziness, sleepiness, headache and weight gain, especially in the first week of treatment. Also due to orthostatic dysregulation caused fluid accumulation in the tissue ( edema ), increased pulse, drop in blood pressure ( hypotension ) especially when getting up and standing, indigestion and constipation ( constipation ), dry mouth ( xerostomia ) and a reversible reduction in the number of white blood cells ( leukopenia ) and a Changes in liver function (increase in liver enzymes ALT, AST) were frequently observed. Restless legs syndrome is uncommon with quetiapine . Rarely occurs neuroleptic malignant syndrome , a rare inflammation of the liver or serious skin disease with fever and blisters on the mucous membranes ( Stevens-Johnson syndrome ) on. In some cases, a prolongation of the QTc interval and, as a result, an increased risk of cardiovascular arrhythmias is observed.

application

Quetiapine is used to prevent relapses in bipolar illness. However, this use is not recommended in the S3 treatment guideline for bipolar disorder.

The effect against depressive phases of bipolar illness was proven in a US study. The approval for quetiapine - the only atypical drug to date - was extended by the FDA in 2006 to include monotherapy for such depressive phases. Quetiapine was approved for this indication in November 2008 in German-speaking countries.

In the case of unipolar depression or major depression , quetiapine has also been used in retarded form for some time as an additional therapy in patients for whom monotherapy with an antidepressant has no or only insufficient effect. This was recognized in October 2010 by the Federal Institute for Drugs and Medical Devices and is therefore no longer off-label use , but officially approved.

Study results suggest that quetiapine can be used in severe forms of post-traumatic stress disorder .

In addition to the areas of application (indications) mentioned, quetiapine is also used in Switzerland in combination with antidepressants to increase the effectiveness (augmentation) in the treatment of therapy-resistant obsessive-compulsive disorders .

An investigation of the quetiapine prescriptions in Norway from 2004 to 2017 showed that only 4% of the prescribed daily doses were compatible with the approved use of quetiapine. Most of the time, the dose was significantly lower. This suggests that the majority of quetiapine uses are improper or not approved. The Federal Institute for Drugs and Medical Devices ( BfArM therefore) advised in a 2016 guide for physicians to Regulation of quetiapine-containing medicines from an improper use ( off-label use ab) of quetiapine. The frequent prescription for sleep, eating and personality disorders as well as in the treatment of substance abuse was particularly criticized. For these indications there is no evidence of efficacy or indications of an unfavorable risk-benefit ratio. Critics complain that the trust in the effects and safety of quetiapine as a sleep aid and other off-label applications is primarily passed on orally and may also result from improper marketing in the past.

synthesis

In chemical synthesis, 11-chlorodibenzothiazepine is first synthesized from the lactam with phosphorus oxychloride . The side chain is then introduced by nucleophilic substitution .

Synthesis of quetiapine

Trade names

Monopreparations
  • Non-delayed formulation: Seroquel (D, A, CH, EU), Sequase (CH), Quetialan (A) and various generics
  • Extended-release preparations: Seroquel Prolong (D), Seroquel XR (A, CH), Quetialan XR (A) and various generics

See also

Web links

Commons : Quetiapine  - collection of pictures, videos and audio files

Individual evidence

  1. ↑ a b Quetiapine fumarate data at Chemicalland21.com .
  2. ^ The Merck Index . An Encyclopaedia of Chemicals, Drugs and Biologicals. 14th edition. 2006, ISBN 0-911910-00-X , p. 1382.
  3. ↑ Entry on quetiapine. In: Römpp Online . Georg Thieme Verlag, accessed on December 25, 2014.
  4. ↑ a b ABDA substance database for quetiapine hemifumarate .
  5. ↑ a b PSU Knowledge Bank kb.psu.ac.th (PDF; 447 kB).
  6. ↑ Template: CL Inventory / not harmonized There is not yet a harmonized classification for this substance . A labeling of 2- [2- (4-dibenzo [b, f] [1,4] thiazepin-11-ylpiperazin-1-yl) ethoxy] ethanol (2E) -but-2 is shown, which is derived from a self-classification by the distributor -enedioate (2: 1) (salt) in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), accessed on March 12, 2019.
  7. ↑ Hasso Scholz, Ulrich Schwabe (ed.): Pocket book of drug treatment: applied pharmacology . 13., revised. and updated edition. Springer, Berlin / Heidelberg 2005, ISBN 3-540-20821-6 , pp. 804 .
  8. ^ HJ Möller: The Quetiapine Dossier. Schattauer, 2005, ISBN 3-7945-2398-9 .
  9. ^ GFI-online: Antidepressant quetiapine. ( Memento from September 24, 2015 in the Internet Archive ) Neuro-Depesche, edition 10/2008.
  10. ↑ a b Fachinfo-Service package insert for Seroquel (PDF).
  11. ↑ a b c d Björn Lemmer , Kay Brune (ed.): Pharmacotherapy, clinical pharmacology . 14., revised. and updated edition. Springer, Heidelberg 2010, ISBN 978-3-642-10540-1 , pp. 83; 89 f .
  12. ↑ Data sheet ( Memento from February 6, 2013 in the Internet Archive ) (PDF; 137 kB) from Medsafe (New Zealand Medicines and Medical Devices Safety Authority).
  13. ↑ Niels H. Jensen, Ramona M. Rodriguiz, Marc G. Caron, William C. Wetsel, Richard B. Rothman, Bryan L. Roth: N-Desalkylquetiapine, a Potent Norepinephrine Reuptake Inhibitor and Partial 5-HT1A Agonist, as a Putative Mediator of Quetiapine's Antidepressant Activity . In: Neuropsychopharmacology . tape 33 , no. 10 , December 2007, p. 2303-2312 , doi : 10.1038 / sj.npp.1301646 , PMID 18059438 .
  14. ↑ Entry on Restless Legs Syndrome in Pharmawiki , accessed on January 28, 2017.
  15. ↑ Product information Seroquel 25 mg / 100 mg / 200 mg / 300 mg film-coated tablets (AstraZeneca GmbH). As of January 2010.
  16. ↑ DGBS e. V. and DGPPN e. V .: S3 guideline for diagnosis and therapy of bipolar disorders. Long version July 1, 2012, p. 259 ( ddfruehdran.de ( Memento from December 3, 2013 in the Internet Archive ) PDF; 6.8 MB).
  17. ↑ ME Thase include: Efficacy of quetiapine monotherapy in bipolar I and II depression: a double-blind, placebo-controlled study (the BOLDER II study) . In: J. Clin. Psychopharmacol. Volume 26, 2006, pp. 600-609. PMID 17110817 .
  18. ^ AstraZeneca, press release October 20, 2006 ( memento of January 2, 2010 in the Internet Archive ).
  19. ↑ Press release of the Federal Institute for Drugs and Medical Devices (BfArM)
  20. ^ Nursing Journal
  21. ↑ Ahearn et al.: Quetiapine as an adjunctive treatment for post-traumatic stress disorder: an 8-week open-label study . In: Int Clin Psychopharmacol . Volume 21, No. 1, January 2006, pp. 29-33. PMID 16317314 .
  22. ↑ Drug treatment of obsessive-compulsive disorder .
  23. ↑ P. Gjerden et al .: The antipsychotic agent quetiapine is increasingly not used as such: dispensed prescriptions in Norway 2004–2015 . In: European Journal of Clinical Pharmacology . tape 73 , 2017, p. 1173-1179 .
  24. ↑ Guide for physicians on the prescription of quetiapine-containing drugs. (PDF) In: Blue Hand Letter. Federal Institute for Drugs and Medical Devices, Pharmacovigilance Dept., 2016, accessed on February 16, 2020 .
  25. ↑ Quetiapine is not a sleep aid . In: WD Ludwig, J. Schuler (ed.): The drug letter . tape 54 , 2020, p. 10 .
  26. ^ H. Hahn, P. Thomas: Drug Giant AstraZeneca to Pay $ 520 Million to Settle Fraud Case . In: ABC News . April 27, 2010 ( abcnews.go.com ).
  27. ↑ Patent US4879288 : Novel dibenzothiazepine antipsychotic. Published November 7, 1989 , Inventors: Edward J. Warawa, Bernard M. Migler. ‌