Ketanserin

Structural formula
General
Non-proprietary name	Ketanserin
other names	R-41468 3- {2- [4- (4-fluorobenzoyl) piperidin-1-yl] ethyl} quinazolin-2,4 (1 H , 3 H ) -dione
Molecular formula	C 22 H 22 FN 3 O 3
External identifiers / databases
CAS number 74050-98-9 EC number 277-680-2 ECHA InfoCard 100,070,598 PubChem 3822 ChemSpider 3690 DrugBank DB12465 Wikidata Q415997
Drug information
ATC code	C02 KD01
Drug class	Antihypertensive drugs
properties
Molar mass	395.43 g · mol -1
Melting point	227-235 ° C
pK s value	7.5
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances Caution H and P phrases H: 302 P: ?
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Ketanserin is a drug from the group of serotonin antagonists that is used to treat high blood pressure (hypertension). Ketanserin is not approved for therapy in German-speaking countries. In experimental pharmacology , ketanserin is used in the investigation of drug mechanisms. The active ingredient was patented by Janssen Pharmaceutica in 1980 .

chemistry

Ketanserin is a polycyclic chemical compound that belongs to the aromatic ketones , lactams and piperidine derivatives. Tartrate is used as a medicinal substance.

synthesis

Various processes starting from 4- (4-fluorobenzoyl) piperidine have been described for the production of ketanserin. A synthesis starting from 2,3-dihydro-5 H -oxazol [2,3-b] quinazolin-5-one and 4- (4-fluorobenzoyl) piperidine is possible. The condensation of 3- (2-chloroethyl) -2,4- (1 H , 3 H ) -quinazolindione with 4- (4-fluorobenzoyl) piperidine in the presence of sodium carbonate in 4-methyl-2-pentanone leads to the end product ketanserine . To produce ketanserin radioactively labeled with ³ H or ¹⁴ C is a multi-stage process based on a condensation of 4- (4-fluorobenzoyl) piperidine with N - (2-bromoethyl) -2-nitrobenzamide, a reduction with hydrogen under platinum - coal - catalysis and cyclization with urea based described. The radioactive isotope is inserted in the form of hydrogen or urea.

pharmacology

Mode of action (pharmacodynamics)

Ketanserin is a moderately selective serotonin antagonist. It has its highest affinity for the serotonin receptor 5-HT _2A , which it already inhibits in concentrations of around 1 nmol / l. In higher concentrations, ketanserin can also inhibit other serotonin receptors, in particular 5-HT _2C .

The blood pressure lowering effect of ketanserine is primarily associated with an inhibition of adrenoceptors of the α ₁ type , which ketanserin also blocks in therapeutic doses. Ketanserin is also able to bind to histamine receptors of the H ₁ type in therapeutic concentrations. Thus, its pharmacological effects can be traced back to a complex inhibition of serotonin , ( nor ) adrenaline and histamine- mediated signal transmission pathways .

In higher concentrations, ketanserin also inhibits hERG potassium channels, among other things, and can thus lead to a prolongation of the QT time in the ECG and thus cardiac arrhythmias .

Pharmacokinetics

After its release from an oral dosage form , about 50% of ketanserin is absorbed into the systemic circulation. In the bloodstream it is 95% bound to plasma proteins. Ketanserin is highly metabolized. Its main metabolite is the pharmacologically inactive ketanserinol, which is mainly excreted in the urine. The elimination takes place with triphasic kinetics, the terminal plasma half-life being about 14 hours.

Clinical application

Application areas (indications)

Ketanserin is a blood pressure lowering agent ( antihypertensive ). It is not approved for this purpose in German-speaking countries. The possible areas of application for ketanserin have also been severely restricted in other countries. For this reason, ketanserin is practically only used as a reserve in the event of critical increases in blood pressure, especially during an operation or gestosis .

Due to its antagonism at the serotonin receptor 5-HT _2A , ketanserin blocks the effect of many classic psychedelics that bind to this type of receptor, such as. B. LSD or psilocybin , for this reason it is used by consumers as a remedy for overdoses ( off-label use ).

Contraindications (contraindications)

Due to the possibility of prolonging the QT interval on the electrocardiogram is ketanserin in various cardiac arrhythmias, including atrioventricular block second or third degree, bradycardia with less than 50 beats per minute, ventricular tachycardia , ventricular fibrillation and sick sinus syndrome , contraindicated . In addition, ketanserin should not be used in cases of known hypersensitivity to this active ingredient and hypokalaemia .

Adverse drug effects

The most common side effects seen with ketanserin use include dry mouth, weight gain, drowsiness, tiredness, and headache. Several cases of QTc prolongation to more severe cardiac arrhythmias, including ventricular tachycardia and torsades de pointes , have also been observed in clinical trials .

Commercial preparations

In Europe, ketanserin is currently only on the market in the Netherlands under the brand name Ketesin . Ketanserin preparations that were previously on the market in other European countries, such as Aseranox (GB), Perketan (I), Serepress (I) and Sufrexal (B, CH, CZ, DK, P, PL, T), are now out of trade.

Individual evidence

1. ↑ ^{a b c d} Entry on ketanserin. In: Römpp Online . Georg Thieme Verlag, accessed on July 12, 2019.
2. ↑ There is not yet a harmonized classification for this substance . A labeling of ketanserin in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), which was retrieved on July 3, 2020, is reproduced from a self-classification by the distributor .
3. ^ Signorini R, Verga A. (1982). Process for preparing ketanserine. EP 0098499, IT 1155357
4. ↑ Blancafort P et al. : Ketanserin . In: Drugs Fut . 6, No. 11, 1981, p. 684.
5. ↑ Janssen CG, Lenoir HA, Thijssen JB, Knaeps AG, Verluyten WL, Heykants JJ: Synthesis of 3H- and 14C-ketanserin . In: J Label Compd Radiopharm . 25, No. 7, 1988, pp. 783-792.
6. ↑ van Zwieten PA, Blauw GJ, van Brummelen P: Pharmacological profile of antihypertensive drugs with serotonin receptor and alpha-adrenoceptor activity . In: Drugs . 40, No. Suppl 4, 1990, pp. 1-8; discussion 28-30. PMID 1982649 .
7. ↑ Marin J, Reviriego J, Fernandez-Alfonso MS: Ability of ketanserin to block different receptors in human placental vessels . In: J. Pharm. Pharmacol. . 42, No. 3, March 1990, pp. 217-220. PMID 1974625 .
8. ↑ Tang Q, Li ZQ, Li W, et al. : The 5-HT2 antagonist ketanserin is an open channel blocker of human cardiac ether-à-go-go-related gene (hERG) potassium channels . In: Br J Pharmacol . . 155, No. 3, October 2008, pp. 365-373. doi : 10.1038 / bjp.2008.261 . PMID 18574455 . PMC 2567890 (free full text).
9. ↑ Persson B, Heykants J, Hedner T: Clinical Pharmacokinetics of ketanserin . In: Clin Pharmacokinet . 20, No. 4, April 1991, pp. 263-279. PMID 2036747 .
10. ↑ ^{a b} Vanhoutte P, Amery A, Birkenhäger W, et al. : Serotoninergic mechanisms in hypertension. Focus on the effects of ketanserin . In: Hypertension . 11, No. 2, February 1988, pp. 111-133. PMID 3277910 .
11. ↑ Steyn DW, Odendaal HJ: Serotonin antagonism and serotonin antagonists in pregnancy: role of ketanserin . In: Obstet Gynecol Surv . 55, No. 9, September 2000, pp. 582-9. PMID 10975485 .
12. Jump up ↑ Franz X. Vollenweider, Erich Seifritz, Jan Flemming, Thomas Pokorny, Leonhard Schilbach: Role of the 5-HT2A Receptor in Self- and Other-Initiated Social Interaction in Lysergic Acid Diethylamide-Induced States: A Pharmacological fMRI Study . In: Journal of Neuroscience . tape 38 , no. 14 , April 4, 2018, p. 3603–3611 , doi : 10.1523 / JNEUROSCI.1939-17.2018 , PMID 29555857 ( jneurosci.org [accessed February 11, 2019]).
13. ↑ Torsten Kratz, Albert Diefenbacher: Psychopharmacotherapy in old age. Avoidance of drug interactions and polypharmacy. In: Deutsches Ärzteblatt. Volume 116, Issue 29 f. (July 22) 2019, pp. 508-517, p. 512.
14. ↑ JustScience: IndexNominum: Monograph: Ketanserin (Rec.INN) . Retrieved July 19, 2010.

This article is about a health issue. It is not used for self-diagnosis and does not replace a diagnosis by a doctor. Please note the information on health issues !