Prothipendyl

Structural formula
General
Non-proprietary name	Prothipendyl
other names	10- (3- (Dimethylamino) propyl) -10 H -pyrido [3,2- b ] [1,4] benzothiazine ( IUPAC ) ; N , N -Dimethyl-3-pyrido [3,2- b ] [1,4] benzothiazin-10-ylpropan-1-amine ( IUPAC ) ; N , N -dimethyl-10 H -pyrido [3,2- b ] [1,4] benzothiazine-10-propanamine; Prothipendylum (INN Latin) ;
Molecular formula	C 16 H 19 N 3 S.; C 16 H 19 N 3 S HCl (prothipendyl hydrochloride ) ; C 16 H 19 N 3 S HCl H 2 O (prothipendyl hydrochloride monohydrate) ;
External identifiers / databases
EC number	608-469-9
ECHA InfoCard	100.132.989
PubChem	14670
ChemSpider	14002
DrugBank	DB12958
Wikidata	Q903551
Drug information
ATC code	N05 AX07
Drug class	Azaphenothiazine - neuroleptics
properties
Molar mass	285.41 g · mol -1 (prothipendyl) ; 339.88 g mol −1 (prothipendyl hydrochloride monohydrate) ;
Melting point	<25 ° C (prothipendyl)
boiling point	195–198 ° C (66.7 Pa ) (prothipendyl)
pK s value	2.3 (25 ° C)
solubility	easily soluble in water and methanol (prothipendyl) ; practically insoluble in petroleum ether and diethyl ether (prothipendyl hydrochloride )
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: ?
Toxicological data	415 mg kg −1 ( LD 50 , mouse , oral ) ; 25 mg kg −1 ( LD 50 , rat , iv ) ;
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Prothipendyl , ( trade name in Germany and Austria Dominal ) is one of Wilhelm Schuler discovered drug from the group of weak effective tricyclic Azaphenothiazin - neuroleptics .

History

Prothipendyl was invented by Louis Yale Harry and Jack Bernstein and patented by Olin Mathieson in 1960 . Today Prothipendyl is sold by AWD.pharma under the trade name Dominal . The fictitious drug approval for ampoules (old registration according to the drug law of 1961) has expired in Germany.

Chemical properties

Phenothiazine backbone

Azaphenothiazine backbone

Prothipendyl is the only representative from the subgroup of azaphenothiazines . There is a close chemical structural relationship to the phenothiazines . In the case of prothipendyl, a benzene ring in the phenothiazine molecule has been replaced by a pyridine ring . The salt prothipendyl hydrochloride-1-water ( INN ) is used pharmaceutically . It is a pastel yellow to yellow-greenish, crystalline , odorless powder with the formula C ₁₆ H ₁₉ N ₃ S · HCl · H ₂ O and a melting point of 108 to 112 ° C (as anhydrate 177 to 178 ° C, after sintering at 176 ° C).

Pharmacological properties

Mechanism of action (pharmacodynamics)

Prothipendyl is one of the weak-acting, tricyclic neuroleptics of the first generation. In addition to its antipsychotic effect, Prothipendyl has antihistaminergic , antiemetic and sedating properties. In higher doses, the drug has a sleep-inducing effect due to its sedative-hypnotic effect. Pharmacologically, prothipendyl is an antagonist of dopamine at the D ₂ -D ₁ receptors and at the serotonin receptor 5-HT _2A . It has no affinity for the GABA receptor (to which benzodiazepines bind). The D ₂ -receptor blockade in the area postrema of the brain stem is responsible for the antiemetic effect. The neuroleptic potency is given as the “chlorpromazine index” (CPZi) and is 0.7 for prothipendyl (compared to the reference substance chlorpromazine 1.0).

Absorption and distribution in the body (pharmacokinetics)

The oral bioavailability is 8 to 15 percent for drops and film-coated tablets, it is slightly lower for coated tablets. After taking the drops, the maximum effective level is reached after about an hour; it takes one to one and a half hours for the film-coated tablets or dragees. Because of the first-pass effect in the liver, the plasma concentrations are lower after oral administration than after parenteral administration . Effects (tiredness, sleep) are already observed at plasma levels of 5 ng / ml. The active ingredient is strongly bound to plasma proteins. The plasma half-life of Prothipendyl is two to three hours, making it the shortest of all common phenothiazines . After parenteral administration, renal clearance is 13 ml / kg / min, which is relatively high. The volume of distribution is 3 l / kg in a normal range for the substance class. Bioaccumulation is not to be expected even after repeated administration . Prothipendyl is primarily metabolized by the liver and excreted in the urine and feces. The terminal elimination phase can last up to three weeks.

Clinical information

Prothipendyl has a weak anti- psychotic potency. It has a strong antihistamine effect as well as musculotropic, spasmolytic and antiemetic properties. In higher doses, Prothipendyl has a sleep-inducing effect due to its sedative-hypnotic effect. Because of its weak antipsychotic effect, the drug is rarely used as a basic neuroleptic despite its minor side effects.

Application areas (indications)

For dampening psychomotor restlessness and excitement in the context of underlying psychiatric illnesses. Psychomotor restlessness and excitement in schizophrenia , bipolar disorders , agitated- depressive moods of other origins, epileptic irritability, symptomatic psychoses , organic psychosyndrome , withdrawal treatments, organ neuroses , anxiety and obsessive-compulsive disorders or atherosclerosis of the cerebral vessels.

Contraindications (contraindications)

Known hypersensitivity to Prothipendyl. Acute intoxication with alcohol, sleeping pills, analgesics and psychotropic drugs, as the effects of these substances can be intensified. Comatose states.

Drug interactions

When combined with drugs that depress the central nervous system, such as benzodiazepines , sleeping pills , antihistamines , alcohol and drugs that lower blood pressure ( antihypertensive drugs ), the pharmacodynamic effects of their own can lead to mutual reinforcement of the effects. The effects of levodopa may be reduced. Prothipendyl due to its adrenolytic the property vasoconstrictive effects of adrenaline and phenylephrine antagonize .

Use during pregnancy and breastfeeding

Pregnancy : Treatment with Prothipendyl in the first trimester is contraindicated . In the second and third trimester, use should only be made according to strict indications and in the lowest effective dose, taking into account the risk to mother and child. To prevent extrapyramidal syndrome or withdrawal syndrome in the newborn, the drug must not be used during the last ten days of pregnancy.
Breast-feeding : It is not known whether Prothipendyl is excreted in breast milk . Therefore, Prothipendyl should not be used during breastfeeding.

Adverse effects (side effects)

Since Prothipendyl has slightly hypotensive properties, orthostatic circulatory disorders can occur , especially at the beginning of therapy . Possible symptoms include arterial hypotension , vertigo , tachycardia , in individual cases - after oral administration of 80 mg and after intramuscular administration of 40 mg and more - up to syncope . Slight weight gain on long-term treatment is common and in part due to blockade of the 5-HT _2A receptor . Dry mouth has been reported. There are isolated cases of priapism or phototoxia .

After prolonged use in very high doses (240 mg / d im or 800 mg / d po ), extrapyramidal motor disorders ( late dyskinesia , tongue throat syndrome , Parkinsonoid ) or seizures can rarely occur.

toxicology

Symptoms of overdose:

In the case of poisoning , disorders of consciousness such as drowsiness , somnolence (sleepiness or a tendency to sleep), anxiety disorders , hallucinations and even coma occur most frequently

Blood circulation : tachycardia (continuously accelerated pulse), drop in blood pressure

Eye problems: miosis (narrowing of the pupil) and mydriasis (widening of the pupil)

Extrapyramidal motor system : muscle hypotension , dyskinesia and ataxia

Special warnings for safe use

The dose should be reduced in patients with heart failure , impaired liver function, jaundice , pheochromocytoma , advanced CO ₂ retention or Parkinson's disease . Prothipendyl reduces the coordination skills, which is why caution is required when driving and using machines.

literature

Florian Holsboer, Gerhard founder, Otto Benkert: Manual of psychopharmacotherapy with 155 tables. Springer, Heidelberg 2008, ISBN 978-3-540-20475-6 .

References and comments

↑ ^a ^b ^c Entry on prothipendyl in the ChemIDplus database of the United States National Library of Medicine (NLM), accessed on July 27, 2020.
^ ^A ^b ^c The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals, 14th Edition (Merck & Co., Inc.), Whitehouse Station, NJ, USA, 2006; ISBN 978-0-911910-00-1 .
↑ Sean Sweetman (Ed.): Martindale: The Complete Drug Reference, 35th Edition: Book and CD-ROM Package . Pharmaceutical Press, ISBN 978-0-85369-704-6 .
↑ Template: CL Inventory / not harmonized There is not yet a harmonized classification for this substance . A labeling of Prothipendyl in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), which was accessed on July 6, 2020, is reproduced from a self-classification by the distributor .
↑ Patent US2943086 : Published June 28, 1960 . ‌
↑ W. Schuler , H. Klebe: 4-Azaphenothiazines and their 10-aminoalkyl derivatives , in Liebigs Ann. 1962 , 653 , 172-180; doi: 10.1002 / jlac.19626530120 .
↑ Entry on Prothipendyl. In: Römpp Online . Georg Thieme Verlag, accessed on May 30, 2014.
↑ ^a ^b W. Forth, D. Henschler, W. Rummel: General and special pharmacology and toxicology . 9th edition. Urban & Fischer, Munich 2005, ISBN 3-437-42521-8 .
↑ ^a ^b Specialist information for Dominal from AWD.pharma GmbH & Co. KG. Status: July 2001 .
↑ Dominal technical information, as of January 2007.
↑ Jasek, Wolfgang: Austria Codex specialist information 2005/2006. Volume 1. Vienna 2005. Pages 2026–2027.
↑ O. Benkert, H. Hippius: Psychiatrische Pharmakotherapie . 6th edition. Springer, 1996, ISBN 3-540-58149-9 .

[ChemIDplus-1] Entry on prothipendyl in the ChemIDplus database of the United States National Library of Medicine (NLM), accessed on July 27, 2020.

[MERCK_Index-2] A ^b ^c The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals, 14th Edition (Merck & Co., Inc.), Whitehouse Station, NJ, USA, 2006; ISBN 978-0-911910-00-1 .

[Martindale-3] Sean Sweetman (Ed.): Martindale: The Complete Drug Reference, 35th Edition: Book and CD-ROM Package . Pharmaceutical Press, ISBN 978-0-85369-704-6 .

[4] Template: CL Inventory / not harmonized There is not yet a harmonized classification for this substance . A labeling of Prothipendyl in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), which was accessed on July 6, 2020, is reproduced from a self-classification by the distributor .

[5] Patent US2943086 : Published June 28, 1960 . ‌

[SCHULER-6] W. Schuler , H. Klebe: 4-Azaphenothiazines and their 10-aminoalkyl derivatives , in Liebigs Ann. 1962 , 653 , 172-180; doi: 10.1002 / jlac.19626530120 .

[RÖMPP_Online-7] Entry on Prothipendyl. In: Römpp Online . Georg Thieme Verlag, accessed on May 30, 2014.

[Forth-8] W. Forth, D. Henschler, W. Rummel: General and special pharmacology and toxicology . 9th edition. Urban & Fischer, Munich 2005, ISBN 3-437-42521-8 .

[Dominal-9] Specialist information for Dominal from AWD.pharma GmbH & Co. KG. Status: July 2001 .

[FI2007-10] Dominal technical information, as of January 2007.

[11] Jasek, Wolfgang: Austria Codex specialist information 2005/2006. Volume 1. Vienna 2005. Pages 2026–2027.

[12] O. Benkert, H. Hippius: Psychiatrische Pharmakotherapie . 6th edition. Springer, 1996, ISBN 3-540-58149-9 .