Phenytoin

Structural formula
General
Non-proprietary name	Phenytoin
other names	5,5-diphenylimidazolidine-2,4-dione; 5,5-diphenylhydantoin;
Molecular formula	C 15 H 12 N 2 O 2
External identifiers / databases
EC number	200-328-6
ECHA InfoCard	100,000,298
PubChem	1775
ChemSpider	1710
DrugBank	DB00252
Wikidata	Q410400
Drug information
ATC code	N03 AB02
Drug class	Anticonvulsant; Antiarrhythmic;
properties
Molar mass	252.3 g mol −1
Physical state	firmly
Melting point	286 ° C
pK s value	8.33
solubility	Water: 32 mg l −1 (22 ° C); good in ethanol, acetone; moderately in diethyl ether, benzene;
safety instructions
	Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
H and P phrases	H: 302-350-360
	P: 201-308 + 313
Toxicological data	1635 mg kg −1 ( LD 50 , rat , oral ) ; 100 mg kg −1 ( LD 50 , mouse , ip ) ;
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Phenytoin is a hydantoin - derivative , which as a drug for the maintenance treatment of epilepsy ( anticonvulsant is used) and, moreover, in the treatment of heart rhythm disorders ( antiarrhythmic agent , off-label use is effective). Phenytoin requires a doctor's prescription .

pharmacology

Mode of action

The presumed mechanism of action is based on an inhibition of sodium channels and the stabilization of the membrane potential resulting from this.

application areas

Phenytoin is approved for the long-term treatment of focal seizures (simple focal seizures, complex focal seizures), focally initiated and primarily generalized tonic-clonic seizures (grand mal) and for the prophylaxis of seizures (e.g. during neurosurgical interventions). It is also used as an iv therapy for status epilepticus . Another approval exists for the treatment of neurogenic pain conditions if other therapeutic measures were unsuccessful or cannot be carried out.

Side effects

Characteristic side effects that can occur during therapy with phenytoin are bradycardia (therefore administration only under intensive monitoring), disorders of the coordination of movements ( tremor , ataxia ), especially associated with nystagmus , dizziness , megaloblastic anemia , osteomalacia , gum growths ( gingival hyperplasia ), and acne-shaped Skin rash, generalized lymphadenopathy , and disorders of intellectual performance (impaired perception and memory, fatigue, headache ) . Hypertrichosis can also occur. Sometimes DRESS syndrome can also occur. Phenytoin is considered to be teratogenic .

Phenytoin has also been causally linked to pleural effusion .

Since phenytoin has only a narrow therapeutic range , the plasma level should be checked regularly.

Interactions

Phenytoin is metabolized by the cytochrome P450 enzyme system CYP 3A4. Inhibitors of this enzyme system, such as cimetidine , erythromycin , ciprofloxacin , sertraline and fluoxetine , can increase the plasma concentration of phenytoin and thus increase its effects and side effects. Valproic acid also leads to an increase in the effects and side effects of phenytoin via competition for the same plasma protein binding site.

CYP 3A4 inducers, such as carbamazepine and St. John's wort , accelerate the breakdown of phenytoin and can thus limit its effectiveness. In addition, phenytoin induces CYP 3A4, which is known as autoinduction. As a result, the activity of CYP 3A4 is increased in the course of therapy, which may make it necessary to increase the dose. This is one of the reasons for the complicated pharmacokinetics of phenytoin.

Misindications

Phenytoin has no effect on generalized seizures of the absence type (“petit mal”).

history

Phenytoin was first synthesized in 1908 by Heinrich Biltz . In this benzil and urea is heated, whereby after benzilic acid rearrangement was formed phenytoin.

Phenytoin was introduced in 1938 by Tracy Jackson Putnam (1894–1975) and Hiram Houston Merritt (1902–1979) as an anti- epileptic. It was only later that Robert Hutson Kokernot (1921-2016) reported on the effectiveness in ventricular tachycardia.

Trade names

Phenytoin is in Europe u. a. under the trade names Epanutin, Phenhydan and Zentropil (was withdrawn from the market by HEXAL in 2017 and deleted without replacement), sold in Austria as Epilan, in the USA as Dilantin and is also available as a generic .

Web links

Phenytoin (English)

Individual evidence

↑ ^a ^b ^c ^d ^e Entry on phenytoin in the ChemIDplus database of the United States National Library of Medicine (NLM) .
↑ ^a ^b David R. Lide (Ed.): CRC Handbook of Chemistry and Physics . 89th edition. (Internet version: 2009), CRC Press / Taylor and Francis, Boca Raton, FL, Physical Constants of Organic Compounds, pp. 3-434.
↑ ^a ^b data sheet 5,5-diphenylhydantoin from Sigma-Aldrich , accessed on April 19, 2011 ( PDF ).
↑ Martin Wehling: Clinical Pharmacology . Georg Thieme Verlag, Stuttgart 2005, ISBN 978-3-13-126821-1 , p. 416 .
↑ Phenytoin at the Berlin Charité , accessed on November 13, 2017.
↑ Berthold Jany, Tobias Welte: Pleural effusion in adults - causes, diagnosis and therapy. In: Deutsches Ärzteblatt. Volume 116, No. 21, (May) 2019, pp. 377-385, here: p. 380.
↑ Graefe et al .: Pharmacology and Toxicology . Georg Thieme Verlag, Stuttgart 2011, ISBN 978-3-13-142861-5 , p. 294 .
^ Wolf-Dieter Müller-Jahncke , Christoph Friedrich , Ulrich Meyer: Medicinal history . 2., revised. and exp. Ed. Wiss. Verl.-Ges, Stuttgart 2005, ISBN 978-3-8047-2113-5 , pp. 164 .

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

[CRC89-2] David R. Lide (Ed.): CRC Handbook of Chemistry and Physics . 89th edition. (Internet version: 2009), CRC Press / Taylor and Francis, Boca Raton, FL, Physical Constants of Organic Compounds, pp. 3-434.

[Sigma-3] ta sheet 5,5-diphenylhydantoin from Sigma-Aldrich , accessed on April 19, 2011 ( PDF ).

[KlinPharm416-4] Martin Wehling: Clinical Pharmacology . Georg Thieme Verlag, Stuttgart 2005, ISBN 978-3-13-126821-1 , p. 416 .

[5] Phenytoin at the Berlin Charité , accessed on November 13, 2017.

[6] Berthold Jany, Tobias Welte: Pleural effusion in adults - causes, diagnosis and therapy. In: Deutsches Ärzteblatt. Volume 116, No. 21, (May) 2019, pp. 377-385, here: p. 380.

[DRPharm294-7] Graefe et al .: Pharmacology and Toxicology . Georg Thieme Verlag, Stuttgart 2011, ISBN 978-3-13-142861-5 , p. 294 .

[8] Wolf-Dieter Müller-Jahncke , Christoph Friedrich , Ulrich Meyer: Medicinal history . 2., revised. and exp. Ed. Wiss. Verl.-Ges, Stuttgart 2005, ISBN 978-3-8047-2113-5 , pp. 164 .