Phenobarbital
- CAS NO.:50-06-6
- Empirical Formula: C12H12N2O3
- Molecular Weight: 232.24
- MDL number: MFCD00066494
- EINECS: 200-007-0
- SAFETY DATA SHEET (SDS)
- Update Date: 2023-06-08 09:02:48
What is Phenobarbital?
Absorption
Absorbed in varying degrees following oral, rectal or parenteral administration. The salts are more rapidly absorbed than are the acids. The rate of absorption is increased if the sodium salt is ingested as a dilute solution or taken on an empty stomach.
Toxicity
CNS and respiratory depression which may progress to Cheyne-Stokes respiration, areflexia, constriction of the pupils to a slight degree (though in severe poisoning they may wshow paralytic dilation), oliguria, tachycardia, hypotension, lowered body temperature, and coma. Typical shock syndrome (apnea, circulatory collapse, respiratory arrest, and death) may occur.
Description
Phenobarbital (Item No. 9001494) is an analytical reference material categorized as a barbiturate. Phenobarbital is regulated as a Schedule IV compound in the United States. This product is intended for research and forensic applications.
Chemical properties
Crystalline Solid
Originator
Phenobarbital ,Inter-Chemical Ltd.
The Uses of Phenobarbital
Phenobarbital exhibits relaxant, soporific, and anticonvulsant activities. It is widely used in treating epilepsy, chorea, and spastic paralysis, and is used as a component of a large number of combined drugs, valocordin and corvalol in particular.
The Uses of Phenobarbital
This is a controlled substance (depressant). Anticonvulsant; sedative; hypnotic
Background
A barbituric acid derivative that acts as a nonselective central nervous system depressant. It promotes binding to inhibitory gamma-aminobutyric acid subtype receptors, and modulates chloride currents through receptor channels. It also inhibits glutamate induced depolarizations.
Indications
For the treatment of all types of seizures except absence seizures.
Definition
ChEBI: A member of the class of barbiturates, the structure of which is that of barbituric acid substituted at C-5 by ethyl and phenyl groups.
Indications
Phenobarbital can reduce cholestatic pruritus, possibly by enhancing hepatic microsomal function. Phenobarbital is sedating and may interfere with the metabolism of many drugs.
Manufacturing Process
528 g phenylethyl malonic diethyl ester is dissolved in 500 ml of absolute alcohol. There is then added 140 g urea to the mixture. To this mixture is then added a solution of 57.5 g sodium in 1000 ml absolute alcohol, at such rate that one-half the solution is added during the first hour, a quarter the second hour; an eighth the third hour, and the final eighth during the 4 hours. Then the alcohol is distilled from the reaction mixture. When the alcohol has all been removed, 250 ml xylol is added to the mixture. The reaction mixture is cooled to room temperature and 3 L of water added. The xylene layer was separated and the water solution washed with another 200 ml portion of xylene There is then added to the water solution a 10% excess of a 50% by weight solution of sulfuric acid. The phenobarbital is precipitated as nearly white fluffy crystals, which are filtered off. When dried, they showed 100% phenobarbital by titration. This product may be purified by recrystallization. The unreacted ester in the xylene solution was recovered by distilling off the xylene, and then the phenylethyl malonic ester.
brand name
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Therapeutic Function
Anticonvulsant, Antiepileptic, Hypnotic, Sedative
World Health Organization (WHO)
Phenobarbital is a long-acting barbiturate which is controlled under Schedule IV of the 1971 Convention on Psychotropic Substances. Phenobarbital is of value in the treatment of epilepsy and preparations for such use are included in the WHO Model List of Essential Drugs. See also WHO comment for barbiturates. (Reference: (UNCPS4) United Nations Convention on Psychotropic Substances (IV), , , 1971)
General Description
Odorless white crystalline powder or colorless crystals. A saturated aqueous solution is acid to litmus (approximately pH 5). Slightly bitter taste.
General Description
Phenobarbital, 5-ethyl-5-phenylbarbituricacid (Luminal), is a long-acting sedative and hypnotic.It is also a valuable anticonvulsant, especially in generalizedtonic–clonic and partial seizures (see the discussionon anticonvulsants). Metabolism to the p-hydroxylphenylcompound followed by glucuronidation accounts for about90% of a dose.
Air & Water Reactions
Sensitive to hydrolysis. Alkaline solutions react more rapidly than acidic solutions. At pH 7 and 176°F, has a half life of 74 hours. Insoluble in water.
Reactivity Profile
Phenobarbital is also sensitive to prolonged exposure to light. Incompatible with strong oxidizing agents. Forms a complex of reduced solubility with macrogol 4000. Able to form metal derivatives .
Fire Hazard
Phenobarbital is combustible.
Pharmacokinetics
Phenobarbital, the longest-acting barbiturate, is used for its anticonvulsant and sedative-hypnotic properties in the management of all seizure disorders except absence (petit mal).
Clinical Use
Antiepileptic
Safety Profile
Confirmed carcinogen with experimental carcinogenic, neoplastigenic, tumorigenic, and teratogenic data. A human poison by ingestion. An experimental poison by ingestion, intraperitoneal, subcutaneous, intravenous, and rectal routes. Human systemic effects by ingestion: somnolence, motor activity changes, pulmonary changes, allergc dermatitis, and fever. Human reproductive effects by ingestion: drug dependence and other postnatal measures or effects. Human teratogenic effects include developmental abnormalities of the central nervous system, body wall, musculoskeletal, respiratory, gastrointestinal, and urogenital systems. Experimental reproductive effects. Human mutation data reported. Used as a drug in the treatment of epilepsy, and as a hypnotic and sedative. When heated to decomposition it emits toxic fumes of NOx.See also BARBITURATES.
Synthesis
Phenobarbital, 5-ethyl-5-phenylbarbituric acid or 5-ethyl-5-phenylhexahydropyrimindin-2,4,6-trione (4.1.4), has been synthesized in several different ways [1¨C4]. There is no major difference between them. The first method consists of ethanolysis of benzyl cyanide in the presence of acid, giving phenylacetic acid ethyl ether, the methylene group of which undergoes acylation using the diethyloxalate, giving diethyl ester of phenyloxobutandioic acid (4.1.1), which upon heating easily loses carbon oxide and turns into phenylmalonic ester (4.1.2). Alkylation of the obtained product using ethylbromide in the presence of sodium ethoxide leads to the formation of |á-phenyl-|á- ethylmalonic ester (4.1.3), the condensation of which with urea gives phenobarbital (4.1.4) [1].
Another method of phenobarbital synthesis starts with condensation of benzyl cyanide with diethylcarbonate in the presence of sodium ethoxide to give |á-phenylcyanoacetic ester (4.1.5). Alkylation of the ester (4.1.5) using ethylbromide gives |á-phenyl-|á-ethylcyanoacetic ester (4.1.6), which is further converted into the 4-iminoderivative (4.1.7). Acidic hydrolysis of the resulting product gives phenobarbital (4.1.4) [2].
Drug interactions
Potentially hazardous interactions with other drugs
Aminophylline and theophylline: metabolism of
aminophylline and theophylline increased, reduced
effect.
Anthelmintics: concentration of albendazole and
praziquantel reduced.
Anti-arrhythmics: reduced concentration of
disopyramide; possibly reduced concentration of
dronedarone - avoid; possibly increases metabolism
of propafenone.
Antibacterials: reduced concentration of
chloramphenicol, doxycycline, metronidazole,
telithromycin and rifampicin - avoid with
telithromycin.
Anticoagulants: increased metabolism of coumarins
(reduced effect); concentration of apixaban, edoxaban
and rivaroxaban reduced.
Antidepressants: antagonise anticonvulsant effect;
reduces concentration of paroxetine, reboxetine,
mianserin and tricyclics; concentration reduced by St
John’s wort - avoid.
Antiepileptics: concentration increased by
oxcarbazepine, phenytoin, stripentol and valproate
and possibly carbamazepine, also active metabolite of
oxcarbazepine reduced and valproate concentration
reduced, concentration of fosphenytoin and
phenytoin usually reduced but can also be increased;
concentration of ethosuximide, rufinamide and
topiramate possibly reduced; concentration of
lamotrigine, tiagabine and zonisamide reduced.
Antifungals: possibly reduced concentration of
itraconazole, isavuconazole, posaconazole and
voriconazole - avoid with voriconazole; reduced
absorption of griseofulvin (reduced effect).
Antimalarials: avoid with piperaquine with
artenimol; anticonvulsant effect antagonised by
mefloquine.
Antimuscarinics: possibly reduces active metabolite
of fesoterodine - avoid.
Antipsychotics: antagonise anticonvulsant effect;
metabolism of haloperidol increased; possibly
reduces aripiprazole concentration - increase
aripiprazole dose; concentration of both drugs
reduced with chlorpromazine; possibly reduces
clozapine concentration; possibly reduces lurasidone
concentration - avoid.
Antivirals: concentration of abacavir, boceprevir,
darunavir, fosamprenavir, indinavir, lopinavir,
rilpivirine and saquinavir possibly reduced; avoid
with boceprevir and rilpivirine; possibly reduces
daclatasvir, dasabuvir, ombitasvir, paritaprevir
and simeprevir concentration - avoid; avoid with
elvitegravir, etravirine, ledipasvir, sofosbuvir and
telaprevir; possibly reduces concentration of
dolutegravir.
Apremilast: possibly reduces concentration of
apremilast - avoid.
Bile acids: avoid with cholic acid.
Calcium-channel blockers: effects of calcium-channel
blockers probably reduced - avoid with isradipine
and nimodipine.
Cannabis extract: possibly reduces concentration of
cannabis extract - avoid.
Ciclosporin: reduced ciclosporin levels.
Cobicistat: possibly reduces concentration of
cobicistat - avoid.
Corticosteroids: metabolism of corticosteroids
accelerated, reduced effect.
Cytotoxics: possibly reduced concentration
of axitinib, increase axitinib dose; possibly
reduced concentration of bortezomib, bosutinib,
cabozantinib, ceritinib, crizotinib, dasatinib,
ponatinib and vandetanib - avoid; avoid with
cabazitaxel, ceritinib, dabrafenib, gefitinib, olaparib
and panobinostat; concentration of irinotecan and
its active metabolite and possibly etoposide reduced;
possible increased hypersensitivity reactions with
procarbazine.
Diuretics: concentration of eplerenone reduced -
avoid; increased risk of osteomalacia with carbonic
anhydrase inhibitors.
Guanfacine: concentration of guanfacine possibly
reduced - increase dose of guanfacine.
Hormone antagonists: possibly reduced
concentration of abiraterone - avoid; metabolism of
toremifene accelerated.
Ivacaftor: possibly reduced concentration of ivacaftor
- avoid.
Oestrogens and progestogens: metabolism
accelerated, reduced contraceptive effect.
Orlistat: possibly increased risk of convulsions.
Sodium oxybate: enhanced effects of sodium oxybate
- avoid.
Tacrolimus: concentration of tacrolimus reduced.
Ulipristal: contraceptive effect reduced - avoid.
Metabolism
Hepatic (mostly via CYP2C19).
Metabolism
Partly metabolised in the liver.
25% of a dose is excreted in the urine unchanged at
normal urinary pH.
Properties of Phenobarbital
Melting point: | 174°C |
Boiling point: | 374.4°C (rough estimate) |
Density | 1.2243 (rough estimate) |
refractive index | 1.6660 (estimate) |
Flash point: | 11 °C |
storage temp. | 2-8°C |
solubility | Very slightly soluble in water, freely soluble in ethanol (96 per cent). It forms water-soluble compounds with alkali hydroxides, carbonates and ammonia. |
pka | 7.3, 11.8(at 25℃) |
form | Solid |
color | White to Off-White |
Water Solubility | <0.01 g/100 mL at 14 ºC |
Merck | 13,7319 |
Stability: | Stable. Combustible. Incompatible with strong oxidizing agents. |
CAS DataBase Reference | 50-06-6(CAS DataBase Reference) |
NIST Chemistry Reference | Barbituric acid, 5-ethyl-5-phenyl-,(50-06-6) |
IARC | 2B (Vol. Sup 7, 79) 2001 |
EPA Substance Registry System | Phenobarbital (50-06-6) |
Safety information for Phenobarbital
Computed Descriptors for Phenobarbital
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