Butabarbital

Butabarbital

Systematic (IUPAC) name
5-butan-2-yl-5-ethyl-1,3-diazinane-2,4,6-trione
Clinical data
AHFS/Drugs.com	Consumer Drug Information
MedlinePlus	a682417
Legal status	CA: Schedule III US: Schedule III
Pharmacokinetic data
Half-life	100 hours.[1]
Excretion	Urine[2]
Identifiers
CAS Registry Number	125-40-6 Y
ATC code	None
PubChem	CID 2479
DrugBank	DB00237 Y
ChemSpider	2385 Y
UNII	P0078O25A9 Y
KEGG	D03180 Y
ChEBI	CHEBI:3228 Y
ChEMBL	CHEMBL449 Y
Synonyms	Butabarbital, Butisol
Chemical data
Formula	C10H16N2O3
Molecular mass	212.246 g/mol
SMILES O=C1NC(=O)NC(=O)C1(C(C)CC)CC
InChI InChI=1S/C10H16N2O3/c1-4-6(3)10(5-2)7(13)11-9(15)12-8(10)14/h6H,4-5H2,1-3H3,(H2,11,12,13,14,15)  Y Key:ZRIHAIZYIMGOAB-UHFFFAOYSA-N  Y
Y (what is this?)  (verify)

Butabarbital (trade name Butisol) is a prescription barbiturate sleep aid. Butabarbital has a particularly fast onset of effects and short duration of action compared to other barbiturates, which makes it useful for certain applications such as treating severe insomnia and relieving anxiety before surgical procedures; however it is also relatively dangerous particularly when combined with alcohol, and so is now rarely used, although it is still prescribed in some Eastern European and South American countries. Its intermediate duration of action gives butabarbital an abuse potential slightly lower than secobarbital.

Butabarbital is also sold in combination with belladonna alkaloids under the brand name Butibel. The belladonna is added for antispasmodic effect. This product contains a low dose of butabarbital combined with a standardised mix of belladonna alkaloids and is used as an antispasmodic taken to relieve cramping and spasms of the stomach and intestines. They are used also to decrease the amount of acid formed in the stomach. Another similar product is Donnatal, which contains belladonna alkaloids combined with phenobarbital.

History

Barbiturates were first discovered to have medical use in 1903, when a research at Baeyer showed barbital to be an effective sedative for dogs.^[3] It was not until the mid 20th century that the habit forming nature of barbiturates and behavioral side effects were first noted^[4]

Butabarbital was approved for medical use in 2007 under the brand name Butisol Sodium.^[5] Butisol sodium is manufactured by Meda Pharmaceuticals as a Schedule III controlled substance due to its high risk for abuse and dependence.^[6] Other brand names include Mysoline, and Seconal in the US, and Nova Rectal in Canada as a Schedule III drug as well.^[7] Benzodiazapines are more commonly administered today for their similar sedative and hypnotic properties, and reduced risk of physical dependence. Barbiturate drugs such as butabarbital sodium are used now for short-term and acute treatment under strict doctor supervision only^[8]

Treatment & Clinical Uses

Barbiturates are non-selective depressants of the central nervous system, inducing drowsieness and mild sedative effects. Barbiturate hypnotics are used in the treatment of sleep and anxiety disorders for their calming and sedative properties, however are usually restricted to short term use due to risk of dependency.^[9]

Butabarbital, most commonly known as Butisol commercially, is an approved Schedule III drug in the US and Canada used in the short term treatment of anxiety disorders and as a pre-surgical sedative aid. Approved commercial forms are available in tablet or elixir forms.^[10]

Administration

It is most often administered orally as either sodium solution or tablet, however can also be given by intravenous injection. Tablets contain either 30 mg or 50 mg of butabarbital sodium, or 30 mg/5mL with 7% alcohol/vol in solution. For preoperative sedation, adults are administered 50–100 mg 60-90min prior to surgery, with varying doses for pediatric and geriatric patients.^[11]

Clinical Effects & Elimination

Effects from oral doses often are felt within an hour of administration, lasting somewhere from six to eight hours in effect.^[12] A non-selective depressant of the CNS, Butabarbital sodium is used as a sedative hypnotic, depending on dose, to induce drowsiness or sleep, or reduce anxiety and tension.^[13] Butabarbital sodium can be used as a pre-surgical anesthetic aid or in the short-term treatment of sleep and anxiety disorders. For short term sleep maintenance and induction butabarbital sodium treatment is recommended to be limited to two weeks, after which it begins to lose efficacy.^[14] The half life is approximately 100hrs, eliminated primarily by hepatic microsomal enzymes and excreted in the urine.

Overdose & Abuse

Butabarbital sodium is a Schedule III controlled substance in the US and Canada due to risk of abuse and dependence. A psychoactive substance, butabarbital drugs are often abused with risk of acute intoxication and addiction. Barbiturates such as butabarbital are thought to be habit-forming and addictive, and have severe risks from withdrawal including death.^[15] Due the high risk of dependence and overdose, use of butabarbital is highly regulated and has become less common in clinical application.

Side Effects

Those taking Butabarbital are asked to watch out for signs of severe allergic reaction, such as swelling or difficulty breathing. Less serious side effects include dizziness or drowsiness, excitation, headache, nausea, vomiting, or constipation. Psychiatric disturbances (hallucinations, agitation, confusion, depression, or memory problems), ataxia, difficulty breathing, or slow heartbeat could be signs of serious adverse effects and should be brought to the attention of a doctor immeditley.

Adverse Effects

^[16]

1-10%

• Somnolence

<1%

Apnea Night terrors and sleep disturbances Headache Dizziness Agitation or nervousness Confusion Nausea Vomiting Constipation Hallucinations

Ataxia Bradycardia Hepatotoxicity Hypoventilation Fainting Difficulty breathing or swallowing Rash Psychiatric disturbance

Contradictions

Those with a hypersensitivity to barbiturates or a history of porphyria should discuss with a doctor before using butisol sodium treatment. Butabarbital has also been shown to interact with some medicines; Talk to your doctor if taking Monoamine oxidase inhibitors (MAOIs), beta-blockers, oral-contraceptives, or other medications, as their efficacy may be affected.^[17]

At low doses Butabarbital has been shown clinically to induce drowsiness, depressing the sensory cortex and motor activity. In some rare cases Butabarbital has been shown to produce small bursts of excitement or euphoria prior to the sedative effects. Butabarbital is a highly potent drug however, with addictive properties, and small variations in dose can result in significant escalation of effects.^[18]

Pharmacology

Butabarbital is a sedative hypnotic member of the barbiturate family. It is relatively fast acting, with a short duration, producing a range of effects from mild sedation to hypnosis as a function of dosage.^[19] An overdose of butabarbital can result in deep coma or even death.

Absorption, Distribution and Excretion

Butabarbituates are rapidly distributed and absorbed in the brain, liver and kidneys. One of the more lipophilic barbiturates, butabarbital crosses the blood brain barrier with relative ease, and is slightly more potent then other less liphilic barbiturates such as phenobarbital.^[20] Butabarbital, a weak acid, is most commonly administered orally in its sodium salt form.^[21] 3–4 hours after oral administration butabarbital sodium reaches peak plama concentrations of 203 ug/mL for sedation, or 25 ug/mL to induce sleep, absorbed via the GI tract.^[22]

Once absorbed, butabarbital’s effects have a duration of 6–8 hours if orally administered, or 3–6 hours following intravaneous administration. General consensus has it with a half-life of approximately 100hr, however it has also been reported in one study to have a half life of 34-42 hr.^[23]

The primary way the body terminates activity is by oxidation of radicals at C5, with other biotransformations contributing to a lesser extent.^[24][25] Butabarbital is metabolized almost entirely by the liver, products including polar alcohols, ketones, phenols, or carboxylic acids, before it is renally excreted in the urine.^[26]

Half-Life: ~100 hr Duration: 6-8 hr Onset: 45-60 min Enzymes induced: CYP1A2, CYP2C9/10, CYP3A4 Excretion: Urine

Mechanism of Action

The mechanism of action by which barbiturates exert their effect is not yet completely understood, however they are believed to be involved in the enhancement of GABA inhibitory neurotrasmitter activity in the CNS via GABA_A receptors.^[27] Butabarbital, as a member of this drug class, acutely potentiates inhibitory GABAergic tone by binding with a specific site associated with a Cl⁻ ionopore at the GABA_A receptor.^[28] Butabarbital's binding causes the channel to remain open longer and thus prolongs post-synpatic inhibition by GABA.^[29] Less well characterized effects of barbiturates include direct inhibition of AMPA-type glutamate receptors, suppressing excitatory glutamatergic neurotransmission.^[30]

References

GABAA receptor positive allosteric modulators Alcohols Brometone Butanol Chloralodol Chlorobutanol (cloretone) Ethanol (drinking alcohol) Ethchlorvynol Isobutanol Isopropanol Menthol Methanol Methylpentynol Pentanol Petrichloral Propanol tert-Butanol (2M2P) tert-Pentanol (2M2B) Tribromoethanol Trichloroethanol Triclofos Trifluoroethanol Barbiturates (-)-DMBB Allobarbital Alphenal Amobarbital Aprobarbital Barbexaclone Barbital Benzobarbital Benzylbutylbarbiturate Brallobarbital Brophebarbital Butabarbital/Secbutabarbital Butalbital Buthalital Butobarbital Butallylonal Carbubarb CP-1414S Crotylbarbital Cyclobarbital Cyclopentobarbital Difebarbamate Enallylpropymal Ethallobarbital Eterobarb Febarbamate Heptabarb Heptobarbital Hexethal Hexobarbital Metharbital Methitural Methohexital Methylphenobarbital Narcobarbital Nealbarbital Pentobarbital Phenallymal Phenobarbital Phetharbital Primidone Probarbital Propallylonal Propylbarbital Proxibarbital Reposal Secobarbital Sigmodal Spirobarbital Talbutal Tetrabamate Tetrabarbital Thialbarbital Thiamylal Thiobarbital Thiobutabarbital Thiopental Thiotetrabarbital Valofane Vinbarbital Vinylbital Benzodiazepines 2-Oxoquazepam 3-Hydroxyphenazepam Adinazolam Alprazolam Arfendazam Avizafone Bentazepam Bretazenil Bromazepam Brotizolam Camazepam Carburazepam Chlordiazepoxide Ciclotizolam Cinazepam Cinolazepam Clazolam Climazolam Clobazam Clonazepam Clorazepate Clotiazepam Cloxazolam Cyprazepam Delorazepam Demoxepam Diazepam Diclazepam Doxefazepam Elfazepam Estazolam Ethyl carfluzepate Ethyl dirazepate Ethyl loflazepate Etizolam EVT-201 FG-8205 Fletazepam Flubromazepam Flubromazolam Fludiazepam Flunitrazepam Flurazepam Flutazolam Flutemazepam Flutoprazepam Fosazepam Gidazepam Halazepam Haloxazolam Iclazepam Imidazenil Ketazolam Lofendazam Lopirazepam Loprazolam Lorazepam Lormetazepam Meclonazepam Medazepam Menitrazepam Metaclazepam Mexazolam Midazolam Motrazepam N-Desalkylflurazepam Nimetazepam Nitrazepam Nitrazepate Nordazepam Nortetrazepam Oxazepam Oxazolam Phenazepam Pinazepam Pivoxazepam Prazepam Premazepam Proflazepam Pyrazolam QH-II-66 Quazepam Reclazepam Remimazolam Rilmazafone Ripazepam Ro48-6791 Ro48-8684 SH-053-R-CH3-2′F Sulazepam Temazepam Tetrazepam Tolufazepam Triazolam Triflubazam Triflunordazepam (Ro5-2904) Tuclazepam Uldazepam Zapizolam Zolazepam Zomebazam Carbamates Carisbamate Carisoprodol Clocental Cyclarbamate Difebarbamate Emylcamate Ethinamate Febarbamate Felbamate Hexapropymate Lorbamate Mebutamate Meprobamate Methocarbamol Nisobamate Pentabamate Phenprobamate Procymate Styramate Tetrabamate Tybamate Flavonoids 6-Methylapigenin Ampelopsin (dihydromyricetin) Apigenin Baicalein Baicalin Catechin EGC EGCG Hispidulin Linarin Luteolin Rc-OMe Skullcap constituents (e.g., baicalin) Wogonin Imidazoles Etomidate Metomidate Propoxate Kavalactones Kava Yangonin 10-methoxyyangonin 11-methoxyyangonin 11-hydroxyyangonin Desmethoxyyangonin 11-methoxy-12-hydroxydehydrokavain 7,8-dihydroyangonin Kavain 5-hydroxykavain 5,6-dihydroyangonin 7,8-dihydrokavain 5,6,7,8-tetrahydroyangonin 5,6-dehydromethysticin Methysticin 7,8-dihydromethysticin Neuroactive steroids Acebrochol Allopregnanolone Alfadolone Alfaxalone 3α-Androstanediol Androsterone Cholesterol DHDOC 5α-DHP Etiocholanolone Ganaxolone Hydroxydione Minaxolone Org 20599 Org 21465 Pregnanolone (eltanolone) Renanolone THDOC Nonbenzodiazepines β-Carbolines: Abecarnil Gedocarnil Harmane SL-651,498 ZK-93423; Cyclopyrrolones: Eszopiclone Pagoclone Pazinaclone Suproclone Suriclone Zopiclone; Imidazopyridines: Alpidem DS-1 Necopidem Saripidem Zolpidem; Pyrazolopyrimidines: Divaplon Fasiplon Indiplon Lorediplon Ocinaplon Panadiplon Taniplon Zaleplon; Others: Adipiplon CGS-8216 CGS-9896 CGS-13767 CGS-20625 CL-218,872 CP-615,003 CTP-354 ELB-139 GBLD-345 JM-1232 L-838,417 Lirequinil (Ro41-3696) NS-2664 NS-2710 NS-11394 Pipequaline ROD-188 RWJ-51204 SB-205,384 SX-3228 TP-003 TPA-023 TP-13 U-89843A U-90042 Y-23684 Phenols Fospropofol Propofol Thymol Piperidinediones Glutethimide Methyprylon Piperidione Pyrithyldione Pyrazolopyridines Cartazolate Etazolate ICI-190,622 Tracazolate Quinazolinones Afloqualone Cloroqualone Diproqualone Etaqualone Mebroqualone Mecloqualone Methaqualone Methylmethaqualone Nitromethaqualone SL-164 Volatiles/gases Acetone Acetophenone Acetylglycinamide chloral hydrate Aliflurane Benzene Butane Butylene Centalun Chloral Chloral hydrate Chloroform Cryofluorane Desflurane Dichloralphenazone Dichloromethane Diethyl ether Enflurane Ethyl chloride Ethylene Fluroxene Gasoline Halopropane Halothane Isoflurane Kerosine Methoxyflurane Methoxypropane Nitric oxide Nitrogen Nitrous oxide Norflurane Paraldehyde Propane Propylene Roflurane Sevoflurane Synthane Teflurane Toluene Trichloroethane (methyl chloroform) Trichloroethylene Vinyl ether Others/unsorted 3-Hydroxybutanal α-EMTBL AA-29504 Avermectins (e.g., ivermectin) Bromide compounds (e.g., lithium bromide, potassium bromide, sodium bromide) Carbamazepine Chloralose Chlormezanone Clomethiazole DEABL Dihydroergolines (e.g., dihydroergocryptine, dihydroergosine, dihydroergotamine, ergoloid (dihydroergotoxine)) DS2 Efavirenz Etazepine Etifoxine Fenamates (e.g., flufenamic acid, mefenamic acid, niflumic acid, tolfenamic acid) Fluoxetine Flupirtine Hopantenic acid Lanthanum Lignans (e.g., 4-O-methylhonokiol, honokiol, magnolol, obovatol) Loreclezole Menthyl isovalerate (validolum) Monastrol Niacin Nicotinamide (niacinamide) Org 25,435 Phenytoin Propanidid Retigabine (ezogabine) Safranal Seproxetine Stiripentol Sulfonylalkanes (e.g., sulfonmethane (sulfonal), tetronal, trional) Terpenoids (e.g., borneol) Topiramate Valerian constituents (e.g., isovaleric acid, valerenic acid, valerenol) Unsorted benzodiazepine site PAMs: MRK-409 (MK-0343) TCS-1105 TCS-1205 See also: GABAergics