メホバルビタール

Phenobarbital may decrease the half-life of doxycycline by inducing hepatic microsomal enzymes that metabolize the antibiotic. Concomitant administration of doxycycline and "barbiturates" should be avoided if possible. If concomitant therapy is necessary, doxycycline may be administered at 12-hour intervals and/or doxycycline concentrations should be closely monitored. /Barbiturates General Statement/

Pretreatment with or concurrent administration of phenobarbital in patients receiving oral contraceptives may decrease the effectiveness of oral contraceptives. There have been reports of women receiving anticonvulsants (eg, phenobarbital) who became pregnant while receiving oral contraceptives. Phenobarbital may enhance the metabolism of both the estrogenic and progestinic components of oral contraceptives, presumably by induction of hepatic microsomal enzymes. Because of the risk of contraceptive failure during concomitant use of oral contraceptives and phenobarbital (or mephobarbital), it has been suggested that alternate methods of contraception be considered in patients receiving phenobarbital. /Barbiturates General Statement/

"Barbiturates" may potentiate adverse effects (e.g., respiratory depression) induced by toxic doses of tricyclic antidepressants (e.g., amitriptyline, imipramine). With therapeutic doses of tricyclic antidepressants, "barbiturates" appear to stimulate metabolism and decrease blood concentrations of the antidepressants; however, the clinical importance of this effect has not been established. /Barbiturates General Statement/

"Barbiturates", especially phenobarbital, may decrease absorption of dicumarol from the GI tract. In addition, phenobarbital and possibly other "barbiturates" may induce hepatic microsomal enzymes resulting in increased metabolism of coumarin anticoagulants and decreased anticoagulant response. Patients maintained on both "barbiturates" and a coumarin anticoagulant have a risk of hemorrhage if the barbiturate is discontinued and the dosage of the anticoagulant is not adjusted. Barbiturate therapy should not be initiated or discontinued in patients receiving oral anticoagulants without careful attention to the possible need for adjusting anticoagulant dosage.

For more Interactions (Complete) data for Methylphenobarbital (37 total), please visit the HSDB record page.

/SIGNS AND SYMPTOMS/ Neonates born to women who receive barbiturates throughout the last trimester of pregnancy may show withdrawal symptoms from 1-14 days after birth. Withdrawal symptoms, which resemble congenital opiate withdrawal symptoms, include hyperactivity, restlessness, disturbed sleep, tremor, and hyperreflexia. /Barbiturates General Statement/

/SIGNS AND SYMPTOMS/ Symptoms of barbiturate dependence are similar to those of chronic alcoholism, but can be more severe than those associated with alcohol or opiate abstinence syndrome and may result in fatalities. Withdrawal symptoms (which usually appear after 8-12 hours of abstinence) may vary from mild, consisting only of weakness, anxiety, muscle twitches, insomnia, nausea, vomiting, postural hypotension, and/or weight loss, to more severe hallucinations, delirium, and seizures. Seizures, clinically indistinguishable from tonic-clonic (grand mal) seizures, may occur as early as 16 hours after the last dose of barbiturate or may be delayed for as long as 5 days. Some fatalities resulting from cardiovascular collapse have occurred. /Barbiturates General Statement/

/SIGNS AND SYMPTOMS/ Overdosage of barbiturates produces CNS depression ranging from sleep to profound coma to death; respiratory depression which may progress to Cheyne-Stokes respiration, central hypoventilation, and cyanosis; cold, clammy skin and/or hypothermia or later fever, areflexia, tachycardia, hypotension, loss of peripheral vascular resistance, muscular hyperactivity (twitching to convulsive-like movements) seizures, allergic reactions, and decreased urine formation. Pupils usually are slightly constricted but may be dilated in severe poisoning. Patients with severe overdosage often experience typical shock syndrome; apnea, circulatory collapse with loss of peripheral vascular tone, cardiac arrest, respiratory arrest, and death may occur. Complications such as pneumonia, pulmonary edema, or renal failure may also prove fatal. Other complications which may occur are congestive heart failure, cardiac arrhythmias, and urinary tract infections. Some patients have bullous cutaneous lesions which heal slowly. Sweat gland necrosis may also occur. /Barbiturates General Statement/

/CASE REPORTS/ The authors report the case of a 32-year-old man who had been treated for anxiety and obsessive-compulsive disorder and had received 800 mg methylphenobarbital (MPB). After switching to a barbiturate-free schedule, his condition continued to be unstable for more than 21 MPB half-lives (approx. 30 days) and did not stabilize until MPB-metabolites dropped below their urinary detection limit. Considering that this article provides findings from a single patient, the authors use this experience to discuss and emphasize the importance of clinical control of barbiturates in psychiatry.

For more Human Toxicity Excerpts (Complete) data for Methylphenobarbital (10 total), please visit the HSDB record page.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

methylphenobarbital

DILI Positive

DOI:10.1016/j.drudis.2019.09.022

/LABORATORY ANIMALS: Acute Exposure/ The authors examined the capability of N-substituted morpholinoalkyl derivated of phenobarbiral methylphenobarbital and glutetimide to induce drug-dissimilated enzymes in liver microsomes as those newly syntesized compounds were compared with the initial substances, which were enzyme inductors. They examined the following indices: duration of hexobarbital narcosis after a six day treatment of male white rats with one of the substances liver weight, related to the percentage of the whole body weight, protein content in liver homogenates and in microsomal fraction of liver, the activity of N-demetilase in liver. There was a considerable shortening of the duration of hexobarbital sleep due to barbiturates, more manifested in animals, treated with methylphenobarbital. Glutetimide shortened the /CNS depression/ statisticaly insignificant. The respective morpholonoalkylic derivatives not only did not shortened the /CNS depression/ sleep, but even slightly prolonged. it. The liver weight of the rats, treated with barbiturates, was increased with 25-30% while that of the rats treated with morpholinoalkylic derivatives did not differ from the liver weight of the control animals. The protein content in liver homogenates did not show statistically significant differences in the single groups. The protein content of the microsomal liver fraciton was increased in the animals, treated with barbiturates and glutetimide, while in the rats, treated with morphoalkylic derivatives the protein content did not differ from that of the controls, but it was even reduced after treatment with a derivative of glutetimide. Phenobarbital and methylphenobarbital increased significantly the activity of pyrimidone N-demetilase, while their N-substituted morpholinc-alkyli derivatives inhibited it.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ The authors carried out histologic and electrone microscopic studies of liver in rats, treated with phenobarbital, methylphenobarbital, with their N-substituted morpholinoethye derivatives as well as in rats from the control group of animals. It was established that phenobarbital and methylphenobarbital caused hypertrophy and vacuolization of endoplasmatic reticulum, but the first preparation of the myelin degeneration of mitochindria as well. Morpholinethyl derivatives of the mentioned two compounds induced above all activation of lysosomes as well as reaction of Goldgi apparatus in the parenchymatous cells of liver. The observed ultrastructural changes were connected with differences in the induced drug-metabolizing enzymic properties of the two groups of compounds ...

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Phenobarbital sodium is carcinogenic in mice and rats following lifetime administration; in mice, the drug produced benign and malignant liver cell tumors and, in rats, benign liver cell tumors very late in life. /Barbiturates General Statement/

Geriatric patients may react to usual doses of barbiturates with excitement, confusion, or depression. Many patients experience increased dreaming, nightmares, or increased insomnia when hypnotic doses of barbiturates are discontinued. /Barbiturates General Statement/

Phenobarbital frequently produces paradoxical excitement and hyperactivity in children or exacerbates existing hyperactivity. Geriatric patients may react to usual doses of barbiturates with excitement, confusion, or depression, probably as a result of the drugs' depressant effects on inhibitory centers of the cerebral cortex. /Barbiturates General Statement/

Barbiturates lower serum bilirubin concentrations in neonates and patients with congenital nonhemolytic unconjugated hyperbilirubinemia, presumably by induction of glucuronyl transferase, the enzyme that conjugates bilirubin. /Barbiturates General Statement/

/Investigators/ sequenced all nine exons and exon-intron junctions of the cytochrome P450 2C19 (CYP2C19) gene from a Japanese subject with a lowered capacity of CYP2C19-mediated 4'-hydroxylation after an oral administration of mephobarbital. /Investigators/ found a novel single nucleotide polymorphism (SNP) of CYP2C19 gene as follows: SNP, 040110MoritaJ001; GENENAME: CYP2C19; ACCESSION NUMBER: NT_030059.8; LENGTH; 25 bases; 5'-GAGGGCCTGGCCC/TGCATGGAGCTGT-3'. The SNP (168946C>T) induced an amino acid alteration (Arg442Cys) located in exon 9 close to the heme-binding region of CYP2C19, which may result in the decrease in the catalytic properties of CYP2C19. A new allele having this SNP was designated as CYP2C19*16.

A 38-yr-old woman who by history ingested 13 g methylphenobarbital, alcohol, and 6 g acetaminophen became comatose slowly over 4 days. Acute hepatic injury appeared to impair the oxidative N-demethylation of methylphenobarbital to its product, phenobarbital. On the eighth day after ingestion she was treated because of protracted coma with Amberlite XAD-4 resin hemoperfusion. Hemoperfusion, which removed 0.83 g methylphenobarbital and 2.10 g phenobarbital, led to transient clinical improvement. When supportive patient management fails to produce a satisfactory clinical course in a methylphenobarbital-intoxicated patient, hemoperfusion could be a useful adjunct to therapy.

Treatment of overdosage is mainly supportive including maintenance of an adequate airway and assisted respiration and oxygen administration if needed. Resuscitative measures should be initiated promptly. Standard treatment for shock should be administered if necessary. Management of hypotension may include administration of iv fluids, elevation of the lower extremities, and/or use of vasopressor or inotropic agents. For seizures, iv diazepam and phenytoin may be used; in case of refractory seizures, general anesthesia and paralysis induced by a neuromuscular blocking agent may be necessary. Activated charcoal is an effective barbiturate adsorbant when administered within 30 minutes following ingestion of the drugs. Gastric lavage or gastric aspiration is not recommended unless there is evidence that the drug has been ingested recently (within 4 hours); care should be taken to prevent pulmonary aspiration of gastric contents. Multiple-dose, nasogastric administration of activated charcoal has been used effectively to treat phenobarbital overdose; activated charcoal enhances elimination of the drug and shortens the duration of coma. The patient's vital signs, fluid intake, blood gases, and serum electrolytes should be monitored closely. Analeptic drugs should not be administered because they may produce paroxysmal cerebral activity which may result in generalized seizures. In addition, it has been demonstrated that analeptics are incapable of stimulating respiration and exerting an arousal effect in patients with severe barbiturate poisoning and profound CNS depression. If renal function is normal, forced diuresis may be of benefit. In addition, alkalinization of the urine increases renal excretion of phenobarbital, aprobarbital, and mephobarbital which is metabolized to phenobarbital. Peritoneal dialysis or hemodialysis may be useful in severe barbiturate intoxication and/or if the patient is anuric or in shock. /Barbiturates General Statement/

Orally administered activated charcoal has been shown to enhance the elimination of phenobarbital. Following iv administration of phenobarbital in healthy adults in one study, orally administered activated charcoal decreased the mean serum half-life of phenobarbital and increased mean total body and nonrenal clearances of the drug. /Barbiturates General Statement/

LD50 Rat ip 130 mg/kg

LD50 Mouse oral 300 mg/kg

LD50 Cat oral 230 mg/kg

LD50 Rabbit oral 400 mg/kg

Schedule IV shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. Depressants. Unless specifically excepted or unless listed in another schedule, any material, compound, mixture, or preparation which contains any quantity of the following substances, including its salts, isomers, and salts of isomers whenever the existence of such salts, isomers, and salts of isomers is possible within the specific chemical designation: Methylphenobarbital (DEA Code Number: 2250) is included on this list.

... DEA /schedule IV /controlled substance

THERAPEUTIC CATEGORY: Anticonvulsant; sedative; hypnotic

THERAPEUTIC CATEGORY (Vet): Anticonvulsant; sedative; hypnotic

MEDICATION

Phenobarbital + dimethyl sulfate (methylation)

The 5,5-disubstituted barbituric acids are still synthesized by the classical condensation of substituted malonic esters, malonic amides, or cyanoacetic esters with urea, thiourea, guanidine, or dicyanodiamide, followed by the hydrolysis of the resulting imino- or cyanobarbiturate. /5,5-Disubstituted barbituric acids/