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PubMed1991

Effects of barbiturates on GABA system: comparison to alcohol and benzodiazepines.

Central nervous system depressants, e.g. barbiturates, alcohol and benzodiazepines, have a wide spectrum of activity in humans and animals. Evidence accumulated suggests that some of the pharmacological actions exerted by these agents may be mediated through GABA system by mimicking GABAergic transmission. This proceeding briefly summarizes the evidence presented in our previous review (Yu S and Ho Ik: Alcohol 7: 261, 1990) as to how the GABA system plays a part in the barbiturate actions and the development of tolerance to and physical dependence on barbiturates. The comparisons of the effects of alcohol, barbiturates and benzodiazepines at different steps of GABA synapse are also discussed. Furthermore, the results which have been reported in the literature are inconsistent. This may be due to differences in (a) animal models used; (b) brain regions used; (c) protocols (dose, duration, form and route of administration, etc.) used in treating animals and/or (d) techniques (pharmacological, biochemical, physiological, etc.) used.

Animals↗
PubMed1999

Barbiturates inhibit progesterone synthesis in cultured Leydig tumor cells and human granulosa cells.

Screening drugs used in obstetrical practice for effects on steroid hormone synthesis revealed that phenobarbital inhibited progesterone synthesis in MA-10 Leydig tumor cells. The inhibition was apparently a drug class effect since it could be reproduced by other barbiturates. Barbiturate blockade was reversible and could be bypassed in the MA-10 cells by using 22-hydroxycholesterol. Human granulosa cell progesterone synthesis was also inhibited in a dose dependent fashion by phenobarbital, secobarbital and barbituric acid. Significant inhibition occurred in dose ranges that would be therapeutic for treating epilepsy. From these data we conclude that barbiturates block steroidogenesis by inhibiting cholesterol transport to the cholesterol side chain cleavage enzyme.

Anticonvulsants↗
PubMed1976

Mass screening and confirmation of barbiturates in urine by RIA/gas chromatography.

A rapid, sensitive and specific procedure is described for the mass screening and confirmation of barbiturates in urine specimens. The method is sensitive to 0.5 mug/ml levels of the commonly used barbiturates. The urine samples are screened by radioimmuno-assay. Specimens screened positive are confirmed by gas-liquid chromatography using a flame ionization detector. The barbiturates are analyzed as free acids on a 10% UC W-98 column and as their dimethyl derivatives on a 3% OV-17 column. This dual approach eliminates false positives caused by interfering substances which may be present in the urine, thus resulting in a method specific for the barbiturates.

Barbiturates↗
PubMed1980

Gas chromatographic properties of 1,3-dialkyl barbiturate derivatives.

The gas chromatographic properties of 1,3-dialkyl barbiturates have been studied. The retention times for 56 different 1,3-dialkyl derivatives of both aprobarbital and phenobarbital, and for 65 different 1,3-dialkyl derivatives of secobarbital were determined by gas-liquid chromatography (GLC) using a 3% SE-30 column. Retention times were found to increase with the number of carbons added. A plot of the log of the retention time versus the number of carbons in the alkyl group added for 3-alkyl derivatives of 1-alkylbarbiturates was made for each of the three barbiturates studied. A linear relationship was found to exist for derivatives having butyl or greater groups attached to the second nitrogen of the 1-alkylbarbiturates. The slopes of the graphs for the 3-alkyl derivatives of 10 different 1-alkylbarbiturates for each barbiturate studied were all found to be identical with a similar plot for straight chain hydrocarbons. This linear relationship allowed calculation of the retention times of large N,N-dialkyl barbiturates, such as N,N-eicosanylsecobarbital, which are not readily synthesized or chromatographed.

Barbiturates↗
PubMed1981

Barbiturates--structure versus RIA reactivity.

Over 90 different compounds having structural similarities to barbituric acid were analyzed by radioimmunoassay (RIA) using 125I-secobarbital reagents (Roche). Affinities were compared with molecular structures and a number of observations are made. It was found that all definitive components of the 5,5-dialkyl barbituric acid ring structure were essential for reactivity with the Roche RIA reagents; structural changes at any position of the ring reduced reactivity. No compounds studied were found to be more reactive than secobarbital [5-allyl-3-(1-methylbutyl) barbituric acid] and RO-2-1126[5-allyl-5-(1-carbamoylisopropyl) barbituric acid (the hapten used to prepare the RIA antibody)]. Changes in the 5-allyl and/or the 5-(1-methylbutyl) groups of secobarbital resulted in decreased reactivity.

Barbiturates↗
PubMedDate not supplied

[Barbiturate withdrawal syndrome: a case associated with the abuse of a headache medication].

Barbiturates can produce psychological and physical dependence and produce a withdrawal syndrome on the second to fourth day after the drug is suspended. Symptoms include anxiety, restlessness, insomnia, rhythmic intention tremor, dizziness, seizures, and psychosis. If the syndrome is not recognized and correctly treated, hyperthermia, circulatory failure, and death may ensue. Although barbiturates are less frequently used nowadays, they are employed in combination with other drugs in many medications used for the treatment of headache. We report the case of a 54-year-old woman who developed a barbiturate abstinence syndrome when she suspended self-administration of a drug containing butalbital. The patient had been using barbiturates, 900 mg/die, for 2+ years for persistent headache. She was admitted to the hospital because of seizures, hallucinations and delirium not controlled by benzodiazepine and phenothiazine administration. Her symptoms resolved after parenteral phenobarbital administration.

Analgesics↗
PubMed2000

Is there an indication for the use of barbiturate-containing analgesic agents in the treatment of pain? Guidelines for their safe use and withdrawal management. Canadian Pharmacists Association.

OBJECTIVE: To provide medical and pharmaceutical practitioners with information on the effectiveness, safety and risks associated with barbiturate-containing analgesic (BCA) agents and an approach to management of withdrawal from BCAs. METHODS: The benefits of using BCAs in the treatment of pain (compared with using non-BCAs) were weighed against potential risks. The procedures for discontinuation of BCAs in patients with pain were considered, and evidence showing that BCAs constitute a public health risk was reviewed. The evidence serving as the basis for the clinical guidelines was compiled from a number of sources, including key papers in the field, published and unpublished papers, and reports by Addiction Research Foundation researchers, a MEDLINE search from 1967 to November 1996, and communication with Canadian manufacturers of BCAs. RESULTS: There is no evidence that there is a clinically important enhancement of analgesic efficacy of BCAs due to the barbiturate constituent. No epidemiological studies on the relative frequency of abuse and dependence, or studies that have analyzed combination product use from a public health and social benefit to risk perspective, have been published to clarify the issues about the nature, extent and seriousness of these problems. RECOMMENDATIONS: No evidence exists to show a clinically important enhancement of analgesic efficacy of BCAs due to the barbiturate constituents. Because BCAs do not have a therapeutic advantage, there is no clinical reason to choose such a combination product when a simpler and often less expensive analgesic formulation (eg, acetaminophen, acetylsalicylic acid, nonsteroidal anti-inflammatory drug or narcotic) or a more specific anti-migraine drug (eg, dihydroergotamine or sumatriptan) is available. BCAs should be avoided in elderly people and should not be used in children. Extrapolation from published reports on abuse and withdrawal syndrome with these drugs suggests that BCAs have the potential to produce drug dependence and addictive behaviour, especially with regular use. In BCA overdose, the barbiturate component is only one of the clinically significant contributors to any morbidity, but its presence can complicate the management of additive or synergistic toxicities. Therefore, there is no reason to choose a combination product when a simpler product may be a safer alternative by minimizing the potential for addiction and the occurrence of additive side effects or toxicities. It is further recommended that prescribers re-evaluate treatment for patients using BCAs. Recommendations for withdrawal are provided, based on estimated consumption.

Analgesics↗
PubMed1975

Column chromatographic analysis of barbiturates in their dosage forms. II. secobarbital, amobarbital, and pentobarbital.

A general method for the analysis of barbiturates, using column parition chromatography, was extended to the assay of secobarbital, amobarbital, and pentobarbital. A solution of the barbiturate constitutes the immobile phase in the chromatographic system. It is eluted with ether-isooctane (1+9) and passed onto a K3PO4 column, which retains the barbiturate while extraneous materials are washed out. The barbiturate is removed from the column with etherisooctane (3+1), extracted from the eluate with NH3, and measured spectrophotometrically.

Amobarbital↗
PubMed1975

Local anesthetics and barbiturates: effects on evoked potentials in isolated mammalian cortex.

Slices of olfactory cortex from guinea pig, incorporating the lateral olfactory tract (LOT), were maintained in a glucose-bicarbonate solution in vitro. Stimulation of the LOT produced: 1) A summed LOT action potential; 2) A monosynaptic surface-negative wave (N-wave); and 3) A polysynaptic surface-positive wave (P-wave) as recorded from the pial surface of the slice at 24 degrees C. During a period of single stimulus pulses to the LOT, local anesthetics and barbiturates, applied to the incubating solution, depressed the amplitude of the action potential (while increasing its latency and threshold) with the following potencies: tetracaine greater than cocaine greater than lidocaine greater than procaine greater than pentobarbital greater than phenobarbital. The order of potencies was similar for the synaptic potentials. Each local anesthetic or bartiturate first depressed the P-wave, the N-wave and then the LOT potential, with all three potentials being affected within a narrow range of drug concentrations. There was a good linear relationship between drug potency on all potentials and the distribution coefficients of the drugs in octanol-water. During a period of double stimulus pulses to the LOT, up to 10 seconds apart, low concentrations of barbiturates depressed the N-wave to the second pulse with little effect on the first, conditioning pulse, an effect not seen with local anesthetics. The bath concentrations required for this effect of both barbiturates were similar to previous reports of blood concentrations required for general anesthesia. It appears that local anesthetics have actions on brain similar to those reported for other tissues and that barbiturates share some of the actions of local anesthetics, but exert a selective depression on repetitively elicited synaptic potentials.

Anesthetics, Local↗
PubMed1975

Antagonism of barbiturate by DNA pyrimidines and allied compounds.

The mortality caused by barbiturate poisoning in mice is reduced by the combined action of the DNA pyrimidines thymine and 5-hydroxymethylcytosine (5-HMC) and the structurally related vitamins, pyridoxal, nicotinamide and thiamine, given intraperitoneally. The acute hypnotic effect of sodium pentobarbital at moderate to high dosages is also antagonized by these compounds. All five compounds are required for activity. The structural similiarity between these antagonist components and the barbiturates had suggested that the former's reactions as cofactors or as the constituents of more complex molecules might be points of drug inhibition. It therefore appeared that this inhibition might be reversed by administration of these cellular constituents. The obligatory requirement for both thymine and 5-HMC as components of this antagonist raises the possibility that a metabolically reactive DNA species in brain may be one site of barbiturate action. At the dosages employed, this antagonist produces no behavioral or symptomatic response in non-narcotized animals and may thus provide a basis for treatment of barbiturate poisoning.

Animals↗
PubMed1976

Barbiturate intoxication. Morbidity and mortality.

The complications encountered in caring for 185 patients intoxicated with barbiturates were reviewed. The population consisted of 142 patients with long-acting barbiturate concentrations of 8 mg per 100 ml or greater, 20 patients with short-acting barbiturate concentrations of 3 mg per 100 ml or greater and 23 consecutive patients with short-acting barbiturate intoxication referred for monitoring. Pneumonia was the major cause of morbidity and mortality and correlated best with the initial depth of coma and the use of an endotracheal tube in treatment. Cardiovascular instability manifested by pulmonary edema was the next leading cause of morbidity and mortality and correlated best with the initial depth of coma and the quantity of intravenous fluid administered. In retrospect, use of eliminative measures such as dialysis would probably not have altered the outcome in most of the patients who died and attempts at forced diuresis may have contributed to several deaths. Particular emphasis should be placed on the problems of sepsis and fluid therapy in the management of these patients.

Adolescent↗
PubMed1952

Acute and chronic barbiturate intoxication recent advances in therapeutic management.

The increase of addiction to barbiturates and in the number of deaths from overdoses constitutes a growing and serious health problem. Although the symptoms of both acute and chronic barbiturate intoxication resemble those of other drug intoxications, correct diagnosis can be made through an accurate history, a physical examination and the finding of increased nonprotein nitrogen in the blood and of a characteristic fast pattern in an electroencephalogram.Metrazol(R) and electrostimulation, with adjuvant therapy, are discussed as the most advantageous methods of treating acute barbiturate intoxication; the addition of emetics to barbiturates to prevent overdosage is considered. Carefully controlled withdrawal and psychiatric rehabilitation are necessary to treatment of addiction, but as patients are usually uncooperative the prognosis is poor.

Barbiturates↗
PubMedDate not supplied

Alcohol intoxication results in rapid loss in free magnesium in brain and disturbances in brain bioenergetics: relation to cerebrovasospasm, alcohol-induced strokes, and barbiturate anesthesia-induced deaths.

In vivo 31P-nuclear magnetic resonance (31P-NMR) spectroscopy and ion-selective electrode measurements were undertaken to determine if administration of acute doses of alcohol (ALC, 0.2-6.6 g/kg), and lethal doses of barbiturate anesthesia, exert any influence on: (1) brain cellular bioenergetics, intracellular free Mg ([Mg2+]i) and intracellular pH (pHi), and (2) serum levels of ionized Mg (IMg2+), ionized calcium (ICa2+) and K+. Approximately 20-30 min after intraperitoneal administration of ALC to anesthetized rats, brain phosphocreatine (PCr)/ATP and PCr/inorganic phosphate (P(i)) ratios dropped from 2.5 to 1.7 and from 6.6 to 2.2, respectively, P(i) rose 20-200% (depending upon ALC dose), and free ADP and creatine rose significantly. ALC induced rapid decreases in the cytosolic phosphorylation potential (CPP) and free energy of ATP hydrolysis (-delta G/delta E). Following ALC administration, brain [Mg2+]i dropped rapidly (within 4-30 min) and significantly; the greater the dose of ALC, the greater the loss in brain [Mg2+]. Correlations were found between [Mg2+]i, PCr/ATP, CPP and delta G/delta E after ALC but not in control brains. Rats that exhibited ALC-induced strokes and death (unlike barbiturate death) exhibited huge elevations in [Mg2+]i. Although ALC administration does not alter brain pHi at least (up to 70 min), ALC- and barbiturate-induced death produces rapid brain intracellular acidosis. Concomitant with ALC-induced alterations in [Mg2+]i and brain cellular bioenergetics, we noted that ALC administration results in rapid elevations in serum IMg2+ and K+ but not ICa2+. These results suggest that ALC administration and heavy or binge-drinking of ALC (1) can result in rapid alterations in brain bioenergetics, [Mg2+]i and pHi, and (2) result in rapid elevations in serum IMg2+ and K+ in rats. In addition, ALC- and barbiturate-induced deaths do not appear to produce identical alterations in brain bioenergetics and [Mg2+]i, and lastly binge or heavy drinking of ALC may result in stroke-like events and sudden death via rapid alterations in brain cellular bioenergetics.

Alcoholic Intoxication↗
PubMed1989

[Inhibition by local anesthetics and barbiturates of the active transport of H+ in the synaptic vesicle membranes of the brain].

The effects of local anesthetics and barbiturates on the ATP-dependent H+ transport in synaptic vesicle membranes from rat brain were studied using a fluorescent probe, acridine orange. Local anesthetics depressed the active H+ transport with the following order of potencies: tetracaine trimecaine lidocaine procaine. Respective IC50 values were 0.07, 0.28, 0.46 and 0.60 mM. The local anesthetics also disrupted the endogenous pH gradient seen in the absence of ATP. Barbiturates inhibited the active H+ transport showing IC50 values in the range of 2-5 mM except for benzobarbital and barbital characterized by IC50 values of 0.5 and 20 mM, respectively. The order of potencies was benzobarbital hexobarbital amobarbital pentobarbital phenobarbital barbital. The endogenous pH gradient was not affected by the barbiturates. The results show that local anesthetics disrupt the H+ transport by acting as permeable weak bases (uncouplers) whereas barbiturates are likely to block and anion channel which maintains electroneutrality of the H+ transport in the membrane of synaptic vesicles.

Acridine Orange↗
PubMed1989

[Deregistration of barbiturates. A follow-up study after 1 year].

On January 1st 1986, all hypnotics and sedatives containing barbiturates were removed from the Danish Drug Register. After one year, a follow-up investigation of previous barbiturate users was undertaken with the object of investigating the significance of various factors for cessation or continuation of use of psychotropic drugs in connection with the removal of barbiturates from the Danish Drug Register. The investigation was carried out of a questionnaire investigation in general practice with participation of 82 practices. Information was obtained concerning 141 previous barbiturate users. Twenty-four of these had stopped (17%, 95% confidence limits 11-23) having psychotropic drugs prescribed during the course of the year in question. In particular, patients without or with slight mental conditions ceased using drugs (p = 0.02). An age and sex stratified analysis revealed that more patients who had obtained the preparation by direct doctor-patient contact stopped the habit (odds ratio 3.00, 95% confidence limits 1.04-8.61). Other factors were without significant significance for continued use or cessation, respectively. In 75% of the patients, adjustment was, in the opinion of the general practitioner, easy. Out of 105 patients who continued to have psychotropic drugs prescribed and where the preparation employed was known, 90 (86%) were prescribed benzodiazepines.

Adult↗
PubMed1988

Barbiturate anesthesia and alcohol tolerance in a rat model.

Anesthetic responses to a variety of barbiturates were examined in adult male rats rendered alcohol-tolerant by administration of an ethanol-containing balanced liquid diet for 3 weeks. Within 9 hours of withdrawing the diets, groups of 10-15 ethanol-fed rats and pair-fed controls were injected intraperitoneally with one of the following drug/dose combinations: thiamylal 20, 40, or 60 mg/kg; methohexital 10, 20, or 40 mg/kg; secobarbital 20, 30, or 40 mg/kg; pentobarbital 10, 20, or 40 mg/kg; or phenobarbital 80, 120, or 160 mg/kg. Each animal was monitored for time to loss of righting reflex (onset of anesthesia), absence of response to a painful stimulus (analgesia), and sleeping time (duration of anesthesia). None of these three anesthetic responses differed significantly in ethanol-fed and control rats with any dose of thiamylal, methohexital, or secobarbital. In contrast, all three responses were significantly less in rats given the middle dose of pentobarbital (20 mg/kg) than they were in control rats. Onset and duration of anesthesia were also shorter with the middle dose of phenobarbital (120 mg/kg), but analgesia was not. The results of this study, in combination with others, suggest that 1) cross-tolerance to anesthetic effects of barbiturates in ethanol-tolerant rats is not uniform with all barbiturates: and 2) because shorter-acting barbiturates show negligible cross-tolerance with alcohol, higher doses of these agents may not be required for satisfactory anesthesia in chronically alcoholic humans.

Animals↗
PubMedDate not supplied

[Characteristics of barbiturate adsorption on activated charcoal].

Equilibration patterns of barbiturates adsorption on activated charcoals were studied using aqueous solutions of barbital and sodium barbital and commercially available charcoals BAU, AR-3, AR-B, AR-A, SKT-6A. The rate of barbiturates adsorption was described as an additive function of concentrations of amide, ionized and non-ionized imidol forms calculated considering the reactions of dissociation and hydrolysis. Relatively low equilibrium concentrations of barbiturates in the solid phase and simultaneous sorption of the barbital anion as well as of its non-ionized form were related to the considerable rate of the substance ionization due to both tautomeric transformation and dissociation of the acid formed. The procedure for calculation of equilibrium described assumes that the rate of barbital and sodium barbital adsorption on activated charcoals of various brands might be estimated at various pH values of a solution, based on dissociation and hydrolysis reactions, which is of importance under conditions of the barbiturates enterosorption.

Adsorption↗
PubMed1986

Cerebral arteriovenous oxygen content difference during barbiturate therapy in patients with acute brain damage.

This study evaluated the reliability of cerebral blood flow equivalent (CBFE), which was calculated as the reciprocal of cerebral arteriovenous oxygen content difference (C(av)DO2) as a monitor during barbiturate therapy in patients with cerebral ischemic insults. A barbiturate (thiamylal) was administered at a rate of 3 mg . kg-1 . hr-1 for 2-5 days to four patients who had suffered cardiac arrest, four with acute focal ischemia, two with postoperative brain edema after neurosurgery, and one with brain damage due to asphyxia. Four of the 11 patients completely recovered neurologically (recovery group), and others had neurological sequelae or died (nonrecovery group). The mean value of CBFE in the recovery group decreased significantly with barbiturate therapy to 13 +/- 1 ml blood/ml O2 from 39 +/- 3 ml blood/ml O2 but did not decrease in the nonrecovery group. We conclude that CBFE can be useful for monitoring the effect of barbiturate therapy in ischemic brain insults.

Adolescent↗