Changing pattern of drugs used for self-poisoning.

In 1967-76 the annual number of admissions to a poisoning treatment centre rose from 964 to 2134. The proportion of admissions caused by taking barbiturate hypnotics and methaqualone fell considerably while that caused by taking benzodiazepines and tricyclic antidepressants increased. As a result the proportion of patients admitted unconscious fell from 23% to 15%. The declining contributions of barbiturates and methaqualone and increased importance of tricyclic antidepressants were significant in all grades of coma. The change in drugs taken, however, has not yet reduced the percentage of unconscious patients needing endotracheal intubation or assisted ventilation, and hypothermia remains as common. Only hypotension has become less frequent as antidepressants replace barbiturates as the main cause of drug-induced coma. The use of salicylates for self-poisoning is declining slowly, and paracetamol poisoning is now as common.     

Toxicological Statistics for Barbiturates,Other Sedatives,and Tranquillizers in Ontario: A 10-Year Survey

A steady increase in the number of cases of poisoning due to barbiturates, tranquillizers and non-barbiturate sedatives has been noted for Ontario by the Attorney-General''s Laboratory, Toronto, during the period 1955-1964 on the basis of submitted material. Five cases of poisoning by barbiturates were recorded in 1955 and 193 in 1964.Urine and blood samples from persons charged with driving motor vehicles while under the influence of drugs were also examined. In 1958 only one such case was reported to the Laboratory, whereas 25 cases were recorded in 1964; barbiturates were detected in 18 of these 25. Patients must be warned of the risks of ingesting alcohol while receiving barbiturate treatment.     

Sleep and Barbiturates: some Experiments and Observations

To determine the effect of barbiturates on sleep two subjects, after a control period, received 200 mg. of sodium amylobarbitone for 26 nights. All night sleep records taken during this period showed that the barbiturate shortened the delay to sleep, increased the total sleep period, lengthened the delay to rapid eye movement (R.E.M.) sleep, and depressed R.E.M. sleep. After five nights R.E.M. sleep returned to baseline values —that is, showed tolerance. On stopping the drug withdrawal phenomena were seen, even to this small dose of the drug.In a second experiment a subject dependent on 600 mg. of Tuinal was found to have low normal R.E.M. sleep while on drugs. On withdrawal, delay to sleep increased and total sleep time fell. R.E.M. sleep was doubled and the delay to R.E.M. became abnormally short.These findings suggest that hypnotics allow sleep to be “borrowed,” and that patients should be supported while they are being withdrawn.     

Acute drug poisoning in the adult

In a prospective study of 349 patients with acute poisoning treated at The Montreal General Hospital in 1972 benzodiazepines and non-barbiturate hypnotics were found to be the most frequent putative drugs. Of the 108 patients admitted to hospital 37% had taken an overdose of a drug prescribed for them by their psychiatrist or other physician; 48% had formerly taken an overdose of drugs and 44% had had previous psychiatric treatment. Unconsciousness, respiratory depression, metabolic acidosis and acidemia, and hypokalemia were the most frequent clinical abnormalities observed. Treatment was supportive. There were six deaths. The average duration of coma was short; only five surviving patients remained unconscious for more than 24 hours. Respiratory complications were frequent.It is recommended that more attention be paid to recognizing patients whose behaviour pattern might include such an impulsive gesture, and that alternatives be found for barbiturate and non-barbiturate hypnotics.     

Barbiturate Mortality as an Index of Barbiturate Use,Canada, 1950-1963

Changes in Canadian rates of mortality from barbiturates are examined, and their relation to barbiturate use in the general population is discussed. While the number of deaths attributed to barbiturates quadrupled, from 63 in 1950 to 232 in 1963, there has been a concomitant decrease in the number of deaths from inhalation of utility gas.Combined rates for deaths from utility gas and barbiturates declined steadily for most age groups between 1950-52, 1955-57, and 1959-63. It is possible that the increased mortality from barbiturates represents a change in fashion in regard to method of suicide. Changed mortality from barbiturates is not a valid measure of the extent to which consumption of barbiturates has increased in the Canadian population.     

Prescribing of psychoactive drugs for chronically ill elderly patients.

The prescribing of psychoactive drugs for 1431 chronically ill elderly patients being assessed for long-term institutional or community care was surveyed. Psychoactive drugs had been prescribed for about one quarter of the patients; benzodiazepines were the most frequently prescribed group. Judging from the extensive prescribing of flurazepam and chloral hydrate, commonly used hypnotics, the main reason psychoactive drugs were prescribed was to provide night-time sedation. Antidepressants and drugs promoted as useful in improving cognitive function were infrequently prescribed. Commendable prescribing practices included the infrequent use of "cerebral vasodilators" and barbiturates. Questionable prescribing practices included the infrequent use of tricyclic antidepressants in severely depressed patients and the use of tranquilizers in patients described by their attending physician as markedly or extremely withdrawn.     

The use of sedative-hypnotic drugs in a university teaching hospital.

We reviewed the charts of 476 patients admitted to a university teaching hospital to determine whether sedative-hypnotic drugs (SHDs) were being used excessively and to examine the use of SHDs as hypnotics. The frequency of medical and surgical indications for barbiturates and benzodiazepines or other minor tranquillizers as well as the use of such drugs were compared among different groups of patients and specialty wards. Of the patients 29% had a regular order and 40% had a PRN order; only 77% of the PRN orders were administered. A total of 215 patients (45%) received an SHD during their hospital stay, and 160 (34%) received the drug as a hypnotic. Medical indications accounted for 49% of the regular orders but only 2% of the PRN orders; moreover, 89% of all the PRN orders were for insomnia. On average, patients receiving SHDs as hypnotics were older (p less than 0.05) and stayed longer in hospital (p less than 0.01) than those who did not; however, no patient on the geriatric or pediatric ward received an SHD as a hypnotic during the hospital stay. The differences in use between patient groups may have been influenced by orientation of ward staff. Physicians should review their rationale for prescribing hypnotics and avoid routine orders on admission.     

A BARBITURATE ANTIDOTE—Use of Methylethylglutarimide in Barbiturate Intoxication and in Terminating Barbiturate Anesthesia

Methylethylglutarimide was administered to 488 patients ranging in age from 7 to 89 years, in a study on sleep-reversal after harbiturate anesthesia. Sodium surital or sodium pentothal were the barbiturates used. The drug was administered intravenously in doses varying from 25 to 200 mg. Dosage below 25 mg. was found to be ineffective. Almost all patients showed signs of awakening as evidenced by the return of corneal and conjunctival reflexes, the opening of the eyes, and stirring or moving about. Many responded to questioning. Almost all showed evidence of greater responsiveness within five minutes. No untoward reactions were noted. No convulsions were produced.Five patients ranging in age from 24 to 70 years were treated for barbiturate poisoning with Mikedimide® given intravenously in doses varying from 550 mg. to 1950 mg. All recovered consciousness within 30 minutes to an hour. No convulsions were produced.While it is not known whether Mikedimide is a direct barbiturate antagonist, or whether it is an analeptic, it appears to be a useful drug in reversing the respiratory depression and the cerebral depression produced by harbiturate intoxication and barbiturate anesthesia.     

MEDICAL GROUP PRACTICE IN CALIFORNIA

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.     

Respiration rate, heart rate, and body temperature values in cynomolgus monkeys (Macaca fascicularis) during barbiturate anesthesia

Respiration rate, heart rate, and body temperature values were obtained from 14 cynomolgus monkeys (Macaca fascicularis) during neurosurgery under barbiturate anesthesia. Vital sign values markedly declined below baseline during the early stages of surgery, steadily increased as surgery progressed and neared completion, and finally returned to baseline by the end of the postsurgical recovery period. There was considerable variability among the 14 monkeys, but the ranking of each monkey relative to the others remained constant across the period of observation. The findings suggested that the cynomolgus monkey may be more sensitive to barbiturates than the rhesus monkey, and cynomolgus monkeys may exhibit considerable individual differences in their sensitivity to barbiturates.     

Biochemical pharmacology of the gamma-aminobutyric acid receptor/ionophore protein

The synaptic receptor sites for the neurotransmitter gamma-aminobutyric acid (GABA) can be assayed in vitro with several radiolabeled agonists and one antagonist. Numerous criteria of specificity have been met for these binding sites. All of the ligands show heterogeneity in binding affinities. The subpopulations thus defined have a remarkably similar specificity for GABA analogs, which suggests an intimate relationship and possible interconvertibility. Modulation of GABA receptor binding by barbiturates, anions, and other membrane treatments that affect agonists and antagonists in an opposite manner suggests a three-state model of interconvertible affinities. The complex of GABA receptor and chloride ion channel contains modulatory sites for barbiturates and benzodiazepines, drugs that enhance GABA responses in neurons. The receptor complex can be solubilized in detergent with the three mutually interacting receptor activities intact. The complex has an apparent molecular weight of 355,000 and has been partially purified. GABA agonist function has been assayed at the biochemical level by measuring the activation of 36Cl- efflux from preloaded hippocampal slices by GABA, muscimol, and barbiturates. This response is blocked by the antagonists of the GABA site (bicuculline) and the barbiturate site (picrotoxin). Comparison of binding and function on the same tissue should be useful in analyzing the mechanism of action of GABA.     

The Use of Ethamivan in the Treatment of Barbiturate Poisoning

Ethamivan was used as a respiratory analeptic in the treatment of nine cases of severe barbiturate poisoning. Initial intravenous injections of 100 to 150 mg. of ethamivan increased the depth of respirations within a minute. Prolonged respiratory stimulation was achieved by a continuous intravenous infusion of 500 to 3000 mg. of ethamivan per litre of fluid. If hypotension occurred, an intravenous drip of noradrenaline was used; fluid overloading was avoided by adjusting the concentrations of drugs given, so that no more than a total of 125 c.c. of fluid per hour was administered. The chief side effect of overdosage of ethamivan was muscular twitching. This did not prove to be a problem and was of some value in determining the amount of drug given. The nine patients survived. It was concluded that ethamivan is a useful agent in the treatment of barbiturate poisoning.     

Barbiturates inhibit intracellular Ca2+ rise induced by thrombin in rat platelets

The effects of a number of barbiturates (anesthetic as well as anticonvulsant) on thrombin-induced calcium mobilization were tested in rat platelets using the fluorescent Ca2+ probe Fura-2. All drugs, except barbituric acid and Na-barbital, inhibited the thrombin-induced intracellular Ca2+ rise. Both the uptake of extracellular Ca2+ and the release of calcium from intracellular organelles were affected but influx was inhibited more strongly and at lower concentrations of the drugs (e.g. IC50 of thiopental was 0.83 mM for influx and 1.2 mM for intracellular release). Inhibitory potencies of the various barbiturates were markedly different. Thiopental was the most and barbital the least potent inhibitor. The order of inhibitory potency of the drugs appeared generally to follow their lipid solubility and the order of their hypnotic efficiency, with hexobarbital as the most conspicuous exception. Therefore, barbiturate treatment of cells perturbs agonist-induced calcium mobilization. This effect may be partially linked to their previously reported inhibitory action on two kinases, protein kinase C and phosphatidylinositol 4-phosphate kinase [1, 2].     

Interactions between phospholipids and barbiturates.

The effects of a number of barbiturates on the temperature of the lipid phase transition have been studied using chlorophyll a as a fluorescence probe. The barbiturates cause a reduction in the temperature of the phase transitions of dipalmitoyl phosphatidylcholine and dipalmitoyl phosphatidylethanolamine, the effects being greatest at lower pH values where more of the barbiturate is present in the uncharged form. There was no significant interaction between the barbiturates and dipalmitoyl phosphatidylserine. These and other observations on the actions of local anaesthetics are used to develop a model for local anaesthesia. It is suggested that the sodium channel is surrounded by an annulus of lipid in the gel state, this rigid microenvironment preventing the sodium channel relaxing from its active configuration to an inactive one. Local anaesthetics, which reduce the temperature of lipid phase transitions, trigger a change of the annular lipid from the gel to the liquid-crystalline state, with a consequent relaxation of the sodium channel to an inactive configuration, in which the sodium current is reduced or blocked.     

Effect of xylocaine and carbachol applied to the caudate nucleus of rats on barbiturate sleeping time

Since lesion of subcortical structures may affect the barbiturate sleeping time (bST), we decided with the present study to elucidate the role of the caudate nucleus in the determination of central sensitivity to barbiturates. Rats implanted with a cannula in the caudate nucleus of one or both sides, as well as with a jugular cannula, were utilized. Intravenous injections of sodium pentobarbital (40 mg/kg), intracerebral injections of Xylocaine (0.04 microgram), carbachol (0.2 micrograms) or artificial cerebrospinal fluid (ACF) into the caudate nucleus were performed. Both Xylocaine and carbachol, but not ACF, increased the bST regardless of the preparation used, the only exception being Xylocaine which did not alter the bST, if injected into the left caudate nucleus. The results suggest that the caudate nucleus may act as a modulator of the central sensitivity to barbiturates.     

Effect of tidal volume and anesthetic agent on airway responsiveness to histamine

Dose-response relationships for bronchoconstriction in response to aerosal histamine were assessed before and after vagotomy in 11 dogs anesthetized with barbiturates and in 9 dogs anesthetized with alpha-chloralose-urethan. The dose-response relationships following vagotomy were assessed during spontaneous ventilation and during muscular paralysis and mechanical ventilation with tidal volume (VT) similar to each animal's VT prior to vagotomy. After vagotomy the spontaneous VT of both groups increased but the VT of the alpha-chloralose-urethan group was significantly less than that of the barbiturate group. The histamine responsiveness of the animals anesthetized with barbiturates was significantly greater during mechanical ventilation when VT was reduced to prevagotomy levels compared with during spontaneous ventilation. In contrast, the histamine responsiveness of the alpha-chloralose-urethan group was not significantly changed by reducing VT to prevagotomy levels. In six other dogs anesthetized with pentobarbital sodium and studied after vagotomy, responsiveness to histamine aerosol during controlled ventilation with breaths of prevagotomy VT was greater than responsiveness during mechanical ventilation with large volume breaths given immediately afterward. Thus the magnitude of VT of dogs after vagotomy may influence airway responsiveness, and the influence of anesthetic agents on airway responsiveness after vagotomy may in part be due to their effects on VT. Furthermore, bronchodilation accompanying large volume ventilation persists after vagotomy, suggesting that it is not exclusively mediated by changes in parasympathetic activity.     

Interaction of barbiturates with dihydropicrotoxinin binding sites related to the GABA receptor-ionophore system.

Barbiturate drugs of diverse chemical structure inhibited the binding of [³H] α-dihydropicrotoxinin to rat brain membranes. This biologically active analoque of picrotoxin labels membrane sites related to the convulsant action of these drugs in inhibiting GABA postsynaptic receptor-ionophore function at a site distinct from the GABA receptor. Depressant barbiturates such as pentobarbital inhibited dihydropicrotoxinin binding competitively at therapeutic concentrations (IC₅₀ = 50 μM) whereas the drug does not alter GABA receptors, uptake, or release at this concentration. Antiepileptics such as phenobarbital (IC₅₀=400 μM), were weaker inhibitors of binding. Convulsant barbiturates, however, such as dimethylbutylbarbiturate (IC₅₀=0.05 μM) and cyclohexylidene-ethyl barbiturate (IC₅₀=0.7 μM), were potent inhibitors. The displacement of radioactive dihydropicrotoxinin binding by the convulsant barbiturates had different slopes and Hill numnbers (0.4) compared to displacement by depressant barbiturates and picrotoxinin itself (Hill numbers = 1.0), indicating heterogeneity of binding sites or negative cooperativity. These potent intractions of barbiturates with dihydropicrotoxinin binding sites are consistent with neurophysiological evidence that depressant or convulsant action of barbiturates may involve modulation of CNS inhibitory synaptic transmission at the level of the postsynaptic GABA receptor-ionophores.     

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.