Action Of Barbiturates Research Articles

CLINICAL STUDIES OF INDUCTION AGENTS XVII: RELATIONSHIP BETWEEN DOSAGE AND SIDE EFFECTS OF INTRAVENOUS BARBITURATES

SUMMARY A retrospective analysis of the records of about 9,000 intravenous anaesthetics showed a striking relationship between dosage and induction complications. While the incidence of excitatory phenomena increased with dosage of thiobarbiturates, this effect was more marked with methylated barbiturates. The greater frequency of respiratory complications (cough, hiccough and laryngospasm) with high dosage was similar for both groups of drugs. Opiate premedications reduced the incidence of excitatory phenomena but had no effect on the respiratory complications. It is suggested that the “convulsive” element in the action of barbiturates predominates with higher dosage and the respiratory complications may be related to the action of the drugs on the parasympathetic nervous system.

The effect of cerebellar stimulation on neuronal activity in the motor cortex

Electrophysiological studies with extracellular microelectrodes demonstrate that, in anesthetized cats, high-frequency stimulation of the cerebellar nuclei could cause an increase or a decrease in spike activity recorded from neurons of the ipsilateral and contralateral motor cortex. Some of these neurons were also responsive to antidromic stimulation. This suggests that the cerebellum can exert and influence not only on the cortical interneurons but also on neurons directly concerned with motor function. In unanesthetized animals, responses of neurons in the ipsilateral and contralateral motor cortex could be evoked by a single stimuli applied to the cerebellar nuclei. No change was produced by ablation of the contralateral motor cortex. Thus, the possibility of transcallosal transmission was eliminated. The absence of any evoked response to single stimulus in animals under barbiturate anesthesia indicates that, aside from the well-known cerebellothalamocortical pathway, there are other cerebellocortical pathways which are resistant to barbiturate action and which probably involve the reticular formation of the midbrain and other basal structures of the cerebrum.

DIFFERENTIATION OF TWO TYPES OF PAIN BY ANESTHETICS.

The pain thresholds, to a cutaneous thermal stimulus and to a tibial pressure stimulus were measured before, during, and after the administration of nitrous oxide (25–30 per cent in oxygen), halothanc (0.5 per cent) and sodium thiopcntal (100–150 mg. in 10 minutes). The thermal pain and the tibial pressure pain thresholds rose with nitrous oxide and halothane. The thermal pain threshold rose with sodium thiopcntal but simultaneously the tibial pressure pain threshold fell. It is deduced that the sensations produced by these two stimuli are neurologically different and that the known differences between the actions of barbiturates and inhalational anesthetic drugs on presynaptic inhibition in the spinal cord can account for this differentiation.

Variations in Water Ingestion: The Response to Barbiturates

In this chapter, various findings with respect to barbiturate actions upon drinking are reviewed. It discusses a range of phenomena and classifies those phenomena in terms of variables and models that describe them. The first model is based upon the notion that hypnotic dosage or some function of it suffices to describe the barbiturate facilitation of drinking. A hypnotic dimension of barbiturate action is discussed in the chapter. An implication of simple additivity of effects of various barbiturates follows from the postulated dimension of action that appears to obtain among barbiturate antagonists but not among barbiturate synergists. The finding that various hypnotic barbiturates facilitated drinking to differing degrees necessitated the postulation of at least one dimension of action other than the hypnotic dimension. The chapter discusses the chronic effects and withdrawal after a chronic barbiturate course. When phenobarbital is given with ad lib , food and water intake rise for a very short time and fall rapidly to control levels. Pentobarbital has no effect under these conditions. The withdrawal of phenobarbital results in a marked hypodipsia and hypophagia. A few days after withdrawal, the animals return to a state comparable to controls in terms of food and water intake.

EFFECTS OF INSECTICIDE SYNERGISTS ON DURATION OF SLEEP INDUCED IN MICE BY BARBITURATES.

A NUMBER of otherwise pharmacologically inactive compounds are known to prolong sleep induced by barbiturates in mammals1. The most widely investigated of these is ‘SKF 525A’ (2-diethylaminoethyl 2,2-diphenylpentanoate), which prolongs the action of barbiturates and other drugs by inhibiting liver microsomal enzymes which degrade a wide variety of drugs1. When applied to insects, ‘SKF 525A’ synergizes pyrethroid insecticides and antagonizes the toxicity of the organophosphorus poison, malathion2. In these respects, ‘SKF 525A’ mimics the action of commonly used insecticide synergists such as piperonyl butoxide2. Although piperonyl butoxide and other chemically related synergists have been included in insecticide formulations for many years, their effects on drug activity in mammals have not been examined. In this communication the effects of two insecticide synergists on the hypnotic action of barbiturates are described.

Analysis of the depressant action of D,L- and D-cycloserine on the central nervous system

A study was made of the influence of D,L- and D-cycloserine on the depressive action of chloral hydrate, ethyl alcohol, and barbiturates (luminal, ethaminal, and thiopental). It was established that D,L-cycloserine potentiates the action of the mentioned substances. The potentiating effect of D-cycloserine was observed only in respect to ethaminal and thiopental and was much weaker.

TREATMENT FOR BARBITURATE INTOXICATION.

To the Editor:— A communication in the Sept 21, 1963, issue ofThe Journal( 185 :936) by Drs. Myschetzky and Lassen reported the efficacy of alkalinization and osmotic diuresis for barbiturate coma. Their selection of patients whose blood barbiturate level was greater than 10 mg/100 ml may have biased the study, since levels are often much lower in deep coma induced by barbiturates having short or intermediate action. Likewise, to attribute shortened duration of coma to augmented renal elimination of the drug is not necessarily warranted. Acidosis potentiates the anesthetizing action of barbiturates, and, since respiratory acidosis occurs regularly in barbiturate coma, perhaps alkalinization per se was responsible for improvement of the treated group. The authors stated: Only severe cases involving the relatively slowly eliminated barbiturates were accepted for treatment. This is misleading, since nearly one half of the treated patients ingested phenobarbital or barbital. Of all barbiturates, these are

Dose and time as variables in barbiturate action upon water ingestion.

The effect of phenobarbital, amobarbital, and secobarbital upon the volume of water ingested by thirsty rats was investigated shortly after injection, 1 day later, and 2 days later. The first effect was the characteristic rise in water intake at low dosages, and a fall at higher dosages. Twenty-four hours later there is a fall at the lower dosages, and a rise at the higher quantities. Two days after injection, there was some quite slight residual effect of both amobarbital and secobarbital but equilibration was nearly complete. Phenobarbital demonstrates some depressant activity at this time. When phenobarbital is administered and water ingestion held at a constant level for 2 days, the depressant effect is still obtained. These data indicate that the barbiturates have sequential effects upon water ingestion which are to some large degree independent of water balance per se.

Dose related effects of pentobarbital on somatosensory evoked responses and recovery cycles

The interrelationships among the amplitude of primary evoked somatosensory responses, the recovery cycle of these responses and dose level of pentobarbital sodium were investigated. Although pentobarbital reduced both the amplitude and the degree of recovery of evoked potentials, only the recovery changes during the relative unresponsive period provided a dose sensitive indicator. Amplitude was affected only at maximum dose levels. These results were discussed in relation to previous work on the effects of state of alertness on the recovery cycle and to the formulation of King et al. (1957) with regard to the mechanism of action of barbiturates. It was concluded that state of alertness and barbiturates probably affect the recovery cycle through mechanisms in the brain stem reticular formation that are at least partially independent. Low doses of barbiturates probably affect reticular mechanisms controlling recovery and higher doses probably exert an additional, depressant action on the thalamic relay nuclei.

Ritalin (methylphenidate): clinical experiences.

In our experience, Ritalin is effective m antagonizing the actions of barbiturates. The action does not appear to be a specific antagonism but rather an independent central nervous system stimulation which raises the level of alertness or wakefulness. In moderate doses it has little effect on the blood pressure, pulse, and respirations. In larger doses, it would appear to increase the blood pressure without affecting the pulse and respirations. In our one case of severe depression from barbiturate poisoning, it rapidly returned all three to normal.

The cytocidal action of barbiturates on lymphocytes in vitro

Rat lymph nodes were maintained in vitro in a synthetic medium by an organ culture technique. The toxic effect of barbiturates was studied quantitatively by counting the number of dead lymphocytes after exposure to various concentrations for various times. Seconal was found to be the most toxic, followed by Nembutal, Amytal and Pentothal, in that order. Barbitone itself was non-toxic under the same conditions. Evidence that barbiturates produce a specific biochemical lesion (in other tissues) is examined and some proposed antagonists, namely succinate, ascorbic acid and megimide were tested. Apart from a small effect of succinate, none of these protected lymphocytes at all. It was also found that, compared with barbiturates, colchicine and cortisone were more toxic, cyanide was about equally toxic, while ethanol, acetone and urelhanc were relatively non-toxic.

Studies on the nature of the joint action of ethanol and barbiturates

The 24-hour LD 50's of 30% and 50% ethanol and of secobarbitone sodium and phenobarbitone sodium, all administered intraperitoneally, and of 30% ethanol administered intravenously have been established in mice. The toxicity of a given amount of ethanol, administered intraperitoneally to mice, appears to be proportional to the concentration in which it is administered. Secobarbitone sodium and phenobarbitone sodium, when administered to mice in combination with ethanol, exhibit a negatively correlated independent additive joint action. Results of intravenous infusion of ethanol and pentobarbitone sodium, individually and in combination in the rabbit, confirm the conclusion that ethanol interacts with barbiturates in an independent additive fashion.

Modified method for measuring potentiation of barbiturate anesthesia and its relationship to hypothermia.

SummaryA modified test for measurement of the property of a phenothiazine derivative to potentiate the action of barbiturates has been described. Using this technic, it has been shown that although there is some correlation between degree of hypothermia produced and potency of such a derivative to potentiate barbiturate sedation, these pharmacologic properties are primarily independent of each other.

The action of barbiturates on the intestine.

The action of barbiturates on the intestine.

Pharmacology of (+)-, (+)-and (-)-2:2-diphenyl-3-methyl-4-morpholino-butyrylpyrrolidine.

Abstract (±)-2:2-Diphenyl-3-methyl-4-morpholino-butyrylpyrrolidine (R610) is a more active analgesic agent in mice, rats and guinea pigs than morphine. The analgesic activity is due to the (+)-isomer (R875). The (–)-isomer (R898) is nearly inactive. R610 lowers the body temperature to below control levels in immobilised rats, inhibits the respiration in unnarcotised rats, lowers the blood pressure in unnarcotised rats with experimental renal hypertension, and causes mydriasis in mice. It also augments the action of barbiturates in mice. In all these respects the (+)-isomer is the active compound of the racemic mixture. The (–)-isomer is almost as toxic as the (+)-isomer, which has a broader therapeutic margin than the (±)-form. The dosage-toxicity relation of highly active analgesic agents in mice and rats is irregular especially in the lower dosage range.

Further aspects of bemegride activity and its relation to barbiturate action.

Australian Journal of Experimental Biology and Medical ScienceVolume 34, Issue 6 p. 471-478 Original Article FURTHER ASPECTS OF BEMEGRIDE ACTIVITY AND ITS RELATION TO BARBITURATE ACTION A Shulman, A Shulman Department of Physiology, University of Melbourne This work has been supported by grants from the Australian National Health and Medical Research Council and from Nicholas Pty. Ltd. (Aust.).Search for more papers by this author A Shulman, A Shulman Department of Physiology, University of Melbourne This work has been supported by grants from the Australian National Health and Medical Research Council and from Nicholas Pty. Ltd. (Aust.).Search for more papers by this author First published: 01 December 1956 https://doi.org/10.1038/icb.1956.57Citations: 6 AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume34, Issue6December 1956Pages 471-478 Journal of the Australian and New Zealand Society for Immunology RelatedInformation

Management of acutely disturbed patients with promazine (sparine).

• Promazine was administered either orally or parenterally to 407 acutely disturbed patients. The series consisted of 103 psychotic patients, 42 addicts experiencing withdrawal symptoms, and 262 alcoholics. The last group included 110 patients with full-blown delirium tremens, 55 with acute inebriation, and 97 with acute tremulousness and/or hallucinosis. The initial dose of promazine, ranging from 50 to 400 mg., was effective in inducing sleep in these disturbed subjects. A maintenance dose every four to six hours in most instances kept these patients in a quiescent, detached state, from which they could be easily aroused to care for their personal needs. In the agitated psychotic patients the induction of sleep was frequently associated with a dramatic return toward normal of both blood pressure and heart rate. Orthostatic hypotensive phenomena observed most frequently in the alcoholic group were not serious. Neither acute vascular collapse nor pain from intramuscular injection has been noted. Promazine appeared to potentiate the action of barbiturates and to have an antiemetic effect. During the relatively short period of treatment in these acutely disturbed patients, none of the complications reported after the use of other phenothiazine derivatives were noted.

Some factors influencing distribution, metabolism and action of barbiturates; a review.

Some factors influencing distribution, metabolism and action of barbiturates; a review.

Experiments with animals on the combined action of procaine and barbiturates

Procaine prolonged the sleep of guinea-pigs induced by pentobarbital. Procaine could re-induce sleep in guinea-pigs and rabbits after the apparent effects of pentobarbital or thiopental respectively had ceased. This is evidence of an hypnotic effect of procaine rather than of an influence on the elimination of the barbiturate. The hypnotic and the convulsive effects seem to represent two independent actions of procaine. The effect of procaine on the toxicity of pentobarbital was nearly additive. The effect of pentobarbital on the toxicity of prpcaine was antagonistic. The distribution of standard errors of the sleeping times allowed the conclusion that the duration of the sleep could be better predicted if induced by the combinatin of pentobarbital and procaine than by pentobarbital alone. However, we appeared to lose on the margin of safety with this combination of drugs.

Changes in symbolic expression with amytal sodium.

1. Attitudes toward and recognition of illness and hospitalization were studied before and during the intravenous administration of amobarbital sodium. Changes in language patterns and nonverbal aspects of behavior were compared in 50 patients with pre-existing brain disease and a like number of normal subjects with comparable disabilities. 2. Prior to receiving the drug, all patients expressed awareness of illness, were completely oriented for place, and identified the examiners correctly. With the drug, explicit denial of illness, disorientation for place, and gross misidentification of the examiners occurred only in some of the patients with brain damage. In the normal group, subjects talked of illness in terms of a third person, used more "concrete" symbols, selectively misinterpreted questions about illness and misnamed the examiners in "paraphasic" fashion. 3. Amobarbital sodium did not necessarily make patients more communicative. Thirty patients in both groups showed no changes in verbal or nonverbal behavior. Some talked more, others less. 4. Euphoria was noted in II patients in the normal group and in 17 with brain disease. The euphoria frequently alternated with paranoid and depressed attitudes. It was not related to the dosage of the drug and in some instances came on after the interview was terminated. Ludicrous aspects of behavior were prominent. 5. The euphoria, drowsiness, dysarthria, and dystaxia produced, unlike the nystagmus, cannot be explained in terms of any particular neurophysiologic mechanism of action of barbiturates but must be considered in symbolic as well as physiological concepts. 6. Amobarbital sodium, given under the conditions described, appeared to provide a milieu of brain function in which not new motivations but new symbolic forms for their expression could be evolved and maintained. These are best interpreted not in terms of "release of repressed material" but as an adaptive, more effective defense in a situation of greater stress. 7. The productions of patients under the influence of amobarbital sodium should be interpreted not only in a factual referential context but as a symbolic representation of wishes and feelings expressed in personal, spatial, and temporal terms. 8. The observed behavior could not be explained in physiological or psychophysiological terms as "cortical depression" or "release of inhibition." It is suggested that much of the behavior ascribed to such mechanisms may be largely manifestations of a particular observer-subject relationship.