Effect of intermittent hypobaric hypoxia on efficacy & clearance of drugs.

BACKGROUND & OBJECTIVES: People travelling to high altitude for occupational, recreational or religious purposes are mostly healthy and fit but sometimes they use drugs for common ailments like influenza, acute mountain sickness or chronic disease like diabetes. Limitation of oxygen at high altitude may compromise metabolism of drugs. Hence, we undertook this study to assess the effect of hypobaric hypoxia on some commonly used drugs in rats and rabbits. METHODS: Effect of intermittent hypobaric hypoxia on phenotypic expression of anesthetic drugs pentabarbitone, thiopentone and zoxazolamine (sleeping time) was assessed in rats exposed to 282.4 mm Hg equivalent to 25000 feet in a decompression chamber. Plasma clearance of some commonly used drugs was investigated in rabbits exposed to 429 mm Hg equivalent to 15000 feet. Pharmacokinetic parameters were computed by plotting drug concentration versus time curve on semi log scale. RESULTS: A significant delay in regaining rightening reflex was observed in rats exposed to intermittent hypobaric hypoxia in response to zoxazolamine, pentobarbitone and thiopentone sodium. Pharmacokinetics of acetyl salicylic acid, gentamicin, phenobarbitone and acetazolamide showed increase in plasma half life (t 1/2), decrease in elimination rate constant (k el) and hence prolonged residence of these drugs in hypoxic animals. INTERPRETATION & CONCLUSIONS: This experimental study showed that hypoxia altered therapeutic effectiveness and clearance of several drugs, in rats and rabbits exposed to intermittent hypobaric hypoxia. s0 uch studies need to be done in human volunteers to see the effect of hypoxia on pharmacokinetics of some common drugs.

Thiopental inhibits function of different inward rectifying potassium channel isoforms by a similar mechanism.

Thiopental is a well-known intravenous barbiturate anesthetic with important cardiac side effects. The actions of thiopental on the transmembrane ionic currents that determine the resting potential and action potential duration in cardiomyocytes have been studied widely. We aimed at elucidating the characteristics and mechanism of inhibition by thiopental on members of the subfamily of inward rectifying Kir2.x (Kir2.1, 2.2 and 2.3), Kir1.1 and Kir6.2/SUR2A channels. These inward rectifier potassium channels were transfected in HEK-293 cells and macroscopic currents were recorded in the whole-cell and inside-out configurations of the patch-clamp technique. Thiopental inhibited Kir2.1, Kir2.2, Kir2.3, Kir1.1 and Kir6.2/SUR2A currents with similar potency; in whole-cell experiments 30 microM thiopental decreased Kir2.1, Kir2.2, Kir2.3 and Kir1.1 currents to 55+/-6, 39+/-8, 42+/-5 and 49+/-5% at -120 mV, respectively. Point mutations on Kir2.3 (I213L) or Kir2.1 (L222I) did not modify the potency of block. Thiopental inhibited all Kir channels in a concentration-dependent and voltage-independent manner. Also, the time course of thiopental inhibition was slow (T(1/2) approximately 4 min) and independent of external or internal drug application. However, in the presence of PIP(2), inhibition by thiopental on Kir2.1 was significantly decreased. Thiopental at clinically relevant concentrations significantly inhibited all Kir channels evaluated in this work. The reduction of thiopental effects during PIP(2) treatment suggests that thiopental inhibition on Kir2.1 channels is related to channel-PIP(2) interaction.

Propofol sedation is reduced by delta9-tetrahydrocannabinol in mice.

BACKGROUND: Delta9-tetrahydrocannabinol (Delta9-THC) induces analgesic effects and alterations of alertness. It has been reported that propofol increases endocannabinoid levels in the brain, but the effects of Delta9-THC on propofol sedation remain unclear. Our aim was to characterize the interaction between Delta9-THC and propofol in terms of sedation and analgesia. METHODS: Sedation was monitored by a rota-rod and analgesia by tail-flick latencies. Twenty mice received intraperitoneal injections of 50 mg/kg Delta9-THC with 50, 75 and 100 mg/kg propofol after baseline values were established for each drug. Control experiments were performed with Delta9-THC and thiopental or Intralipid. RESULTS: Injection of 50 mg/kg propofol caused a rapid onset of sedation with a minimum of 24 s on the rota-rod. Fifty mg/kg Delta9-THC alone had no sedative effects. Administration of Delta9-THC significantly reduced the sedative effect of propofol to at least 60 s on the rota-rod (P < 0.001). After increasing the propofol dose to 100 mg/kg in the presence of Delta9-THC, sedation was re-established with 27 s on the rota-rod. Thiopental sedation was significantly reduced (P < 0.01) in the presence of Delta9-THC. CONCLUSION: The results indicate a dose-dependent antagonistic interaction between Delta9-THC and propofol, and also between Delta9-THC and thiopental.

Effect of thiopental, propofol, and etomidate on vincristine toxicity in PC12 cells.

Neurotoxicity is the dose-limiting side-effect of vincristine in cancer therapy. Using the nerve growth factor (NGF)-dependent neurite outgrowth and cell proliferation of the PC12 pheochromocytoma cell line as an in vitro assay, the protective effect of different intravenous anesthetics was assessed. Vincristine (1 nmol/L) significantly decreased the percentage of neurite-forming cells from 68% +/- 9% to 27% +/- 7% within a 3-day incubation period. The longer neurites (> 2 x cell body) in particular proved to be extremely sensitive to vincristine (from 17% +/- 4% to 0% of total neurite-expressing cells). Flow cytometry results revealed an S-phase percentage of 15.85% +/- 3.25% after NGF induction, with vincristine reducing this percentage to 0.68% +/- 0.38%. Reversal of the inhibitory effect of vincristine was noted in the cells treated with thiopental or propofol but not etomidate. Bicuculline partially antagonized the protective effect of thiopental and propofol in both studies. We conclude that thiopental and propofol, but not etomidate, have a protective effect in vincristine-induced neurotoxicity. The protective effect produced by thiopental and propofol is probably secondary to activation of GABAA receptors.

The cardiovascular and respiratory effects of medetomidine and thiopentone anaesthesia in dogs breathing at an altitude of 1486 m.

The purpose of this study was to evaluate the cardio-respiratory effects of the combination of medetomidine and thiopentone followed by reversal with atipamezole as a combination for anaesthesia in 10 healthy German Shepherd dogs breathing spontaneously in a room at an altitude of 1486 m above sea level with an ambient air pressure of 651 mmHg. After the placement of intravenous and intra-arterial catheters, baseline samples were collected. Medetomidine (0.010 mg/kg) was administered intravenously and blood pressure and heart rate were recorded every minute for 5 minutes. Thiopentone was then slowly administered until intubation conditions were ideal. An endotracheal tube was placed and the dogs breathed room air spontaneously. Blood pressure, pulse oximetry, respiratory and heart rate, capnography, blood gas analysis and arterial lactate were performed or recorded every 10 minutes for the duration of the trial. Thiopentone was administered to maintain anaesthesia. After 60 minutes, atipamezole (0.025 mg/kg) was given intramuscularly. Data were recorded for the next 30 minutes. A dose of 8.7 mg/kg of thiopentone was required to anaesthetise the dogs after the administration of 0.010 mg/kg of medetomidine. Heart rate decreased from 96.7 at baseline to 38.5 5 minutes after the administration of medetomidine (P < 0.05). Heart rate then increased with the administration of thiopentone to 103.2 (P < 0.05). Blood pressure increased from 169.4/86.2 mmHg to 253.2/143.0 mmHg 5 minutes after the administration of medetomidine (P < 0.05). Blood pressure then slowly returned towards normal. Heart rate and blood pressure returned to baseline values after the administration of atipamezole. Arterial oxygen tension decreased from baseline levels (84.1 mmHg) to 57.8 mmHg after the administration of medetomidine and thiopentone (P < 0.05). This was accompanied by arterial desaturation from 94.7 to 79.7% (P < 0.05). A decrease in respiratory rate from 71.8 bpm to 12.2 bpm was seen during the same period. Respiratory rates slowly increased over the next hour to 27.0 bpm and a further increases 51.4 bpm after the administration of atipamezole was seen (P < 0.05). This was maintained until the end of the observation period. Arterial oxygen tension slowly returned towards normal over the observation period. No significant changes in blood lactate were seen. No correlation was found between arterial saturation as determined by blood gas analysis and pulse oximetry. Recovery after the administration of atipamezole was rapid (5.9 minutes). In healthy dogs, anaesthesia can be maintained with a combination of medetomidine and thiopentone, significant anaesthetic sparing effects have been noted and recovery from anaesthesia is not unduly delayed. Hypoxaemia may be problematic. Appropriate monitoring should be done and oxygen supplementation and ventilatory support should be available. A poor correlation between SpO2 and SaO2 and ETCO2 and PaCO2 was found.

Effects of thiopental on airway calibre in dogs: direct visualization method using a superfine fibreoptic bronchoscope.

Induction of anaesthesia with thiopental sometimes causes bronchospasm. Although the mechanism by which thiopental induces bronchospasm may involve cholinergic stimulation, direct spastic effect and histamine release, the spastic effects of thiopental have not been comprehensively defined. In this study, we have assessed the effect of thiopental on in vivo airway smooth muscle tone using direct visualization method with a superfine fibreoptic bronchoscope as previously reported. Twenty-one mongrel dogs were anaesthetized with pentobarbital (30 mg kg-1) and paralysed with pancuronium (200 micrograms kg-1 h-1). The trachea was intubated with a tube that had a second lumen for insertion of the bronchoscope (od: 2.2 mm) to continuously measure bronchial cross-sectional area. The tip of the bronchoscope was placed between the second and third bronchial bifurcation of the right lung. The dogs were allocated to three groups of seven: group T, A+T, H+T. In group T, thiopental 0 (saline), 0.1, 1.0 and 10 mg kg-1 was given i.v. In group A+T, saline i.v., 5 min later atropine 0.1 mg kg-1 i.v., and 5 min later thiopental 10 mg kg-1 was administered. In group H+T, bronchoconstriction was produced with histamine 10 micrograms kg-1 i.v. followed by infusion at 500 micrograms kg-1 h-1. Thirty minutes later, thiopental 0, 1.0 and 10 mg kg-1 were given. Arterial blood sampling was performed for measurement of plasma catecholamines and histamine. In group T, thiopental significantly reduced bronchial cross-sectional area (maximally by 28.7 (5.6% at 0.5 min after thiopental 10 mg kg-1), which returned to the baseline in 3 min, while any changes in plasma concentrations of catecholamines and histamine were not observed except norepinephrine level at 1 min following thiopental 10 mg kg-1 i.v. Atropine pretreatment completely prevented thiopental-induced bronchospasm in group A+T. In group H+T, thiopental 10 mg kg-1 transiently but significantly decreases bronchial cross-sectional area. Therefore, the present study indicates that the mechanism of thiopental bronchospasm may result from cholinergic nerve stimulation.

Nitrous oxide produces a non-linear reduction in thiopentone requirements.

We studied 88 healthy, ASA I patients (aged 20-45 yr), to determine if nitrous oxide affects thiopentone requirements for achieving 50% probability of no movement in response to verbal commands (CP,50). Patients were allocated randomly to one of four nitrous oxide concentration groups (0%, 20%, 40% and 60%). Patients in each group were also allocated randomly to receive predetermined target plasma concentrations of thiopentone. Computer-controlled continuous infusion was used to maintain the target plasma thiopentone concentration, and this concentration was held constant for 6 min to ensure equilibration. The CP,50, value of thiopentone in the absence of nitrous oxide was 14.8 micrograms ml-1. The reduction in CP,50 by nitrous oxide was non-linear, and the interaction coefficient between nitrous oxide and thiopentone was significantly smaller than zero (P = 0.0274), indicating that nitrous oxide antagonized the ability of thiopentone to prevent response to verbal commands.

The reversal effect of low dose aminophylline on thiopental-induced sedation.

Fifty-two ASA (American Society of Anesthesiologists) class I-II female patients, from 22 to 66 years of age, undergoing D & C (dilatation and curettage) procedure, were randomly divided into 2 groups in a double-blind and placebo-controlled design to investigate whether aminophylline could reverse the sedative effect of thiopental. Patients of both groups were anesthetized with fentanyl (2 micrograms/kg, i.v.) and thiopental (4 mg/kg, i.v. and 1 mg/kg, i.v. repeated if necessary). Postoperatively, they were intravenously given aminophylline (2 mg/kg) or normal saline in an equal volume solution over 5 minutes. The results showed that patients in the aminophylline group were more sedated (p < 0.05) than in the saline group 5 minutes after reversal, but were less sedated (p < 0.05) at minute 20. No significant differences between groups were found at other times. The total time spent in the postanesthetic unit was shorter in the aminophylline group (92 +/- 27 min.) than in the normal saline group (109 +/- 30 min.) (p < 0.05). The serum theophylline levels in some cases in the aminophylline group ranged between 3.2 and 4.9 micrograms/ml (4.3 +/- 0.7 micrograms/ml, n = 10). No apparent side effects, including tachyarrhythmias, were noted. We conclude that low dose aminophylline (2 mg/kg, i.v.) can partially reverse thiopental-induced sedation with safety in the early phase of recovery and it can reduce the total time spent in the postanesthetic unit.

Flumazenil reduces the duration of thiopentone but not of propofol anaesthesia in humans.

The effect of flumazenil (F) on the duration of anaesthesia produced by a single dose of thiopentone (T) and propofol (P) was investigated in a placebo-controlled double-blind trial. Eighty-four patients anaesthetized with N2O in O2 and either thiopentone 7 mg.kg-1 or propofol 3 mg.kg-1 for minor gynaecological procedures were studied. Patients were randomly allocated to pretreatment with either 0.5 mg of flumazenil (F) or 5 ml of normal saline (NS) in one of the following groups: T/NS, T/F, P/NS, or P/F. Anaesthetic requirements were assessed by recording the time between the injection of anaesthetic and the first movement observed during the procedure. The time elapsed from the administration of thiopentone to the first movement was 6.5 +/- 1.6 min for the T/NS group and 5.3 +/- 2.4 min for the T/F group (P < 0.05). The first movement after propofol administration was observed at 7.0 +/- 2.2 min in the P/NS group and at 7.1 +/- 4.5 min in the P/F group (NS). These data suggest that pretreatment with 0.5 mg of flumazenil iv reduces the duration of thiopentone but not of propofol anaesthesia.

[Experimental substantiation of the method of pharmaco-metabolic brain protection against hypoxia in severe craniocerebral injury]. / Eksperimental'noe obosnovanie sposoba farmakometabolicheskoi zashchity mozga ot gipoksii pri tiazheloi cherepno-mozgovoi travme.

The experiment has shown that a complex of functionally related vitamins including thiamine, lipoate, D-pantothenate, nicotinate and riboflavine in "pyruvate-dehydrogenase" ratios decreases inhibition of the activity of alpha-keto acid dehydrogenases in the brain and liver with thiopental anesthesia, intensifies arrival of [35S]-lipoate to the brain and decreases acute toxicity of sodium thiopental (TnNa). The same complex (where thiamine, pantothenate and riboflavine are substituted by the corresponding coenzyme forms) complemented by the components stimulating the function of GABA-bypath of the brain as administered to rats with serious craniocerebral injury on the background of prolonged anaesthesia effect improves recovery of the brain functions, that is followed by normalization of ketoglutarate-dehydrogenase activity, maintenance of GABA-bypath function and by a decrease of GABA and glutamate content in the brain. The results obtained substantiate the advisability to use vitamin-coenzyme-metabolic complex in the acute period of traumatic brain disease aimed to increase efficiency of the antihypoxic TnNa effect and to correct its undesirable effects.

[Does flumazenil antagonize the anesthetic effect of ketamine, etomidate or thiopental?].

The effect of flumazenil, a benzodiazepine antagonist, was assessed in a random, double-blind clinical study in which each of the four groups of surgical outpatients comprising 20 in each was given either ketamine 100 mg (K), etomidate 20 mg (E), thiopental 300 mg (T) or flunitrazepam 4 mg (F) for induction of anesthesia. On emergence, patients in each group were randomly given 2cc of either 2 coded solutions, one of which contained 0.2 mg flumazenil and the other of which was normal saline. Following injection of coded solution, all patients were assessed at 0, 5, 15, 30, 60 and 120 min for wakefulness. All 10 patients of group F who received flumazenil were alert and able to recall at 5 min, whereas in group T this was noted from 15 to 30 min. Patients of group E and K responded alike in a manner as of those who received normal saline placebo with onset of wakefulness at 30 and 60 min respectively. These results confirm that flumazenil antagonizes flunitrazepam (within 5 min) and also indicate that the antagonizing effect occurs 30 min following injection for thiopental, suggestive of some cross-reactivity between these two drugs.

Nitrous oxide reduces thiopental-induced prolongation of survival in hypoxic and anoxic mice.

Arnfred's mouse model was used to test the effect of thiopental during hypoxia (5% O2) and anoxia, with and without simultaneous administration of nitrous oxide. As found by Arnfred and others, thiopental without N2O more than doubled survival time during hypoxia (from 5.2 +/- 0.6 to 13.9 +/- 2.6 min). This effect was completely offset by simultaneous use of N2O (from 13.9 +/- 2.6 to 4.8 +/- 0.7 min). Thiopental without N2O also increased survival time during complete anoxia (from 26 +/- 1 to 59 +/- 1 sec). This effect was diminished by 58% when N2O was added (from 59 +/- 1 to 40 +/- 1 sec). We conclude that nitrous oxide diminishes the effect of barbiturates upon survival time in hypoxic and anoxic mice.

[Effect of clofelin on blood coagulability]. / Vliianie klofelina na svertyvaemost' krovi.

In experiments on rabbits single intravenous injections of clopheline (0.002 mg/kg) and droperidol (1 mg/kg) reduced coagulatory properties of the blood. Preliminary administration of the drugs excluded the development of sodium thiopental hypercoagulatory effect.

Aminophylline shortens thiopental sleep-time and enhances noradrenergic neurotransmission in rats.

We investigated the effect of aminophylline on thiopental sleep-times and monoamine neurotransmitter turnover rates in discrete brain areas. Aminophylline-treated rats had shorter thiopental sleep-times than saline-treated controls. Noradrenergic neurotransmission was greater following aminophylline treatment in thiopental-anesthetized rats in all brain areas while turnover in other monoaminergic pathways was unchanged. These data suggest that acute aminophylline treatment increases central noradrenergic neurotransmission which pharmacodynamically diminishes the hypnotic response to thiopental.

Reversal of sedation and respiratory depression after anaesthesia by the combined use of physostigmine and naloxone in neurosurgical patients.

A clinical trial of the combination of naloxone in a low dose (1-1.5 micrograms X kg-1 body weight) with physostigmine (0.5-1.0 mg i.v.) was made to elucidate whether this combination could reverse postanaesthetic overdosing in neurosurgical patients without increasing postoperative pain. The investigation was made following previous findings that physostigmine has analgesic properties in addition to its systemic antisedative and anticholinergic effects as well as a stimulatory effect on morphine-depressed ventilation. Altogether 198 neurosurgical patients were investigated. The results showed that postanaesthetic over-sedation can be safely treated by a combination of naloxone and physostigmine in the dosages named above, resulting in the rapid reversal of sedation, where opiates, neuroleptics and benzodiazepines have been used. In contrast, this combination has very little effect on sedation following the administration of agents such as halothane and isoflurane. In the great majority of patients (95%), the treatment resulted in excellent analgesia during the first postoperative hour. The incidence of nausea and vomiting was increased somewhat by this treatment, but these side-effects could be minimized by decreasing the rate of drug administration. Physostigmine is contra-indicated in patients having symptoms and signs similar to those of Parkinson's disease, and the dose of physostigmine should also be reduced to 0.5 mg i.v. in all patients over the age of 65.

Blocking effect of diltiazem on thiopentone-induced vasoconstriction in isolated canine internal carotid arteries.

Stainless-steel cannulas were inserted into isolated internal carotid arteries of the dog to observe vasoconstrictor responses to thiopentone. Thiopentone at a relatively large dose (100-3,000 micrograms) induced vasoconstrictor responses in a dose-dependent manner. A dose of 1 mg thiopentone usually produced a definite increase in perfusion pressure of greater than 50 mm Hg. These effects were not influenced by treatment with phentolamine in doses that significantly suppressed noradrenaline-induced vasoconstrictor responses. Diltiazem inhibited the constriction in response to thiopentone as well as that to potassium chloride in a noncompetitive antagonistic manner. It is suggested that the constriction induced by thiopentone may be due in part to activation of the calcium-inward channel in the wall of the internal carotid artery.

Reversal of thiopental-induced anesthesia by 4-aminopyridine, yohimbine, and doxapram in dogs pretreated with xylazine or acepromazine.

Groups of atropinized dogs (6 dogs/group) were sedated, using xylazine HCl (2.2 mg/kg of body weight, IM) or acepromazine maleate (0.25 mg/kg, IM), and were anesthetized to loss of pedal reflexes, using thiopental, IV. The dogs were given 1 of the following test antagonists, IV: saline solution (2 ml; control group), 4-aminopyridine (4-AP; 0.5 mg/kg), yohimbine (0.4 mg/kg), doxapram (5.0 mg/kg), or dual combinations of the latter 3 substances in the same doses as used for each agent. In xylazine-treated dogs, the mean dosage of thiopental required to induce anesthesia was 4.8 mg/kg. Control mean arousal time (MAT) and walk time (MWT) were 37.1 minutes and 53.8 minutes, respectively. These values were decreased to less than 2 minutes and less than 3 minutes, respectively, by yohimbine, 4-AP + yohimbine, and doxapram + yohimbine. With doxapram and with 4-AP + doxapram, MAT was less than 2 minutes and MWT was less than 8 minutes. In acepromazine-treated dogs, the mean dosage of thiopental required for anesthesia was 15.0 mg/kg. Control MAT and MWT were 20.7 minutes and 36.5 minutes, respectively. These values were decreased to 8.1 minutes and 18.1 minutes, respectively, by doxapram, and to 3.5 minutes and 19.9 minutes, respectively, by doxapram + yohimbine. Doxapram, 4-AP + doxapram, and doxapram + yohimbine caused periodic extensor rigidity before and during arousal. This rigidity was accompanied by opisthotonos in 2 dogs of the doxapram + yohimbine group and may have been mild tonic seizures.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of naloxone on the loss of consciousness induced by i.v. anaesthetic agents in man.

The effect of a specific opioid antagonist, naloxone, was studied in two comparable groups of patients who received i.v. the dose of an anaesthetic agent required to produce loss of consciousness in 50% of subjects. The first group received naloxone 0.006 mg kg-1 5 min before induction of anaesthesia; the second group received a similar volume of saline solution. Thiopentone, Althesin, diazepam, ketamine and propanidid were studied. The differences in percentage of unconscious patients between the naloxone-treated group and the control group were statistically significant for diazepam, ketamine and propanidid. Naloxone did not modify the induction of anaesthesia with thiopentone or Althesin.

Effect of high pressure on EEG burst suppression dose of thiopental in rats.

The anesthetic induction dose of thiopental in rats was studied at 1 ATA air, 1 ATA helium-oxygen (He-O2), 4 ATA air, and at 4 ATA air plus 67 ATA helium (71 ATA). The compression rate was 0.3 ATA/min, and 1 h was spent at pressure before the experiment started. Thiopental was infused at a rate of 7.5 mg X kg-1 X min-1. The depth of anesthesia was assessed by electroencephalographic (EEG) recording using burst suppression of 1 s as the biological end point. The mean induction dose at 1 ATA air was 53.1 mg/kg and at 71 ATA was 74.7 mg/kg, an increase of 41%. The induction doses at 1 ATA He-O2 and 4 ATA air were 46.4 mg/kg and 45.3 mg/kg, respectively.

Naloxone fails to antagonize thiopental anesthesia.

A study was undertaken to determine the effect in man of naloxone on the central nervous system depression produced by IV thiopental. Eight normal volunteers were given 5 mg/kg thiopental IV. On a separate occasion the same 8 volunteers were given 50 microgram/kg naloxone IV 5 minutes prior to 5 mg/kg thiopental. Naloxone had no significant effect on the rate of return of consciousness following administration of thiopental. Naloxone also had no significant effect on the responses of blood pressure, heart rate, or respiratory rate to thiopental.