General intravenous anesthetics - pharmacodynamics, pharmacokinetics and chiral properties.

In continuation of our published review on general inhalational anesthetics, the current article presents a survey of intravenous agents for general anaesthesia. From chemical point of view these compounds belong to structurally diverse categories, such as barbiturates - thiopental (Sodium pentothal®, Trapanal®, Pentothal®), methohexital (Brevital®), and hexobarbital (Evipan®, Hexenal®, Citopan®, Tobinal®); non-barbiturate derivatives - ketamine (Ketalar® Ketaset®), esketamine (Ketanest®), and etomidate (Amidate®, Hypnomidate®), phenolic derivatives - propofol (Diprivan®); steroid derivatives - mixture of alfadolone and alfaxalone (Althesin® in human and Saffan® in veterinary anesthesia); and derivatives of phenylacetic acid - propanidid (Epontol®, Sombrevin®). Most of these compounds are chiral, with the exception of propofol and propanidid. Apart from etomidate and esketamine, they are used in the form of their racemates. Besides their characteristics and mechanism of action, attention is centred also on their chiral properties.

The effect of ketamine and saffan on the beta-endorphin and ACTH response to hemorrhage in the minipig.

The endocrine response is an important component of the physiological response to blood loss. There is some variability in reported levels of certain hormones during hemorrhage such as the stress hormone adrenocorticotrophic hormone (ACTH). Therefore, the effect of two anesthetic agents, ketamine and saffan, on ACTH and beta-endorphin levels during hemorrhage was assessed in 12 minipigs. The animals were divided into two groups, group I saffan and group II ketamine (n=6). Pigs were subjected to a continuous fixed volume hemorrhage under one of the above anesthetics while spontaneously breathing. Blood pressure and heart rate responses were recorded together with beta-endorphin and ACTH levels both before and at 10, 20, 30, 40 min after the onset of bleeding. ACTH levels were higher in the ketamine-anesthetized pigs and rose significantly faster with falling blood pressure than ACTH measured in pigs under saffan anesthesia. In contrast, the hemorrhage induced beta-endorphin increase was not significantly different between the two anesthetic groups. These results indicate that choice of anesthetic agent is important when investigating the hormone response to hemorrhage and may account for the variable hormone levels in the published literature to date.

The effects of general anaesthetics on glucose and phosphate transport across the membrane of the human erythrocyte.

A study has been carried out into the effects of clinically important general anaesthetics, althesin, thiopentone and propanidid, on the transport of glucose and phosphate across the membrane of the human erythrocyte. In general these three substances all inhibit both transport processes but with characteristic inhibition profiles and varying degrees of efficacy. Glucose transport was more sensitive to the hydrophobic steroids and phosphate transport to propanidid. Some hydrophobic agents, e.g., iodobenzene and its azide, were not inhibitory. Removal of cholesterol to some extent augmented the inhibitory effects of most of these compounds (not propanidid). It is argued that these effects are due to the penetration of the anaesthetics into the lipid bilayer and either subsequent disruption of the lipid annuli surrounding the integral membrane proteins and/or direct anaesthetic-protein interaction.

The effect of etomidate on adrenocortical function in dogs before and during hemorrhagic shock.

The effects of the hypnotic agent ethyl phenylethyl imidazole carboxylate (etomidate), on corticosteroidogenesis were studied in greyhound dogs during a 2-h period of anesthetic followed by a further 2 h of anesthetic combined with hemorrhage. Three groups of dogs were studied. The first, a control, received thiopentone and pentobartitone for induction and maintenance of anesthesia. A second control group received the chemically unrelated hypnotic preparation, althesin, after induction with thiopentone and pentobarbitone. In the first control group and the althesin-treated control group, changes in plasma ACTH and in plasma renin and angiotensin II concentrations were followed closely by changes in the levels of their respective dependent corticosteroids. A third experimental group received etomidate after induction of anesthesia with thiopentone and pentobarbitone. In these, in contrast, plasma levels of progesterone, 17 alpha-hydroxyprogesterone, corticosterone, cortisol, and aldosterone decreased during the experiment even failing to respond to massive rises in plasma ACTH concentration, renin, and angiotensin II levels after hemorrhage. However, the ability of 11-deoxycortisol and 11-deoxycorticosterone to respond was retained. These results suggest that etomidate inhibits corticosteroidogenesis directly, probably acting at more than one point in the biosynthetic pathway. It is suggested that it inhibits mitochondrial steroid hydroxylation (e.g. side chain cleavage, 11 beta-hydroxylation), but not 21-hydroxylation which occurs outside the mitochondrion.

A magnetic resonance spectroscopic imaging study of adult nonhuman primates exposed to early-life stressors.

BACKGROUND: Long-term behavioral, immunologic, and neurochemical alterations have been found in primates exposed to adverse early rearing. METHODS: Bonnet macaque (Macaca radiata) mother-infant dyads were exposed to uncertain requirements for food procurement (variable foraging demand, VFD) for a few months. Ten years later, these offspring and age- and gender-matched control subjects were studied using proton magnetic resonance spectroscopic imaging (MRSI). RESULTS: In anterior cingulate, VFD-reared subjects displayed significantly decreased N-acetylaspartate (NAA) resonance and significantly increased glutamate-glutamine-gamma-aminobutyric acid (Glx) resonance relative to the stable neurometabolite creatine (Cr). Across all subjects, NAA/Cr and Glx/Cr ratios in the anterior cingulate were negatively correlated (r = -.638, p =.014). In the medial temporal lobe, the ratio of choline-containing compounds to Cr was significantly increased in VFD subjects. CONCLUSIONS: These findings indicate that adverse early rearing in primates has an enduring impact on adult MRSI measures considered reflective of neuronal integrity and metabolism, membrane structure and glial function, and cerebral glutamate content, and that these alterations occur in the same brain regions implicated in trauma-related psychiatric disorders.

Antinociceptive properties of neurosteroids II. Experiments with Saffan and its components alphaxalone and alphadolone to reveal separation of anaesthetic and antinociceptive effects and the involvement of spinal cord GABA(A) receptors.

Studies have shown that the steroid anaesthetic alphaxalone positively modulates gamma-aminobutyric acid (GABA) receptors in vitro. It has also been reported that positive modulation of GABA(A) receptors in the rat spinal cord can produce antinociception in vivo. This present study looks at the interaction of an intraperitoneal injection (i.p.) of the steroid anaesthetic combination Saffan (alphaxalone 9 mg/ml, alphadolone acetate 3 mg/ml) with GABA(A) receptors in the spinal cord. Full recovery from anaesthesia induced by Saffan 2 ml/kg i.p., as assessed by the rotarod test, occurred after 28.78 +/- 0.86 min. Residual antinociceptive effects were assessed by application of electrical current at two skin sites (neck and tail) and also tail withdrawal from noxious heat. Residual antinociception was observed at both skin sites assessed by the electrical test but not when assessed by noxious heat. The antinociceptive effects in the tail but not the neck were suppressed by intrathecal administration of GABA(A) antagonists (bicuculline and SR-95531). In a separate group of experiments alphaxalone and alphadolone were given i.p. individually at the same doses that were given when formulated in Saffan. Alphaxalone produced sedative and anaesthetic effects with no antinociception. Alphadolone caused no sedation but it did cause antinociceptive effects equal in magnitude to those produced by Saffan. We conclude that Saffan produces antinociception in rats when given i.p. by an interaction with spinal GABA(A) receptors. Furthermore, this antinociception is due to the alphadolone content of the neurosteroid anaesthetic and not the alphaxalone.

A simple electrophoretic technique for the estimation of complement C3 conversion: specific application to the investigation of anaphylactoid response to I.V. agents.

A simple electrophoretic technique employing commercially available agarose films is described for the routine estimation of plasma complement C3 conversion. This technique has particular value in the investigation of anaphylactoid responses in patients following the administration of intravenous hypnotic drugs, plasma substitutes or radio-contrast media.

Non-anesthetic steroids ameliorate the high pressure neurological syndrome in rats.

The hypothesis that non-anaesthetic compounds, structurally related to specific anaesthetics, can protect against the high pressure neurological syndrome was tested. Infusion of two structural analogues of alphaxalone (3 alpha-hydroxy-5 alpha pregnane-11,20 dione) during pressurisation of rats with helium and oxygen gas mixtures (total pressure 80-100 ATA; inspired oxygen partial pressure 0.5 ATA) ameliorated the severe tremors associated with the high pressure neurological syndrome without any shift in tremor frequency (11-14 Hz). The steroid analogues which were selected (delta 16 and 3 beta-hydroxy-alphaxalone) have no known general anaesthetic effects and present an unexpected structural approach to the pharmacology of the syndrome. It may now be possible to investigate, treat or prevent the syndrome by the use of selective drugs without more generalised anaesthetic effects.

Actions of the anaesthetic Saffan on rat sympathetic preganglionic neurones in vitro.

1. Whole-cell patch-clamp recordings were used to investigate the effects of the anaesthetic Saffan on the electrophysiological properties of sympathetic preganglionic neurones (SPNs) in rat spinal cord slices. 2. Saffan (1-54 microM) abolished or reduced the frequency of spontaneous action potential firing and abolished spontaneous, sub-threshold membrane potential oscillations. Saffan caused dose-dependent decreases in input resistance and depending upon the initial resting membrane potential, either a depolarization, a hyperpolarization or no change in membrane potential. 3. Responses to Saffan were blocked by the GABAA receptor antagonists bicuculline (5-20 microM) and picrotoxin (20 microM), but not by the glycine receptor antagonist strychnine (20 microM) indicating that they were mediated by GABAA receptors. 4. Changes in the properties of SPN action potentials were also observed. In the presence of Saffan the amplitude and duration of the action potential after-hyperpolarization were reduced and larger depolarizations were required in order to evoke trains of action potentials. 5. To examine the effects of Saffan on electrotonic coupling between SPNs, experiments were performed with the Na+ channel blocker QX-314 in the intracellular solution and antidromic oscillations were evoked by ventral root stimulation. Saffan failed to abolish antidromic oscillations, but reduced their amplitude and duration. This indicates that the abolition of spontaneous membrane potential oscillations was not a direct effect on the coupling between SPNs, but was a result of the abolition of spontaneous activity by Saffan. 6. The responses to Saffan occurred within the plasma concentration range of Saffan during anaesthesia, suggesting that the electrophysiological properties of SPNs may be altered during anaesthesia with Saffan. This would be expected to lead to changes in sympathetic tone and in the integration of sympathetic output.

The effects of intravenous anaesthetics on the cardiovascular system of the rabbit.

1 A pithed rabbit preparation is described that allows selective stimulation of the vertebral outflows. 2 The responses to stimulation of sympathetic vasopressor fibres were blocked by hexamethonium and phentolamine but potentiated by cocaine, whereas the responses to stimulation of cardioaccelerator fibres were blocked by propranolol. 3 Ketamine, althesin and pentobarbitone enhanced the effects of noradrenaline and attenuated the effects of sympathetic nerve stimulation. Thiopentone enhanced the effects of both noradrenaline and sympathetic nerve stimulation. 4 In pithed rabbits a transient, dose-related cardiovascular depression was produced by each agent irrespective of whether vasomotor tone was present whereas in decerebrate rabbits the corresponding cardiovascular depression was longer lasting. 5 It is concluded that the cardiovascular depression produced by intravenous anaesthetics in intact rabbits is due to a combination of central and peripheral effects.

Evidence that central 5-HT2A and 5-HT2B/C receptors regulate 5-HT cell firing in the dorsal raphe nucleus of the anaesthetised rat.

1. Systemic administration of phenethylamine-derived, 5-hydroxytryptamine(2) (5-HT(2)) receptor agonists inhibits the firing of midbrain 5-HT neurones, but the 5-HT receptors involved are poorly defined, and the contribution of peripheral mechanisms is uncertain. This study addresses these issues using extracellular recordings of 5-HT neurones in the dorsal raphe nucleus of anaesthetised rats. 2. The 5-HT(2) receptor agonists DOI ((+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride) and DOB ((+/-)-2,5-dimethoxy-4-bromoamphetamine hydrobromide), caused a dose-related (10-100 micro g kg(-1) i.v.) inhibition of 5-HT neuronal activity, with the highest dose reducing firing rates by >80%. 3. Pretreatment with the 5-HT(2) receptor antagonist ritanserin (1 mg kg(-1) i.v.) completely blocked the action of DOI. The 5-HT(2A) receptor antagonist MDL 100,907 (0.2 mg kg(-1) i.v.) blocked the action of both DOI and DOB. In comparison, the 5-HT(2B/C) receptor antagonist SB 206553 (0.5 mg kg(-1) i.v.) caused a small, but statistically significant, shift to the right in the dose response to DOI and DOB. 4. Pretreatment with the peripherally acting 5-HT(2) receptor antagonist BW 501C67 (0.1 mg kg(-1) i.v.) had no effect on the DOI-induced inhibition of 5-HT cell firing, but completely blocked the DOI-induced rise in mean arterial blood pressure. 5. These data indicate that the inhibition of 5-HT cell firing induced by systemic administration of DOI and DOB is mediated predominantly by the 5-HT(2A) receptor-subtype, but that 5-HT(2B/C) receptors also play a minor role. Moreover, central and not peripheral mechanisms are involved. Given evidence that 5-HT(2) receptors are not located on 5-HT neurones, postsynaptic 5-HT feedback mechanisms are implicated.

Anaesthetic suppression of transmitter actions in neocortex.

1. The effects of general anaesthetics were investigated on neuronal sensitivities to transmitter substances, which were determined by iontophoretic applications of acetylcholine, glutamate, N-methyl-D-aspartate (NMDA) and gamma-aminobutyrate (GABA) during intracellular recording in in vitro slice preparations of neocortex (guinea-pig). 2. In most of the 65 neurones studied, perfusion of isoflurane (0.5-2.5 minimum alveolar concentration (MAC)) or Althesin (25-200 microM) and, in some cases, halothane (0.5-2 MAC), markedly reduced the depolarizing responses and associated membrane conductance changes evoked by dendritic applications of acetylcholine, glutamate, NMDA and GABA. 3. The order of depression was acetylcholine greater than glutamate or NMDA much greater than GABA. This selectivity could also be assessed from the EC50 for the isoflurane-induced depression of the just-maximal responses to acetylcholine, which was 0.9 MAC compared with an EC50 = 1.9 MAC for the suppression of glutamate responses. The selectivity was less pronounced in the case of the actions of Althesin, where the EC50s were 75 microM for the depression of acetylcholine responses and 90 microM for the depression of glutamate responses. 4. The hyperpolarizing responses observed when GABA was applied near the perikaryon in 7 neurones, were slightly reduced (approximately 15%) in 4, and unchanged in 3 neurones during anaesthetic application. 5. The pronounced depression of the responsiveness to the putative arousal transmitters and an observed blockade of acetylcholine-induced potentiation of glutamate actions suggest that anaesthetics produce unconsciousness, at least in part, by interfering with subsynaptic mechanisms of neocortical activation.

Effect of various anaesthetics on resting plasma concentrations of luteinizing hormone, follicle-stimulating hormone and prolactin in ovariectomized ewes.

Effects of various anaesthetics on plasma LH, FSH and prolactin levels were studied in ovariectomized ewes. In the first experimental series, conducted between June and November (late breeding season, early anoestrous season), the following treatments were given: saline (i.v.) (n = 7); single thiopentone injection (i.v.) (n = 4); induction of anaesthesia for 2 h with thiopentone (n = 5), ketamine/thiopentone mixture (n = 6), Alphathesin (n = 6) or induction with thiopentone and maintenance with halothane (n = 6). The major findings were: (1) halothane anaesthesia reduced mean plasma LH levels by preventing pulsatile secretion of LH; (2) Alphathesin had the least effect on tonic LH concentration; (3) a single thiopentone injection did not affect LH levels; (4) continuous thiopentone anaesthesia increased LH pulse amplitude; (5) plasma FSH concentration was not affected by any of the treatments; (6) ketamine/thiopentone-induced and Alphathesin-induced anaesthesia increased plasma prolactin levels. In a second experimental series four ovariectomized ewes were anaesthetized with thiopentone for 3 h in January. In contrast to the results obtained with thiopentone in August, treatment in January reduced plasma LH pulse amplitude and mean plasma LH levels. These latter results support the hypothesis that there may be seasonal variation in responses to barbiturate anaesthesia.

Constant light blocks diurnal but not pulsatile release of luteinizing hormone in the ovariectomized rat.

We have investigated the effects of constant light on the patterns of LH release in long-term ovariectomized rats. Some animals were implanted with a silicone elastomer capsule containing oestradiol-17 beta. Plasma samples in anaesthetized animals were taken from the external jugular vein and in conscious animals from an indwelling intra-atrial catheter. The pulsatile release of LH that occurred in animals not treated with oestrogen was unaffected by constant light or the steroid anaesthetic alphaxalone plus alphadolone acetate (Althesin), but was abolished by sodium pentobarbitone. However, the diurnal release of LH produced by increasing the concentrations of plasma oestradiol in conscious animals was blocked by constant light. Thus, these two rhythms of LH release are controlled by different neural pathways; the one concerned with diurnal LH release being suppressed by exposure to constant light.

The effect of delta 9-tetrahydrocannabinol, cannabidiol, and cannabinol on the anaesthesia induced by various anaesthetic agents in mice.

delta 9-Tetrahydrocannabinol (2.5-80.0 mg/kg) significantly prolonged the anaesthesia induced by ketamine, pentobarbitone, thiopentone, propanidid, and Alfathesin in a dose-dependent manner. Cannabinol and cannabidiol (both 5.0-80.0 mg/kg) were essentially inactive, except that cannabidiol prolonged pentobarbitone-induced anaesthesia. The interaction of delta 9-tetrahydrocannabinol with the anaesthetic agents was postulated to be due to a centrally mediated action, whereas the effect of cannabidiol on pentobarbitone-induced anaesthesia probably depended on a metabolic interaction. The interaction between the cannabinoids in influencing anaesthesia induced by the above agents was examined, and the interactions were found to be complex.

Continuous EEG and ICP monitoring as a guide to the administration of althesin sedation in severe head injury.

The effects of 142 intravenous boluses of althesin (0.05 ml/kg) on cerebral perfusion pressure (CPP) were studied in twelve head injured comatose patients. The data were divided into those where the mean pre-bolus intracranial pressure (ICP) was above or below 20 mmHg and then subdivided into those where the minimum pre-bolus voltage of the cerebral function monitor (CFM) was above or below 5 microV (representing marked reduction in cortical electrical activity). The pre-bolus ICP influenced the extent of the fall in ICP and thus the direction of the resulting change in CPP. A mean reduction in CPP was observed in both groups in which ICP was below 20 mmHg irrespective of the CFM voltage. In the subgroups with high ICP, CPP increased when CFM was not depressed and fell when CFM was below 5 microV. The effects of individual boluses varied within and between the subgroups and, occasionally, severe and unpredictable hypotension occurred. If althesin administration had been restricted to the high CFM and high ICP group, 90% of the episodes of reduced CPP would have been avoided. In fact, when cortical electrical activity is already severely depressed, further administration of hypnotic anaesthetic agents produces only small reductions in ICP and usually a fall in CPP. These findings suggest that the minimum voltage of the CFM trace is a clinically useful guide to the administration of intravenous anaesthetic agents and offers a relevant prediction of their effects on CPP.

Effects of administration of oxytocin in association with gonadotropin-releasing hormone on luteinizing hormone levels in rats in vivo.

Gonadotropin-releasing hormone (GnRH) and oxytocin both stimulate the secretion of luteinizing hormone (LH), although with different characteristics. Therefore, interaction between oxytocin and GnRH in the control of LH may be postulated. We developed models for investigating whether oxytocin can modulate GnRH action on LH in vivo. Pentobarbitone is known to pharmacologically isolate the pituitary from hypothalamic GnRH. We found that after pentobarbitone anesthesia of female rats at proestrus, oxytocin caused a synergistically enhanced LH response to administered GnRH (p < 0.04). In a second series of experiments, female proestrous rats were anesthetized with althesin. This anesthetic allows transport of endogenous GnRH from the hypothalamus to the pituitary. In control animals, which received no exogenous hormone, there was a surge in the mean LH concentration on the evening of proestrus, indicating the presence of endogenous GnRH activity. Thus, the novel model enables detection of interactions of administered hormones with endogenous GnRH. Administration of GnRH plus oxytocin in the afternoon of proestrus caused a reduction (p < 0.01) in the mean level of LH observed in the evening. The reduction was larger than if GnRH alone was administered. Following althesin anesthesia, rats sometimes had low LH levels on the afternoon of proestrus. There was a statistically significant difference between the number of rats that received oxytocin plus GnRH and had low LH levels and the number with low LH levels in the control group (p < 0.02). Neither of the hormones administered alone had a significant effect. Thus, it appears that oxytocin accentuated the effect of GnRH in reducing LH concentrations in althesin-anesthetized rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Local changes in cerebral 2-deoxyglucose uptake during alphaxalone anaesthesia with special reference to the habenulo-interpeduncular system.

The effects of the steroid anaesthetic Althesin (alphaxalone plus alphadolone acetate) on regional cerebral metabolism was studied in female rats. [14C]2-Deoxyglucose (2-DG) uptake was measured in 19 discrete anatomical areas by quantitative autoradiography. Under Althesin anaesthesia metabolic activity, relative to the corpus callosum ( rma ), was significantly (24-46%) increased in the locus coeruleus, medial (but not lateral) habenula (Hb) and interpeduncular nucleus (IPN). The Hb-IPN tract, not discernible in autoradiograms from conscious rats, became readily apparent in films from anaesthetized rats. However, the increased metabolic activity of this pathway was not associated with a significant change in the tissue concentrations of substance P in either the Hb or IPN. In sensorimotor and visual cortex, caudate nucleus, thalamic nuclei and the medial geniculate body rma was significantly (26-38%) depressed. Metabolic activity in the other 8 areas measured was unaffected by Althesin. Destruction of the stria medullaris input to the habenulae prevented the Althesin-induced increase in 2-DG uptake by the MHb and LHb.

Effects of anesthesia on efferent phrenic activity in neonatal swine.

The effects of two levels of Saffan anesthesia (standard recording level: 2-4 mg/kg/min, and 10X recording level) and a single level of pentobarbital (5 mg/kg) on the power spectral density of efferent phrenic discharge were investigated in piglets aged from less than 1 day to 50 days. The phrenic high frequency oscillation (HFO) was present in decerebrate, unanesthetized piglets and in piglets anesthetized with Saffan, albeit reduced at 10 times recording level, but was absent under pentobarbital. The results indicate that Saffan does not have a significantly depressant effect on the phrenic HFO in developing swine.