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.

Design, synthesis and evaluation of heterocyclic 2-phenylacetate derivatives as water-soluble rapid recovery hypnotics.

In this work, a series of novel heterocyclic 2-phenylacetate derivatives were designed and synthesized as water-soluble and rapid recovery hypnotic agents. After introducing heterocyclic ring to the amide group of propanidid, the obtained propanidid derivatives showed greatly improved hydrophilicity and good anesthetic activity. In three animal experiments (mice, rats, and rabbits), compounds 13-15 showed potent hypnotic potency (HD50 = 7.6, 6.5, 7.4 mg/kg in rabbits, respectively) and higher therapeutic indexes (TI = 17.3, 16.6, 15.2 in rabbits, respectively) than propanidid (TI = 14.7 in rabbits) or propofol (TI = 5.4 in rabbits). Moreover, the recovery time of compounds 13-15 (time to walk, 96.6, 79.6, 81.4 s in rabbits, respectively) were shorter than that of propanidid (124.5 s in rabbits) or propofol (425.3 s in rabbits). The experimental results suggested the potential of compounds 13-15 as water-soluble anesthetics with rapid recovery profile.

In vitro and in vivo GABAA Receptor Interaction of the Propanidid Metabolite 4-(2-[Diethylamino]-2-Oxoethoxy)-3-Methoxy-Benzeneacetic Acid.

BACKGROUND: Propanidid is a γ-aminobutyric acid type A (GABAA) receptor agonist general anesthetic and its primary metabolite is 4-(2-[diethylamino]-2-oxoethoxy)-3-methoxy-benzeneacetic acid (DOMBA). Despite having a high water solubility at physiologic pH that might predict low-affinity GABAA receptor interactions, DOMBA is reported to have no effect on GABAA receptor currents, possibly because the DOMBA concentrations studied were simply insufficient to modulate GABAA receptors. Our objectives were to measure the propanidid and DOMBA concentration responses on -GABAA receptors and to measure the behavioral responses of DOMBA in mice at concentrations that affect GABAA receptor currents in vitro. METHODS: GABAA receptors were expressed in oocytes using clones for the human GABAA α1, ß2 and γ2s subunits. The effects of DOMBA (0.2-10 mmol/L) and propanidid (0.001-1 mmol/L) on oocyte GABAA currents were studied using standard 2-electrode voltage clamp techniques. Based on in vitro results, 6 mice received -DOMBA 32 mg intraperitoneal and were observed for occurrence of neurologic effects and DOMBA plasma concentration was measured by liquid chromatography tandem mass spectrometry. RESULTS: DOMBA both directly activates GABAA receptors and antagonizes its GABA-mediated opening in a concentration-dependent manner at concentrations between 5-10 and 0.5-10 mmol/L respectively. In vivo, DOMBA produced rapid onset sedation at plasma concentrations that correlate with direct GABAA receptor activation. CONCLUSION: DOMBA modulation of GABAA receptors is associated with sedation in mice. Metabolites of propanidid analogues currently in development may similarly modulate GABAA, and impaired elimination of these metabolites could produce clinically relevant neurophysiologic effects.

Possible binding sites and interactions of propanidid and AZD3043 within the γ-aminobutyric acid type A receptor (GABAAR).

Propanidid is an intravenous anesthetic with transient action and rapid recovery features, but it is clinically unacceptable due to its side effects. AZD-3043, an analog of propanidid with the methoxy group substituted by the ethoxy group, has become the focus of recent development efforts. Although propanidid and AZD-3043 are known to act by potentiating the γ-aminobutyric acid type A receptors (GABAARs), their action sites and binding modes in the recognition of target proteins still remain unclear. In this study, molecular docking and ONIOM calculations were performed to explore the possible binding sites and binding modes of propanidid and AZD-3043 with the GABAAR. The predicted active region located in the transmembrane domain (TMD) of GABAAR was identified as the most favorable binding site for propanidid and AZD-3043, with the highest docking score (-39.69 and -39.44 kcal/mol, respectively) and the largest binding energy (-88.478 and -78.439 kcal/mol, respectively). The important role of amino acids Asp245, Asp424, Asp425, Arg428, Phe307, and Ser308 in determining the binding modes of propanidid or AZD-3043 with GABAAR was revealed. The detailed molecular interactions between propanidid and AZD-3043 and the GABAAR were revealed for the first time. This could improve our understanding of the action mechanism of general anesthetics and will be helpful for the design of more potential lead-like molecules.

Synthesis and evaluation of fluorine-substituted phenyl acetate derivatives as ultra-short recovery sedative/hypnotic agents.

BACKGROUND: Soft drugs are molecules that are purposefully designed to be rapidly metabolized (metabolically labile). In anesthesia, the soft drug is useful because it enables precise titration to effect and rapid recovery, which might allow swift and clear-headed recovery of consciousness and early home readiness. Propofol may cause delayed awakening after prolonged infusion. Propanidid and AZD3043 have a different metabolic pathway compared to propofol, resulting in a short-acting clinical profile. Fluorine imparts a variety of properties to certain medicines, including an enhanced absorption rate and improved drug transport across the blood-brain barrier. We hypothesized that the introduction of fluorine to the frame structure of propanidid and AZD3043 would further accelerate the swift and clear-headed recovery of consciousness. To test this hypothesis, we developed a series of fluorine-containing phenyl acetate derivatives. METHODOLOGY/PRINCIPAL FINDINGS: Fluorine-containing phenyl acetate derivatives were synthesized, and their hypnotic potencies and durations of LORR following bolus or infusion administration were determined in mice, rats and rabbits. The metabolic half-lives in the blood of various species were determined chromatographically. In vitro radioligand binding and γ-aminobutyric acidA (GABAA) receptor electrophysiology studies were performed. Among the 12 synthesized fluorine-containing phenyl acetate derivatives, compound 5j induced comparable duration of LORR with AZD3043, but more rapid recovery than AZD3043, propanidid and propofol. The time of compound 5j to return to walk and behavioral recovery are approximately reduced by more than 50% compared to AZD3043 in mice and rats and rabbits. The HD50 of compound 5j decreased with increasing animal size. CONCLUSIONS/SIGNIFICANCE: The rapid recovery might make compound 5j suitable for precise titration and allow swift and clear-headed recovery of consciousness and early home readiness.

Analysis of spontaneous activity patterns of human thalamic ventrolateral neurons and their modifications due to functional brain changes.

In the human thalamic ventralis lateralis nucleus the spontaneous activity of 235 single units during 38 stereotactic operations in locally anaesthetized parkinsonian patients was analysed. Two basic cell types (A and B) were shown to exist in this nucleus: (i) with unitary irregular (2-40/s) discharges characterized by a tendency to spike grouping in the range of 4-6 Hz and 10-30 Hz (A-type, 74%), (ii) with bursting discharges firing in short trains (5-30 ms) characterized by an unstable rhythmic 3-6 Hz pattern similar to a low-threshold Ca2+ intrinsic burst structure of discharges (B-type, 26%). The functional brain changes after a motor tests performance were accompanied by the appearance of two different transient modifications of activity of A-cells pattern into rhythmic burst discharges: (i) in the range of 3-6 Hz, similar to the bursts found for B-cells and recorded mainly in the anterior ventrolateral region in rigid patients, (ii) in the range of 5 +/- 1 Hz, characterized by other interspike interval and recorded in the posterior ventrolateral region in patients with tremor. Modifications during short-term anaesthesia resulted in 10-15 Hz burst discharges that were associated with gradual disappearance of A-cells activity. In contrast to what happens for A-cells, the activity of bursting B-units was characterized by an invariant intrinsic structure of discharges irrespective of the functional brain changes or the forms of parkinsonian pathology. The nature of A- and B-units as well as the mechanisms of transient modifications of their spontaneous activity patterns due to the functional brain changes are discussed.

[Readaptation after total intravenous anesthesia in one-day surgery]. / Readaptatsiia posle total'noi vnutrivennoi anestezii v khirurgii odnogo dnia.

The authors analyze the stages of readaptation and recovery of clear consciousness in the immediate postoperative period in 200 patients administered one of the four variants of intravenous anesthesia in a one-day surgical hospital. The purpose of this work was to optimize the anesthetic care and the readaptation period. The stages of readaptation were assessed by psychophysiological testing. This process coursed most smoothly after propofol-phentanyl and hypnomidate-phentanyl anesthesia. Readaptation after sombrevin-phentanyl coursed reliably slower. The longest recovery was observed after calipsol-diazepam anesthesia, despite drug stimulation. This type of narcosis is irrational for one-day surgery, for it requires prolonged postoperative monitoring and thus makes the hospital stay longer.

[Anesthesia with propanidid in a liposomal preparation. An experimental study in swine]. / Anästhesie mit Propanidid in liposomaler Zubereitung. Eine experimentelle Studie am Schwein.

BACKGROUND: Propanidid was widely used as a short-acting i.v. anaesthetic until it was withdrawn due to severe haemodynamic side effects. It was presumed that anaphylactoid reactions with massive histamine release were caused by the solvent cremophor rather than by propanidid itself. A new liposomal preparation of propanidid was examined in this animal study and compared with propanidid in cremophor solution and with propofol. METHODS: Eighteen pigs were randomly assigned to one of the following groups: Group 1 (n = 6): Propanidid in liposomal preparation (PropaLip; Braun Melsungen, Germany). Anaesthesia was induced with 60 mg/kg, followed by continuous infusion of 400 mg/kg.h. Group 2 (n = 6): Propanidid in cremophor solution (PropaCrem; Sombrevin, Gedeon Richter, Budapest) 15 mg/kg, 100 mg/kg.h. Group 3 (n = 6): Propofol (Disoprivan, Zeneca, Plankstadt, Germany) 5 mg/kg, 20 mg/kg.h. After induction and tracheal intubation, the animals were ventilated with 50% oxygen in air. Basic monitoring included noninvasive blood pressure measurements, electrocardiographic monitoring, and capnography. In a short surgical procedure, arterial and pulmonary artery catheters were placed via the right carotid artery and right internal jugular vein, respectively. As soon as the animals responded to a pain stimulus a second anaesthetic induction was performed, followed by a 60-min continuous infusion of the agent studied with invasive haemodynamic monitoring including arterial and pulmonary arterial pressures and cardiac output. Blood samples were taken for the measurement of serum levels of adrenaline, noradrenaline, cortisol, aldosterone, adrenocorticotropic hormone, and histamine. RESULTS: Intubation conditions and quality of anaesthesia were best in propofol animals, followed by PropaCrem animals. In spite of the large dose of 410 mg/kg.h, resulting in a volume load of as much as 16.4 ml/kg.h, the PropaLip animals showed evidence of poor anaesthetic quality. In group 1 we recorded the highest increases in heart rate (91 vs. 115/min), cardiac output (5.4 vs. 7.7 l/min), plasma catecholamine levels, and histamine concentrations (124-268 ng/ml). CONCLUSIONS: In our animal study, propanidid in liposomal preparation failed to show promise as a new anaesthetic agent. Our results are discussed in view of a drug targeting the cells of the reticuloendothelial system, especially the liver, where liposomes are eliminated from the blood. This may result in the transport of propanidid to one of its major places of inactivation.

[Transcranial Doppler sonographic study of the effect of electroconvulsive therapy on the circulation in the median cerebral artery]. / Az electroconvulsiv kezelés transcranialis Doppler sonographiás módszerrel megfigyelt hatása az arteria cerebri media keringésére.

The authors monitored the circulation of middle cerebral artery in subdominant hemisphere using the transcranial Doppler sonographic method during electroconvulsive treatment. They intravenously administered the patient 500 mg propanididum to put him/her to sleep and 150 mg of suxamethonium for muscle relaxation. The phasis of narcosis and awakening were continuously recorded under the treatment. After the administration of propanididum a sudden brief rise in flow velocity was measured with transient bradycardia followed by tachycardia. After the muscle relaxation the peak flow velocity diminished long lasting and the mean flow velocity fell from 60 cm per second to 30 cm per second average. At the beginning of the electroconvulsive treatment the velocity suddenly rose. The flow velocity increased significantly during the clonic phase of convulsive jerks with the pulsatility indices falling rapidly. Very low pulsatility indices lasted for long period of time during and following clonic convulsions.

[Anesthesiologic efficacy of propanidid as a liposome dispersion. An experimental study with rats]. / Anästhesiologische Wirksamkeit von Propanidid als Liposomendispersion. Eine experimentelle studie mit ratten.

BACKGROUND: Propanidid, an ultra-short-acting i.v. anaesthetic agent, was widely used in the 1960s. Reports of anaphylactoid reactions in patients associated with release of histamine following administration of the drug, however, led to withdrawal of this useful anaesthetic. Since the adverse side effects of the former solution could be attributed to the solvent cremophor, attempts have recently been made to produce a propanidid solution without addition of the solvent. We report on comparative investigations employing a new liposomal solution (B. Braun, Melsungen, FRG) and the conventional cremophor preparation with regard to anaesthetic properties, haemodynamic side effects, and electroencephalographic effects (EEG). METHODS: Sprague-Dawley rats (n = 46) were implanted with venous and arterial lines and epidural EEG electrodes during chloral-hydrate anaesthesia. The following day, arterial blood pressure (ABP), heart rate (HR), and EEG were monitored in awake animals and then after induction of anaesthesia by a bolus of the respective propanidid preparation, followed by an infusion period of 15 min in six different experimental groups. Animals of groups L-60, L-90, L-120, or C-60, C-90, or C-120 groups received 60, 90, or 120 mg.100 g-1.h-1 of the liposomal (L) or cremophor (C) preparation. During anaesthesia, the corneal reflex and nociception to tail-clamping were also tested. At termination of the infusion, blood samples were drawn for determination of plasma propanidid concentrations. RESULTS: Both preparations were similarly effective in induction and maintenance of anaesthesia in a dose-dependent manner; both similarly lowered ABP and HR. The corneal reflex and nociceptive responses to tail clamping were also comparably suppressed. However, whereas the liposomal preparation was well tolerated at higher dose levels, the cremophor preparation caused considerable dose-dependent mortality of 11%, 86%, and 86% in animals in groups C-60, C-90, and C-120, respectively. Both preparations were found to induce a burst-suppression pattern in the EEG associated with clonic seizures, with a lower incidence with the liposomal preparation (22% and 50% in groups L-90 and L-120) as compared to the cremophor preparation (100% and 89% in groups C-90 and C-120). A remarkable variability in propanidid plasma concentrations was found at the end of the infusion period, although no differences were observed between both preparations. Discontinuation of infusion of propanidid resulted in rapid awakening (less than 5 min), irrespective of whether the liposomal or conventional preparation was employed. CONCLUSION: The present findings demonstrate largely identical anaesthetic potencies of a new liposomal solution as compared to the conventional cremophor preparation of propanidid. The liposomal preparation, however, was superior as far as tolerance and incidence of clonic seizures was concerned. The present findings should prompt further studies on the suitability of liposomal propanidid as a short-acting anaesthetic agent in patients.

[The visual cortex "on command": 2 modes of operation of neuronal mechanisms (a topical article)]. / Zritel'naia kora "po zakazu": dva rezhima raboty neironnykh mekhanizmov (problemnaia stat'ia).

Orientation tuning (TO) of 152 single units in the 17th area of cat cerebral cortex was studied under different contrasts of the light bar flashed in RF (2.3, 10 and 100) and also under local and general anaesthesia (Sombrevin, 4 mg/kg or Nembutal, 35 mg/kg). An invariance of preferred orientation to contrast or anaesthesia was revealed in 40-50% of cells. Noninvariant cells shifted significantly their preferred orientation on 22-90 degrees. Invariant units more often have a simple RF, more sharp OT and preferred horizontal and vertical orientations. Under the low-contrast conditions or under general anaesthesia, noninvariant neurons shifted their preferred diagonal orientations. Different role of the two neuronal groups in detection of the reper (horizontal and vertical) and other orientations in a normal conditions (high-contrast, alert state) in comparison with their behavior under worse conditions (low-contrast, narcosis or sleep) is discussed.

[High-performance liquid chromatographic determination of propanidid and etomidate]. / Oznaczenie propanidydu i etomidatu we krwi metoda wysokosprawnej chromatografii cieczowej.

High-performance reversed-phase liquid chromatographic determination of propanidid and etomidate was performed on ODS silica, after precipitation of the proteins in plasma with methanol, extraction of the drugs with diethyl ether, evaporation and dissolving in a mobile phase: acetonitrile-phosphate buffer pH 4.44 (7:3, v/v); UV detection at 254 nm. Dionine hydrochloride was used as an internal standard. Propanidid was determined in a range 5-25 microg/cm3 of plasma and etomidate in 0.1-0.5 microg/cm3 of plasma, thus enables the analysis of therapeutic levels of the drugs.

[Propanidid and etomidate identification from the blood by thin-layer chromatography]. / Identyfikacja propanidydu i etomidatu we krwi za pomoca chromatografii cienkowarstwowej.

Propanidid and etomidate were extracted from blood with diethyl ether at pH ca. 8 (phosphate buffer), then separated and identified by thin-layer chromatography on silica gel, using diethyl ether-acetone (3:1, v/v) for propanidid or dioxane-acetic acid (47:3, v/v) for etomidate as the mobile phase. Both compounds can be revealed on dried chromatograms using sodium carbonate solution up to the amount 1 microg/cm3 of plasma, and it is sufficient sensivity for propanidid adhibited in therapeutic doses, whereas this limits the detection of etomidate for overdosed patients only.

[Comparative evaluation of anesthesia with etomidate and propanidid in patients undergoing electric cardioversion]. / Porównawcza ocena anestezji etomidatem i propanididem u chorych poddanych kardiowersji elektrycznej.

Cardioversion is one of the most effective treatment in cardiac arrhythmias. However, this technique is painful it requires proper anaesthesia assuring stable circulatory and respiratory functions. The authors compared two anaesthetics: etomidate and propanidid. No significant difference in their effects on both circulation and respiration has been noted. Some differences between both drugs in the produced adverse reactions were however noted. Etomidate caused pain at the site of injection, propanidid allergic reactions in the form of skin rash.

[Intravenous anesthesia for cesarean section. Comparison of propanidid and methohexital]. / Anesthésie intraveineuse pour césarienne. Comparaison du propanidide et du métohexital.

Propanidid and methohexital were compared retrospectively to assess the possible neonatal depression following general anesthesia for caesarean section: both have rapid onset and short duration of action and their transplacental passages are similar. Anesthesia was induced with equivalent doses of the two agents in 90 women (45 in each group). For each anesthetic agent, three subgroups were defined according to the indications, depending on emergency criteria and fetal state. There was no significant statistical difference (Student test) regarding clinical and biochemical criteria except for the fetal arterial pH which was more acidic in the propanidid group. In both groups, Apgar scores, arterial and venous pH were significantly more altered when caesarean section was performed for acute fetal depression.

[Variants of intravenous anesthesia during lung surgery in conditions of high-frequency artificial ventilation]. / Varianty vnutrivennoi anestezii pri operatsiiakh na legkikh v usloviiakh vysokochastotnoi iskusstvennoi ventiliatsii.

Basic systemic hemodynamic parameters were compared during intravenous anesthesia with calypsol (ketamine) and diazepam, promedol and diazepam, fentanyl and diazepam, fentanyl and sombrevin in 120 patients operated on the lungs with conventional and high-frequency jet ventilation. The studies have shown that in conventional controlled lung ventilation there were no distinctions in hemodynamic parameters depending on the type of the anesthesia. In high-frequency jet ventilation, specific hemodynamic effects of calypsol were observed. Unlike other anesthetics, calypsol administration is associated with elevated central venous pressure, increased cardiac output and enhanced left ventricular work, which can be accounted for by higher venous return.