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Open Access 27.10.2024 | Review Article

The Role of GABA Receptors in Anesthesia and Sedation: An Updated Review

verfasst von: Annlin Bejoy Philip, Janette Brohan, Basavana Goudra

Erschienen in: CNS Drugs | Ausgabe 1/2025

Abstract

GABA (γ-aminobutyric acid) receptors are constituents of many inhibitory synapses within the central nervous system. They are formed by 5 subunits out of 19 various subunits: α1–6, β1–3, γ1–3, δ, ε, θ, π, and ρ1–3. Two main subtypes of GABA receptors have been identified, namely GABAA and GABAB. The GABAA receptor (GABAAR) is formed by a variety of combinations of five subunits, although both α and β subunits must be included to produce a GABA-gated ion channel. Other subunits are γ, δ, ε, π, and ϴ. GABAAR has many isoforms, that dictate, among other properties, their differing affinities and conductance. Drugs acting on GABAAR form the cornerstone of anesthesia and sedation practice. Some such GABAAR agonists used in anesthesia practice are propofol, etomidate, methohexital, thiopental, isoflurane, sevoflurane, and desflurane. Ketamine, nitrous oxide, and xenon are not GABAR agonists and instead inhibit glutamate receptors—mainly NMDA receptors. Inspite of its many drawbacks such as pain in injection, quick and uncontrolled conversion from sedation to general anesthesia and dose-related cardiovascular depression, propofol remains the most popular GABAR agonist employed by anesthesia providers. In addition, being formulated in a lipid emulsion, contamination and bacterial growth is possible. Literature is rife with newer propofol formulations, aiming to address many of these drawbacks, and with some degree of success. A nonemulsion propofol formulation has been developed with cyclodextrins, which form inclusion complexes with drugs having lipophilic properties while maintaining aqueous solubility. Inhalational anesthetics are also GABA agonists. The binding sites are primarily located within α⁺/β⁻ and β⁺/α⁻ subunit interfaces, with residues in the α⁺/γ⁻ interface. Isoflurane and sevoflurane might have slightly different binding sites providing unexpected degree of selectivity. Methoxyflurane has made a comeback in Europe for rapid provision of analgesia in the emergency departments. Penthrox (Galen, UK) is the special device designed for its administration. With better understanding of pharmacology of GABAAR agonists, newer sedative agents have been developed, which utilize “soft pharmacology,” a term pertaining to agents that are rapidly metabolized into inactive metabolites after producing desired therapeutic effect(s). These newer “soft” GABAAR agonists have many properties of ideal sedative agents, as they can offer well-controlled, titratable activity and ultrashort action. Remimazolam, a modified midazolam and methoxycarbonyl-etomidate (MOC-etomidate), an ultrashort-acting etomidate analog are two such examples. Cyclopropyl methoxycarbonyl metomidate is another second-generation soft etomidate analog that has a greater potency and longer half-life than MOC-etomidate. Additionally, it might not cause adrenal axis suppression. Carboetomidate is another soft analog of etomidate with low affinity for 11β-hydroxylase and is, therefore, unlikely to have clinically significant adrenocortical suppressant effects. Alphaxalone, a GABAAR agonist, is recently formulated in combination with 7-sulfobutylether-β-cyclodextrin (SBECD), which has a low hypersensitivity profile.

Key Points

Nearly all anesthetics and sedatives apart from ketamine, nitrous oxide, and xenon are GABAR agonists.

Many “soft” analog of existing GABAR agonists are undergoing trial and likely to become available soon.

Methoxyflurane has made a resurgence in Europe as a rapid acting analgesic in the emergency room. It requires a special apparatus Penthrox, (Galen, UK) to administer.

1 Introduction

Gamma aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system. There are two main classes of receptors involved in GABA signaling—namely GABAA and GABAB receptors [1].

GABAA receptors are targeted in the treatment of neuropsychiatric disorders such as epilepsy, insomnia, and anxiety [2, 3]. These receptors are also involved in the action of many anesthetic drugs used in procedural sedation and general anesthesia. GABAB receptors are involved in neurological and psychiatric disorders [4]. A new subtype of GABA receptors called GABAc are now considered part of GABAA receptors.

1.1 Structure of GABA_A Receptors

GABAARs are members of the Cys-loop family of pentameric transmembrane ligand-gated ion channels [4]. There are numerous subunit isoforms for the GABAAR, which determine the receptors affinity, conductance, and other properties [5]. The subtypes in existence in humans are as follows [6]:

Six types of α subunits (GABRα1, GABRα2, GABRα3, GABRα4, GABRα5, and GABRα6), three β (GABRβ1, GABRβ2, and GABRβ3), three γ (GABRγ1, GABRγ2, and GABRγ3), three ρ (GABRρ1, GABRρ2, and GABRρ3), and a δ (GABRδ), an ε (GABRε), a π (GABRπ), and a ϴ (GABRϴ).

Altogether, the GABA receptors are formed by 5 subunits out of 19 various subunits: α1–6, β1–3, γ1–3, δ, ε, θ, π, and ρ1–3. GABAARs can be formed by a variety of combinations of five subunits, although both α and β subunits must be included to produce a GABA-gated ion channel [6]. Other subunits can be included in the structure of the GABAAR, such as γ, δ, ε, π, and ϴ. The most common form of GABAAR in the brain involves a combination of two α, two s, and a γ (α1β2γ2) [5]. The main adult isoform is formed of α1, β2, and γ2 subunits arranged as γ2β2α1β2α1 counterclockwise (Fig. 1). The GABA binding sites are located at the junction of β⁺/α⁻, whereas benzodiazepines (BZs) are located at α⁺/γ⁻ interface. Anesthetic medications bind to different sites, whereas barbiturates bind to α⁺/β⁻, and γ⁺/β⁻ interfaces, while etomidate binds to β⁺/α⁻ interface.

Activation of GABAAR results in opening of the ligand-gated ion channel that allows the inward movement of mainly chloride ions. This results in cell membrane hyperpolarization and inhibition of signal transmission. Three main components of general anesthesia are mediated by GABAARs: hypnosis [7], depression of spinal reflexes [8], and amnesia [9]. Distinct sites within the GABAAR bind to general anesthetics and sedatives, resulting in modulation of the action of GABA and enhancement of the inhibitory activity of the GABAAR within the CNS [6]. The specific effects of GABA-aminergic anesthetic and sedative agents have been linked to different GABAAR subtypes present in different brain regions. For example, the α1-GABAAR subtype mediates the sedative but not the anxiolytic effects of benzodiazepines [10], whereas α2-containing GABAARs in the limbic system have been found to be involved in mediating the anxiolytic effects of benzodiazepines [11].

In comparison with GABAARs, GABAB receptors (GABABRs) are less well defined. These receptors are members of the C family of G-protein-coupled receptors (GPCRs), linked to potassium channels via G-proteins [12]. As a result of influx of potassium, there is hyperpolarization of the presynaptic cell. This decreases the influx of calcium, with a resultant reduction in the release of neurotransmitters. GABABRs are involved in behavioral attributes of γ-hydroxybutyric acid (GHB) [13] and ethanol [14], as well as in pain transmission [15]. Baclofen is a selective GABABR agonist [16]. GABABRs are not discussed further, as there is little role for GABABR agonism in anesthesia and sedation.

The GABAAR has a central role in modern anesthesia and sedation practice. Of the ten intravenous and inhalational anesthetics traditionally used in general anesthesia practice (nitrous oxide, isoflurane, sevoflurane, desflurane, xenon, propofol, etomidate, ketamine, methohexital, and thiopental), seven agents are GABAAR agonists. Ketamine, nitrous oxide, and xenon are not GABAR agonists and instead inhibit glutamate receptors—mainly NMDA receptors. Benzodiazepines exert their hypnotic and amnesic effects by activation of the GABAAR [17, 18]. This updated review outlines the role that GABAAR agonists play in sedation and anesthesia, in addition to discussing role of novel GABAAR agonists in anesthesia and sedation.

2 GABA-Minergic Agents Currently Used in Anesthesia and Sedation

2.1 Propofol

Since its introduction in 1977, propofol has become established as the most popular agent for induction of anesthesia, in addition to becoming a favored intravenous sedative agent. Propofol is a dialkyl phenol. It potentiates the response to GABA at GABAARs and activates them [19]. The α, β, and γ subunits of GABAAR are all sensitive to propofol [20, 21], although propofol is more efficacious at β1-containing receptors than at those containing β2 or β3 subunits [22].

Propofol has many features of the conceptually ideal drug for sedation [23, 24], namely ease of use, rapid onset, rapid offset, and minimal residual sedation. There are also additional benefits to the use of propofol. The antioxidant properties of propofol may provide a degree of cardioprotection in patients undergoing coronary bypass surgery [25]. Propofol reduces cerebral blood flow (CBF) and decreases the cerebral metabolic rate in a dose-dependent manner; this has cerebroprotective benefits in the context of brain injury or tumors [26, 27].

As an intravenous agent, propofol is employed for both and maintenance of anesthesia including as the main component of total IV anesthesia (TIVA) [28, 29]. The initial attraction of propofol target-controlled infusion (TCI) systems was the appeal of ease with balancing of the depth of anesthesia with respiratory and cardiovascular stability [30]. The propofol TCI system utilizes infusion control algorithms, which target a specified blood concentration of propofol based on a pharmacokinetic model. Additionally, propofol infusions can also be used as a part of a loop feedback system to alter infusion rates depending on patients’ depth of anesthesia as monitored by measures such as the Bispectral index [31]. TIVA is commonly used by anesthesia providers; however, there have not been proven advantages of propofol TCI over manually controlled infusions in terms of adverse effects or quality of anesthesia [32].

The beneficial immunomodulating effects of propofol that appear to be significant during in vivo studies are controversial and at best unproven [33, 34]. Earlier studies suggested that propofol can improve anticancer immunity by activating lymphocytes such as natural killer (NK) cells and T cell lymphocytes, leading to a cytotoxic effect, which is advantageous in cancer surgery. It was also suggested to counteract the repression of the immune system by cancer surgery which causes dissemination of cancer cells [35, 36]. Claims, such as propofol being an immunoregulatory agent for cancer treatment, as well as wound healing for regulation of sterile inflammation, need to be evaluated. Two trials, General Anesthetics in Cancer Resection (GA-CARES)-which is a phase 3 multicenter randomized controlled trial (RCT) and Volatile Anesthesia and Perioperative Outcomes Related to Cancer (VAPOR-Cl), another large, international, randomized clinical trial of inhalational volatile or intravenous propofol anesthesia and intravenous lidocaine/placebo to improve disease-free survival after surgery for colorectal cancer and lung cancer will hopefully resolve this issue [37, 38].

Propofol does have some disadvantages, however. Pain on IV injection of propofol is experienced by up to 30% of patients [39]. As a sedative agent, propofol has a “narrow therapeutic window,” and as a result, there can be a sudden uncontrolled conversion from sedation to general anesthesia [23, 39, 40]. In addition, propofol causes dose-related cardiovascular depression, with decrease in sympathetic tone, reduced systemic vascular resistance, and resultant hypotension [41]. Following propofol administration, dose-dependent respiratory depression occurs as a result of reduced central chemoreceptor responsiveness to hypercapnia and reduced metabolic ventilatory control [42, 43]. Propofol infusion syndrome, originally described in the context of propofol infusions in children [44], is a condition with the features of myocardial failure, cardiovascular collapse, lipidemia, rhabdomyolysis, liver failure, and metabolic acidosis [45]. Propofol infusion syndrome is associated with propofol infusions at doses greater than 4 mg/kg/h and is proposed to be caused by either impaired mitochondrial fatty acid metabolism or a direct mitochondrial respiratory chain inhibition [45]. Commercially marked propofol is a lipid emulsion and contains soybean oil, glycerol, and egg lecithin. It is a suitable medium for micro-organism proliferation, and bacterial contamination of propofol has become a recognized issue [46‐48].

Newer derivatives of propofol have been developed to target the issues of pain on injection, the need for antimicrobial agents, and hyperlipidemia [49]. The standard propofol emulsions are made of oil droplets between 0.15 and 0.5 μm [50]. Microemulsions with droplet size < 0.1 μm has been developed. For example, Aquafol (Daewon Pharmaceuticals, Seoul, Korea) is a 1% propofol microemulsion in 8% polyethylene glycol 600 hydroxy stearate and purified poloxamer [51]. Time to loss of consciousness and recovery was prolonged with Aquafol and was associated with more severe and intense injection pain, leading to discontinuation of trials. Another approach was to manufacture a formulation, which can be made and stored as a microemulsion and diluted to a macroemulsion, leading to greater stability and longer shelf life with absence of pain on injection compared with microemulsions [52]. Ciprofol, a short-acting intravenous sedative based on the structural modification of propofol, carries lower incidence of pain on injection [51].

Propofol formulations with an increased concentration of medium chain triglycerides in the emulsion have been developed. These are metabolized rapidly but may produce toxic metabolites such as acetoacetate or octanoate [53]. Such formulations include IDD-D propofol (SkyePharma Inc., New York, NY), AM149 (AMRAD Pharmaceuticals, Victoria, Australia), and Propofol-Lipuro (B. Braun, Meslungen, Germany). IDD-D propofol caused greater pain on injection and had a prolonged induction time and, henceforth, trials have been discontinued. Propofol-Lipuro, which is a mixed MCT-LCT propofol formulation, has the same pharmacokinetics and pharmacodynamics of propofol. It causes less pain on injection and faster elimination of triglycerides [54, 55]. Even though this agent is available in other countries, it is not available in USA due to absence of EDTA in the solvent [49]. Emulsion modification by adding albumin to form nanoparticles called Nab Propofol has been attempted. It has reduced oil content, decreasing the possibility of hyperlipidemia.

A nonemulsion propofol formulation has been developed with cyclodextrins, which form inclusion complexes with drugs having lipophilic properties while maintaining aqueous solubility [56]. This formulation has been shown to reduce induction times and have a longer duration of action in animal studies. Major drawbacks for this formulation are increased pain on injection, renal toxicity, hemolysis, and interference with other lipophilic drugs [57, 58].

Propofol micelle formations have been developed. Propofol-PM (Paladin Labs, Inc., Montreal, Canada) has the possible advantages of enhanced stability, spontaneous micelle formation, and possible sterilization [57, 59].

Studies have shown similar pharmacokinetics and similar duration of anesthesia as standard propofol emulsion.

Propofol prodrugs are developed that are water-soluble and can be converted to propofol in vivo. Fospropofol disodium is one such prodrug and the only one that got approval from the US Food and Drug Administration (FDA) [49]. It was used in many clinical trials for procedural sedation but never became popular. Even though it did not cause pain on injection, it carried many unpleasant side effects such as perineal paresthesia (47.6%) and pruritus (14.7%) [60]. It was not cleared by FDA for use by providers not trained in airway management, and its manufacturing and marketing stopped soon after. HX0507 is another water-soluble prodrug; however, it causes significant cardiac side effects such as hypotension and QT prolongation [61]. HX0969w, a water-soluble phosphate ester prodrug of propofol, is similar to fospropofol but releases γ -hydroxybutyrate instead of formaldehyde [62]. PF0713 is a potent GABA receptor agonist and similar in hypnotic potency to propofol but has slower onset and prolonged duration of action [63].

Another propofol derivative, a structural analog of propanidid, is AZD-3043(AstraZeneca US, Wilmington, DE). Due to the risk of anaphylaxis, propanidid was discontinued in the 1960s. AZD-3043 produces rapid-onset hypnosis and rapid recovery upon infusion termination, even after prolonged continuous infusion [43]. It has been shown to have high systemic clearance and low volume of distribution and has rapid onset and offset profile. More research and development are needed for these drugs to come into clinical use.

2.2 Barbiturates

Thiopental is a thiobarbiturate and was the first intravenous (IV) anesthetic drug to be commonly used in the USA. Following Dr. John S. Lundy’s initial publication [64], thiopental was rapidly adopted and integrated into anesthesia practice.

A modified thiobarbiturate compound, methohexital was developed later [65], and it had an established role in anesthesia for electroconvulsive treatment (ECT) [66]. There is evidence suggesting that the actions of barbiturates on the GABAAR are more complex than other anesthetic agents [67]. The site of action of barbiturate was once considered to reside within the β subunit of the GABAAR; however, there are now suggestions of a potential role for the α6 and δ subunits on GABAARs [68, 69]. Thiopental has classically been used in rapid sequence induction of general anesthesia due to its rapid induction and its reliable endpoint.

However, its use has largely now been overtaken by propofol in many parts of the world. Despite this, it retains its role as an anesthetic agent, an anticonvulsant, and as a sedative drug in neurointensive care in the context of traumatic brain injury and raised intracranial pressure. Thiopental is an appealing agent for neurosurgical patients due to its cerebroprotective effects, particularly in the context of high intracranial pressure [70]. However, following the withdrawal of a major manufacturer and subsequent restriction of supply, the use of thiopental has declined in the USA. Thiopental has many disadvantages, including the induction of hepatic enzymes, which alters the metabolism of coadministered drugs [71]. In addition, pentobarbitone, an active metabolite of thiopental, can accumulate in renal failure [72] and is a trigger agent for porphyria [73]. Extravasation of injected thiopentone causes pain and erythema, while accidental intra-arterial injection of thiopental results in intense pain and can cause distal gangrene due to endothelial damage and resultant inflammatory reaction [74]. Due to its zero-order kinetics and rapid rise in context sensitive half time (the time taken for blood plasma concentration of a drug to decline by one half after an infusion designed to maintain a steady state has been stopped), thiopental infusion is an uncommon sedation strategy. Because of its zero-order kinetics, accumulation of thiopental may result in prolonged sedation [75].

2.3 Etomidate

Etomidate was first synthesized in 1964 [76] and was introduced into anesthesia practice in 1972 [77]. It was the first nonbarbiturate intravenous anesthetic introduced into the market [78]. This compound was initially developed as an antifungal agent [79, 80]; however, the potent hypnotic activity of etomidate was observed during initial animal testing. Etomidate is a rapidly acting imidazole based IV hypnotic agent that is used to induce general anesthesia through potentiation of GABAAR activation [81‐83]. It has the greatest selectivity for GABAAR when compared with other anesthetic agents. Etomidate binds to the GABA binding site between the α and β subunits of the GABAAR (Fig. 1) and as a result the receptor undergoes a conformational change, allowing the center ion channel pore to open [86]. GABAARs containing β2 and/or β3 subunits are activated by etomidate, while those containing α1 are much less sensitive to etomidate actions [87]. Further, the channel becomes leaky to chloride ions that pass from the extracellular to the intracellular space, resulting in hyperpolarization of the neuron, inhibiting the activity of that cell [84]. Etomidate affinity is also enhanced by the presence of a γ subunit [88] and weakly by the α subtype [87]. Cyclopropyl–methoxycarbonyl etomidate (ABP-700) is a soft analog of etomidate that binds to the same site on the GABA_A receptor as etomidate [85].

One of the main advantages of etomidate over other induction agents is its ability to maintain hemodynamic stability even in the setting of cardiovascular compromise [89]. Etomidate does not inhibit sympathetic tone or myocardial function, and it is considered by many to be the ideal agent for induction of anesthesia in cardiac compromised or hypovolemic patients. In fact, the use of etomidate use is associated with less hypotension than ketamine for emergency department sepsis intubations [90]. In this National Emergency Airway Registry (NEAR) data set analysis of a total of 531 patients that were intubated for sepsis (71% with etomidate), ketamine was associated with more postprocedural hypotension than etomidate.

Etomidate causes rapid onset of anesthesia with loss of eye lash reflex within 118 s, and continuous infusion causes loss of consciousness within 6 min [91, 92]. It has no analgesic effect, however, so responses to laryngoscopy and endotracheal intubation need to be blunted by simultaneous administration of opioids [86]. Pain on injection is a common side effect, the extent depends on the formulation and size of vein injected. Dose-dependent myoclonus and or involuntary muscle movements, especially in patients that are not premedicated, are seen with etomidate and its analog [93, 94].

The main disadvantage of etomidate, however, is adrenocortical suppression. Initial reports highlighted increased mortality in intensive care patients receiving etomidate infusions for sedation [95, 96]. Subsequently, the physiological cortisol and aldosterone increases following surgery was found to be suppressed by etomidate, in addition to it suppressing adrenal responses to corticotrophin [97, 98]. In addition to inhibiting other enzymes involved in steroidogenesis, etomidate is a potent inhibitor of adrenal mitochondrial 11β-hydroxylase. This rate- limiting enzyme is responsible for the final conversion of 11-deoxycortisol to cortisol, in a dose-dependent fashion. Although hemodynamic stability is an attractive feature of this drug (in the context of patients with cardiovascular compromise), there are ongoing discussions about the appropriateness of etomidate use in patients with sepsis [99, 100]. Following a single dose of etomidate there may be adrenal suppression lasting 6–8 h [101‐103], and an etomidate infusion will prolong adrenal suppression to more than 24 h [104]. There is a geographical variation in the current use of etomidate, with continued use of etomidate in the USA and more limited use in Europe [105, 106].

2.4 Inhalational Anesthetic Agents

Following the development of the first inhalational anesthetic agents in the nineteenth century, their use as anesthetic agents rapidly became commonplace. The introduction of halothane in 1956, the first fluorinated anesthetic to obtain widespread acceptability, was a milestone in the development of modern volatile agents [107].

Subsequent to the development of halothane, newer volatile agents (enflurane, isoflurane, sevoflurane, and desflurane) were developed. Although these agents are similar in structure, there are variations in their pharmacokinetic and pharmacodynamic profiles, that factors such as individual boiling points, oil:gas coefficients, and blood:gas coefficients. Enflurane and isoflurane are structural isomers. Although enflurane was commonly used in the 1970s and 1980s, its use has now been overtaken by newer volatile agents. Isoflurane continues to have a role in modern anesthetic practice. Desflurane has some characteristics that make it a unique anesthetic agent, including a higher vapor pressure and lower boiling point, which necessitates a custom-designed desflurane vaporizer. Since its introduction in 1990, sevoflurane has gained widespread popularity for both inhalational induction and maintenance [108, 109]. Methoxyflurane (Penthrox, Galen, UK) has made a resurgence and been used for rapid provision of analgesia in the emergency departments. Penthrox is a methoxyflurane autoinhaler licenced in Europe [110]. Life-cycle impact assessment found that Penthrox has a climate change effect of 0.84 kg carbon dioxide equivalent. In this regard, the overall “cradle-to-grave” environmental impact of Penthrox is less than nitrous oxide; however, the impact of equivalent dose of intravenous morphine was even lower [111].

The anesthetic effect of inhalational anesthetic agents is predominantly mediated by the α1-subunit of the GABAAR [112, 113]. Sites of action of many intravenous anesthetics have been identified in GABA_A receptors by using photolabeling [114]. Using photoactivatable analogs of isoflurane and sevoflurane, it was found that the binding sites were primarily located within α⁺/β⁻ and β⁺/α⁻ subunit interfaces, with residues in the α⁺/γ⁻ interface. The authors also noted that isoflurane and sevoflurane did not always share binding sites, suggesting possible and an unexpected degree of selectivity. Isoflurane, desflurane, and sevoflurane all enhance the response at the GABAAR to endogenous GABA and prolong the duration of GABA-mediated synaptic inhibition. At supraclinical concentrations there is “direct activation” of the GABAAR, whereby there is opening of the receptor’s anion channel in the absence of GABA [115].

All volatile anesthetics cause a concentration-dependent myocardial depression by decreasing trans sarcolemmal calcium entry in the myocardium [116]. Isoflurane (and prolofol), in both intact and skinned rat preparations, depressed maximum Ca²⁺-activated force and increased the intracellular (Ca²⁺) required for 50% of activation [117]. Both are shown to have binding sites in both actin and myosin and directly depress the myofilament Ca²⁺ responsiveness in key regions responsible for myocardial contraction. Vasodilatation with a resultant reduction in systemic vascular resistance are also common characteristic effects of volatile agents [118]. All halogenated ethers cause a dose-dependent respiratory depression [119], and malignant hyperthermia can be triggered by all volatile anesthetics [120]. Hepatotoxicity caused by inhalational anesthetics was originally recognized in the nineteenth century in patients anesthetized by chloroform. Since then, hepatotoxicity has been found with halogenated anesthetics, in particular, with halothane use, due to the formation of reactive metabolites produced in their metabolism [120]. There have been case reports of nephrogenic diabetes insipidus with prolonged use of sevoflurane for critical care sedation with anesthetic reflector devices.

Sevoflurane is the most commonly used inhalational anesthetic agent in children on account of hemodynamic stability, absence of airway irritation, and rapid induction and emergence [121]. However, the main drawback of sevoflurane anesthesia in these patients is its association with emergence agitation and delirium, with an incidence between 10% and 80% [122]. Emergence delirium is characterized by inconsolability, incoherence, thrashing, restlessness, and nonpurposeful movement [123]. Studies have shown that propofol has a role in the prevention and treatment of emergence delirium during emergence from sevoflurane anesthesia. Prophylactic dose of propofol at the end of surgery or procedure prevented emergence agitation and decreased the severity of emergence agitation in children under sevoflurane anesthesia. In particular, 3 mg/kg propofol probably provided more pronounced effects without extending the time spent in the PACU but which requires further study [124]. More recently, both remimazolam and dexmedetomidine have recently been shown to limit the development of delirium in children [125, 126].

2.5 Benzodiazepines

Benzodiazepines (BZDs) are a class of drugs whose core chemical structure involves the fusion of a benzene ring and a diazepine ring. Chlordiazepoxide, which has been available since 1960, was the first drug of this class. Subsequent drug developments within this class include short acting (midazolam), medium acting (diazepam), and long acting (lorazepam) BZDs. BZDs have been used in the treatment of anxiety, insomnia, muscle relaxation, relief from spasticity caused by CNS pathology, and epilepsy [127, 128]. BZDs have a role in sedation and anesthetic practice due to their amnesic, anxiolytic, and sedative properties. BZDs are one of the most widely prescribed pharmacologic agents in the USA [129].

The BZD binding site is at the intersection between of the α and γ subunits of the GABAAR (Fig. 1). Isoforms 1, 2, 3, and 5 of the α subunit have a high affinity for BZDs. In contrast, isoforms 4 and 6 of the α subunit do not have an affinity for BZDs [130]. The binding of BZDs to the pocket created by the α and γ subunits results in a conformational change in the GABAAR, which allows GABA to bind. The BZD receptor is subclassified depending on α subunit isoforms, in addition to the clinical effects involved. BZ1 receptors contain the α1 isoform and are highly concentrated in the cortex, thalamus, and cerebellum [131, 132]. The BZ1 receptor mediates the sedative effects [133] and amnesic effects of BZDs and some of the anticonvulsive effects of diazepam [134]. BZ2 receptors contain the α2 isoform [131] and is responsible for the anxiolytic and myorelaxant effects of BZDs [133]. These receptors are highly concentrated in areas such as the limbic system, motor neurons, and the dorsal horn of the spinal cord [134].

Midazolam has the shortest half-life of all of the traditional BZDs. Because of this, it is commonly used for procedural sedation. However, there are two main limitations with BZD use for procedural sedation: prolonged sedation beyond the duration of the procedure as a result of the distribution and prolonged elimination of BZDs, and the absence of analgesic properties. Although midazolam has the shortest half-life of any of the traditional BZDs, there can be prolonged sedation and unpredictable recovery owing to midazolam’s half-life of 1.8–6.4 h, in addition to the accumulation of an active metabolite, α-hydroxy-midazolam [128, 135‐137]. There is a dose dependent spectrum of neurological effects with BZDs, ranging from anxiolysis with low doses to sedation,

amnesia, and eventually anesthesia with escalating doses. The change in clinical effects from sedation to anesthesia can be difficult to predict and deep sedation with respiratory depression can occur unpredictably at doses too low to induce anesthesia.

Depth of anesthesia monitoring has been shown to be less reliable with midazolam than with propofol or sevoflurane [138]. High doses of BZDs are required if BZDs are being used for induction of anesthesia, with resultant prolonged sedation and amnesia. This is due to the prolonged context sensitive half-times of the traditional BZDs. Because of these factors, BZDs are not generally used routinely as induction agents [139].

3 Newer GABA-Minergic Agents

The characteristics of the ideal sedative or anesthetic agent include:

Ease of use

Fast onset of effect

Rapid recovery once administration discontinuation

Minimal residual sedation

There have been developments toward this ideal drug in recent years [139, 140]. Several new agents have been developed as analogs of parent compounds. The term “soft pharmacology” is used to describe the pharmacology of these agents, whereby the chemical structure allows rapid metabolism into inactive metabolites after the desired therapeutic effect(s) has occurred [141]. Newer “soft” GABAAR agonists have many of the characteristics of the ideal sedative or anesthetic agent, as they can offer well controlled, titratable activity and ultrashort action.

3.1 Fospropofol

Propofol has disadvantages as a sedative agent, including pain on injection and a narrow therapeutic window. There has been the development of several water-soluble analogs of propofol, which potentially avoid these disadvantages. Fospropofol is a water-soluble prodrug of propofol with a pharmacokinetic profile that differs from that of propofol. The linkage of the propofol moiety with a charged phosphate group results in electronegativity and polarity within the molecule, and as a result, fospropofol is water soluble (Fig. 2).

Fospropofol is metabolized by endothelial alkaline phosphatases to its active metabolite propofol, in addition to phosphate and formaldehyde. The liberation of propofol and subsequent potentiation of GABA-inhibitory pathways at the GABAAR results in the sedative and anesthetic properties of fospropofol. Following the metabolism of 1 mg of fospropofol, 0.54 mg of propofol is released [142]. Fospropofol has a number of suggested advantages over propofol. Patients may experience less severe pain on injection of fospropofol, due to the water-soluble nature of the compound [143]. Compared with the lipid emulsion of propofol, fospropofol is likely to be less of a medium for bacterial growth.

There has previously been a suggested role for fospropofol in procedural sedation, particularly in the out-of- operating room setting [144, 145]. Since fospropofol administration results in time-dependent enzymatic release of propofol, there is a slower onset of sedation, more sustained levels of bioavailable propofol, and a longer duration of action than when administering propofol [146]. Due to this pharmacokinetic profile, fospropofol may be an attractive agent for use in brief day-case or outpatient procedures where a single loading dose may be sufficient for an entire procedure. However, because propofol is only released and becomes bioavailable after metabolism of fospropofol, there is a delay in onset of clinical effect following fospropofol administration, and additional boluses could lead to a deeper level of sedation than intended.

The US Food and Drug Administration (FDA) has approved fospropofol for monitored anesthesia care (MAC) sedation in adult patients undergoing diagnostic and therapeutic procedures [147], with the example of bronchoscopies and colonoscopies [60, 148]. Additional suggested roles for fospropofol include maintenance of sedation intensive care unit (ICU) setting, in addition to IV maintenance of anesthesia for coronary artery bypass surgery [149, 150]. An additional advantage of fospropofol is that, unlike its parent compound propofol, it does not have a lipophilic formulation that supports bacterial growth [151]. Endothelial alkaline phosphates are responsible for the metabolism of fospropofol and the release of propofol, phosphate, and formaldehyde.

Propofol is metabolized by the liver into various inactive sulfate and glucuronide compounds. Formaldehyde is converted to formate by aldehyde dehydrogenase, which is subsequently oxidized to water and carbon dioxide in the presence of tetrahydrofolate. Formate is an end metabolite of fospropofol. Toxic effects due to accumulation of formate include metabolic acidosis and retinal toxicity resulting in blindness.

Adverse effects with fospropofol include paraesthesia, including perineal discomfort or burning sensation (incidence 50–70%) and pruritus (incidence 16–20%) [144, 152‐154]. These adverse effects experienced are mild and self-limiting, lasting 1–2 min [152]. Due to propofol liberation from fospropofol metabolism, respiratory depression and hypoxemia can occur (incidence 4%). The use of supplemental oxygen and appropriate positioning of the patient reduces the risk of occurrence of these adverse effects [155].

In addition, hypotension has been reported to occur with fospropofol administration (incidence 4%), most notably in patients with compromised myocardial function, reduced vascular tone, or who have reduced intravascular volume.

Whilst fospropofol was initially approved by the FDA for MAC sedation in adult patients undergoing diagnostic and therapeutic procedures, it has not become widely used since its introduction. The future role of fospropofol in anesthesia and sedation remains uncertain. Fospropofol may have a role in ICU sedation or TIVA; however, this has not been well established. Prior to completion of clinical trials in its role as an agent for induction of anesthesia, production of the drug was discontinued in the USA [156].

3.2 Etomidate Analogues

The advantage of the hemodynamic stability that etomidate use affords is somewhat overshadowed by the issue surrounding adrenocortical suppression with etomidate use. Etomidate analogues are currently being developed, with the aim of developing rapidly metabolized etomidate alternatives with the hemodynamic stability of etomidate but without the underlying issue of adrenocortical suppression.

Methoxycarbonyl-etomidate (MOC-etomidate) was the first soft etomidate analog to be developed. This is an ultrashort-acting etomidate analog that does not produce prolonged adrenocortical suppression in animal models [157]. Similar to its parent compound, MOC-etomidate is a potent GABAAR agonist that produces a brief loss of righting reflex in rats following administration [157, 158]. The ester moiety of MOC-etomidate is rapidly hydrolyzed by esterases to form a carboxylic acid metabolite [157] (Fig. 3). There may be accumulation of this carboxylic acid metabolite in patients with renal failure [159]; however, this metabolite is 300-fold less potent than MOC-etomidate. Due to this pharmacokinetics, there are suggestions that MOC-etomidate may have a prolonged context-sensitive half-time following infusion [160].

Cyclopropyl methoxycarbonyl metomidate (CPMM, now ABP-700; The Medicines Company, Troy Hills, NJ) is a second-generation soft etomidate analog that was developed following the initial animal studies of MOC-etomidate. In animal models, ABP-700 has a greater potency and longer half-life than MOC-etomidate [161]. In contrast to MOC-etomidate, ABP-700 does not accumulate and its context-sensitive half-time is unchanged following infusion [162]. Also, in contrast to MOC-etomidate, the carboxylic acid metabolite of ABP-700 does not accumulate to hypnotic levels even after prolonged infusion [163]. There has been shown to be a more rapid and predictable hypnotic recovery following administration of ABP-700 than following propofol administration [164]. Clinical studies have not highlighted issues surrounding adrenal axis suppression with this agent [86]. There may be a role for ABP-700 as an anesthetic agent in the setting of sepsis [165]. In an initial phase I study of ABP-700, this agent was shown to be safe and well tolerated after single-bolus injections of up to 1 mg/kg, however, bolus doses of 0.25 and 0.35 mg/kg were shown to have the most beneficial clinical effect:adverse effect ratio [166].

Carboetomidate is an additional soft analog of etomidate. The imidazole ring of etomidate, which is responsible for the binding and inhibition of 11β-hydroxylase by etomidate, is replaced by a pyrrole ring in carboetomidate [167]. As a result, carboetomidate has a low affinity for 11β-hydroxylase and is, therefore, unlikely to have clinically significant adrenocortical suppressant effects. Carboetomidate is a less potent inhibitor of in vitro cortisol synthesis than etomidate and does not suppress steroid synthesis in rats [168]. Similar to etomidate, carboetomidate is a GABAAR agonist but with the additional benefit of being a cardiovascularly stable agent [167]. Carboetomidate also contains an ester moiety that is hydrolyzed by esterases to form the same carboxylic acid metabolite as MOC-etomidate. Similar to the case with MOC-etomidate, this carboxylic acid metabolite may accumulate in patients with renal impairment.

ET-26 hydrochloride is another etomidate analogue that has stable hemodynamic and recovery profile similar to etomidate, but in in vivo sepsis models in rats, adrenocortical suppression is nonexistent. [169, 170]. Further data are awaited from the trials.

3.3 Remimazolam

Remimazolam is an ester-based BDZ that undergoes organ-independent ester hydrolysis, similar to remifentanil [171]. By deliberately adding a carboxylic ester linkage into the structure of midazolam, Glaxo Wellcome, who created remifentanil, synthesized remimazolam in 1990s. This addition results in rapid-tissue ester hydrolysis of remimazolam to an inactive carboxylic acid metabolite (CNS 7054) (Fig. 4). Similar to midazolam, remimazolam binds to the BZD binding site on GABAARs to potentiate the effects of GABA. BZDs can have an unpredictable and prolonged duration of sedation [126]. In contrast to this limitation with more established BZDs, remimazolam may have many of the properties of the ideal sedative agent [143, 171, 172].

Remimazolam was shown to have rapid onset and offset when compared with midazolam, with respective recovery times of 10 and 40 min [173, 174]. Flumazenil reverses remimazolam, and recovery appears to be context insensitive following prolonged infusions [175]. Administration of remimazolam for upper gastrointestinal endoscopy was associated with an improved recovery time and higher rates of procedural success than midazolam [176]. Phase III trials investigating the use of remimazolam as a sedative agent for patients undergoing colonoscopy and bronchoscopy are either completed and pending results or are actively still recruiting [177]. Remimazolam may have a particular role in procedural sedation [178]. Remimazolam has the advantages of dose-dependent sedation, rapid offset of hypnotic effects, and lack of accumulation following infusion in this setting [173‐176]. Studies have shown that remimazolam has significantly reduced onset and recovery times compared with placebo [177‐180]. The incidence of treatment-emergent adverse events, such as hypotension, hypertension, and hypoxia, are lower with remimazolam when compared with midazolam [181].

Reversal with flumazenil was not required in any of the remimazolam recipients [181]. Higher cumulative doses with fentanyl were associated with more ADRs in trials [182]. Remimazolam is also currently being evaluated for efficacy and safety as a sedative agent in high-risk patients (American Society of Anesthesiologists [ASA] class III and IV) undergoing colonoscopy, as a sedative agent in patients with hepatic impairment and as an adjunctive agent for induction of general anesthesia [183].

3.4 Alphaxalone/Cyclodextrin Compounds

Alphaxalone is a neurosteroid analog of progesterone and the metabolite of progesterone 3α-hydroxy-5α-pregnan-20-one (allopregnanolone). Alphaxalone is a GABAAR agonist and has sedating, anesthetic, anticonvulsant, and neuroprotective properties [184, 185]. This drug was originally marketed in the 1970s and 1980s in combination with a small amount of a related compound, alphadolone, and with a formulation vehicle Cremophor (as Althesin and Alfathesin). The characteristics of this agent included rapid onset and offset of hypnotic effect, in addition to minor cardiovascular and respiratory depressant effects [186]. However, due to hypersensitivity reaction, including anaphylaxis, to the Cremophor element of the drug, alphaxalone was withdrawn [187].

More recently, alphaxalone has been formulated in combination with 7-sulfobutylether-β-cyclodextrin (SBECD), which has a low hypersensitivity profile [188, 189]. A phase I trial found that this new aqueous formulation of alphaxalone and propofol has a similar potency to its predecessor (Althesin) and has similar onset and offset times as propofol. This new compound may have many of the advantages of propofol as a fast- onset, fast-offset IV anesthetic but without the negative aspects of propofol such as pain on injection, cardiorespiratory depression, and the risk of solvent toxicity [190]. Animal studies have proposed that early exposure to commonly used GA causes widespread neurotoxicity due to apoptosis in areas especially related to cognition and socioemotional development [191]. The most vulnerable period is the time of synaptogenesis, which in humans begins from fetal period and reaches maximum by the second year of life [192]. According to the statement released by the US Food and Drug Administration, there is a potential risk for neurodevelopmental impairments in children prenatally or postnatally exposed to repeated or prolonged general anesthesia [193]. The search for alternative agents has led to the identification of neuroactive steroids, such as alphaxolone, alphadolone, hydroxydione, and minaxolone, that have better neuroprotection and potential as anesthetic/hypnotic agents. The initial attempts were risky due to significant adverse effects from the pharmaceutical preparations to dissolve them. Over the last decade, three neurosteroids have been developed: 3 B OH, CDNC24, and alphaxalone [191]. They are potent hypnotics when compared with propofol and ketamine in a dose-dependent manner and had lack of neurotoxicity when exposed for prolong periods in 7-day-old rat pups [194, 195].

4 Conclusions

There is a central role for GABAAR agonists in anesthesia and sedation. Propofol is the most popular agent for induction of anesthesia, in addition to being a popular agent for provision of sedation. There is a geographical variation in the use of other GABAAR such as thiopental and etomidate, although these agents are not used as uniformly as propofol. Newer GABAAR agonists based on parent compounds have been developed following the integration of knowledge regarding existing GABAAR agonist pharmacology. Many of these agents are still in development and undergoing trials; however, these agents may have many characteristics of the ideal sedative agent and, as a result, may have an increasing role in anesthesia and sedation in the future.

Declarations

Funding

No funding was received for the preparation or publication of this manuscript.

Conflicts of Interest

The authors declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

Ethics Approval

Not applicable.

Availability of Data and Materials

Data sharing is not applicable to this article, as no datasets were generated or analyzed during the current study.

Code Availability

Not applicable.

Author Contributions

A.B.P. and J.B. were involved in updating the manuscript, while B.G. provided the guidelines and reviewed the manuscript.

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

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Titel: The Role of GABA Receptors in Anesthesia and Sedation: An Updated Review
verfasst von: Annlin Bejoy Philip
Janette Brohan
Basavana Goudra
Publikationsdatum: 27.10.2024
Verlag: Springer International Publishing
Erschienen in: CNS Drugs / Ausgabe 1/2025
Print ISSN: 1172-7047
Elektronische ISSN: 1179-1934
DOI: https://doi.org/10.1007/s40263-024-01128-6

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Ein Forschungsteam aus Deutschland und Kanada hat eine Reihe metabolischer, okulärer, muskuloskelettaler, gastrointestinaler und kardiovaskulärer Symptome identifiziert, die bei Kindern und Jugendlichen der Diagnose einer multiplen Sklerose (MS) vorausgehen können.

Migräne verstehen und psychotherapeutisch behandeln

31.12.2024
Migräne
Podcast

Das Wissen über die Mechanismen, die im Gehirn bei einer Migräneattacke ablaufen, und mögliche Auslöser wird immer breiter. Der psychologische Psychotherapeut Dr. Dipl.-Psych. Timo Klan fasst den aktuellen Erkenntnisstand zusammen. Und er gibt Tipps für eine differenzierte, individuelle Diagnostik auch von Begleiterkrankungen und beschreibt erfolgreiche psychotherapeutische Interventionen.

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Bildnachweise

Die Leitlinien für Ärztinnen und Ärzte, Arzt und Ärztin unkenntlich diskutieren Gehirn-Scans/© gorodenkoff / Getty Images / iStock (Symbolbild mit Fotomodellen), Senior mit Kopfschmerz/© Motortion / Getty Images / iStock (Symbolbild mit Fotomodell), Kind wird von einer Ärztin befragt/© Monkey Business / Stock.adobe.com (Symbolbild mit Fotomodellen), Springer Medizin Podcast - Migräne/© (M) Foto: goodluz / stock.adobe.com (Symbolbild mit Fotomodell)

Springer Medizin

Abstract

1 Introduction

1.1 Structure of GABAA Receptors

2 GABA-Minergic Agents Currently Used in Anesthesia and Sedation

2.1 Propofol

2.2 Barbiturates

2.3 Etomidate

2.4 Inhalational Anesthetic Agents

2.5 Benzodiazepines

3 Newer GABA-Minergic Agents

3.1 Fospropofol

3.2 Etomidate Analogues

3.3 Remimazolam

3.4 Alphaxalone/Cyclodextrin Compounds

4 Conclusions

Declarations

Funding

Conflicts of Interest

Ethics Approval

Consent to Participate/Publish

Availability of Data and Materials

Code Availability

Author Contributions

Unsere Produktempfehlungen

e.Med Interdisziplinär

e.Med Neurologie

e.Med Neurologie & Psychiatrie

e.Dent – Das Online-Abo der Zahnmedizin

1.1 Structure of GABA_A Receptors