GABA(A) receptor-targeted drug development -New perspectives in perioperative anesthesia

ABSTRACT

Introduction: Perioperative anesthesia delivers pre-, intra-, and postoperative care to meet the needs of patients undergoing diagnostic and surgical procedures. Major challenges are patients at the extremes of age and individuals with a pre-existing disease burden. Frequent problems are the development of chronic pain and cognitive dysfunction upon surgery. Current perioperative pharmacotherapy utilizes a number of drugs acting at GABA_A receptors.

Area covered: This review evaluates novel formulations and newly designed GABAergic drugs, offering future improvements in perioperative anesthesia, especially for reducing mortality and avoiding cognitive dysfunction and chronic pain as an outcome of surgery.

Expert opinion: There are multiple reasons for mounting efforts in the development of novel GABAergic medications. First, requirements in perioperative anesthesia care have substantially changed during the last two decades. In this respect, the dramatic increase in life expectancy is the most important factor. Moreover, research has considerably expanded our knowledge of how drugs in current clinical use act on the molecular level. Almost all ongoing developmental programs choose chemical structures of well-tried agents as a starting point for exploring the properties of structural analogs. This strategy aims to maintain the clinically desired actions of mother compounds while attempting to extinguish adverse side effects.

Trial registration: ClinicalTrials.gov identifier: NCT02358538.

Trial registration: ClinicalTrials.gov identifier: NCT01725152.

KEYWORDS:

• Benzodiazepine
• translocator protein
• neurosteroid
• propofol
• etomidate
• cognitive dysfunction
• chronic pain

Article Highlights

• The definition of anesthesia care substantially changed during the last two decades. Formerly restricted to a short time window around surgery, it now includes long-term postoperative quality of life as an important parameter of outcome.

• Propofol is the most frequently used intravenous anesthetic. The modification of emulsions, the design of prodrugs and alternative compounds aim to attenuate propofol’s adverse effects including the risk of bacterial infection, pain upon injection and cardiovascular depression.

• Developmental programs on etomidate analogs that are devoid of adrenocortical toxicity may deliver potent hypnotic agents with a high margin of safety and minimal adverse side effects.

• Neurosteroid anesthetics are derived from the chemical structure of steroids synthetized in the brain. There is evidence that these drugs have a favorable side effect profile and a high margin of safety.

• Translocator protein (18 kDa) ligands produce anxiolysis, are neuroprotective and reduce neuroinflammation. These compounds may lower the risk of postoperative cognitive decline.

• Benzodiazepine site agonists preferring α2-subunit containing GABA_A receptors are non-sedating drugs for providing anxiolysis and analgesia. These agents may open novel opportunities in the therapy of critically ill patients.

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Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The manuscript was funded in part by the German Research Foundation (DFG) via grant AN 325-1 (awarded to B Antkowiak) and by the Eberhard-Karls-University, Tübingen.