Benefits of Developing Anesthetics with Favorable Pharmacokinetics

Cameron Bosinski, MD, MS

The development of anesthetics with favorable pharmacokinetics has allowed for patients to wake up from anesthesia faster and more comfortably. However, there are several situations in which it would be beneficial to further reduce the time for patients to emerge from anesthesia and return to their cognitive baseline. In the Society for Neuroscience in Anesthesiology and Critical Care plenary session, “Applying Molecular and Systems Neuroscience to Develop Reversal Agents for General Anesthesia,” held on Friday, March 18 at the IARS 2022 Annual Meeting, the speakers discussed potential therapies to reverse general anesthesia.

Ken Solt, MD, an associate professor at Massachusetts General Hospital began the session with a presentation entitled “Activating Dopaminergic Neurotransmission to Reverse General Anesthesia.” Although there have been advances in anesthetic pharmacokinetics, there are still several clinical scenarios in which anesthetic reversal would be useful, including can’t ventilate/can’t intubate situations, delayed emergence, and sustained wakefulness after neurological or bariatric surgery. Several classes of medications, paralytics, opioids, benzodiazepines and others have reversal agents, but due to their complex molecular mechanisms of action, there are no specific reversal agents for anesthetics.

Arousal is controlled by multiple subcortical nuclei. The ventral tegmental area (VTA) is a dopaminergic center that is important for reward, but also for arousal. Electrical stimulation of the VTA in rats reverses propofol and isoflurane anesthesia (Solt, Anesthesiology 2014). Dr. Solt has recently shown that electrical stimulation of the VTA can reverse fentanyl or dexmedetomidine-induced unconsciousness, but not ketamine-induced unconsciousness. Male and female rats had similar time to emergence after VTA stimulation.

D-amphetamine significantly accelerates the return of righting reflex and respiratory function after fentanyl-induced unconsciousness (Moody, Front Pharmacol 2020). D-amphetamine reverses dexmedetomidine-induced unconsciousness, but not ketamine-induced unconsciousness. This effect of D-amphetamine on dexmedetomidine was abolished when animals were pretreated with a dopamine antagonist. Sex differences were observed in which females took longer to wake up after a dexmedetomidine infusion. However, both sexes had similar duration of emergence after injection of D-amphetamine (Kato, Front Pharmacol 2021). D-amphetamine may be a useful method to facilitate emergence from anesthesia induced by propofol, halogenated ethers, dexmedetomidine or fentanyl.

Next, Zheng Xie, MD, PhD, a professor at the University of Chicago, gave a talk entitled, “A New Strategy to Reverse General Anesthesia with Caffeine.” The amount of research performed on the pharmacology of inhaled and intravenous anesthetics has declined since the 1970s, while research on management and monitoring has been on the rise since then. Recently, there has been a shift to focus on reducing postoperative delirium and cognitive impairment following surgery, especially in children and the elderly. Facilitating emergence may lead to reduced OR time, reduced PACU stay and improved functional recovery, especially in vulnerable populations.

Anesthetics are known to have many targets, including cholinergic, adrenergic, GABAergic, dopaminergic, orexin, adenosine, and cAMP (Kelz, Escape from Oblivion). Caffeine and theophylline inhibit phosphodiesterase and adenosine receptors, which causes an increase in cAMP and leads to increased neurotransmitter release. Forskolin directly stimulates adenylate cyclase to increase intracellular cAMP. Dr. Xie was able to show that all three of these drugs reduce time to emergence from isoflurane in rats, with caffeine having the largest effect (Fong, Neurophys 2017). The combination of forskolin with an adenosine A2A receptor antagonist can recapitulate the effect size seen after caffeine administration alone. Caffeine was also able to facilitate time to emergence after a single bolus of propofol. When isoflurane was used, rats had a return of righting at a higher end-tidal concentration compared to controls (0.86% vs 0.42%). In addition, rats had less burst suppression at 2% isoflurane after they received caffeine compared to saline controls.

A crossover trial was performed in humans and showed that caffeine reduces emergence from 1.2% isoflurane on average by 5 minutes. In addition, BIS scores recovered faster, patients woke up with a higher end-tidal concentration of isoflurane and did not have any changes of vital signs compared to controls. More patients treated with caffeine were able to complete a psychomotor task at 15 minutes (Fong, Anesthesiology 2018).

Dexmedetomidine is known to reduce intracellular cAMP by activating alpha-2 receptors on presynaptic nerve terminals, but can have prolonged time to recovery (Brown, Anesth Analg, Multimodal General Anesthesia 2018).  Atipamezole is an alpha-2 receptor antagonist that is often used in rodents to reverse xylazine general anesthesia. Dr. Xie induced general anesthesia in rats with 10/mcg/kg bolus of dexmedetomidine then injected atipamezole alone or atipamezole in combination with 25 mg/kg of caffeine. He found that emergence time was reduced by 15 minutes after atipamezole administration. After injection of both atipamezole and caffeine, emergence was reduced by nearly 30 minutes.

Paul S. García, MD, PhD, an associate professor at Columbia University, spoke on “Inducing Emergence from General Anesthesia with Flumazenil and Atipamezole.” While an MD/PhD student, Dr. Garcia investigated whether GABA antagonists (flumazenil and clarithromycin) could be used to treat disorders of hypersomnia (Rye, Science Translational Medicine 2012, Bichler< J Neurophys 2017). He found that flumazenil administration can hasten emergence from anesthesia in rats. Emergence was associated with increased corticocortical neuronal activity as evidenced by increased activity in the beta range (Safavynia, Anesthesiology 2016). Flumazenil may facilitate a cortical, top-down influence on anesthetic emergence.

Medical providers are often vague about the differences between emergence and recovery. Emergence is when a patient regains awareness. Recovery is when a patient returns to their cognitive baseline. Problems of emergence include delayed arousal and agitation. Problems of recovery include delirium and persistent neurocognitive dysfunction.

Dr. García induced anesthesia with a mixture of ketamine and xylazine (α-2 agonist) and then administered either yohimbine and atipamezole to rats (Mess, PLOS One 2018). Atipamezole has a much greater selectivity for the α-2 vs α-1 receptor compared to yohimbine. Yohimbine and atipamezole were both able to significantly reduce the time to emergence after administration of the ketamine and xylazine mixture as determined by whisker-flicking, respiratory rate and forelimb movement. Atipamezole was able to significantly decrease time to recovery as indicated by the return of righting reflex, ambulation ataxia and sticky dot test. However, this effect on emergence was less robust after administration of yohimbine. The ability to decrease time to recovery was blocked after administration of prazosin and is likely due to cortical α-1 antagonism. This indicates that cortical activity may have a greater impact on recovery than emergence.

Prehabilitating of the cortical tissue may also have beneficial effects for emergence and recovery. In order to test this, Dr. García exposed rats to ten 20-minute sessions of direct current stimulation over the motor cortex prior to isoflurane exposure. After cortical electrical stimulation, animals were able to emerge from anesthesia and recover more quickly without any negative effects on sleep or home cage activity.