Anaesthetic Drugs: Linking Molecular Actions to Clinical Effects

Abstract

The use of general anaesthetics has facilitated great advantages in surgery within the last 150 years. General anaesthesia is composed of several components including analgesia, amnesia, hypnosis and immobility. To achieve these components, general anaesthetics have to act via multiple molecular targets at different anatomical sites in the central nervous system. Much of our current understanding of how anaesthetics work has been obtained within the last few years on the basis of genetic approaches, in particular knock-out or knock-in mice. Anaesthetic drugs can be grouped into volatile and intravenous anaesthetics according to their route of administration. Common volatile anaesthetics induce immobility via molecular targets in the spinal cord, including glycine receptors, GABA(A) receptors, glutamate receptors, and TREK-1 potassium channels. In contrast, intravenous anaesthetics cause immobility almost exclusively via GABA(A) receptors harbouring beta3 subunits. Hypnosis is predominantly mediated by beta3-subunit containing GABA(A) receptors in the brain, whereas beta2 subunit containing receptors, which make up more than 50% of all GABA(A) receptors in the central nervous system, mediate sedation. At clinically relevant concentrations, ketamine and nitrous oxide block NMDA receptors. Unlike all other anaesthetics in clinical use they produce analgesia. Not only desired actions of anaesthetics, but also undesired side effects are linked to certain receptors. Respiratory depression involves beta3 containing GABA(A) receptors whereas hypothermia is largely mediated by GABA(A) receptors containing beta2 subunits. These recent insights into the clinically desired and undesired actions of anaesthetic agents provide new avenues for the design of drugs with an improved side-effect profile. Such agents would be especially beneficial for the treatment of newborn children, elderly patients and patients undergoing ambulatory surgery.

Anesthesia induces stress in Atlantic salmon (Salmo salar), Atlantic cod (Gadus morhua) and Atlantic halibut (Hippoglossus hippoglossus)

“…Metomidate causes sedation and hypnosis by affecting GABA A receptors. One of the side effects linked to agents that act via these receptors is respiratory depression (Grasshoff et al 2006;Zeller et al 2005). If lower dosages inhibit the respiratory capacity but not the perception of blood gases indicating a respiratory insufficiency the fish might respond by stress.…”

“…Isoeugenol is similar to eugenol, a widely used analgesic in dentistry which inhibits sodium, potassium, and calcium channels, inhibits N-methyl-D-aspartate (NMDA) receptors and potentiates inhibitory gamma-aminobutyric acid type A (GABA A ) receptors (Aoshima and Hamamoto 1999;Lee et al 2005;Li et al 2007;Park et al 2006;Wie et al 1997). Metomidate is a methyl analogue of etomidate, a non-barbiturate hypnotic that modulates and activates GABA A receptors (Ashton and Wauquier 1985;Grasshoff et al 2006;Rusch et al 2004;Yang and Uchida 1996). Metomidate has been found to inhibit the cortisol stress response in fish (Olsen et al 1995;Thomas and Robertson 1991).…”

Anaesthesia of farmed fish: implications for welfare

“…The increased chloride conductance drives the membrane potential towards the reversal potential of the Cl¯ion, thus inhibiting the firing of new action potentials. GABA A receptor activation produces sedation and hypnosis, but limited analgesia and immobilisation (Grasshoff et al 2006). Etomidate is commonly used in human and veterinary medicine as a sedative and for inducing anaesthesia (Ching and Baum 2009;Darrouj et al 2009;Falk and Zed 2004;Sams et al 2008).…”

Modulation of Presynaptic β3-Containing GABAAReceptors Limits the Immobilizing Actions of GABAergic Anesthetics

“…General anesthetics like etomidate and propofol, which act almost exclusively via GABA A receptors, are potent hypnotics, but their efficacy in depressing spontaneous and evoked movements is clearly limited (Ashworth and Smith, 1998;Smith and Thwaites, 1999;Watson and Shah, 2000;Rudolph and Antkowiak, 2004;Grasshoff et al, 2006a). In clinical practice, these agents are routinely used for providing hypnosis and amnesia but rarely are administered to achieve immobility.…”