Mechanism of Volatile Anesthetics: Current Research

While anesthesia, such as volatile anesthetics, has been used in clinical practice since the end of the 19^th century, their mechanism of action is not well understood. This presents a problem in clinical practice; without an understanding of the mechanism of action of such ubiquitously used pharmacological agents, it can be difficult to control their effects. An earlier theory, the Meyers-Overton theory, postulated that anesthesia bonds to and dissolves lipids in biological membranes¹. While this theory would explain why lipid solubility is so interrelated with anesthesia potency, it is not well supported by current evidence.  

Today, a significant body of research backs the claim that anesthetics work by acting directly on target proteins, particularly two-pore domain potassium proteins⁴. This class of receptors works to maintain cell membrane potential in both excitable and non-excitable cells all over the body, which could explain why some types of anesthesia have such non-specific effects, some of which are related to post-operative complications⁴.  

An acute clinical post-operative complication caused by anesthesia is postoperative hypoxemia, in which the body’s reflex to hyperventilate in low oxygen states is inhibited². This reflex is mediated by two pore-domain potassium channels, specifically by TWIK-related –acid-sensitive (TASK) receptors in the carotid bodies. TASK receptors are constitutively active in normal physiological states. A drop in pH or P_O2 (as occurs in states of low O₂) inhibits these receptors, triggering hyperventilation². 

Current research on the mechanism of volatile anesthetics has shown that volatile anesthetics act on TASK-1 and TASK-3 receptors in the carotid bodies, hyperactivating them to inhibit the hyperventilation reflex⁵. This is required during surgery to stop the patient from fighting intubation; the problem occurs because the inhibition of TASK-1 and TASK-3 can persist long after surgery, resulting in hypoxemia and further complications². There are no widely accepted theories as to the how this effect occurs, but recent publications propose a hybrid between the earlier lipid theory and the receptor model: lipid raft disruption^3,5. Many target receptors being investigated are hydrophobic, only accessible to anesthesia molecules dissolved in lipid. Such dissolution could lead to a perturbation of the lipid rafts that make up membranes and affect membrane protein function and possibly inhibit the hyperventilation reflex³.

Because volatile anesthetics act on specific targets, the natural conclusion is that they compete for binding sites. Until now, these competitive interactions have been additive, as measured by the degree of anesthesia-induced paralysis. However, a recent study has recorded antagonizing effects between two volatile anesthetics — the administration of halothane and isoflurane caused a lesser effect than halothane alone⁵. The proposed mechanism of this antagonism lies in the fact that such two pore-domain proteins have multiple binding sites, and not all copies of the proteins have the same specific sites. Isoflurane and halothane likely bind to the same binding site, isoflurane binding with a lesser efficacy than halothane. Thus, when both agents are introduced, they compete for the same binding site, and isoflurane acts as a competitive antagonist on halothane⁵. If confirmed, this phenomenon may result in more targeted prevention against postoperative hypoxemia with fewer side effects than the current therapies⁵. 

References  

1. Borghese CM: Molecular Pharmacology of Volatile Anesthetics. International Anesthesiology Clinics 2015; 53: 28-39. doi: 10.1097/AIA.0000000000000060 

2. Forman SA: New evidence of receptor-based pharmacology underlying a volatile anesthetic effect. Anesthesiology 2020; 133: 973-75. doi: 10.1097/ALN.0000000000003559 

3. Mahmud AP, Petersen EN, Wang H, Lerner RA, Hansen SB: Studies on the mechanism of general anesthesia. PNAS 2020; 117: 13757-66. doi: 10.1073/pnas.2004259117 

4. Mathie A, Veale EL, Cunningham KP, Holden RG, Wright PD: Two-Pore Domain Protein Channels as Drug Targets: Anesthesiology and Beyond. Annual Review of Pharmacology and Toxicology 2021. doi: 10.1146/annurev-pharmtox-030920-111536 

5. Pandit JJ, Huskens N, O’Donohoe PB, Buckler KJ: Competitive interactions between halothane and isoflurane at the carotid body and TASK channels. Anesthesiology 2020; 133:1046–59. doi: 10.1097/ALN.0000000000003520