Minutes of the meeting held on Thursday 23rd May 2019 at the Liverpool Medical Institution
‘General Anaesthesia and the Illusion of Rational Drug Design’
The meeting opened with the AGM after which, Prof Hunter introduced the 5th T.Cecil Gray BJA Medal Lecture and the evening’s speaker, Prof Hugh C Hemmings Jr. Editor-in-Chief of the British Journal of Anaesthesia (BJA) and welcomed Prof David Lambert, Chair of the BJA Board. She went on to outline the many connections between Prof Gray and anaesthesia in Liverpool with Prof Hemmings’ career in Cornell University and the wider United States.
Prof Hemmings started his lecture outlining that general anaesthetics work at multiple sites and have distinct mechanisms which generally reduce excitation and enhance inhibition. He outlined the essential components of unconsciousness, immobility and amnesia (plus ideally analgesia and depressions of autonomic responses) then compared this with Prof T Cecil Gray’s view of balanced anaesthesia being narcosis, paralysis and analgesia and control of the autonomic reflexes.
He then focused on the connection between Prof Gray and Sir Charles Sherrington’s work looking at spinal reflexes and Prof Gray’s play on words in writing ‘Disintegration of the Nervous System’ outlined in his Joseph Clover lecture given at the RCS (T.C.Gray, 1954).
Prof Hemmings went onto explain that each anaesthetic endpoint has distinct potencies and CNS sites of action and showed graphs explaining this. Sedation/amnesia had sites of action in the frontal cortex and hippocampus, unconsciousness had sites in the cortical networks and immobility, sites in the spinal cord. He described how extraordinary chemical diversity produced similar anaesthetic states which were especially seen with the inhalational anaesthetic agents. He spoke about the Myer-Overton correlation which led to the non-specific lipid based hypothesis which accounted for chemical diversity but was not supported by biophysical studies attempting to demonstrate changes in the properties of the lipid bilayer. This led to the protein target hypothesis of general anaesthetics.
With the focus shifting to protein sites of anaesthetic action in the 1980s, he spoke about the criteria to discern the important pharmacological effects from the toxic effects. These included reversibility, use in clinically relevant concentrations, and target expression in the part of the nervous system where the effect is known to occur (such as immobility being spinal and memory, frontal cortex). He said once these filters are applied, some agents can be eliminated. He referred back to Sir Charles Sherrington’s work, studying the effects of chloroform on synaptic transmission using the neuromuscular junction (Sherrigton, 1911). These showed that synaptic transmission was more important to mechanism of action of anaesthetics than transmission along the axon itself. This work was commissioned by the Chloroform Committee in the early 1900s to understand why so many people were dying from chloroform. Today, synaptic function can be measured in brain slices and Prof Hemmings showed data from excitatory and inhibitory potentials in a hippocampal slice (involved in learning and memory). The excitatory potential was followed by a prolonged inhibitory hyperpolarisation in the hippocampus and if an anaesthetic agent like Halothane was applied. The excitatory synaptic potential was markedly depressed with significant potentiation of the inhibitory potential. He said that he still finds it remarkable that a drug can affect neurotransmission by two different transmitters in different directions. More work is currently being done to identify the specific target sites for the actions of anaesthetic agents.
Prof Hemmings then discussed current knowledge of the principle protein targets being ligand gated and voltage gated ion channels. The main inhibitory transmitter is known to be GABAA with NMDA being the main excitatory transmitter.
He described anaesthetics being divided into three classes:
- The potent inhaled volatiles: which are the most non-specific and target multiple sites.
- The gaseous inhaled anaesthetics (e.g. Cyclopropane, Xe, N20): which are less promiscuous, block NMDA and have no effect on GABAA.
- The intravenous anaesthetics: which are the most selective. Propofol and etomidate potentiate GABAA almost exclusively at clinical concentration. Ketamine blocks NMDA & HCN1 channels almost exclusively.
He spoke more about the GABAA receptor and the potentiation of it by volatile and intravenous anaesthetics. He showed work on receptor mutations in mice to try to elucidate the specific binding sites. He went over some drug receptor basics regarding agonists, antagonists and allosteric modulation. He then looked at the effects of volatile anaesthetic agents on voltage gated sodium channels. He showed some of his work using tetrodotoxin, which inhibits sodium channels and therefore should decrease MAC and veratridine, a toxin that opens sodium channels causing a depolarisation block which should increase MAC. This had indeed been the case and therefore did strongly implicate spinal sodium channels in anaesthetic mechanisms of action.
Prof Hemmings ended with a summary stating his view that general anaesthetics are a composite of pharmacological effects involving distinct sites and molecular targets. Their overall physiological outcome is enhanced inhibition and depressed excitation leading to altered communication in the brain and spinal cord resulting in unconsciousness, amnesia, and immobility. Voltage gated sodium channels are plausible targets and identification of the structure of these channels is under way. The next step will be to establish exactly where the binding sites are that agents affect and try to develop more specific and potent drugs to rationalise future drug design.
Minutes written by Dr Gemma Roberts 23.5.19.