Anaesthesia

Back to General Themes

Questions Received:

  1. We are university students doing a project on how anaesthetics work, we were wondering whether or not you could send us an e-mail of all the latest or most likely theories? And any other information which might be useful.

  2. I am a student doing a report on the cellular basis of ketamine. If someone could offer me any kind of related information please let me know.

Responses:

We are university students doing a project on how anaesthetics work, we were wondering whether or not you could send us an e-mail of all the latest or most likely theories? And any other information which might be useful. thank you.

11th October 1999

How do anaesthetics work? This is an intriguing question, and requires us to examine what we understand about consciousness and its relationship with patterns of brain activity. We know that the brain is made up of astronomical numbers of interconnected neurons, and we are gaining an insight into how those neural networks function. We know in great detail how neurons receive, process, and transmit information. What is less clear is how our experience of consciousness and the associated feelings of ‘self’, pain, and emotion might be linked to complex patterns of neuronal firing. Therefore we shall be hard-pressed to link what we know about the action of anaesthetics at the neuronal level to changes in the level of consciousness of the patient.

This gap in understanding between material and mental events is probably the result of the directive given some 300 years ago by the mathematician and philosopher Rene Descartes, who believed that the only legitimate realm for science is the study of material objects and their interaction, while the mental realm is best left to other disciplines such as philosophy and the arts. More recently, though, increasing numbers of scientists, many of them well-known in their particular fields of research, have taken up the challenge of trying to explain consciousness in a scientific way. A good way to follow the unfolding of the continuing debate is to go through the Journal of Consciousness Studies from its inception in 1994. An author who may be of particular relevance to your search for information is Stuart Hameroff, who is an anaesthetist with a special interest in explaining consciousness (see for example Hameroff, 1998). Hameroff has collaborated with Roger Penrose to develop an explanation of consciousness founded on quantum theory, so be prepared for some subtle ideas...

Operations are carried out routinely on anaesthetised patients in every hospital, and yet we have no way at present of being sure that the patient is really unconscious. Some patients are able after the operation to report events that took place during the operation when they should have been fully anaesthetised. The experience can be distressing for the patient. The search is on to find an objective way of monitoring levels of consciousness. It has been noted that 40 Hz neuronal oscillations occur in the brains of awake people, so that may be a useful sign to monitor in patients during operations (Kulli and Koch, 1991). However, at the present time the phenomenon of conscious is a very private one, and we really have no reliable way of knowing whether another person or another animal is conscious.

A bewildering array of chemicals can induce anaesthesia: alcohols, alkanes, ketones, ethers, barbiturates, isoflurane - even the so-called inert gases such as xenon! It is difficult to imagine that such a diverse range of chemical types would all act in the same way. However, studies focusing on the neuronal level of anaesthetic action are beginning to make progress. There is now evidence that general anaesthetics work by influencing the activity of channel proteins in the cell membranes of neurons (Davies et al, 1997; Krasowski and Harrison, 1999). The result is that the transmission of nerve impulses through neural networks becomes modified. Another possibility is that anaesthetics interfere with signal transduction from the receptor proteins in the cell membrane into the cytoplasm (Slater et al, 1993).

Anaesthetics affect not only the release of neurotransmitters from neurons, but also the responsiveness of neurons to the effects of neurotransmitters. Neurotransmitter released from a pre-synaptic terminal binds to specific, ligand-gated receptors in the post-synaptic membrane of the next neuron to open up ion channels in the cell membrane. The flow of ions through these channels generates electrical signals in the post-synaptic neuron. Post-synaptic proteins are particularly sensitive to anaesthetic action (Pocock and Richards, 1993; Richards, 1995; Franks and Lieb, 1998; Richards, 1998). One class of receptor responds to a neurotransmitter called GABA that is released from nerve endings and which has an inhibitory effect on most neurons. It seems that most general anaesthetics enhance the action of GABA or even produce an inhibitory effect in the absence of GABA, causing widespread inhibition of neuronal activity and the loss of consciousness and sensation. Xenon also affects synaptic transmission, but in this case the receptors are excitatory NMDA receptor channels that are known to be involved in learning, memory, and pain (Franks et al, 1998).

The patch-clamp technique allows the measurement of very small electrical currents crossing cell membranes, and the techniques of molecular biology have allowed the subunits of most ligand-gated ion channels to be cloned and sequenced. Cryo-electronmicroscopy has also been helpful in revealing the structure of ion channels, and their changes in conformation when activated by anaesthetics and other chemicals (Charlesworth, Pocock, and Richards, 1992; Gage, 1998). There are many factors modulating the anesthetic sensitivity of ion channels, including the make-up of the cell membrane lipid in which they are embedded, electrolyte environment, ion channel subtype, and the functional state of the neural network (Urban and Friederich, 1998).

For good reviews of the cellular mechanisms of general anaesthesia see Franks and Lieb (1994, 1997).

References

I am a student doing a report on the cellular basis of ketamine. If someone could offer me any kind of related information please let me know.

27th November 1999

A useful review of the actions and uses of ketamine can be found in Hirota and Lambert (1996).

Ketamine has been in clinical use for about 4 decades (Albrecht et al, 1996; Hempelmann and Kuhn, 1997). It induces anaesthesia, analgesia, sleep, and activation of the sympathetic nervous system (Reboso Morales and Gonzalez Miranda, 1999). The different effects of ketamine are mediated by different sites of action. In essence, though, ketamine interacts with a variety of receptors carried by neurons, especially the N-methyl-D-aspartate (NMDA) receptors (Detsch and Kochs, 1997; Kress, 1997; Adams, 1998).

Ketamine has rapid onset after intravenous injection and provides acceptable anaesthesia when administered in continuous infusion. It allows for gentle anaesthetic induction in children (Green et al, 1998; Kruger, 1998; Slonim and Ognibene, 1998; Bergman, 1999). In adults ketamine is most often used for major surgery, particularly in the elderly and in high risk patients who benefit from the sympathomimetic properties (Adams, 1997a,b; Brown and Wagner, 1999). However, ketamine should not be used in patients who suffer from arterial hypertension and coronary artery disease (Zielmann et al, 1997). The adverse effects include hallucinations and hypersalivation, and these can be controlled by the use of a hypnotic or sedative drug (Engelhardt, 1997).

Ketamine may be given before, during, and after surgery to prevent or diminish operative pain (Fletcher, 1998; Goodwin, 1998; Schmid, Sandler, and Katz, 1999). Ketamine can also be used at low doses for the management of chronic pain (Ahmedzai, 1997; Coe, 1997; Wiesenfeld-Hallin, 1998; Enarson, Hays, and Woodroffe, 1999).

Ketamine is generally administered as a mixture of equal amounts of two optical isomers, S(+)and R(-).The isomers are chemically identical in all respects except for the direction with which they rotate plane-polarized light, a result of the three-dimensional arrangement of their constituent atoms. When the isomer and its corresponding enantiomer are present in equal proportions, they are called racemic mixture. (A racemic mixture does not rotate polarized light since the optical activities of the two isomers cancel each other.) However, the molecules that make up the body usually react more readily with one isomer than the other since they have a matching three-dimensional form. For this reason, S(+)-ketamine is about three times more potent than R(-) (Albrecht et al, 1996). New production techniques are making it possible to use pure isomers, and this reduces unwanted side effects (Graf and Martin, 1998).

Initially there were concerns that ketamine might induce convulsions, but recent studies have demonstrated that it has anticonvulsive and even neuroprotective properties (Detsch and Kochs, 1997; Mantz, 1999). It appears that ketamine, especially the S(+) form, helps to regulate intracellular calcium and energy levels in damaged neurons by blocking excessive NMDA-receptor stimulation. This may reduce progressive neuronal degeneration and cell death (Pfenninger and Himmelseher, 1997).

Ketamine can accentuate the symptoms of schizophrenia (Tamminga, 1999). Since ketamine reduces neurotransmission at glutamate-using synapses in the brain, it has been suggested that perhaps schizophrenia is a consequence of below normal activity in synapses of the hippocampus and its target areas, particularly the anterior cingulate cortex (Abi-Saab et al, 1998; Vollenweider, 1998; Jentsch and Roth, 1999; Tamminga, 1999).

References

Back to General Themes