Pharmacology for Anaesthesia and Intensive Care

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SECTION II Coredrugs in anaesthetic practice

8

General anaesthetic agents

Our understanding of the mechanisms involved in the action of general anaesthetics

has increased considerably in recent times and is discussed below. This is followed

bysections discussing intravenous and inhaled anaesthetic agents.

Mechanisms of general anaesthetic action

Any mechanism of general anaesthetic action must be able to explain: loss of con-

scious awareness, loss of response to noxious stimuli (anti-nociceptive effect) and

perhaps most important of all, reversibility.

Anatomical sites of action

General anaesthetic agents affect both brain and spinal cord to account for phys-

iological responses to nociception, loss of consciousness and inhibition of explicit

memory. Auditory and sensory evoked potential data implicate the thalamus as the

most likely primary target, but secondary sites such as the limbic system (associated

with memory) and certain cortical areas are also important. Halogenated volatile

anaesthetics appear to have a greater influence on spinal cord than do the intra-

venous agents.

Molecular theories

Atthe beginning of the 19th century, Overton and Meyer independently described

the linear correlation between the lipid solubility of anaesthetic agents and their

potency (Figure8.1). This correlation was so impressive, given the great variation

in structure of these agents, that it suggested a non-specific mechanism of action

based on this physicochemical property. Later interpretation pointed out that any

highly lipophilic area was a potential site of action, with cell membranes being the

most likely contender given the high concentration of lipids. There are problems

with a unified theory based on lipid interactions: some general anaesthetics, such as

ketamine, are extreme outliers, and the stereoisomers R-etomidate and S-etomidate

have identical lipid solubility but only R-etomidate has anaesthetic properties.

Membrane lipids

There are several potential lipophilic sites in cell membranes, including the lipid

bilayer itself and the annular lipids surrounding ionic channels.