Index · Topics · The Agents

03The Agents

Every substance in this index arrived as chemistry before it arrived as medicine. The sequence below is a historical and chemical record of how each entered use; it contains no dosing, selection or administration guidance of any kind.

Chemistry first

The striking feature of the agent record is how long each substance sat on the shelf. Ether was described in 1540 and used surgically in the 1840s. Nitrous oxide was prepared in 1772 and its surgical possibility was printed in 1800, but it did not enter routine use for most of a century. The gap is not an accident of communication. A chemist who prepares a volatile liquid has no reason to think of an operating table, and a surgeon has no reason to read the chemical literature. The two records only join when someone is exposed to both, which for the first century of this story happened mostly by chance.

The inhalational line

Halothane deserves particular attention because it marks a change of method. The earlier agents were discovered: someone inhaled a substance that already existed and noticed what happened. Halothane was specified. The properties wanted were written down first, including non-flammability, chemical stability, sufficient volatility and low reactivity, and a molecule was then designed to meet them. That is a different intellectual operation, and it is the point at which the agent record stops being a history of accidents.

The local line

Running alongside, and largely independent of it, is the history of local anaesthesia, which begins in 1884 with the demonstration that a substance applied to the surface of the eye abolished sensation there without touching consciousness at all. Within a year the same principle was applied to nerve trunks, producing insensibility in the territory a nerve supplies, and in 1898 to the spinal fluid, producing it below the level of injection.

Conceptually this is a separate discovery. General anaesthesia removes the person who would feel the pain; local anaesthesia removes the signal before it arrives. That the two were pursued as one subject is a fact about professional organisation rather than about the underlying science, and it is one reason the mechanistic literature stayed confused for so long: local anaesthetic action on nerve conduction was understood decades before anything useful could be said about general anaesthetic action on the brain.

Injection and the separation of effects

Two twentieth-century developments changed what an agent was expected to do. The first was the arrival of short-acting intravenous induction in the 1930s, which meant that the unpleasant early minutes of inhalation could be skipped entirely. The second, in 1942, was the report of a plant-derived compound that produced muscular relaxation without producing unconsciousness.

That second development is more significant than it sounds. Before it, relaxation of the muscles had to be obtained by giving enough inhalational agent to reach a depth at which the muscles relaxed, which is to say by pushing the patient a long way down. Once relaxation could be produced separately, the depth required fell sharply, and the target of anaesthesia stopped being a single state and became a set of separable components: unconsciousness, absence of movement, and suppression of the responses to injury. Those components can be produced by different substances acting in different places, and that insight organises everything written about mechanism afterwards.