If you’ve ever needed a tooth out, or had surgery of any kind, chances are you’ll have experienced use of an inhalational anaesthetic. All of the compounds shown above can induce general anaesthesia, and a range have been utilised since the initial discovery of nitrous oxide in the mid-1800s. Often, intravenous drugs will be used for induction of anaesthesia, but inhalational agents may then be used to maintain this – this graphic looks at how the drugs in use for this purpose have varied over the years.
The mechanism by which these anaesthetics act is, strangely, one about which we know comparatively little. It is seemingly unrelated to chemical structure, with a range of varied compounds capable of inducing anaesthetic effects. There are two main theories about the manner in which these compounds act. One suggests that they interact with the lipid-based membranes of neurons; this theory is backed by the fact that the lipid solubility of the anaesthetic agents correlates well with their potencies. Another theory suggests they may bind to specific sites in certain proteins, but as both theories have their detractions, there is still no consensus on how they function.
Whilst we may know little as to how they work, the stages of anaesthesia when these agents are administered are well-defined. The induction stage, that between the agent being administered and the patient losing consciousness, is characterised by drowsiness, and a degree of analgesia that varies with the particular agent being used. The ‘excitement stage’ follows – at this stage, the patient is unconscious, but still responds reflexively, with some reflexes appearing exaggerated. Uncontrolled movement, vomiting, and breath-holding can occur; additionally, irregular respiration and heart rates can be observed. This can obviously be of potential danger to the patient, and as such any procedure will be designed to minimise the time spent in this state, or even bypass it entirely.
The third stage, ‘surgical anaesthesia’, is the stage at which muscles relax, and breathing rate decreases. At this stage, the patient is unconscious and ready for surgery. Care must be taken not to progress to the fourth stage, that of overdose, where too much anaesthetic has been given to the patient and respiration ceases. This stage can result in death without intervention.
Important factors in the suitability of an anaesthetic are how quickly its effects kick in, and how quickly they abate. These factors are determined by the solubility of the anaesthetic agent in blood and in lipids (fats). Those anaesthetics which exhibit a low solubility in blood have a quicker onset and offset than those which are more soluble. Meanwhile, if they have a high lipid solubility, prolonged use can lead to after effects being felt.
Though a number of anaesthetic agents have been utilised over the years, a number of them are now consigned to history due to adverse effects. With that said, the very first inhalational anaesthetic, nitrous oxide, is still used today, though as it is itself a weak anaesthetic, it is often used as a carrier gas for other, more potent drugs. Inhaling it can have a euphoric effect, hence the more commonly known name of ‘laughing gas’. Ether is also still used on rare occasions, though in developed countries it has been largely replaced by newer agents.
Chloroform, another well-known substance, was once widely used as an anaesthetic, but this use abruptly ceased after its toxicity and tendency to cause fatalities unless doses were carefully regulated was noted. It’s a drug whose name seems to weirdly persist in the public consciousness, however; many a non-chemist will have an awareness of chloroform. Perhaps this stems from the reputation of it being used in criminal activities, or, more specifically, the concept of the rag soaked in chloroform.
Popular opinion might claim that a whiff of chloroform is enough to induce unconsciousness, but the reality is somewhat less dramatic. Whilst it was undoubtedly employed with this purpose in mind on numerous occasions, there is no evidence of it ever proving particularly successful. Generally, inhalation of chloroform in such a manner would require approximately five minutes to produce anaesthesia, making its use as a weapon of surprise somewhat limited. Medical journal The Lancet, in response to the myth surrounding chloroform, proclaimed a general challenge in 1865 to provide evidence that chloroform was capable of such instant incapacitation. To the present day, no evidence has emerged.
Other agents, too, have been discarded after relatively short periods of use. Cyclopropane fell out of favour due to its high cost and explosive nature, though it is still used developing countries in some cases. Others, like trichloroethene, were simply replaced by faster-acting agents, or, in the case of fluoroxene, simply because they provided no distinct advantages over anaesthetics already available. More serious health effects were to blame for the demise of others: the use of halothane was drastically reduced due to its links with hepatitis and cardiac arrhythmia. Methoxyflurane, another drug, has also been largely withdrawn from use due to links to kidney toxicity, though it is still used as an emergency agent in some cases in Australia.
The currently utilised inhalational anaesthetics, particularly the most recently discovered agents desflurane and sevoflurane, minimise irritation to the airways and are also non-flammable, making their use safer. The exclusion of all halogen atoms except fluorine also makes them more resistant to metabolism than some of the previous anaesthetics. Additionally, it makes their solubility in lipids lower, meaning that their onset and offset is generally much faster. A final agent that is currently utilised, but not included in the graphic, is xenon. Whilst its expense has generally prohibited its use, advances in its recovery and recycling have made its use more plausible. It is more potent than nitrous oxide, and as such has potential to be used in its place.
Of course, inhalational anaesthetics are not the only anaesthetics available; in the present day, intravenous anaesthetics are also utilised, and are a group of drugs we’ll consider in a future graphic. In the meantime, be sure to check out the previous entries in the Medicinal Chemistry series on antibiotics and painkillers!
References & Further Reading
- A brief history of anaesthesia – R Hirst, The Internet Journal of Anaesthesiology
- Sevoflurane, desflurane & xenon – C C Natalini
- Pharmacology – H P Rang & M M Dale