How do anesthetics work?
The barbiturates were the first class of drugs to be used as intravenous anaesthetics, though they were first discovered many years before their first clinical use in this capacity. They were first synthesised in 1854, and in the late 19th century were often used as hypnotic agents for the treatment of insomnia. A huge number of different related agents were synthesised, but only around a dozen or so were commonly used.
The first barbiturate to be used for anaesthesia was sodium sec-butyl-(2-bromo-allyl)-barbiturate (given the slightly shorter brand name of Pernocton). The first to be introduced to clinical anaesthesia was hexobarbital in 1932, and others soon followed. They would be the main drugs used as intravenous anaesthetics until the mid-20th century; though we don’t really know exactly how any anaesthetics work, it’s thought that the barbiturates work by prolonging the action of the neurotransmitter GABA on its receptors. However, they are not without their controversies, particularly in recent years.
One of the past uses of some of the barbiturates, particularly sodium thiopental and thioamylal, was as ‘truth serum.’ Investigators would on occasion give these drugs to suspects in order to try and obtain a confession. Though the validity of these confessions under the disinhibiting influence of the drugs have been called into question, they have resulted in criminal convictions in the past, and barbiturates are still sometimes used for this purpose today.
Another controversial use of barbiturates is in lethal injections in the United States. Previously, thiopental, in the form of its sodium salt, was the first of three drugs given during the course of the lethal injection in the majority of US states in which the death penalty is enforced. However, in recent years, the main US manufacturer of the drug ceased production, the drug has been barred from export from the EU for the purpose of use in lethal injections. As such, other alternatives have had to be found.
In their other uses, barbiturates can also have dangers. They have a capacity to cause dependence, and have also been used in suicides – none more famous than that of Marilyn Monroe, whose death certificate proclaims the cause of death to be due to a barbiturate overdose. It was also theorised that overdose could occur accidentally in some cases, due to the potential amnesia-inducing effects of the drugs.
In the mid-20th century, another class of drugs was discovered which would come to be used as intravenous anaesthetics. These were the benzodiazepines. The most famous of these, diazepam, was discovered in 1963; today, it is just as commonly known by its brand name, valium. Valium was marketed as an anti-anxiety medication, and diazepam became one of the most frequently prescribed medicines in the world for this purpose. It was colloquially referred to as ‘Mother’s Little Helper’, and the benzodiazepines also looked like they could significantly help the medical profession.
The benzodiazepines are thought to work by triggering the release of the neurotransmitter GABA, and they don’t cause respiratory depression, which had always been a concern with barbiturates. However, like the barbiturates, they also had the potential for abuse. In the context of their other major use as anti-anxiety medication, further research has led to the recommendation that they should not be prescribed for longer than a 4 week period, but in many cases this is still exceeded by patients. Additionally, tolerance to these drugs can be acquired, meaning that increasing amounts are required to achieve the same effect.
Benzodiazepines are purely sedatives, which means they must be administered with other anaesthetics. However, they can still be useful because they can reduce the quantity of other anaesthetics that are required. They can also have an amnesia-inducing effect, which can be beneficial for the purposes of dental surgery, or potentially unpleasant awakenings after surgery. As we mentioned the use of barbiturates in lethal injections, it’s worth pointing out that the inability to continue the use of thiopental has led in many cases to midazolam’s use as its replacement.
The barbiturates are today much less frequently used as intravenous anaesthetics, because they’ve been largely superseded by another anaesthetic: propofol. Propofol is probably the most widely used intravenous anaesthetic, as it has a number of benefits over the other featured here. Firstly, awakening and recovery from anaesthesia with propofol is relatively quick, and it can also sometimes be accompanied by a mild euphoric feeling, which has obvious benefits for patients. Additionally, its use has been associated with decreased post-operation vomiting. It does come with a larger price tag than some of the other drugs used for anaesthesia, but its use is often preferable. It is often administered with opioid drugs in order to help provide an analgesic effect (we talked about opioid painkillers in another previous graphic).
As the graphic shows, other intravenous anaesthetics are also still in use, and often a combination of drugs are used in order to maintain the patient in comfortable anaesthesia for the duration of the surgery. For other operations, local or topical anaesthetics may be used – and we’ll look at these in another future graphic.
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