`Healthy discontent is a prelude to progress' – Mahatma Gandhi
Over time humankind has employed an array of natural medicines and physical methods to alleviate pain and suffering. Ancient Indian and Chinese texts record the beneficial analgesic effects of cannabis and henbane. In Egypt around 3000 B.C., the opium poppy, hellebore, beer, and the legendary mandrake were used for similar purposes [1
]. Other approaches to deal with surgical trauma and pain relied on physical methods such as cold, nerve compression, carotid artery occlusion or infliction of a cerebral concussion. The effectiveness of these historical agents is unknown but allude to an ever present need.
A new era of anaesthesia arose as one of the advancements of the Enlightenment. It began with the isolation of oxygen and the synthesis of nitrous oxide in the 1770’s by Joseph Priestley. Initially, nitrous oxide was used solely as an intoxicant. American dentist, Horace Wells was the first to recognize the anesthetizing potential of nitrous oxide; however, his attempt to produce surgical anaesthesia in 1845 with this weak anaesthetic was a miserable failure.
Another compound, known as `sweet vitriol' by Paracelsus and renamed ether in 1730 by German chemist Frobenius proved to be more potent. It was used for the first successful public demonstration of surgical anaesthesia, conducted by William Thomas Green Morton in Boston in 1846, the year after Wells’ failure [1
]. Prior to this, Crawford Long, an American physician practicing in Georgia had performed surgery under ether anaesthesia as early as 1842. In 1847, Scottish physician Sir James Young Simpson succeeded in demonstrating anaesthesia with chloroform, which had been discovered in 1831 by Souberain, Guthrie and Liebig. Chloroform was used by John Snow to oversee the painless delivery of Queen Victoria’s eighth child, Leopold, in 1850 [1
]. Fast forward to today, a large number of drugs are available to the modern anaesthetist to produce general anaesthesia, from intravenously administered hypnotics to halogenated vapours and gaseous agents such as xenon. The intravenous hypnotics, which provide a smooth induction of anaesthesia, include barbiturates such as sodium pentothal, introduced in 1934 in America by Lundy; etomidate, introduced and studied by Doenicke in 1973, and propofol, which has been widely accepted since its introduction in 1977. The structures of these disparate agents and others are shown in . This review will take a broad look at the mechanisms of action of both inhalational and injectable anaesthetics and attempt to discriminate where they may overlap and where they may diverge.
Overview of the most important, clinically used anaesthetics showing their chemical formulas and the year of their first clinical use.
Research efforts have pursued a reductionist path to approach the difficult problem of assigning the clinical effect of an anaesthetic to action at a single biological site. This so-called `unitary theory' has animated efforts to produce a single molecular definition of the site of anaesthesic action. Subsequent research has revealed a multitude of targets and produced a more complex picture of how clinically relevant doses of anaesthetics affect molecular targets throughout the central nervous system (CNS). Ironically, in recent years research groups have discovered that a few discrete sites within the CNS may indeed mediate the action of some general anaesthetics.