Category:Anesthetics

The anesthetics are the medicines that abolish pain and awareness for surgery, and their arrival is one of the genuine turning points in the history of medicine. For all of human history before the middle of the nineteenth century, surgery meant pain: operations were brief, brutal, and dreaded, and the skill most prized in a surgeon was speed. The discovery that a medicine could render a patient wholly insensible, and then return them unharmed, changed what surgery could be. The story is best told as a history of that discovery and of the classes of medicine that followed from it.

The wish to dull the pain of surgery is ancient. Opium, mandrake, henbane, and alcohol were all pressed into service, and from roughly the ninth century the "soporific sponge", a sponge steeped in such plant extracts and held to the face, was used across medieval Europe and the Islamic world. These methods were unreliable and dangerous: the dose that dulled pain and the dose that killed were not far apart, and none produced anything like dependable insensibility. For practical purposes, surgery remained an ordeal to be survived.

The decisive event took place on October 16, 1846, at the Massachusetts General Hospital in Boston. The dentist William T. G. Morton publicly administered diethyl ether to a surgical patient, and the surgeon John Collins Warren removed a tumour from the patient's neck without the patient feeling pain. Warren's remark to the watching audience, "Gentlemen, this is no humbug", marked the moment the world changed: news of the demonstration spread within months across Europe and beyond.^[1] The room is remembered as the "Ether Dome".

Credit for the discovery is not Morton's alone. The physician Crawford Long had used ether for surgery in Georgia as early as 1842 but did not publish his results until years later; the dentist Horace Wells had demonstrated nitrous oxide for a dental extraction in 1845, but the demonstration was judged a failure at the time. It was Morton's 1846 demonstration that was public, successful, and decisive. Soon afterward Oliver Wendell Holmes proposed the words "anaesthesia" and "anaesthetic" for the new state and the agents that produced it.

The ether that revolutionized surgery had a long prior life. It had been described in the sixteenth century, Paracelsus is said to have noted its effect on animals, and by the early nineteenth century it was familiar enough to be inhaled for amusement at "ether frolics". For a time in the nineteenth century ether was also taken recreationally as a substitute for alcohol; the novelist John Irving, whose The Cider House Rules centers on an ether-addicted physician, called it "the perfect addiction for a conservative", and the poet Allen Ginsberg wrote a poem, "Aether", recording an ether experience.

Within a year of Ether Day a rival agent appeared. In 1847 the Scottish obstetrician James Young Simpson introduced chloroform, which acted faster than ether and did not have its pungency. Chloroform spread quickly, and its acceptance was helped by John Snow, the first physician to make anesthesia a full-time practice, who administered it to Queen Victoria for the birth of two of her children in the 1850s, which did much to quiet religious and medical objections to the relief of labour pain. Chloroform, however, carried a darker risk than ether: it could cause sudden fatal disturbances of heart rhythm, even in otherwise healthy patients, and over the following decades this slowly drove it out of use in favour of safer agents.

The anesthetics so far described produced unconsciousness; a separate line of discovery sought to abolish pain in one part of the body while the patient remained awake. The opening came in 1884, when the Viennese ophthalmologist Karl Koller found that cocaine, applied to the eye, made eye surgery painless. The discovery that a drug could block sensation in a region of the body founded local and regional anesthesia. Cocaine itself was too toxic and too liable to cause dependence for general use, and it was progressively replaced by safer synthetic local anesthetics developed through the twentieth century, the family that includes procaine, lidocaine, and bupivacaine.

For a long time ether and chloroform, later joined by other agents, remained the mainstays. The twentieth century transformed the field along two lines.

The first was intravenous induction. In 1934 the barbiturate thiopental was introduced, allowing anesthesia to be induced by injection: a rapid and far more comfortable passage into unconsciousness than the slow inhalation of a pungent vapour. Thiopental became the standard induction agent for decades and was, much later, largely displaced by propofol, introduced in the 1980s, which allows both rapid induction and rapid, clear-headed recovery and is now the most widely used intravenous induction agent.^[2]

The second was a generation of better inhalational agents. In 1956 halothane was introduced; it was potent, pleasant to breathe, and, importantly, not flammable, which removed the ever-present danger of operating-room fires that ether had carried. Halothane was in time succeeded by the halogenated ethers in use today, isoflurane, sevoflurane, and desflurane.^[2]

A third strand made modern surgery possible: the use of medicines to relax or paralyse the muscles. In 1942 the anesthetist Harold Griffith introduced curare, long known as a South American arrow poison, into anesthetic practice, so that surgical muscle relaxation could be achieved without deepening unconsciousness to dangerous levels.^[3] These agents, the neuromuscular blockers, are covered as a class on their own page. Their arrival completed what is now called "balanced anesthesia": the modern practice of combining separate medicines for the distinct goals of unconsciousness, pain relief, and muscle relaxation, rather than relying on a single agent to do everything.

The anesthetics are best understood as several distinct groups, gathered by a shared purpose rather than a shared chemistry. The inhalational anesthetics are the volatile agents and gases, among them the modern halogenated ethers isoflurane, sevoflurane, and desflurane, and the gas nitrous oxide. The intravenous (general) anesthetics are the injected induction agents, chief among them propofol, together with thiopental, etomidate, and others. The local anesthetics block sensation in a part of the body, and include lidocaine, bupivacaine, and their relatives. The dissociative anesthetics, notably ketamine, produce a distinctive trance-like state and are discussed more fully under their own grouping; some are also used outside anesthesia. The neuromuscular blockers, used alongside anesthetics to relax muscle, are a separate class with their own page. The list is not exhaustive, and some agents are used in more than one role.

How the general anesthetics work is, remarkably, still not fully understood, and it is one of the genuine open questions of pharmacology. It is established that the inhalational and intravenous general anesthetics act on the brain to produce reversible unconsciousness, and that many of them are understood to do so in part by enhancing the activity of inhibitory signalling in the nervous system, particularly at the GABA-A receptor, the receptor for the brain's principal inhibitory neurotransmitter. Several agents act at other targets as well: nitrous oxide and the dissociative anesthetics, for instance, are understood to act substantially by blocking the NMDA receptor, a receptor for excitatory signalling. The local anesthetics work by an entirely different and better-understood mechanism: they block the sodium channels that nerves use to carry electrical signals, so that a nerve in contact with the medicine cannot transmit the message of pain. That these medicines have these actions is well established; how, exactly, the general anesthetics convert those molecular actions into the disappearance of conscious awareness remains incompletely answered.

Modern anesthesia is, by any historical measure, remarkably safe: serious harm directly attributable to anesthesia is now an uncommon event, where once it was a real risk of every operation. That safety is the achievement not only of better medicines but of monitoring, training, and the rise of anesthesiology as a specialty in its own right. Risk is not absent. The anesthetics are medicines with a narrow margin between the intended effect and dangerous depression of breathing and circulation, which is why they are given by trained practitioners with continuous monitoring. Particular hazards include malignant hyperthermia, a rare and dangerous inherited reaction to certain anesthetic agents; postoperative nausea and vomiting; and, debated and still under study, questions about the effects of anesthesia on the very young and the very old. The local anesthetics, if enough reaches the bloodstream, can affect the heart and nervous system. As with all medicines, figures for these risks are population estimates that vary between studies, and individual response varies considerably between people.