Blessing and misuse: The Discovery of Anaesthetic drug

Knowledge of the history of anesthesia enhances our appreciation of current practice and intimates where we are headed. Hence this overview of how Anaesthesia drugs developed from extract of madrake plant, soporofic sponge and alcohol in ‘pre-ether era’ to Sevoflurane, Fentanyl and Propofol in modern era.

In 1846, WTG Morton publicly demonstrated that surgery can be performed with ’pain put to sleep’, still frequency of operations did not rise rapidly. Several years passed before anaesthesia was universally recommended.

Although ether was remarkably safe even in untrained hands, it was flammable, had unpleasant odour, prolonged induction time and caused PONV. Hence search for other agents began. Use of Chloroform was published in The Lancet by Simpson in 1847 and it became popular after John Snow used it to deliver last two children of Queen Victoria. But its use was limited due to hepatic and cardiac toxicity.

Nitrous Oxide was used by Humphry Davy in 1798. But because of embarrassing public demonstration by Wells, revival of Nitrous oxide as surgical anesthetic was delayed. It was reintroduced into operating rooms and was used with air and then oxygen. It is still being used, though the use is decreasing due to its green house gas effect.

Ethyl chloride introduced in 19^th century, was unique. It was first used as a spray to induce local anaesthesia and if inhaled, it also produced general anaesthesia. Ethylene was not successful because high concentration was required, it was explosive and had unpleasant smell. Cyclopropane was discovered accidentally in 1929. In 1930, Divinyl ether was studied. But all the potent anesthetics of this period were explosive,  hence anaesthetic explosion was a rare but devastating risk. It prevented use of cautery and electronic monitoring. Then trichloroethylene was introduced, which was non-inflammatory but decomposed to toxic nerve poison dechloroacetylene in presence of soda lime and produced phosgene, a severe respiratory irritant, when electrocautery was used. Clearly, new directions were needed. 

Flourinated hydrocarbons then revolutionized inhalational anaesthesia. In 1951, Charles Suckling created Halothane. It became popular after Johnstone endorsed it. Halothane replaced the older agents because of pleasant smell, higher potency, non-inflammability and low toxicity.  But its use later became restricted due to Halothane Hepatitis.

Methoxyflourane came in 1960, but its use was limited due to nephrotoxicity. Enflurane use was also restricted due to marked cardiovascular depressant effects and convulsant properties. Isoflurane was introduced in 1965, Desflurane in 1992 and Sevoflurane in 1994. These agents are still popular.

Initial IV anaesthetics used were Chloral hydrate ( 1872), Chloroform and Ether (1909). But there were several postoperative deaths. Elisabeth  Bredenfeld reported use of IV Morphine and Scopolamine , but it failed to show any improvement over inhaled techniques.

First Barbiturate , barbital, was synthesized in 1903. Hexobarbital, first short acting oxybarbiturate, was used clinically in 1932.

Thiopental soon followed and was found to be potent, rapid acting and more satisfactory. It was successfully introduced in clinical practice by John Lundy in 1934.

But during Pearl harbour tragedy, its vasodilatory effects were appreciated when it caused cardiovascular collapse in hypovolemic burned civilians and military patients.

In 1970, Ketamine was released for use as analgesic and induction agent.

Etomidate is in use since 1974 and is used for anaesthetising hemodynamically unstable patients due to its minimal hemodynamic depression and lack of histamine release. It is popular though it causes pain on injection, myoclonus, PONV and inhibition of adrenal steroidogenesis.

Propofol, was synthesized in 1977.  It was withdrawn because Cremaphor EL, solvent with which it was formulated, produced severe anaphylactic reactions. Then it was reformulated with egg lecithin, glycerol and soyabean oil. This drug gained great success due to its excellent induction characteristics, antiemetic properties and ability to suppress pharyngeal reflexes.

Analgesic and sedative properties of  opium have been known since long. The first alkaloid isolated, Morphine, (named after Greek god of dreams, Morpheus) was used as a supplement to inhaled anaesthesia and for postoperative analgesia in later half of 19^th century. Weaker analgesic, Codeine, was isolated in 1832. Meperidine, first synthetic opioid was developed in 1939. Then fentanyl (1960), Droperidol (1961) , alfentanil and sufentanil followed. Fentanyl is a staple in anaethesia practice till date.

Remifentanil, an ultra-short acting opioid was introduced in 1996.

Ketorolac (1990)  was first parenteral NSAID indicated for postoperative pain. But its use was limited due to its side effects.

Muscle relaxants entered anaesthesia practice nearly a century after inhalational anesthetics. Curare was used originally for hunting and tribal warfare. Gallamine, Decamethonium (1948) and Metubine (1970) were used initially. Succinyl Choline was prepared by Daniel Bovet in 1949. Pancuronium , Vecuronium, Pipecuronium, Rocuronium and Rapacuronium were then introduced. Rapacuronium was withdrawn after several cases of intractable bronchospsm led to brain damage and death. Atracurium, Mivacurium, Doxacurium and cis-atracurium,(based on parent drug d-Tubocurarine) also made it to clinical use.  Atracurium and cis-atracurium undergo Hoffman elimination and hence was useful in liver and renal insufficiency.

Interestingly, curare antagonist were developed before muscle relaxants were ever used in surgery. Physostigmine was isolated in 1990 and Neostigmine was synthesized in 1931.

Before use of muscle relaxants, abdominal relaxation was possible only if patients tolerated high concentration of inhaled anesthetic, which used to cause profound respiratory depression and protracted recovery. Premature attempt to intubate under cyclopropane used to result in persistent laryngospasm. Thus muscle relaxants increased the safety of patients and new frontiers opened.

Need of improved patient comfort, reduced side-effects, faster recovery, better control of anaesthesia, enhanced efficiency, targeted action, better pain management, along with diversifying patient population and technological advances is driving ongoing research and development, ultimately enhancing patient safety and outcome in surgical care.

References:

1. Barash P, Clinical Anaesthesia, Lippincott Williiams & Wilkins, a Wolters Kluwer Business. 2013, seventh edition,
2. Miller RD, Miller’s Anesthesia, Churchill Livingstone, an imprint of Elsevier Inc. , 2010, seventh edition,