General anesthesia is medication administered before and during surgery or a medical procedure to induce analgesia, amnesia, and to repress reflexes by targeting the central nervous system (CNS). General anesthesia can be administered intravenously or via inhalation: while inhalational agents were used when anesthesia was first developed, intravenous agents have been developed in the past century and may lead to fewer postoperative complications and better patient outcomes.1 Several different classes of induction agents – the general term for a drug that induces anesthesia – currently exist, each of which have distinct mechanisms of action and other properties.
For most of the 20th century, barbiturates were the most popular intravenous induction agents for general anesthesia.2 Barbiturates, which include thiopental, thiamylal, and methohexital, are weak acids that are poorly soluble and provide anesthesia for brief amounts of time. These induction agents induce anesthesia by enhancing the action of GABA, a neurotransmitter that reduces the excitation of neurons.3 Barbiturates can interact with and reduce the efficacy of other drugs, including steroids, oral contraceptives, and immunosuppressants.4 Barbiturates can and have been abused, and overdosage can result in respiratory failure and hemodynamic instability.5
Barbiturates have fallen out of use among induction agents, and some are no longer available. Sodium thiopental is not produced anymore because high doses of the drug were traditionally used in lethal injections, and its suppliers were pressured by various groups and countries to discontinue production.6 Propofol has largely taken the place of the barbiturates as an intravenous anesthetic agent. In low doses, it can be used to achieve sedation, and can induce general anesthesia in higher doses. Propofol has rapid induction and recovery times, which make it a favorable choice for patients of all ages, including infants and the elderly.7 More controversially, propofol is sometimes used as a sleep aid, but its efficacy as a sleep medicine is as of yet unclear. Propofol is also used in some formulations of the drugs given as part of assisted death.8
Ketamine, while nowadays popular for its use in treating chronic pain and treatment-resistant depression, is primarily used as a sedative or induction agent for general anesthesia. Though it is not routinely used for anesthesia, it can be beneficial for short-term procedures when muscle relaxation is not required, such as in the emergency department setting.9 Ketamine is a racemic mixture of two enantiomers of a cyclohexanone derivative and may induce analgesia and anesthesia by interacting with sigma receptors, and it has a half-life of 45 minutes.9
An entirely separate group of induction agents can also be used for general anesthesia, specifically inhalational agents. Commonly used anesthetic gases include nitrous oxide (known colloquially as “laughing gas”), halothane, isoflurane, sevoflurane, and desflurane, and while their exact mechanisms of action are unknown, they affect central nervous system signaling and GABA receptor behavior.10 The potency of inhalational anesthetics is measured by minimum alveolar concentration (MAC), the minimum concentration of the anesthetic in the alveoli at which 50% of people do not respond to stimuli.11 Each induction agent has its own MAC, which can change based several factors; MAC levels decrease with age after the age of 40 and are increased in patients with a history of alcohol and drug abuse.10
1. Miller, D. et al. Intravenous versus inhalational maintenance of anaesthesia for postoperative cognitive outcomes in elderly people undergoing non‐cardiac surgery. Cochrane Database Syst. Rev. 2018, CD012317 (2018), DOI: 10.1002/14651858.CD012317.pub2
2. Hansen, T. G. Sedative medications outside the operating room and the pharmacology of sedatives. Curr. Opin. Anesthesiol. 28, 446–452 (2015), DOI:10.1097/ACO.0000000000000202
3. Skibiski, J. & Abdijadid, S. Barbiturates. in StatPearls (StatPearls Publishing, 2022).
4. Brodie, M. J. et al. Enzyme induction with antiepileptic drugs: cause for concern? Epilepsia 54, 11–27 (2013), DOI: 10.1111/j.1528-1167.2012.03671.x
5. Hoyland, K., Hoy, M., Austin, R. & Wildman, M. Successful use of haemodialysis to treat phenobarbital overdose. BMJ Case Rep. 2013, bcr2013010011 (2013), DOI: 10.1136/bcr-2013-010011
6. Wehrwein, P. Propofol: the drug that killed Michael Jackson. Harvard Health https://www.health.harvard.edu/blog/propofol-the-drug-that-killed-michael-jackson-201111073772 (2011).
7. Machata, A.-M., Willschke, H., Kabon, B., Kettner, S. C. & Marhofer, P. Propofol-based sedation regimen for infants and children undergoing ambulatory magnetic resonance imaging. Br. J. Anaesth. 101, 239–243 (2008), doi.org/10.1093/bja/aen153
8. Stukalin, I. et al. Medications and dosages used in medical assistance in dying: a cross-sectional study. CMAJ Open 10, E19–E26 (2022), DOI: 10.9778/cmajo.20200268
9. Rosenbaum, S. B., Gupta, V. & Palacios, J. L. Ketamine. in StatPearls (StatPearls Publishing, 2022).
10. Miller, A. L., Theodore, D. & Widrich, J. Inhalational Anesthetic. in StatPearls (StatPearls Publishing, 2022).
11. Aranake, A., Mashour, G. A. & Avidan, M. S. Minimum alveolar concentration: ongoing relevance and clinical utility. Anaesthesia 68, 512–522 (2013), DOI: 10.1111/anae.12168