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Halothane: Biological Mechanisms, Surgical Applications and Side Effects

By February 5, 2020 No Comments

Halothane, also known as fluothane, is a nonflammable, halogenated hydrocarbon and inhalational general anesthetic.1 Halothane was created in the 1950s by Charles Suckling, an English chemist, after two years of research and testing.2,3 At the time, ether and chloroform were common anesthetics, but their flammable nature made them dangerous in the operating room.4 Halothane, which was the first halogenated hydrocarbon volatile anesthetic used in clinical practice, served as a solution to this problem and revolutionized the practice of anesthesiology.4 After several decades of use, halothane has now been replaced by other volatile anesthetics with fewer adverse effects.4

Halothane’s chemical name is 2-bromo-2-chloro-1,1,1-trifluoroethane, and it is the only nonether inhaled anesthetic that is used today.1,5 It is a clear, colorless, highly volatile liquid with a sweet chloroform-like odor.1 About 15 to 20 percent of halothane is metabolized in the body, usually by the enzyme CYP2E1,6 which leads to immune responses resulting in hepatitis.5 This is in contrast to desflurane, which may be metabolized as low as 0.1 percent.7 As with desflurane, isoflurane, sevoflurane and enflurane, the exact biological mechanisms of halothane are unclear. However, it is thought to bind to cholinergic potassium channels, NMDA receptors and calcium channels, causing hyperpolarization in neurons.8 Hyperpolarization prevents neurons from firing; therefore, halothane has an overall inhibitory effect that causes general anesthesia.

There are several surgical applications for halothane, including induction and maintenance of general anesthesia. It creates general anesthesia by depressing nerve conduction, breathing and cardiac contractility, and it is usually combined with other inhalational agents such as nitrous oxide.8,9 It can produce surgical anesthesia within two to five minutes after induction.9 Because halothane does not have a pungent odor, it can be used more easily for induction than some odorous volatile anesthetics.10 Additionally, it does not augment salivary or bronchial secretions, and thus does not cause as much coughing as drugs such as ether.9 The incidence of postoperative nausea and vomiting after halothane is low.9 Halothane has a higher blood/gas coefficient than isoflurane and enflurane and a lower coefficient than methoxyflurane, so its induction and recovery time are faster than methoxyflurane and slower than other volatile anesthetics.11,12 It also reduces cardiac output more than any other volatile anesthetic.11 Halothane is the most soluble of all the currently used anesthetics, but it is also the most potent;5 thus, anesthesia providers must use a calibrated vaporizer and careful monitoring to avoid overdose.13 Though it has significant sleep-inducing effects, it does not serve as an analgesic.14

Because halothane has potentially dangerous side effects, it is no longer used as often as drugs like desflurane and isoflurane.15 For one, halothane metabolites can lead to liver damage ranging from mild hepatitis to acute hepatic failure.15 Liver issues are more likely to occur in patients who are repeatedly anesthetized with halothane within a short period of time.9 As hepatotoxicity can be fatal, researchers do not recommend the use of halothane in adults.16 Additionally, halothane can cause cardiorespiratory instability including hypotension, bradycardia and arrhythmia.5 It potentiates the effects of nondepolarizing muscle relaxants and hypotensive agents, and can increase risk of malignant hyperthermia.9 Furthermore, its slow induction and slow recovery make it less advantageous than more modern anesthetics.17 Overall, halothane is not preferred when compared to drugs like isoflurane or desflurane.15

Halothane was created to replace conventional anesthetics like chloroform and ether, but has since been superseded by more modern anesthetic drugs. Halothane has an inhibitory effect on the nervous and cardiorespiratory systems, which allows it to cause general anesthesia. It can be used to induce or maintain general anesthesia and is quite potent. However, because it is metabolized to a greater extent than the other general anesthetics, it poses greater risk for hepatotoxicity. Additionally, halothane can lead to cardiorespiratory instability and malignant hyperthermia, and it is associated with a slow recovery. Researchers should focus on the possible uses of halothane in new fields,15 or the use of disulfiram in conjunction with halothane to prevent liver damage.6

1.         Halothane. PubChem Database. Web: National Center for Biotechnology Information; 2020.

2.         Suckling CW. Some chemical and physical factors in the development of fluothane. British Journal of Anaesthesia. 1957;29(10):466–472.

3.         O’Brien HD. The introduction of halothane into clinical practice: The Oxford experience. Anaesthesia and Intensive Care. 2006;34(Suppl 1):27–32.

4.         Huang L, Sang CN, Desai MS. Beyond Ether and Chloroform—A Major Breakthrough With Halothane. Journal of Anesthesia History. 2017;3(3):87–102.

5.         Davis PJ, Bosenberg A, Davidson A, et al. Chapter 7—Pharmacology of Pediatric Anesthesia. In: Davis PJ, Cladis FP, Motoyama EK, eds. Smith’s Anesthesia for Infants and Children (Eighth Edition). Philadelphia: Mosby; 2011:179–261.

6.         Atkinson AJ, Markey SP. Chapter 16—Biochemical Mechanisms of Drug Toxicity. In: Atkinson AJ, Abernethy DR, Daniels CE, Dedrick RL, Markey SP, eds. Principles of Clinical Pharmacology (Second Edition). Burlington: Academic Press; 2007:249–271.

7.         Kharasch ED, MD, PhD, Karol MD, PhD, Lanni C, PhD, Sawchuk R, PhD. Clinical Sevoflurane Metabolism and Disposition: I. Sevoflurane and Metabolite Pharmacokinetics. Anesthesiology: The Journal of the American Society of Anesthesiologists. 1995;82(6):1369–1378.

8.         Halothane. DrugBank February 3, 2020; https://www.drugbank.ca/drugs/DB01159.

9.         Halothane. WHO Model Prescribing Information: Drugs Used in Anaesthesia. Web: World Health Organization; December 1, 2019.

10.       Hudson AE, Herold KF, Hemmings HC. Chapter 10—Pharmacology of Inhaled Anesthetics. In: Hemmings HC, Egan TD, eds. Pharmacology and Physiology for Anesthesia. Philadelphia: W.B. Saunders; 2013:159–179.

11.       Nolan JP. Chapter 19—Anaesthesia and neuromuscular block. In: Bennett PN, Brown MJ, Sharma P, eds. Clinical Pharmacology (Eleventh Edition). Oxford: Churchill Livingstone; 2012:295–310.

12.       Lerman J, Gregory GA, Willis MM, Eger EI, 2nd. Age and solubility of volatile anesthetics in blood. Anesthesiology. 1984;61(2):139–143.

13.       Otto K, von Thaden A-K. Chapter 5.4—Anaesthesia, Analgesia and Euthanasia. In: Hedrich HJ, ed. The Laboratory Mouse (Second Edition). Boston: Academic Press; 2012:739–759.

14.       Bowdle TA, Knutsen LJS, Williams M. 6.15—Local and Adjunct Anesthesia. In: Taylor JB, Triggle DJ, eds. Comprehensive Medicinal Chemistry II. Oxford: Elsevier; 2007:351–367.

15.       Dabbagh A, Rajaei S. Halothane: Is there still any place for using the gas as an anesthetic? Hepatitis Monthly. 2011;11(7):511–512.

16.       Peralta R. Halothane Hepatotoxicity. In: Pinsky MR, ed. Medscape. Web: WebMD LLC; December 17, 2019.

17.       Pawson P, Forsyth S. Chapter 5—Anesthetic agents. In: Maddison JE, Page SW, Church DB, eds. Small Animal Clinical Pharmacology (Second Edition). Edinburgh: W.B. Saunders; 2008:83–112.