Halothane is a volatile general anesthetic, a liquid that evaporates into a gas and is inhaled to produce unconsciousness during surgery. First synthesized in 1951 by chemist Charles W. Suckling at Imperial Chemical Industries in Britain and introduced clinically in 1955, it became one of the most widely used inhaled anesthetics in the world for decades. Today it has been largely replaced by newer agents in high-income countries due to its risk of liver damage and heart rhythm disturbances, though it remains in use in some low-resource settings.
How Halothane Works in the Brain
Halothane produces unconsciousness primarily by dampening excitatory signaling in the brain. It inhibits receptors for glutamate, the brain’s main excitatory chemical messenger, reducing the ability of neurons to fire in response to incoming signals. At clinical concentrations, it suppresses both major subtypes of glutamate receptors. It also appears to enhance inhibitory signaling to some degree, though the relative contribution of each mechanism is still debated.
The potency of an inhaled anesthetic is measured by its minimum alveolar concentration, or MAC, the percentage of the gas in the lungs needed to prevent movement in half of patients during a surgical stimulus. Halothane’s MAC is 0.75%, meaning it is quite potent compared to many other inhaled agents. It also has a blood-to-gas partition coefficient of 2.30, which describes how readily it dissolves into the bloodstream from the lungs. A higher number here means the drug is more soluble in blood, which translates to slower onset and slower recovery compared to less soluble agents like sevoflurane.
Why It Was Popular in Pediatric Anesthesia
Halothane earned a particular role in anesthesia for children because it does not irritate the airways. Many inhaled anesthetics cause coughing, breath-holding, or laryngospasm when a child breathes them through a face mask, making the start of anesthesia stressful and potentially dangerous. Halothane’s smooth, non-irritating quality made it well tolerated during mask induction, the technique where a child breathes anesthetic gas until falling asleep, avoiding the need for an IV line in a frightened patient. This property kept halothane in pediatric use even after it had fallen out of favor for adults in many hospitals.
Effects on the Heart
One of halothane’s most significant drawbacks is how it affects cardiac rhythm. It sensitizes the heart to catecholamines, the stress hormones (like adrenaline) that the body releases naturally and that surgeons sometimes inject to control bleeding. Under halothane anesthesia, even normal levels of adrenaline can trigger dangerous irregular heartbeats.
The mechanism involves halothane’s effects on ion channels in heart muscle cells. It alters the shape of the electrical signal that coordinates each heartbeat by unevenly blocking calcium and potassium channels across different regions of the heart. This creates conditions ripe for abnormal electrical impulses. It also slows the speed at which electrical signals travel through cardiac tissue by inhibiting sodium channels, and adrenaline amplifies both of these effects. The result can be reentry arrhythmias, where electrical signals loop back on themselves instead of traveling in an orderly wave.
Newer agents like isoflurane and sevoflurane do not share this problem. Studies comparing the three drugs found that halothane slowed conduction through the heart’s electrical relay system at higher concentrations, while isoflurane and sevoflurane left it unchanged. This difference in cardiac stability is one of the main reasons halothane was phased out.
Liver Toxicity
Halothane causes two distinct types of liver injury, and the more severe form is the reason it carries a serious safety warning.
The milder form, called type 1 hepatotoxicity, occurs in 20% to 30% of patients. It shows up as a temporary rise in liver enzymes after surgery, often without symptoms. This reaction is attributed to a toxic byproduct created when the liver breaks down halothane through one of its metabolic pathways. A free radical formed during this process damages liver cell membranes through a chain reaction called lipid peroxidation. Because halothane has the highest metabolism rate of any common inhaled anesthetic (15% to 20% of each dose is processed by the liver), it generates more of these harmful byproducts than its alternatives.
The more dangerous form, type 2 hepatotoxicity, resembles a severe, sometimes fatal hepatitis. It occurs in roughly 1 in 6,000 to 1 in 20,000 cases after a single exposure, with fatal outcomes in about 1 in 35,000 patients. Those numbers worsen dramatically with repeated use: fatal liver failure rises to approximately 1 in 1,000 patients who receive halothane multiple times. This reaction is thought to be triggered by a different metabolic pathway, in which the liver converts halothane into a reactive compound called trifluoroacetyl chloride. This compound binds to liver proteins and essentially marks them as foreign, provoking an immune attack against the liver itself.
Malignant Hyperthermia Risk
Halothane is one of the strongest triggers of malignant hyperthermia, a rare but life-threatening reaction that occurs in genetically susceptible individuals. People with this susceptibility carry mutations in a specific calcium release channel found in skeletal muscle cells. Under normal conditions, this channel opens briefly to release calcium from internal stores, causing muscles to contract, then closes again. In susceptible individuals, halothane forces the channel into a state of uncontrolled opening, flooding muscle cells with calcium.
The result is sustained, uncontrollable muscle contraction throughout the body. Muscles consume enormous amounts of energy and generate extreme heat, and body temperature can climb rapidly to dangerous levels. Without immediate treatment, the condition is fatal. The genetic mutations that cause susceptibility appear to make the calcium channel less responsive to the natural “off switch” (magnesium) while making it more sensitive to activating signals. Halothane essentially pushes an already unstable channel past its tipping point.
Current Global Status
Halothane has been removed from routine use in most high-income countries, replaced by sevoflurane and isoflurane, which offer smoother cardiac profiles and far less liver toxicity. However, it has remained on the World Health Organization’s Model List of Essential Medicines for years, reflecting its continued use in parts of the world where newer anesthetics are unavailable or unaffordable.
That status is now changing. In 2023, a WHO expert committee recommended flagging halothane for removal from the Essential Medicines list, citing its harm profile and the fact that many countries have already stopped using it. The World Federation of Societies of Anaesthesiologists submitted a request to delay removal until 2027, likely to give low-resource health systems time to transition to safer alternatives. The 2025 expert committee is currently considering that request. Regardless of the timeline, the trajectory is clear: halothane is being phased out globally, closing the chapter on an anesthetic that transformed surgery in the mid-20th century but whose risks are no longer justifiable when safer options exist.