Halothane - Drug Monograph

Introduction

Halothane is a volatile general anesthetic agent that was first introduced into clinical practice in 1956. It belongs to the class of halogenated hydrocarbons and was widely used for many decades as an inhalation anesthetic for induction and maintenance of general anesthesia. While its use has declined significantly in many countries due to safety concerns, it remains an important historical agent and is still used in some resource-limited settings.

Mechanism of Action

Halothane produces general anesthesia through potentiation of GABAergic neurotransmission and inhibition of excitatory neurotransmission. It enhances the activity of gamma-aminobutyric acid (GABA) at GABA_A receptors and glycine at glycine receptors, while simultaneously inhibiting N-methyl-D-aspartate (NMDA) receptors and neuronal nicotinic acetylcholine receptors. These actions result in central nervous system depression, loss of consciousness, amnesia, and immobility in response to painful stimuli.

Indications

• Induction and maintenance of general anesthesia in both inpatient and outpatient surgical procedures
• Can be used in patients of all ages, though caution is advised in pediatric populations
• Particularly useful for procedures requiring rapid induction and emergence from anesthesia

Dosage and Administration

• Induction: 0.5-3% concentration in oxygen or nitrous oxide/oxygen mixture
• Maintenance: 0.5-1.5% concentration titrated to clinical effect
• Minimum Alveolar Concentration (MAC): 0.75% in adults (varies with age and concomitant medications)

• Geriatric patients: Reduced MAC requirements (approximately 0.6%)
• Pediatric patients: Higher MAC requirements (approximately 0.9-1.0% in infants)
• Hepatic impairment: Use with extreme caution or avoid due to hepatotoxicity risk

Pharmacokinetics

Contraindications

• Known hypersensitivity to halothane or related compounds
• Personal or family history of malignant hyperthermia
• Unexplained fever, jaundice, or hepatic dysfunction following previous halothane exposure
• Significant hepatic impairment or active liver disease
• Pregnancy (unless absolutely necessary) due to potential fetal risk

Warnings and Precautions

• Hepatotoxicity: Can cause fulminant hepatic necrosis, typically appearing 2-15 days post-exposure
• Malignant hyperthermia: May trigger hypermetabolic crisis in susceptible individuals
• Cardiac effects: Sensitizes myocardium to catecholamines, increasing risk of arrhythmias
• Respiratory depression: Dose-dependent depression of respiratory drive
• Repeat exposure: Increased risk of hepatotoxicity with multiple exposures; avoid within 3-month period

Drug Interactions

• Catecholamines: Increased risk of ventricular arrhythmias when administered with epinephrine, norepinephrine, or other sympathomimetics
• Aminophylline/theophylline: Increased risk of cardiac arrhythmias
• Non-depolarizing muscle relaxants: Potentiates neuromuscular blockade
• Opioids, benzodiazepines, other CNS depressants: Additive CNS and respiratory depression
• Enzyme inducers (phenobarbital, rifampin): May increase production of hepatotoxic metabolites
• MAO inhibitors, tricyclic antidepressants: Increased risk of hemodynamic instability

Adverse Effects

• Nausea and vomiting
• Postoperative shivering
• Transient hepatic enzyme elevation

• Hepatotoxicity (ranging from mild transaminitis to fulminant hepatic failure)
• Malignant hyperthermia (hypermetabolic crisis with muscle rigidity, hyperthermia, acidosis)
• Cardiac arrhythmias (particularly ventricular)
• Hypotension
• Respiratory depression
• Allergic reactions including eosinophilia and rash

Monitoring Parameters

• Continuous: ECG, blood pressure, oxygen saturation, end-tidal CO₂, temperature
• Perioperative: Heart rate, respiratory rate, anesthetic depth, neuromuscular function
• Laboratory: Liver function tests (preoperative and postoperative if clinically indicated)
• Postoperative: Signs of hepatic dysfunction (jaundice, fever, malaise) for 2-3 weeks
• Malignant hyperthermia: Early signs including increased end-tidal CO₂, tachycardia, muscle rigidity

Patient Education

• Inform your anesthesiologist about any personal or family history of problems with anesthesia
• Report any previous adverse reactions to anesthetics, especially fever or jaundice
• Notify healthcare providers if you have liver disease or drink alcohol regularly
• Be aware of signs of liver problems after surgery: yellowing skin/eyes, dark urine, fever, nausea
• Understand that multiple exposures to halothane within short time periods increase risks
• Follow all preoperative fasting instructions carefully

References

1. Eger EI II. Halothane. J Clin Anesth. 1991;3(1):1-3. 2. Njoku DB. Drug-induced hepatotoxicity: metabolic, genetic and immunological basis. Int J Mol Sci. 2014;15(4):6990-7003. 3. Miller RD, et al. Miller's Anesthesia. 8th ed. Philadelphia: Elsevier Saunders; 2015. 4. FDA prescribing information for halothane. 5. Kenna JG, et al. Halothane hepatitis. Immunol Res. 1991;10(3-4):515-520. 6. Britt BA. Malignant hyperthermia. Can Anaesth Soc J. 1985;32(6):666-677. 7. Stoelting RK, Hillier SC. Pharmacology and Physiology in Anesthetic Practice. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2006.