Pharmacology of Halothane

Chemistry and Formulation

• Halothane is a volatile liquid at room temperature and must be stored in a sealed container.
• It is light-sensitive and subject to spontaneous breakdown, so it is marketed in amber bottles with thymol added as a preservative.
• Mixtures of halothane with oxygen or air are neither flammable nor explosive.

Pharmacokinetics

• Halothane has a relatively high blood:gas partition coefficient and high fat:blood partition coefficient.
• Induction with halothane is relatively slow, and the alveolar halothane concentration remains substantially lower than the inspired halothane concentration for many hours of administration.
• Halothane accumulates in tissues during prolonged administration, lengthening the speed of recovery as a function of duration of administration.
• Approximately 60-80% of halothane taken up by the body is eliminated unchanged via the lungs in the first 24 hours after its administration.
• A substantial amount of the halothane not eliminated in exhaled gas is biotransformed by hepatic CYPs.

Biotransformation

• Trifluoroacetylchloride, an intermediate in oxidative metabolism of halothane, can trifluoroacetylate several proteins in the liver.
• An immune reaction to these altered proteins may be responsible for the rare cases of fulminant halothane-induced hepatic necrosis.

Clinical Use

• Halothane is a potent, nonpungent and well-tolerated agent used for maintenance of anesthesia and inhalation induction of anesthesia, commonly in children.
• Anesthesia is produced by halothane at end-tidal concentrations of 0.7-1%.
• The use of halothane in the U.S. has diminished substantially since the introduction of newer inhalational agents with better pharmacokinetic and side-effect profiles.

Side Effects

Cardiovascular System

• The most predictable side effect of halothane is a dose-dependent reduction in arterial blood pressure, typically decreasing 20-25% at MAC concentrations.
• Halothane-induced reductions in blood pressure and heart rate generally disappear after several hours of constant halothane administration, presumably due to progressive sympathetic stimulation.
• Halothane dilates the vascular beds of the skin and brain, whereas autoregulation of renal, splanchnic, and cerebral blood flow is inhibited, leading to reduced perfusion of these organs in the face of reduced blood pressure.
• Coronary autoregulation is largely preserved.
• Halothane inhibits hypoxic pulmonary vasoconstriction, leading to increased perfusion to poorly ventilated regions of the lung and an increased alveolar:arterial oxygen gradient.
• Sinus bradycardia and atrioventricular rhythms occur frequently during halothane anesthesia but are usually benign and result mainly from a direct depressive effect of halothane on sinoatrial node discharge.
• Halothane can sensitize the myocardium to the arrhythmogenic effects of epinephrine.

Respiratory System

• Spontaneous respiration is rapid and shallow during halothane anesthesia.
• The decreased alveolar ventilation results in an elevation in arterial CO2 tension from 40 mm Hg to >50 mm Hg at 1 MAC.
• Halothane causes a concentration-dependent inhibition of the ventilatory response to CO2.
• Halothane also inhibits peripheral chemoceptor responses to arterial hypoxemia.
• Neither hemodynamic (tachycardia and hypertension) nor ventilatory responses to hypoxemia are observed during halothane anesthesia, making it prudent to monitor arterial oxygenation directly.