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Halothane is 2-bromo-2-chloro-1,1,1-trifluoroethane (Figure 194). Halothane is a volatile

liquid at room temperature and must be stored in a sealed container. Because halothane is a lightsensitive compound that also is subject to spontaneous breakdown, it is marketed in amber
bottles with thymol added as a preservative. Mixtures of halothane with O 2 or air are neither
flammable nor explosive.
Halothane has a relatively high blood:gas partition coefficient and high fat:blood partition
coefficient (Table 191). Induction with halothane therefore is relatively slow, and the alveolar
halothane concentration remains substantially lower than the inspired halothane concentration for
many hours of administration. Because halothane is soluble in fat and other body tissues, it will
accumulate during prolonged administration. Therefore, the speed of recovery from halothane is
lengthened as a function of duration of administration.
Approximately 60-80% of halothane taken up by the body is eliminated unchanged by 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. The major metabolite of halothane
is trifluoroacetic acid, which is formed by removal of bromine and chlorine ions. Trifluoroacetic
acid, bromine, and chlorine all can be detected in the urine. 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. A minor reductive pathway accounts for ~1% of
halothane metabolism that generally is observed only under hypoxic conditions.
Clinical Use
Halothane, introduced in 1956, was the first modern, halogenated inhalational anesthetic used
in clinical practice. It is a potent agent that usually is used for maintenance of anesthesia. It is not
pungent and is therefore well tolerated for inhalation induction of anesthesia. This is most
commonly done in children, in whom preoperative placement of an intravenous catheter can be
difficult. Anesthesia is produced by halothane at end-tidal concentrations of 0.7-1%. The use of
halothane in the U.S. has diminished substantially in the past decade because of the introduction
of newer inhalational agents with better pharmacokinetic and side-effect profiles. Halothane
continues to be extensively used in children because it is well tolerated for inhalation induction

and because the serious side effects appear to be diminished in children. Halothane has a low
cost and therefore is still widely used in developing countries.
Side Effects
Cardiovascular System
The most predictable side effect of halothane is a dose-dependent reduction in arterial
blood pressure. Mean arterial pressure typically decreases ~20-25% at MAC concentrations of
halothane. This reduction in blood pressure is primarily the result of direct myocardial
depression leading to reduced cardiac output (Figure 196). Myocardial depression is thought to
result from attenuation of depolarization-induced intracellular calcium transients. Halothaneinduced hypotension usually is accompanied by either bradycardia or a normal heart rate.
Attenuation of baroreceptor reflex function decreases the chronotropic and inotropic
responses to a reduction in blood pressure (Constant et al., 2004). Heart rate can be increased
during halothane anesthesia by exogenous catecholamine or by sympathoadrenal stimulation.
Halothane-induced reductions in blood pressure and heart rate generally disappear after several
hours of constant halothane administration, presumably because of progressive sympathetic
Halothane does not cause a significant change in systemic vascular resistance.
Nonetheless, it does alter the resistance and autoregulation of specific vascular beds, leading to
redistribution of blood flow. The vascular beds of the skin and brain are dilated directly by
halothane, leading to increased cerebral blood flow and skin perfusion. Conversely,
autoregulation of renal, splanchnic, and cerebral blood flow is inhibited by halothane, leading to
reduced perfusion of these organs in the face of reduced blood pressure. Coronary autoregulation
is largely preserved during halothane anesthesia. Finally, halothane inhibits hypoxic pulmonary
vasoconstriction, leading to increased perfusion to poorly ventilated regions of the lung and an
increased alveolar:arterial O2 gradient.
Halothane also has significant effects on cardiac rhythm. Sinus bradycardia and
atrioventricular rhythms occur frequently during halothane anesthesia but usually are benign.
These rhythms result mainly from a direct depressive effect of halothane on sinoatrial node
discharge. Halothane also can sensitize the myocardium to the arrhythmogenic effects of
epinephrine (Sumikawa et al., 1983). Premature ventricular contractions and sustained

ventricular tachycardia can be observed during halothane anesthesia when exogenous

administration or endogenous adrenal production elevates plasma epinephrine levels.
Respiratory System
Spontaneous respiration is rapid and shallow during halothane anesthesia. The
decreased alveolar ventilation results in an elevation in arterial CO 2 tension from 40 mm
Hg to >50 mm Hg at 1 MAC (Figure 197). The elevated CO 2 does not provoke a compensatory
increase in ventilation, because halothane causes a concentration-dependent inhibition of the
ventilatory response to CO2. This action of halothane is thought to be mediated by depression of
central chemoceptor mechanisms. Halothane also inhibits peripheral chemoceptor responses to
arterial hypoxemia. Thus, neither hemodynamic (tachycardia and hypertension) nor
ventilatory responses to hypoxemia are observed during halothane anesthesia, making it
prudent to monitor arterial O2 directly. Halothane also is an effective bronchodilator
(Yamakage, 1992) and has been effectively used as a treatment of last resort in patients with
status asthmaticus (Gold and Helrich, 1970).
Nervous System
Halothane dilates the cerebral vasculature, increasing cerebral blood flow and cerebral
blood volume. This can result in an increase in intracranial pressure, especially in patients with
space-occupying intracranial masses, brain edema, or preexisting intracranial hypertension.
Halothane attenuates autoregulation of cerebral blood flow in a dose-dependent manner. Hence,
cerebral blood flow can increase even with a modest reduction in arterial pressure. With a
reduction of arterial pressure that is below the lower limit of autoregulation, cerebral blood flow
can decrease significantly. Halothane suppresses cerebral metabolism and cerebral metabolic rate
is decreased.
Halothane causes some relaxation of skeletal muscle by its central depressant effects.
Halothane also potentiates the actions of non-depolarizing muscle relaxants (curariform drugs;
Chapter 11), increasing both their duration of action and the magnitude of their effect.
Halothane and the other halogenated inhalational anesthetics can trigger malignant
hyperthermia, a syndrome characterized by severe muscle contraction, rapid development
of hyperthermia, and a massive increase in metabolic rate in genetically susceptible

patients. This syndrome frequently is fatal and is treated by immediate discontinuation of the
anesthetic and administration of dantrolene.
Uterine smooth muscle is relaxed by halothane. This is a useful property for manipulation
of the fetus (version) in the prenatal period and for delivery of retained placenta postnatally.
However, halothane inhibits uterine contractions during parturition, prolonging labor and
increasing blood loss, and therefore is not used as an analgesic or anesthetic for labor and vaginal
Patients anesthetized with halothane usually produce a small volume of concentrated
urine. This is the consequence of halothane-induced reduction of renal blood flow and
glomerular filtration rate, which may be reduced by 40-50% at 1 MAC. Halothane-induced
changes in renal function are fully reversible and are not associated with long-term
Liver and GI Tract
Halothane reduces splanchnic and hepatic blood flow as a consequence of reduced
perfusion pressure, as discussed above. This reduced blood flow has not been shown to produce
detrimental effects on hepatic or GI function.
Halothane can produce fulminant hepatic necrosis in a small number of patients. This
syndrome generally is characterized by fever, anorexia, nausea, and vomiting, developing several
days after anesthesia and can be accompanied by a rash and peripheral eosinophilia. There is a
rapid progression to hepatic failure, with a fatality rate of ~50%. This syndrome occurs in ~1 in
10,000 patients receiving halothane and is referred to as halothane hepatitis (Study, 1966).
Current thinking is that halothane hepatitis is the result of an immune response to hepatic
proteins that become trifluoroacetylated as a consequence of halothane metabolism (see the
"Pharmacokinetics" section for halothane earlier in the chapter).
Interactions with Other Drugs
Inhaled (volatile) anesthetics potentiate the neuromuscular blockade produced by
nondepolarizing muscle relaxants in a dose-dependent fashion. Of the general anesthetics that
have been studied, inhaled anesthetics augment the effects of muscle relaxants in the following

order: isoflurane (most); sevoflurane, desflurane, enflurane, and halothane; and nitrous oxide
(least). The most important factors involved in this interaction are the following: (1) nervous
system depression at sites proximal to the neuromuscular junction (ie, central nervous system);
(2) increased muscle blood flow (ie, due to peripheral vasodilation produced by volatile
anesthetics), which allows a larger fraction of the injected muscle relaxant to reach the
neuromuscular junction; and (3) decreased sensitivity of the postjunctional membrane to
A rare interaction of succinylcholine with volatile anesthetics results in malignant
hyperthermia, a condition caused by abnormal release of calcium from stores in skeletal muscle.
This condition is treated with dantrolene and is discussed below under Spasmolytic Drugs and in
Chapter 16.
Malignant Hipertermia
Malignant hipertermia adalah kelainan farmakogenetik berupa mutasi pada RYR1. Selain itu,
1% kasus disebabkan oleh mutasi pada gen CACNA1S, gen yang menyandi dihidropiridin
reseptor. Malignant hipertermia biasanya disebabkan karena pemberian anestesi halogen dan
perelaksasi otot depolarisasi. RYR akan aktif bila terjadi peningkatan kalsium intrasel (SOICR).
RYR yang termutasi akan aktif hanya karena kalsium yang sedikit. Penggunaan anestesi volatil
akan menurunkan nilai minimum kalsium untuk tercapainya pengaktifan RYR. Pada MH,
pemberian anestesi volatil dan suksinilkolin akan menyebabkan peningkatan kalsium berulang
kali yang melebihi ambang SOICR yang telah diturunkan (karena mutasi RYR), sehingga akan

kontraksi semua otot yang menyebakan kekakuan, hipermetabolisme yang

menyebabkan peningkatan CO2 dan asidosis, peningkatan jumlah ATP yang dihidrolisis miosin
yang akan menyebabkan terbentuknya panas sehingga terjadi hipertermia. Bila kondisi
hipermetabolisme miosit ini tidak ditangani, akan terjadi rhabdomiolisis yang akan menyebabkan
hiperkalemia, mioglobiuria yang dapat menyebabkan gagal ginjal.
Penatalaksanaan malignant hipertermia adalah pemberian dantrolene secara intravena,
dimana dantrolene berfungsi memblok pengeluaran kalsium dari retikulum sarkoplasma. Selain
itu juga diberikan inhalasi oksigen 100%, pendinginan cepat, dan kontrol terhadap asidosis.