Halothane

Halothane is a general anaesthetic, it is generally offered under the brand names Fluothane and others. It can be used to start anaesthesia or keep it going. One of its advantages is that it does not enhance saliva production, which is very beneficial for people who are difficult to intubate. It is administered by inhalation.

Halothane Structure

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Halothane Mechanism of Action

From the volatile anaesthetic drugs, halothane has the largest blood gas partition coefficient, therefore recovery from halothane anaesthesia is quite slow. Breathing is a pleasurable experience. More than any other volatile anaesthetic, halothane lowers cardiac output. It makes the heart more sensitive to the arrhythmic effects of catecholamines and hypercapnia; arrhythmias, such as atrioventricular dissociation, nodal rhythm, and ventricular extrasystoles, are prevalent. In people who are genetically predisposed, halothane can cause malignant hyperthermia.

About 20% of halothane is metabolised, and it stimulates hepatic enzymes in anaesthetists and operating room personnel. Hepatic injury affects only a small percentage of those who are exposed. Fever usually appears 2–3 days after anaesthesia, along with anorexia, nausea, and vomiting. This is followed by temporary jaundice or, in the most severe cases, catastrophic liver necrosis. In susceptible individuals, severe hepatitis is a consequence of repeated halothane anaesthesia (incidence 1 in 50 000). It occurs as a result of immunological sensitization to an oxidative metabolite of halothane. This significant consequence, combined with halothane's inherent drawbacks and the widespread use of sevoflurane for inhalational induction, has virtually abolished its usage in developed countries. Because it is relatively affordable, it is still widely used in other regions of the world.

How is the Administration of Halothane Done?

The halothane uses are given below:

Halothane is a volatile anaesthetic that is non-flammable, non-explosive, and non-irritating, but it requires a calibrated vaporizer to produce controlled quantities. It has a substantially faster induction and recovery time than methoxyflurane, but it requires strict anaesthetic monitoring to avoid overdose and the use of a calibrated vaporizer. Halothane uses include anaesthetic for surgery. CYP2E1 and, to a lesser extent, CYP2A6 metabolise halothane in hepatocytes to generate trifluoroacetyl chloride, which is chemically reactive and forms trifluoroacetyl adducts with proteins. Hepatic harm occurs in guinea pigs after halothane treatment, which is likely due to direct cytotoxicity caused by the creation of trifluoroacetyl adducts because it begins soon after exposure. Hepatotoxicity requires the conversion of halothane to trifluoroacetyl chloride, and trifluoroacetylated adducts have been found in liver biopsies from halothane-treated people and guinea pigs. The injury was linked to the presence of trifluoroacetyl protein adducts in outbred guinea pigs, implying that the hepatic injury is caused by covalent binding.

Role of Halothane as an Anesthesia

Halothane is a cerebral vasodilator that enhances CBF and decreases cerebrovascular resistance in a dose-dependent manner. The elevation in CBF is quite temporary; after 150 minutes of halothane anaesthesia, CBF returns to baseline. CBV, on the other hand, stays raised by 11 to 12 percent after three hours of halothane treatment. CMRo2 is reduced by 17 to 33 percent when halothane is used. Changes in arterial Paco₂ do not affect the cerebral vasculature. In both adults and neonates, halothane at high concentrations (2.0 MAC) prevents autoregulation of the cerebral circulation in response to changes in MAP. During periods of acute hypertension, halothane affects the permeability of the blood-brain barrier, allowing plasma proteins to extravasate into the normal brain. In dogs, halothane decreases CSF production by 30% and increases CSF reabsorption resistance.

Action of Halothane on Respiratory Route

The respiratory tract is not irritated by halothane. Respiratory depression is caused solely by high halothane concentrations. A degree of bronchodilation is shown, which could explain why halothane was found to be effective in a 17-year-old lady with acute severe asthma who had not responded to conventional treatment.

Even if the ventilatory response to Carbon dioxide is not decreased after halothane anaesthesia, preterm newborns can become apneic during the immediate postoperative period. Only one preterm newborn suffered an episode of apnea up to two days after inguinal herniorrhaphy with halothane/nitrous oxide anaesthesia in a prospective trial of 167 preterm newborns; however, the authors urged vigilant monitoring until complete recovery from anaesthesia had occurred.

Duration of Halothane Action

Until the introduction of sevoflurane, halothane was the gold standard against which all other inhalational anaesthetics were measured. Because it is an alkane, halothane is the only non-ether anaesthetic used today. Because halothane is the most soluble of the commonly employed anaesthetic drugs, it takes the longest to wash in. This means that halothane takes the longest of the anaesthetics to equilibrate inspired and alveolar (or brain) partial pressures. The potency of halothane is the greatest of the anaesthetic drugs, which may be seen as a safety issue. These two characteristics, together with the ability of all vaporizers to provide a maximum inspired concentration of 5% halothane, caused several episodes of cardiorespiratory instability, including hypotension, bradycardia, and arrhythmias. In the 1980s, there was special concern regarding neonates' capacity to withstand halothane anaesthesia due to the hemodynamic effects. Several inferences concerning the prior experience with halothane in paediatric anaesthesia can be drawn based on current knowledge of the pharmacology of this anaesthetic:

• In newborns, the MAC for halothane is lower than in older infants.

• In newborns and toddlers, halothane depresses both circulation and respiration.

• It is simpler to overdose children with halothane than with other anaesthetic agents due to the design of the vaporizer and the potency of halothane.

In humans, halothane is metabolised at a rate of 15% to 20%. Even in children, immune reactions, including hepatitis, have been recorded after repeated halothane anaesthesia. Because of its decreasing use in clinical practise, this agent is unlikely to pose a major harm to children.

Halothane Properties

Halothane is a nonflammable halogenated alkene with a blood/gas coefficient of 2.3, a MAC of 0.74 in 100% oxygen and 0.29 in 70% nitrous oxide, and a blood/gas coefficient of 2.3. The hypnotic action of halothane is better, but it lacks analgesic effects. The use of 1–3 percent halothane in air or oxygen, or 0.8 percent halothane in 65 percent nitrous oxide, can be used to quickly induce anaesthesia. At its MAC, halothane reduces arterial blood pressure in a dose-dependent (20–25 percent) manner and increases cerebral blood flow, rising intracranial pressure. It has little effect on systemic vascular resistance, but it does produce myocardial depression and has inotropic deleterious effects. It makes the myocardium more sensitive to epinephrine's arrhythmogenic effects. Malignant hyperthermia, a potentially fatal hypermetabolic disorder, can be induced by halothane. Because it does not produce coronary artery vasodilation, it does not produce coronary artery steal syndrome. Halothane hepatitis and hepatic necrosis are halothane anaesthetic effects that can be deadly in 1 in 6,000–35,000 cases.

Recovery from Halothane

Of the volatile anaesthetic drugs, halothane has the largest blood/gas partition coefficient, therefore recovery from halothane anaesthesia is quite slow. Breathing is a pleasurable experience. More than any other volatile anaesthetic, halothane lowers cardiac output. It makes the heart more sensitive to the arrhythmic effects of catecholamines and hypercapnia; arrhythmias, such as atrioventricular dissociation, nodal rhythm, and ventricular extrasystoles, are prevalent. In people who are genetically predisposed, halothane can cause malignant hyperthermia.

About 20% of halothane is metabolised, and it stimulates hepatic enzymes in anaesthetists and operating room personnel. Hepatic injury affects only a small percentage of those who are exposed. Fever usually appears 2–3 days after anaesthesia, along with anorexia, nausea, and vomiting. This is followed by temporary jaundice or, in the most severe cases, catastrophic liver necrosis. In susceptible individuals, severe hepatitis is a consequence of repeated halothane anaesthesia (incidence 1 in 50 000). It occurs as a result of immunological sensitization to an oxidative metabolite of halothane. This significant consequence, combined with halothane's inherent drawbacks and the widespread use of sevoflurane for inhalational induction, has nearly abolished its use in the industrialised world. Because it is relatively affordable, it is still widely used in other regions of the world.

Properties of Halothane

Halothane is a volatile anaesthetic that is non-flammable, non-explosive, and non-irritating, but it requires a calibrated vaporizer to produce controlled quantities. It has a substantially faster induction and recovery time than methoxyflurane, but it requires strict anaesthetic monitoring to avoid overdose and the use of a calibrated vaporizer. Halothane is a great anaesthetic for surgery.

Surgical anaesthesia can be successfully established in newborn, spontaneously breathing mice by inhaling 3 percent halothane in a 1 L/min fresh gas flow constituted of an equal N2O:O2 combination and maintained at 1–1.5 percent halothane. Supplemental oxygen (2 L/min) should be used during recovery. In CF-1 mice, halothane (0.25–0.75 percent) was found to be more convenient and reliable than ketamine/xylazine (80 mg/kg + 10 mg/kg i.p.) in terms of rate of induction, reversal, and control of anaesthetic depth, as well as producing significantly less cardiac depression (heart rate, left ventricular fractional shortening, and cardiac output).

However, halothane depresses the cardiovascular and respiratory systems in a dose-dependent manner. Furthermore, halothane, like isoflurane, has been shown to inhibit immune function (interferon stimulation of natural killer (NK) cell activity) in mice, and female CBI mice exposed to halothane anaesthesia multiple times before mating may produce more specific antibody-secreting B cells, as well as microscopic fatty changes in the liver. Although halothane has no effect on reproductive performance, it may reduce offspring survival.

Hepatotoxicity of Halothane

Despite its breakthrough status as a safe-acting inhalation anaesthetic, halothane is subject to a number of side effects, including liver necrosis. As a result, other fluorinated anaesthetics were developed, and halothane is now only used in a few countries.

It is possible to rationalise halothane's hepatotoxicity. Halothane is oxidised by cytochrome P450 (CYP) enzymes32, with trifluoroacetyl chloride 13 being the primary metabolite of halothane oxidation by CYP2E1 and CYP2A6 enzymes, which interacts with the N-terminal amino groups of liver proteins, including CYP2E1, to generate the N-trifluoroacetylated protein adduct, resulting in the creation of neoantigens, which stimulate an immunological response in vulnerable people, eventually leading to liver necrosis and, in extreme circumstances, death. 1.33.34% In vivo, the CYP2E1 inhibitor disulfiram reduces halothane oxidation, indicating that CYP2E1 is involved in halothane oxidation. Protein changes caused by halothane adducts are thought to lead to the production of haptens, which trigger an immunological response and hepatitis. In a mouse model, the clinical aspects of halothane-induced hepatitis are consistent with immune-mediated adverse drug reactions. Hepatitis caused by enflurane, isoflurane, and desflurane is caused by similar processes. The reactivity of halothane to rat hepatic proteins was likewise much higher than that of enflurane and desflurane, according to an enzyme-linked immunosorbent assay (ELISA). The decreased toxicity of the latter anaesthetics may be related to their slower metabolic bioactivation, resulting in substantially lower quantities of the reactive acid chloride 13 than halothane. When contrasted to those anaesthetized with halothane, the vast majority of individuals sedated with enflurane or desflurane do not suffer from liver injury.

Mechanism of Oxidative Degradation of Halothane and Protein Modification

In human liver microsomes, halothane is reductively converted by CYP2A6 and CYP3A4 enzymes to an unstable 1-chloro-2,2,2-trifluoroethyl free radical, which acts as an initiator for lipid peroxidation and has negative effects on respiratory and circulatory systems. Furthermore, this free radical is a generator of the volatile metabolites chlorodifluoroethene and chlorotrifluoroethane, both of which might have negative consequences.

Involvement of the Trifluoroacetyl Chloride Metabolite

CYP2E1 and, to a lesser extent, CYP2A6 metabolise halothane in hepatocytes to generate trifluoroacetyl chloride, which is chemically reactive and forms trifluoroacetyl adducts with proteins. Hepatic harm occurs in guinea pigs after halothane treatment, which is likely due to direct cytotoxicity caused by the creation of trifluoroacetyl adducts because it begins soon after exposure. Hepatotoxicity requires the conversion of halothane to trifluoroacetyl chloride, and trifluoroacetylated adducts have been found in liver biopsies from halothane-treated people and guinea pigs. The injury was linked to the presence of trifluoroacetyl protein adducts in outbred guinea pigs, implying that the hepatic injury is caused by covalent binding.

Role of Halothane

Halothane is a cerebral vasodilator that enhances CBF and decreases cerebrovascular resistance in a dose-dependent manner. The elevation in CBF is quite temporary; after 150 minutes of halothane anaesthesia, CBF returns to baseline. CBV, on the other hand, stays raised by 11 to 12 percent after three hours of halothane treatment. CMRo2 is reduced by 17 to 33 percent when halothane is used. Changes in arterial PaCO2 do not affect the cerebral vasculature. In both adults and neonates, halothane at high concentrations (2.0 MAC) prevents autoregulation of the cerebral circulation in response to changes in MAP. During periods of acute hypertension, halothane affects the permeability of the blood-brain barrier, allowing plasma proteins to extravasate into the normal brain. In dogs, halothane decreases CSF production by 30% and increases CSF reabsorption resistance.

It's not surprising that halothane raises ICP because it's determined by CBV, CSF volume, and brain tissue volume. Peak increases occur in 3 to 13 minutes, however the effect lasts for 3 hours after halothane exposure. Establishing hyperventilation for 10 minutes before the injection of halothane can reduce, but not completely eliminate, the increase in ICP in patients with cerebral mass lesions. Halothane should not be administered in patients with low intracranial compliance until the dura is opened and its effects on the brain can be detected if ICP is not being monitored.

Synthesis of Halothane

The industrial manufacture of halothane begins with trichloroethylene, which is converted to 2-chloro-1,1,1-trifluoroethane by reacting it with hydrogen fluoride in the presence of antimony trichloride at 130°C. At 450 degrees Celsius, this is reacted with bromine to generate halothane.

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Side Effects of Halothane

Hepatotoxicity, as well as an irregular pulse, respiratory depression, and hepatotoxicity, are all possible side effects. It should not be used in persons who have a personal or familial history of malignant hyperthermia, as with all volatile anaesthetics. In porphyria, it appears to be safe. It's uncertain whether using it during pregnancy is dangerous to the baby, and it's not usually suggested for C-sections. Halothane is a racemic combination made up of chiral molecules.

Did You Know

• In 1955, halothane was found. It is listed as an essential medicine by the World Health Organization.

• Ozone depletion is also caused by halothane.