Mechanism of action
Halothane causes general anaethesia due to its actions on multiple ion channels, which ultimately depresses nerve conduction, breathing, cardiac contractility. Its immobilizing effects have been attributed to its binding to potassium channels in cholinergic neurons. Halothane's effect are also likely due to binding to NMDA and calcium channels, causing hyperpolarization.
The precise mechanism by which inhalation anesthetics produce loss of perception of sensations and unconsciousness is not known. Inhaled anesthetics act at many areas of the CNS. The Meyer-Overton theory suggests that the site of action of inhaled anesthetics may be the lipid matrix of neuronal membranes or other lipophilic sites. Anesthetics may cause changes in membrane thickness, which in turn effects the gating properties of ion channels in neurons. Interference with the hydrophobic portion of neuronal ion channel membrane proteins may be an important mechanism.
In vitro muscle contracture tests for malignant hyperthermia screening are routinely performed using standardized protocols. In the present study online monitoring of halothane concn in the gas phase was demonstrated to be an improved test standard. The kinetics of halothane concn and their effect on in vitro muscle contracture tests were evaluated in two test baths, I and II, which contained 3 and 18 ml Krebs-Ringer solution, respectively. The equilibration kinetics for halothane was significantly faster in bath I (half-life = 8.2 sec) compared with bath II (half-life = 25.6 sec). Twenty one pairs of muscle bundles from 21 potentially malignant hyperthermia susceptible patients were investigated, each test bath receiving one bundle from each pair. The variance of muscle contractures was significantly increased in test bath I compared with test bath II. However, there was no influence on malignant hyperthermia diagnosis, suggesting that, within the ranges of half-life = 8.2 sec-25.6 sec, the test bath volumes need not be standardized.
Volatile anesthetics inhibit phagocytic cell function, yet little is known about their effects on target tissues or on the target tissue response to stimulated phagocytes. Experiments were performed to determine how exposure to halothane and isoflurane changes rat pulmonary artery endothelial cell viability in response to the toxic oxygen metabolites produced by stimulated phagocytic cells. Rat pulmonary arterial endothelial cells were grown in monolayer culture. The monolayers were treated with phorbol myristate acetate stimulated human neutrophils at an effector-to-target ratio of 20:1 after equilibration with 0.4% or 1.7% halothane or 0.7% or 2.8% isoflurane. As measured by percent specific release of incorporated (51)Cr label (mean + or - standard error), cytotoxicity in the presence of 1.7% halothane (75.3 + or - 3.4%) was significantly greater (p< 0.02) than cytotoxicity in 5% carbon dioxide in air (44.7 + or - 3.3%) and in 0.4% halothane (57.3 + or - 4.7%). Also, cytotoxicity in 1.7% halothane was significantly greater than in 0.4% halothane (p< 0.02). It was found that rat pulmonary arterial endothelial cells incubated in isoflurane exhibited significantly greater release of (51)Cr than cells incubated in the MAC equivalent concn of halothane: 78.2 + or - 2.6% in 0.7% isoflurane (p= 0.0004) and 83.8 + or - 1% in 2.8% isoflurane (p= 0.005). Because early neutrophil cytotoxicity has been found to be mediated primarily by hydroxyl radical and hydrogen peroxide, hydrogen peroxide production by similar numbers of phorbol myristate acetate stimulated neutrophils under similar exposure conditions was measured. In carrier gas, phorbol myristate acetate stimulated neutrophils produced 20.5 + or - 1.3 nmole hydrogen peroxide/1X10+6 cells/hr. At the higher concn of halothane, hydrogen peroxide production actually was inhibited in comparison with carrier gas (15.4 + or - 1.4 nmole hydrogen peroxide/1X10+6 cells/hr in 1.7% halothane and 16.8 + or - 0.8 in 2.8% halothane), but the degree of inhibition did not reach statistical significance. In isoflurane, however, hydrogen peroxide production was not different from that seen in carrier gas. In other experiments, the monolayers were treated with 0, 200, 500, and 1,000 uM hydrogen peroxide after equilibration with 0.4%, 1.7%, and 2.8% halothane or 0.7%, 2.8%, and 5% isoflurane in 5% carbon dioxide in air. Efficiency of replating was used to measure degree of injury. Both halothane and isoflurane enhance the sensitivity of the rat pulmonary arterial endothelial cell monolayers to injury by hydrogen peroxide. The sensitizing effect of halothane was reversed by removing the anesthetic. Halothane and isoflurane thus enhance rat pulmonary arterial endothelial cell sensitivity to injury by both hydrogen peroxide and phorbol myristate acetate stimulated neutrophils. In increasing rat pulmonary arterial endothelial cell sensitivity to injury by oxygen metabolites, halothane and isoflurane may be inhibiting processes involved in intracellular antioxidant defenses.
Peripheral blood mononuclear cells from patients with halothane hepatitis are unusually susceptible to damage from phenytoin metabolites generated by an in vitro drug metabolising system. In order to provide more information about the nature of this susceptibility factor, the effect of removing calcium ions from the incubation medium of the test system was examined. Phenytoin metabolites were generated by incubating phenytoin with beta-naphthoflavone induced rat liver microsomes in the presence of 1,1,1-trichloropropene oxide, an epoxide hydrase inhibitor. When peripheral blood mononuclear cells from patients who had recovered from halothane hepatitis were incubated in this system and the maintained in calcium ion-containing tissue culture medium (without alpha-tocopherol) for 16 hr, cell death, as measured by trypan blue exclusion, was greatly increased (53% and 78% at 0.06 mmol/l and 0.12 mmol/l phenytoin, respectively) compared with control incubations (1,1,1-trichloropropene oxide omitted). Removal of calcium ions from the tissue culture medium effectively abolished reactive metabolite-induced cell death. Resting cytosolic free calcium ion concn in peripheral blood mononuclear cells was also measured using the quin-2 fluorescence method and total calcium ion content was measured by atomic absorption spectrometry. Although variability appeared greater among patients, mean values for these parameters among 12 patients with halothane hepatitis did not differ from controls. It is concluded that enhanced permeability of peripheral blood mononuclear cells to extracellular calcium ion may be an important factor in the pathogenesis of drug metabolite induced cell death in patients susceptible to halothane hepatitis. Such permeability to calcium ion is not evident in resting cells and presumably results from an interaction between electrophilic metabolites and the pumps which regulate cell calcium homeostasis.
For more Mechanism of Action (Complete) data for 2-BROMO-2-CHLORO-1,1,1-TRIFLUOROETHANE (7 total), please visit the HSDB record page.
Pharmacodynamics
Halothane is a general inhalation anesthetic used for induction and maintenance of general anesthesia. It reduces the blood pressure and frequently decreases the pulse rate and depresses respiration. It induces muscle relaxation and reduces pains sensitivity by altering tissue excitability. It does so by decreasing the extent of gap junction mediated cell-cell coupling and altering the activity of the channels that underlie the action potential.
Pharmacokinetics
Absorption
Most halothane is excreted by the lung unchanged. At least 12% of an absorbed dose is metabolized to chlorine, bromine, and trifluoroacetic acid, with toxic intermediates suspected of causing or contributing to hepatoxicity. Halothane is stored in fatty tissue and has been detected in the expired air of obese patients up to 2 weeks after exposure.
Urinary oxalate crystals were detected in 6 of 14 patients given halothane.
It is not known if halothane is distributed into breast milk.
60 to 80% Excreted unchanged by exhalation.
Inhalation anesthetics cross placenta.
Metabolism
Halothane is metabolized in the liver, primarily by CYP2E1, and to a lesser extent by CYP3A4 and CYP2A6.
Anywhere from 10 to 30 percent of inhaled halothane is metabolized, and metabolites may be detected in the urine for a period of several days after inhaling halothane. Various intermediate metabolites have been isolated; however, trifluoroacetic acid is the principal end-product isolated from the urine.
Halothane biotransformation by cytochrome p 450 produces reactive intermediates along both oxidative (acyl chloride) and reductive (free radical) pathways that ultimately generate the metabolites trifluoroacetic acid and flouride, respectively. Inhibiting oxidative metabolism with deuterated halothane reduces resultant injury in our guinea pig model of acute halothane hepatoxicity. To elucidate whether covalent binding of reactive intermediates to proteins (oxidative pathway) or lipids (reductive pathway) is a mechanism of necrosis, male outbred Hartley guinea pigs (600-725 g), N = 8, were exposed to either 1% (v/v) halothane or deuterated halothane at either 40% or 10% oxygen for 4 hr. One-half of the animals were killed immediately after exposure for binding studies; the remainder at 96 hr post exposure for evaluation of hepatotoxicity. Covalent binding of halothane intermediates to liver protein or lipid was determined by measuring the fluoride content of the bound moieties. The use of deuterated halothane and/or 10% oxygen during exposure led to 63-88% reductions (p< 0.01) in plasma trifluoroacetic acid concn (halothane-40% oxygen = 546; 73 mM, N = 8) which were accompanied by 33-60% decreases (p< 0.01) in binding to liver proteins (halothane-40% oxygen = 1.36; 0.26 nmoles bound fluoride/mg protein, N = 4), 78-84% decreases (p< 0.05) in 48 hr plasma ALT levels (halothane- 40% oxygen = 308; 219, control = 23 + 3, N = 4) and a total amelioration of centilobular necrosis.
Free radicals were detected from the in vitro metabolism of halothane (rat liver microsomes) by the PBN spin trapping method. The detected radical species include the 1-chloro-2,2,2-trifluoro-1-ethyl radical (I), as determined by mass spectral analysis, and lipid type radicals assigned by high resolution ESR spectroscopy with the use of d14-deuterated PBN. The lipid derived radicals are a carbon centered radical with the partially assigned structure CH2R and an oxygen centered radical of the OR' type. From the mass spectral analysis of the spin adduct mixture there is also evidence for a halocarbon double adduct of PBN of the type I-PBN-I.
An analogue of HCFC-123, the common inhalation anesthetic halothane (2-bromo-2-chloro-1,1,1-trifluoroethane), is metabolized by hepatic CYP2E1 to trifluoroacetyl chloride, causing trifluoroacetylation of liver proteins. These include cytochrome P450 itself and other enzymes, many of which have been identified as residing in the lumen of the endoplasmic reticulum and involved in the maturation of newly synthesized proteins. Both halothane and HCFC-123 induce peroxisome proliferation and increased beta-oxidation in rat liver cells. They are also highly effective in inducing excess uncoupled cytochrome P450 activity in rabbit liver microsomes, thus increasing hepatic oxygen consumption and facilitating the oxidation of other cytochrome P450 substrates.
For more Metabolism/Metabolites (Complete) data for 2-BROMO-2-CHLORO-1,1,1-TRIFLUOROETHANE (7 total), please visit the HSDB record page.
External links
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