Halothane sensitivity

Halothane exerts a pronounced hypotensive effect, to which a negative inotropic effect contributes. Enflurane and isoflurane cause less circulatory depression. Halothane sensitizes the myocardium to catecholamines (caution serious tachyarrhythmias or ventricular fibrillation may accompany use of catecholamines as antihypotensives or toco-lytics). This effect is much less pronounced with enflurane and isoflurane. Unlike halothane, enflurane and isoflurane have a muscle-relaxant effect that is additive with that of nondepolarizing neuromuscular blockers. 

Tong, J., Oyamada, H., Demaurex, N., Grinstein, S., McCarthy, T. V., and MacLennan, D. H. (1997). Caffeine and Halothane Sensitivity of Intracellular Ca2+ Release Is Altered by 15 Calcium Release Channel (Ryanodine Receptor) Mutations Associated with Malignant Hyperthermia and/or Central Core Disease. J. Biol. Chem. 272(42) 26332-26339. 

Halothane sensitizes the myocardium to catecholamines arrhythmias may occur in patients with cardiac disease who have high circulating levels of epinephrine and norepinephrine (eg, patients with pheochromocytoma). Other modem anesthetics are considerably less arrhythmo-genic. The answer is (C). 

Oxford University Press, Oxford, pp 380-396 Blake DA, Rozman RS, Cascorbi HF (1967) Biotransformation of fluroxene. I. Metabolism in mice and dogs in vivo. Biochem Pharmacol 16 1237-1248 Bruce DL, Raymon F (1972) Test for halothane sensitivity. N Engl J Med 286 1218-1219 Bruce DL, Wingard DW (1974) Anaesthesia and the immune response. Anesthesology 34 271-282... 

Isoflurane is a respiratory depressant (71). At concentrations which are associated with surgical levels of anesthesia, there is Htde or no depression of myocardial function. In experimental animals, isoflurane is the safest of the oral clinical agents (72). Cardiac output is maintained despite a decrease in stroke volume. This is usually because of an increase in heart rate. The decrease in blood pressure can be used to produce "deHberate hypotension" necessary for some intracranial procedures (73). This agent produces less sensitization of the human heart to epinephrine relative to the other inhaled anesthetics. Isoflurane potentiates the action of neuromuscular blockers and when used alone can produce sufficient muscle relaxation (74). Of all the inhaled agents currently in use, isoflurane is metabolized to the least extent (75). Unlike halothane, isoflurane does not appear to produce Hver injury and unlike methoxyflurane, isoflurane is not associated with renal toxicity. 

Cardiac arrhythmias were induced in rats injected with exogenous epinephrine and exposed to HCFC-141 b at 5,000 ppm. However, the intravenous dose of epinephrine required was 3-fold that which induced arrhythmias in the same rats administered halothane, a common clinical anesthetic. Furthermore, the arrhythmias were characterized as mild. The threshold for cardiac sensitization for dogs was approximately 5,200 ppm. Deaths occurred in one study at 10,000 ppm and in another study at 20,000 ppm (with no deaths between concentrations of 9,000 and 19,000 ppm). 

The channel within the SR membrane is inhibited by a compound known as ryanodine, so that it is known as the ryanodine-sensitive Ca -channel. A mutation in the ryanodine receptor is responsible for the sensitivity, in some individuals, to the anaesthetic halothane. This sensitivity results in severe hyperthermia, a condition known as malignant hyperthermia. The explanation is that the modified receptor allows a massive Ca ion release from the SR, which is then pumped back into the SR. Thus, the rates of both release and uptake are increased, i.e. the rate of the cycle is increased so that the rate of ATP hydrolysis is very high, resulting in heat generation, and hence hyperthermia. This is analogous to an increase in rate of substrate cycles which also leads to transfer of chemical energy from ATP to heat (Chapter 2). How halothane effects the receptor cause to this release of Ca ions is not known. 

Anesthesia Discontinue use prior to general anesthesia with anesthetics that sensitize the myocardium to sympathomimetics (eg, cyclopropane, halothane). Aphakic patients Maculopathy with associated decrease in visual acuity may occur in the aphakic eye if this occurs, promptly discontinue use. 

Isoflurane, an isomer of enflurane, together with sevoflurane are the most commonly used inhalation anesthetics in humans. Isoflurane does not sensitize the myocardium to catecholamines, has muscle relaxing action so less neuromuscular blocker is required and causes less hepatotoxicity and renal toxicity than halothane. 

Halothane administration can result in a marked reduction in arterial blood pressure that is due primarily to direct myocardial depression, which reduces cardiac output. The fall in pressure is not opposed by reflex sympathetic activation, however, since halothane also blunts baroreceptor and carotid reflexes. Systemic vascular resistance is unchanged, although blood flow to various tissues is redistributed. Halothane also sensitizes the heart to the arrhythmogenic effect of catecholamines. Thus, maintenance of the patient s blood pressure with epinephrine must be done cautiously. 

Enflurane (Ethrane) depresses myocardial contractility and lowers systemic vascular resistance. In contrast to halothane, it does not block sympathetic reflexes, and therefore, its administration results in tachycardia. However, the increased heart rate is not sufficient to oppose enflurane s other cardiovascular actions, so cardiac output and blood pressure fall. In addition, enflurane sensitizes the myocardium to catecholamine-induced arrhythmias, although to a lesser extent than with halothane. Enflurane depresses respiration through mechanisms similar to halothane s and requires that the patient s ventilation be assisted. 

E. Reduced peripheral vascular resistance occurs with most halogenated hydrocarbons, and reflex tachycardia may be a concern. Halothane may be the clearest exception, since there appears to be a balance between relaxation and constrictor influences in various vascular beds with this agent so that total peripheral resistance changes very little. Halothane is the agent of concern when sensitization of the myocardium to catecholamine-induced arrhythmias may be important, such as during incidences of hypercapnia. Sevoflurane does not directly influence sympathetic function. However, reflex tachycardia can occur. Reflex sympathetic... 

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) (Figure 27-9). 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 depolarization. 

Halothane (149), first used clinically in the 1950s, is some three times more potent than ether and onset of anesthesia is rapid. Mild, transient hepatotoxicity occurs in about 20% of patients. A much rarer but more severe toxicity has been attributed to a drug-induced hypersensitivity reaction. Under aerobic conditions, halothane is oxidatively metabolized to trifluoroacetyl halide that apparently acylates tissue molecules. The bound trifluoroacetyl moiety functions as a hapten in sensitive individuals triggering the immune response253. 

Ten years ago, it was observed in a model of 5-min global ischemia in gerbils that the expected severe hippocampal neuronal loss could be markedly attenuated by prolonging the period of halothane anesthesia, which blunted the mild postischemic hyperthermia (approx 1,5°C) that would otherwise occur (55). This effect was not specific to halothane but rather could be duplicated by warming the head by a similar amount in its absence. This study established the marked sensitivity of the postischemic brain to even mild hyperthermia. 

Enflurane This gas is less potent than halothane, but it produces rapid induction and recovery. About 2% of the agent is metabolized to fluoride ion, which is excreted by the kidney. Therefore, enflurane [EN floo rane] is contraindicated in patients with kidney failure. Enflurane anesthesia exhibits the following differences from halothane. fewer arrhythmias, less sensitization of the heart to catecholamines, and greater potentiation of muscle relaxants... 

Kamibayachi T, Hayashi Y, Mammoto T et al. (1995) Thoracic epidural anesthesia attenuates halothane-induced myocardial sensitization to dysrhythmogenic effect of epinephrine in dogs. Anesthesiology 82 129-134 Kief H, Bahr H (1970) Epidural tolerance of artecaine in dogs. Personal communication... 

INHALATIONAL- HALOTHANE TERBUTALINE, THEOPHYLLINE Cases of arrhythmias when these bronchodilators are co-administered with halothane Possibly due to sensitization of the myocardium to circulating catecholamines by the volatile anaesthetics to varying degrees Risk of cardiac events is higher with halothane. Desflurane is irritant to the upper respiratory tract, and t secretions can occur and are best avoided in patients with bronchial asthma. Sevoflurane is non-irritant and unlikely to cause serious adverse effects... 

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