Halogenated hydrocarbon anesthetics

Hoffmaim P, Heinroth K, Richards D, et al. 1994. Depression of calcium dynamics in cardiac myoc54es - a common mechanism of halogenated hydrocarbon anesthetics and solvents. J Mol Cell Cardiol 26 579-589. 

Desflurane, like other halogenated hydrocarbon anesthetics, causes a decrease in blood pressure. The reduced pressure occurs primarily as a consequence of decreased vascular resistance, and since cardiac output is well maintained, tissue perfusion is preserved. 

Sevoflurane undergoes hepatic biotransformation (about 3% of the inhaled dose), and it is somewhat degraded by conventional CO2 absorbents. The degradation product from the absorbent has been reported to be nephrotoxic, although the report is controversial and not substantiated by more recent studies. Sevoflurane s actions on skeletal muscle and on vascular regulation within the CNS are similar to those described for the other halogenated hydrocarbon anesthetics. 

Nitrous oxide appears to have little effect on uterine musculature. However, the halogenated hydrocarbon anesthetics are potent uterine muscle relaxants. This pharmacologic effect can be used to advantage when profound uterine relaxation is required for intrauterine fetal manipulation or manual extraction of a retained placenta during delivery. 

In the nucleus accumbens of rats the dopamine concentration was increased by both cyclopropane and halothane anesthesia cyclopropane, but not halothane, also increased the dopamine concentration in the caudate nucleus halothane, but not cyclopropane, significantly reduced the dopamine concentration in the ventral nucleus of the thalamus (4). It has been suggested that potentiation of the actions of dopamine could occur with cyclopropane or halogenated hydrocarbon anesthetics, but there is no direct evidence that this interaction occurs in humans. 

Systemic adverse effects of epinephrine include headache, faintness, increased blood pressure, tachycardia, arrhythmias, tremor, pallor, anxiety, and increased perspiration. Epinephrine should be used with caution in patients with cardiovascular diseases, cerebrovascular diseases, aphakia, CAG, hyperthyroidism, and diabetes melhtus, as well as in patients undergoing anesthesia with halogenated hydrocarbon anesthetics. Using NLO with epinephrine and dipivefrin wiU improve therapeutic response and reduce the risk of systemic adverse effects. ... 

The antihypertensive effects of guanethidine may be partially or totally reversed by the mixed-acting sympathomi-metics. Halogenated hydrocarbon anesthetics may sensitize the myocardium to the effects of catecholamines. Use of vasopressors may lead to serious arrhythmias. MAO inhibitors, such as tranylcypromine, increase the pressor response to mixed-acting vasopressors. Possible hypertensive crisis and intracranial hemorrhage may occur. This interaction may also occur with furazolidone, an antimicrobial with MAO inhibitor activity. In obstetrics, if vasopressor drugs are used either to correct hypotension or are added to the local anesthetic solution, some oxytocics may cause severe persistent hypertension in the presence of mephenteramine. The pressor response of mephenteramine may be attenuated by tricyclic antidepressants, which block the uptake of norepinephrine. 

C. Chloral hydrate and halogenated hydrocarbon anesthetics may enhance the arrhythmogenic effect of dopamine, owing to sensitization of the myocardium to effects of catecholamines. 

Compounds that Cause Kidney Damage Several drugs and some anesthetic compounds such as methoxyflurane cause kidney damage when present at high doses. Kidney-toxic compounds found in occupational environments include mycotoxins, halogenated hydrocarbons, several metals, and solvents (see Table 5.16). 

The halogenated hydrocarbons are generally of low acute toxicity, but several are associated with anesthetic effects and cardiac sensitization. Cardiac sensitization to halogenated alkanes appears related to the number of chlorine or fluorine substitutions. Halogenated alkanes in which >75% of the... 

The mechanism of action of inhalational anesthetics is unknown. The diversity of chemical structures (inert gas xenon hydrocarbons halogenated hydrocarbons) possessing anesthetic activity appears to rule out involvement of specific receptors. According to one hypothesis, uptake into the hydrophobic interior of the plasmalemma of neurons results in inhibition of electrical excitability and impulse propagation in the brain. This concept would explain the correlation between anesthetic potency and lipophilicity of anesthetic drugs (A). However, an interaction with lipophilic domains of membrane proteins is also conceivable. Anesthetic potency can be expressed in terms of the minimal alveolar concentration (MAC) at which 50% of patients remain immobile following a defined painful stimulus (skin incision). Whereas the poorly lipophilic N2O must be inhaled in high concentrations (>70% of inspired air has to be replaced), much smaller concentrations (<5%) are required in the case of the more lipophilic halothane. 

Inhalation anesthetics still in use include nitrous oxide and the halogenated hydrocarbon inhalation anesthetics such as halothane, isoflurane, methoxyflurane and sevoflurane. 

Halogenated hydrocarbon inhalation anesthetics may increase intracranial and CSF pressure. Cardiovascular effects include decreased myocardial contractility and stroke volume leading to lower arterial blood pressure. Malignant hyperthermia may occur with all inhalation anesthetics except nitrous oxide but has most commonly been seen with halothane. Especially halothane but probably also the other halogenated hydrocarbons have the potential for acute or chronic hepatic toxicity. Halothane has been almost completely replaced in modern anesthesia practice by newer agents. 

A) All halogenated hydrocarbon inhalational anesthetics sensitize the myocardium to catecholamine-induced cardiac arrhythmias. 

Nervous system The existence of neurologic disorders (for example, epilepsy, myasthenia gravis) influences the selection of an anesthetic. So, too, would a patient history suggestive of a genetically-determined sensitivity to halogenated hydrocarbon-induced malignant hyperthermia (see p. 113). 

Postoperatively, the anesthesiologist withdraws the anesthetic mixture and monitors the immediate return of the patient to consciousness. For most anesthetic agents, recovery is the reverse of induction that is, redistribution from the site of action rather than metabolism underlies recovery. The anesthesiologist continues to monitor the patient to be sure that there are no delayed toxic reactions, for example, diffusion hypoxia for nitrous oxide, and hepato-toxicity with halogenated hydrocarbons. 

Modern inhalation anesthetics are nonexplosive agents that include the gas nitrous oxide as well as a number of volatile halogenated hydrocarbons. As a group, these agents decrease cerebrovascular resistance, resulting in increased perfusion of the brain. They cause bronchodilation and decrease minute ventilation. Their clinical potency cannot be predicted by their chemical structure, but potency does correlate with their solubility in lipid. The movement of these agents from the lungs to the different body compartments depends upon their solubility in blood and various tissues. Recovery from their effects is due to redistribution from the brain. 

Bindal, M.C., Singh, P. and Gupta, S.P. (1980). Quantitative Correlation of Anesthetic Potencies of Halogenated Hydrocarbons with Boiling Point and Molecular Connectivity. Arzneim. Forsch.,30,234. 

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