General anesthetics metabolism

Malignant hyperthermia (MH) is an autosomal-dominant pharmacogenetic disorder that is triggered by exposure to inhalation of general anesthetics, such as halothane. In susceptible individuals, these drugs can induce tachycardia, a greatly increased body metabolism, muscle contracture and an elevated body temperature (above 40°C) with a rapid rate of increase. Many cases of MH are linked to a gene for type 1 ryanodine receptor (RyRl). 

I. A 55-year-old female given a general anesthetic for a surgical procedure develops hyperthermia, hypertension, hyperkalemia, tachycardia, muscle rigidity and metabolic acidosis. Which of the following general anesthetics did she receive ... 

The answer is d. (Hardman, pp 308-313.) Halothane is a substituted alkane general anesthetic. It undergoes significant metabolism in humans with about 20% of the absorbed dose recovered as metabolites. Halothane can cause postoperative jaundice and hepatic necrosis with repeated administration in rare instances. 

Doring HJ. 1975. Reversible and irreversible forms of contractile failure caused by disturbances by general anesthetics in myocardial ATP utilization. In Fleckenstein A, DhallaNS, eds. Recent Advances in Studies on Cardiac Structure and Metabolism, vol. 5 Basic functions of cations in myocardial activity. Baltimore, MD University Park Press, 395-403. 

Estazolam potentiates the CNS depressant effects of phenothiazines, narcotics, antihistamines, MAOIs, barbiturates, alcohol, general anesthetics, and TCAs. Use with cimetidine, disulfiram, oral contraceptives, and isoniazid may diminish hepatic metabolism and result in increased plasma concentrations of estazolam and increased CNS depressant effects. Fleavy smoking (more than 20 cigarettes/day) accelerates estazolam s clearance. Theophylline antagonizes estazolam s pharmacological effects. 

Halothane is a volatile general anesthetic that was introduced into the practice of clinical anesthesia in 1956. Shortly after its introduction two forms of hepatic injury were noted to occur in patients who received halothane anesthesia. A subclinical increase in blood concentration of transaminase enzymes is observed in 20% of patients and has been attributed to lipid peroxidation caused by the free radical formed by reductive metabolism of halothane as shown in Figure 16.7 (39/ 40). The second form of toxicity is a potentially fatal hepatitis-like reaction that is characterized by severe hepatocellular necrosis and is thought to be initiated by the oxidative formation of trifluoroacetyl chloride (Figure 16.7). Fatal hepatic necrosis occurs in only 1 of 35/000 patients exposed to halothane/ but the risk of this adverse event is greater in females and is increased with repeat exposure/ obesity/ and advancing age (40). Because the onset of halothane hepatitis is delayed but is more frequent and occurs more rapidly following multiple exposures/ and because these patients usually are febrile and demonstrate eosinophilia/ this reaction is suspected... 

Methoxyflurane (Fig. 18.6) is seldom used beoause of its propensity to cause renal toxicity. It is the most potent of the agents discussed here, and it has the highest solubility in blood. Induotion and recovery would be expected to be slow. Chemically, it is rather unstable, and as much as 50% of an administered dose can be metabolized. Toxic metabolites significantly limit its utility as a general anesthetic (Fig. 18.7). 

The MAOIs interfere with the hepatic metabolism of many prescription and nonprescription (over-the-counter) drugs and may potentiate the actions of their pharmacological effects (i.e., cold decongestants, sympathomimetic amines, general anesthetics, barbiturates, and morphine). 

The use of inhalational anesthetics is generally reserved for maintenance of anesthesia. The development of an anesthetic concentration in the brain occurs more slowly with inhalational anesthetics than with IV drugs. Once an anesthetic level has been achieved, however, it is easily adjusted by controlling the rate or concentration of gas delivery from the anesthesia machine. The rate of recovery from a lengthy procedure in which inhalational agents are used is reasonably rapid, since inhalational anesthetics are eliminated by the lungs and do not depend on a slow rate of metabolism for their tissue clearance. Thus, inhalational drugs meet the requirement for a relatively prompt return of the patient s psychomotor competence. 

Local anesthetics generally have only slight endocrine and metabolic adverse effects, without clinical repercussions. 

CRITICAL ASSESSEMENT OF THE METHOD In general pharmacological studies during anesthesia should be assessed appropriately due to the possible interaction between the test compound and the used anesthetic as well as due to the reduced tone of the autonomic nervous system. Enteral administration of the candidate compound should be avoided, because enteral absorption of the test compound might be reduced due to the impaired intestinal motility during anesthesia. With respect to the effect of the aesthetic compound itself on intermediary metabolism the barbiturate pentobarbital sodium is the most inert anesthetic and does not cause alterations of metabolic blood and tissue parameters. In contrast, e.g. urethane as well as isoflurane (inhalation aesthetic) influences by itself substantially metabolic parameters over time (hours). 

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