Ankara Üniversitesi Tıp Fakültesi Mecmuası

0365-8104 1307-5608

Ankara University

Basic Pharmacology

Temel Farmakoloji

New Insights into the Biotransformation of Anesthetic Drugs and Their Effect on Application

Anestezik İlâçların Biyotransformasyonu Ve Uygulamaya Etkisi Yönünden Yeni Görüşler

Paykoç

Refik

ANKARA UNIVERSITY, ANKARA FACULTY OF MEDICINE

06 30 1975

28 1-2 443 458 01 01 1975 06 30 1975

1947

Ankara Üniversitesi Tıp Fakültesi Mecmuası

Abnormal reactions to anesthetic agents are not uncommon during anesthesia. Clinically significant reactions include halothane hepatotoxicity, methoxyflurane nephrotoxicity, and malignant hyperthermia. This article explores new insights into the biotransformation of anesthetic agents and their implications for clinical practice. Currently, a metabolic explanation for abnormal reactions to anesthetic agents appears to be a valid hypothesis.

Anestezi uygulamasında anestezik ajanlara karşı anormal reaksiyonların görülmesi nadir değildir. Bu reaksiyonlar arasın- da klinik önemi olanlar halotan hepatotoksisitesi, methoxyflurane nefrotoksisitesi ve malign hipertermidir. Bu makalede anestezik maddelerin biyotransformasyonunda yeni görüşler ve bunun klinik uygulamaya olan etkisi izah edil- meğe çalışılmaktadır. Bugün için anestezik maddelere karşı gö- rülen anormal reaksiyonların metabolik etki ile izahı geçerli bir hipotez gibi görülmektedir.

anestezi farmakoloji uygulama

**1** Airaksinen MM, Tammisto T. Toxic actions of the metabolites of Halothane LD50 and some metabolic effects of trifluoroethanol and trifluoroacetic acid in mice and guinea pigs. *Ann Med Exp Fenn.* 1968;46:242–248.

**2** Belfrage S, Ahlgren I, Axelson S. Halothane hepatitis in an anesthetist. *Lancet.* 1966;II:1466–1467.

**3** Berman ML, Bochantin JE. Nonspecific stimulation of drug metabolism in rats by Methoxyflurane. *Anesthesiology.* 1970;32:500–506.

**4** Brown RR, Miller JA, Miller EC. The metabolism of methylated amino azo dyes. *J Biol Chem.* 1954;209:211–222.

**5** Brown BR, Vandam LD. A review of current advances in metabolism of inhalation anesthetics. *Ann NY Acad Sci.* 1971;179:235–243.

**6** Brown BR. Hepatic microsomal enzym induction. *Anesthesiology.* 1973;39:178–187.

**7** Brown BR, Sagalyn MA. Hepatic microsomal enzyme induction by inhalation anesthetics. *Anesthesiology.* 1974;40:152–162.

**8** Brown BR Jr. Hepatic microsomal lipoperoxidation and inhalation anesthetics. *Anesthesiology.* 1972;36:458–465.

**9** Cascorbi HF, Blake DA, Helrich M. Differences in the biotransformation of Halothane in man. *Anesthesiology.* 1970;32:119–123.

**10** Cohen PJ, Marshall BE. Effects of Halothane on respiratory control and oxygen consumption of rat liver mitochondria. In: Fink BR, ed. *Toxicity of Anesthetics*. Baltimore: William B. Wilkins; 1968:24–36.

**11** Cohen PJ, Marshall BE, Lecky J. Effect of Halothane on mitochondrial oxygen uptake. Site of action. *Anesthesiology.* 1969;30:337.

**12** Cohen PJ, McIntyre R. The effects of general anesthesia on respiratory control and oxygen consumption of rat liver mitochondria. In: Fink BR, ed. *Toxicity of Anesthetics*. Baltimore: William B. Wilkins; 1972:109–116.

**13** Cohen EN, Belville JW, Brown BW. Anesthesia, pregnancy and miscarriage. *Anesthesiology.* 1971;35:343–347.

**14** Corn M, Rockett JF. Inhibition of bishydroxycoumarin activity by phenobarbital. *Med Ann DC.* 1957;34:578–579.

**15** Cousins MJ, Mazze RI. Dose related nephrotoxicity due to Methoxyflurane in man. Abstracts. *Annual Meeting of the American Society of Anesthesiologists,* Atlanta; 1971:153–151.

**16** Cucinell SA, Conney AH, Sansur M, et al. Drug interactions in man. *Clin Pharmacol Ther.* 1965;6:420–429.

**17** Editorial. *Anesthesiology.* 1973;39:112–114.

**18** Fouts JR, Rogers LA. Morphological changes in the liver accompanying stimulation of microsomal drug metabolizing enzyme activity by phenobarbital, chlordane, benzpyrene or methylcholanthrene in rats. *J Pharmacol Exp Ther.* 1965;147:112–119.

**19** Garfinkel D. Studies on pig liver microsomes. *Arch Biochem Biophys.* 1958;77:493–509.

**20** Gillette JR, Davis DC, Sasame HA. Cytochrome P-450 and its role in drug metabolism. *Annu Rev Pharmacol.* 1972;12:51–84.

**21** Gotell P, Sundell L. Anaesthetists' exposure to Halothane. *Lancet.* 1972;Aug 26:424.

**22** Greim H. Synthesesteigerung und Abbauhemmung bei der mikrosomalen cytochrome P-450 durch phenobarbital. *Naunyn Schmiedebergs Arch Pharmacol.* 1970;266:261–275.

**23** Hallen B, Ehrner-Samuel H, Thomason M. Measurements of Halothane in the atmosphere of an operating theatre and in expired air and blood of personnel during routine anesthetic work. *Acta Anaesth Scand.* 1970;14:17–27.

**24** Heinonen J, Takki S, Jarko L. Plasma lidocaine levels in patients treated with potential inducers of microsomal enzymes. *Acta Anaesth Scand.* 1970;14:89–95.

**25** Harrison GG, Smith JS. Massive lethal hepatic necrosis in rats anesthetized with Fluroxene after microsomal enzyme induction. *Anesthesiology.* 1973;39:619–625.

**26** Johnston RR, Thomas JA. Toxicity of Fluroxene. Abstracts. *Annual Meeting of the American Society of Anesthesiologists,* Atlanta; 1971:153–154.

**27** Klatskin G, Kimberg DV. Recurrent hepatitis attributable to Halothane sensitization in an anesthetist. *N Engl J Med.* 1968;280:515–522.

**28** Klingenberg M. Pigments of rat liver microsomes. *Arch Biochem Biophys.* 1958;75:376–386.

**29** Linde HW, Berman ML. Nonspecific stimulation of drug metabolizing enzymes by inhalation anesthetic agents. *Anesth Analg.* 1971;50:656–667.

**30** Maurer HM, Wolff JA, Poppers PJ, et al. Reduction in concentration of total serum bilirubin in offspring of women treated with phenobarbitone during pregnancy. *Lancet.* 1968;II:122–124.

**31** Mazze RI, Shue GL, Jackson SH. Renal dysfunction associated with Methoxyflurane. *JAMA.* 1971;216:278–288.

**32** Miller KW, Paton WDM, Smith EB. The anesthetic pressures of certain fluorine-containing gases. *Br J Anaesth.* 1967;39:910–918.

**33** Miller KW, Paton WDM, Smith EB, et al. Physiochemical approaches to the mode of action of general anesthetics. *Anesthesiology.* 1972;36:339–351.

**34** Nahrwold ML, Cohen PJ. The effects of Forane and Fluroxene on mitochondrial respiration. Correlation with lipid solubility and in vivo potency. *Anesthesiology.* 1973;38:437–444.

**35** Omura T, Sato R. The carbon monoxide binding pigment of liver microsomes. *J Biol Chem.* 1964;239:2370–2378.

**36** Remmer H, Merker HJ. Effects of drugs on the formation of smooth endoplasmic reticulum and drug metabolizing enzymes. *Ann NY Acad Sci.* 1965;123:79–97.

**37** Remmer H. Drugs as activators of drug enzymes, metabolic factors controlling duration of drug action. In: Brodie BB, ed. *Proc First Int Pharmacology Meeting, Vol. 6.* Pergamon Press; 1962.

**38** Rubin A, Tephly TR, Mannering GJ. Kinetics of drug metabolism by hepatic microsomes. *Biochem Pharmacol.* 1964;13:1007–1016.

**39** Topham JC, Longshaw S. Studies with Halothane. *Anesthesiology.* 1972;37:311–323.

**40** Trolle D. Decrease of total serum bilirubin concentration in newborn infants after phenobarbital treatment. *Lancet.* 1968;II:705–708.

**41** Van Dyke RA, Chenoweth MB, Van Poznak A. Metabolism of volatile anesthetics. *Biochem Pharmacol.* 1964;13:1239–1247.

**42** Van Dyke RA. Metabolism of volatile anesthetics. *J Pharmacol Exp Ther.* 1966;154:364–369.

**43** Whitcher CE, Cohen EN, Trudell JR. Chronic exposure to anesthetic gases in the operating room. *Anesthesiology.* 1971;35:348–353.