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| The UK Society for Intravenous Anaesthesia |
| Based in the UK - as a resource for Anaesthesia Worldwide |
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Annual Scientific Meeting, Belfast; November 2000. Deleterious Drug Interactions in Anaesthetic Practice G ShortenDepartment of Anaesthetics, University Hospital, CorkAnaesthetic practice usually entails administration of drugs in combination. As no drug is perfectly selective in its effects, it is common that administration of one drug will influence the disposition or effect of another. Usually such drug interactions are predictable in nature if not in degree. An understanding of these interactions permits the anaesthetist to take advantage of beneficial effects and to minimize adverse effects. Drug interactions have recently been well reviewed by Bovill (1). They are generally classified as pharmaceutical (or physicochemical), pharmacokinetic and pharmacodynamic. Rather than attempt to present a comprehensive list of known deleterious drug interactions relevant to anaesthesia, I will discuss one concept under each of these three headings.
Pharmaceutical When administered in combination or in rapid succession, sodium thiopentone and either vecuronium or pancuronium form a white precipitate which can occlude intravenous tubing. Formation of this precipitate can result in patient awareness with or without muscle relaxation (2). The extent to which the precipitate causes vascular occlusion in vivo is not known. What is the precipitate and to what extent is it soluble in human plasma? Using ultraviolet spectrophotometry and high performance liquid chromatography, Taniguchi et al (2) demonstrated that the precipitate was thiopentone acid (not a combination of thiopentone and vecuronium) and that it is extremely insoluble in plasma. The potential therefore exists that this precipitate could occlude narrow blood vessels or even cause pulmonary infraction.
Pharmacokinetic Phase 1 metabolism comprises oxidation, reduction or hydrolysis of which the former is usually catalyzed by the cytochrome P450 enzymes located predominantly in the liver. This family of enzymes is classified as CYP1, CYP2 and CYP 3, each of which is further classified based on substrate selectivity. Of the 60 isoforms identified, CYP 2E1 catalyze metabolism of halogenated anaesthetic agents and CYP 3A4 intravenous anaesthetic agents. Commonly administered agents which induce or inhibit the cytochrome P450 enzymes are listed in Table 1. Bartkowski et al (3) reported a case of a 32 yr, 80 kg man who underwent exploratory laparotomy for persistent lower abdominal pain. During the 24 hr prior to surgery, he received erythromycin 1g three times, and intraoperatively (over 2 hr and 15 min) received alfentanil 260 (mg/kg). Twice postoperatively, he required administration of naloxone because he was unrousable and hypoventilating or apneic.
Table 1. Inducers and inhibitors of cytochrome P450 enzymes
Hiller et al (4) reported a case of an 8 yr old boy who received midazolam (0.5 mg/kg) p.o. one hour prior to planned adenoidectomy. When 200 mg (of a prescribed 400 mg) erythromycin has been infused iv, the child became unconscious for 45 min (although haemodynamically stable and breathing spontaneously). Both of these cases were attributed to an inhibitory effect on cytochrome P450 and augmentation of the effect and duration of alfentanil and midazolam. In vitro, erythromycin is N-demethylated and oxidized by cytochrome P-450 (5). One of its metabolites forms an inactive complex with cytochrome P-450, decreasing its oxidative activity. Compared to the child who received erythromycin, the AUC of the (plasma) midazolam concentration/time curve in similarly anaesthetised children who had not received the drug was significantly less (4). This is consistent with the explanation that decreased hepatic clearance accounts for the excessive midazolam effect.
Pharmacodynamic Synergism (i.e a supra-additive effect) has been demonstrated for several drugs commonly administered in combination by anaesthetists (e.g opioids and benzodiazepines). Whether such effects are beneficial or deleterious depends upon whether the anaesthetist takes the interaction into account when choosing the doses to be administered. Quantifying pharmacodynamic drug interaction has been most often carried out using fractional or isobolographic analysis. Using the former, the expression dA/DA + dB/DB is calculated (where DA and DB are potency expressions such as ED 50 for drugs A and B) and dA+dB is a dose combination which produces an equipotent effect as DA or DB. When dA/DA + dB/DB > 1, = 1 and < 1 the interaction is infra-additive, additive or supra-additive respectively. An isobole is a graphic representation of dose combinations of two drugs which, when administered in combination produce the same (defined) effect. When this relationship is linear the drug interaction is additive; when it bows towards the origin it is supra-additive or synergistic. Recently a more sophisticated "response surface" model for quantifying or predicting pharmacodynamic anaesthetic drug interactions has been described (6). References
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