Pharmacokinetic Properties of Succinylmonocholine in Surgical Patients

Abstract

Intoxications with succinylcholine (SUX) lead to a potentially lethal respiratory paralysis, and forensic cases involving accidental or deliberate SUX-application have been reported. Detection of SUX as well as its metabolite succinylmonocholine (SMC) is difficult: both substances are analytically challenging, and the extremely short plasma half-life of SUX additionally hampers detection of the parent compound. Pharmacokinetic data are scarce on SUX and non-existent on SMC. To enhance forensic knowledge concerning SUX intoxications, plasma pharmacokinetics of SMC were investigated in anesthetized patients. Fifteen subjects scheduled for a surgical procedure were included in this study. Muscle-relaxation was initialized with a bolus injection of 80-100 mg SUX. Blood sampling was performed within 6 h after SUX application using paraoxonized tubes. Collected plasma was processed according to a validated isotope dilution high-performance liquid chromatography-tandem mass spectrometry method using ion-pair solid-phase extraction. Pharmacokinetic parameters were derived from a user-defined as well as a three-compartment model. For SMC, peak plasma concentrations were reached after 0.03-2.0 min. In contrast to SUX, SMC was more slowly and more extensively distributed, featuring triphasic plasma concentration time profiles. Pharmacokinetic key parameters were subject to interindividual variation of potential forensic importance, with terminal half-lives of 1-3 h indicating a detection interval of 8-24 h for SMC in plasma. SMC was proven to be the only realistic SUX marker in a forensic context. The present work defines meaningful detection windows for plasmatic SMC after SUX application and offers guideline values for forensic toxicological casework. IntroductionSuccinylcholine (SUX) is a bis-quaternary ammonium compound that, because of its structural resemblance yet prolonged biological activity compared to acetylcholine (delayed degradation by the acetylcholinesterase EC 3.1.1.7), acts as a depolarizing muscle relaxant. The drug is routinely used in anesthesia, during which the resulting respiratory paralysis is compensated for by artificial ventilation, but it also has the reputation of being an undetectable poison: whenever respiratory assistance is not provided, a therapeutic dose of SUX can cause lethal apnea, with the drug being degraded within minutes (1-7) by unspecific cholinesterases (butyrylesterase; EC 3.1.1.8). The primary degradation product is succinylmonocholine (SMC), which is further metabolized into the endogenous substances succinate and choline (Figure 1). The fact that both SUX and SMC are analytically challenging compounds critically hampers forensic investigation. Additionally, the recent report on detection of the more stable SMC in SUX- Pharmacokinetic Properties of Succinylmonocholine in Surgical Patients

Degradation and elimination of succinylcholine and succinylmonocholine and definition of their respective detection windows in blood and urine for forensic purposes

“…3c; cp. [19]); in a second subject (#24), however, no more than 100 ng/ml of SMC were ever detected without stabilization (Fig. 3a).…”

“…Routine medical treatment (anxiolysis/sedation, anesthesia, analgesia, volume substitution etc.) of patients was essentially as described before [19]. Muscle relaxation was initiated by an intravenous bolus injection of 80-100 mg SUX (corresponding to 1.0-1.7 mg/ kg, mean 1.3 mg/kg).…”

“…As before [19], the patients' individual diagnosis and medication shall not be given in detail; however, health issues and therapy regimens were known to the authors and have been carefully considered during data interpretation.…”

“…Blood samples were treated as detailed before [19]; urine samples were snap-frozen in liquid nitrogen without any prior treatment. Samples were stored at −20°C until analysis.…”

“…Having established that no endogenous SMC is present in serum or urine [18], an investigation of in vivo as well as in vitro elimination of SUX and especially SMC seemed worthwhile. A previous work already employed the described analytical tools to establish the degradation kinetics of SMC in blood [19]. Complementing and completing this model, the present study addresses the degradation and elimination of both SUX and SMC in plasma as well as urine, aiming to define significant detection windows for these analytes in the forensically most relevant sample matrices.…”