Pharmacokinetics and Pharmacodynamics of Methylecgonidine, a Crack Cocaine Pyrolyzate

Abstract

Methylecgonidine is formed from cocaine base when smoked and has been identified in biological fluids of crack smokers. Ecgonidine, a metabolite of methylecgonidine formed via esterase activity, also has been identified in similar samples collected from crack smokers. Methylecgonidine and ecgonidine can be used as biomarkers to differentiate smoking from cocaine use via other routes of administration. We determined the pharmacokinetic properties of methylecgonidine and ecgonidine in sheep after intravenous administration of methylecgonidine at doses of 3.0, 5.6, and 10.0 mg/kg using gas chromatography-mass spectrometric assays. Methylecgonidine clears quickly from blood with a half-life of 18 to 21 min, whereas ecgonidine has a longer half-life of 94 to 137 min. Because ecgonidine clears more slowly, it may be a more effective biomarker of cocaine smoking. The cardiovascular stimulant effects of cocaine contrast with reported in vitro muscarinic agonist effects of methylecgonidine, decreasing contractility and stimulating nitric oxide production in cardiac cells and tissues. To test the hypothesis that methylecgonidine produces cardiovascular effects in vivo consistent with muscarinic agonism, methylecgonidine was administered to sheep intravenously (0.1-3.0 mg/kg) while monitoring heart rate and blood pressure. Significant hypotension and tachycardia occurred in all three sheep. Two of the three sheep demonstrated mild bradycardia 3 to 5 min after methylecgonidine injection. Intravenous pretreatment with atropine methyl bromide (15 g/kg) antagonized methylecgonidine-induced hypotension in all three sheep, supporting the hypothesis that methylecgonidine acts as a muscarinic agonist in vivo.Heating cocaine base (smoking crack) produces the pyrolyzate methylecgonidine (anhydroecgonine methylester). Because methylecgonidine is produced via thermal conversion from cocaine, it can be used as a marker to differentiate between smoking and cocaine use via other routes of administration. In forensic cases, methylecgonidine has been detected in urine (Jacob et al

Postmortem toxicology of drugs of abuse

“…Anhydroecgonine methyl ester (methylecgonidine) is only formed during smoking of cocaine as a result of pyrolysis [127,130]. It has a different profile of activity to cocaine acting as a muscarinic agonist to lower blood pressure [131].…”

Focal Pharmacological Modulation of Atrioventricular Nodal Conduction via Implantable Catheter

“…Acetylcholine was considered a good choice for this study because it has a very short half-life, allowing for rapid dose escalation and quick washout times even in the event of systemic spillover. 3 The test was considered positive if third-degree AV block was observed for a duration of Ͼ5 minutes. After the initial verification of correct AVN catheter position, quadripolar EP catheters were placed in the right atrial appendage, the right ventricular apex, and the His bundle.…”

Pesquisa dos indicadores de uso do "crack" em amostras de urina de indivíduos submetidos a exame médico-legal

“…O EMA apresenta ação muscaríca in vitro WOOLF et al, 1997;YANG et al, 2001). Ainda o EMA induziu rápida hipotensão em carneiros sendo este efeito antagonizado competitivamente por metilbrometo de atropina sustentando a hipótese do efeito muscarínico in vivo (SCHEIDWEILER et al, 2003).…”

“…Estudos demonstram que a COC inibe competitivamente os receptores muscarínicos M 2 nos tecidos cardíaco e cerebral, indicando que esta ação anticolinérgica tenha importante papel na cardiotoxicidade (SHARKEY et al, 1988;FLYNN,VAISHNAV,MASH, 1992;SHANOON et al, 1993;MIAO,QUI,MORGAN, 1996). O efeito estimulante cardiovascular da COC contrasta com o efeito agonista muscarínico do éster metilanidroecgonina in vitro, diminuindo a contratilidade e estimulando a produção de óxido nítrico na células cardíacas e tecidos (ERZOUKI et al, 1995;SCHEIDWEILER et al, 2003).…”