Postmortem fatal and non-fatal concentrations of amlodipine.

Amlodipine is a dihydropyridine calcium channel blocker widely used in the treatment of high blood pressure and coronary heart disease. Intoxication can lead to reflex tachycardia following massive hypotension and death. The objective of this work was to study the post-mortem concentrations of amlodipine in 62 patients in order to determine whether the use of the reference concentrations from the living patients was applicable in postmortem setting, and to define more precisely the fatal and non-fatal postmortem concentrations of amlodipine. The amlodipine concentrations were measured in femoral whole blood by LC-MS/MS validated method. When sufficient information was available, the data were classified into 2 different groups, based on the conclusions of the autopsy and toxicological results: G1: non-toxic death and G2: fatal poisoning involving amlodipine alone or as part of a multidrug poisoning. The median concentration of amlodipine [1st quartile - 3rd quartile] of the whole population (n = 62) was 81 [42-134] ng/mL. Twenty-two cases were classified as G1 and thirteen as G2. The observed median [1st quartile - 3rd quartile] concentration of amlodipine was 66 [40.5-79.5] ng/mL in G1 and 240 [170-404] ng/mL in G2. The median concentrations observed in "non-toxic" deaths (66 ng/mL) were three times higher than those usually observed in living patients. Amlodipine distribution ratio between plasma and whole blood concentrations seems insufficient to explain this difference and postmortem redistribution from organs should be considered, and could suggest the same redistribution pattern for other drugs belonging to the same family.

Fatal intoxication with ivabradine: First case report.

Ivabradine is a bradycardic drug used worldwide in the treatment of chronic stable angina and chronic heart failure. We presented here a case of a 61-year-old woman who was admitted to emergency department for overdose. She presented with drowsiness, bradycardia (45bpm) and a low blood pressure (116/21mmHg). She died ten hours after admission from multiple organ failure. Ivabradine was quantified in different matrices sampled during autopsy using a method on LC-MS/MS (TSQ Vantage Thermo Fisher Scientific®), after a double liquid-liquid extraction with a mixture of hexane/ethyl acetate (1/1; v/v) and then chloroform/isopropanol (80/20; v/v). Chromatographic separation was achieved using a Hypersyl gold PFP column (200×2.1mm, 1.9µm) and an acetonitrile/formiate 2mM, 0.1% formic acid buffer gradient. Method was fully validated on whole blood. The mean overall recovery was 90%. Linearity was validated in the 5-500ng/mL range, with intra and inter-day precision lower than 14.3%. The ivabradine concentration found in patient post-mortem blood was 1210ng/mL. Ivabradine was also quantified in different viscera like lung (2910ng/g), kidney (1510ng/g), liver (1050ng/g), heart (900ng/g), and brain (110ng/g). The vitreous humor concentration was 760ng/mL. Pregabalin and zopiclone were also found in blood at 50µg/mL and 206ng/mL, respectively. This case seems to be the first report of a fatal intoxication involving ivabradine and the first published concentrations in organs.