Development and Feasibility of a Porcine Model of Amlodipine Toxicity

Abstract

Introduction Toxicity related to calcium-channel blockers remains a significant cause of morbidity and mortality. Amlodipineinduced shock is unique in that its mechanism of action is thought to occur in part via the release of nitric oxide (NO) in the peripheral vasculature. Specific therapeutic interventions, including methylene blue (an NO scavenger), have been suggested, but efficacy studies are severely limited. To facilitate a larger porcine study into the effect of various interventions on amlodipine toxicity, we undertook this model development and feasibility study. Methods Intravenous amlodipine was prepared by dissolving commercially obtained amlodipine tablets in dimethylsulfoxide. The concentration of the drug was verified using ultraviolet spectroscopy. We administered this solution to three animals in order to determine a toxic dose, capable of facilitating a two-arm study of amlodipine toxicity. ResultsThe first pig died rapidly after the bolus infusion. The second pig developed mild toxicity, but the dissolution of the plastic tubing by the solvent and subsequent leakage limited the interpretability of the result. The third animal developed expected toxicity with an infusion rate between 2.0 and 5.5 mg/kg/h. Conclusion This study demonstrates a potentially repeatable model of amlodipine-induced toxic shock using intravenous administration of amlodipine and several methodological considerations for researchers undertaking similar work.

High‐dose insulin should NOT be used without vasopressors in calcium channel blocker toxicity

“…Amlodipine (in contrast to other dihydropyridines) also shows vasodilatory actions via increasing the release of NO in the peripheral vasculature. 2,23,24 At least theoretically, HDI could cause synergistic vasodilation when used in patients with amlodipine overdose. Therefore, despite increasing cardiac output through positive inotropy and vasodilation, it might also cause low systemic pressures and regional hypoperfusion.…”

“…For example, HDI causes vasodilation, through enhancing eNOS activity. Amlodipine (in contrast to other dihydropyridines) also shows vasodilatory actions via increasing the release of NO in the peripheral vasculature 2,23,24 . At least theoretically, HDI could cause synergistic vasodilation when used in patients with amlodipine overdose.…”

Effect of Methylene Blue on a Porcine Model of Amlodipine Toxicity

“…Furthermore, our research group has had success with previous models utilizing propranolol in a stepwise increasing dose fashion. Based on a pilot study, it was determined that animals began to display signs of toxicity at 0.75 mg/kg/hour, which occurs at approximately 60 minutes after the start of infusion of amlodipine [15]. The initial goal point of toxicity was defined in the pilot study as a 25% decrease in MAP multiplied by CO.…”

“…The optimal dosing of intravenous amlodipine to cause toxicity in swine is unknown. In the pilot portion of the study, we extrapolated the LD 50 of amlodipine from a rat study [14] to determine a presumed toxic dose in swine [15]. We ultimately created a very toxic model that may not be characteristic of the level of toxicity seen in humans.…”

“…Methylene blue has been suggested as an alternative treatment for DHP overdose as it may limit nitric oxide-mediated vasodilation [12][13][14]. In this study, we utilized a newly developed porcine model of amlodipine toxicity [15] to compare time to death between animals treated with methylene blue or traditional vasopressor therapy (norepinephrine).…”