Zero-order metoprolol pharmacokinetics after therapeutic doses: severe toxicity and cardiogenic shock

摘要

Objective: Acute beta-blocker overdose can cause severe cardiac dysfunction. Chronic toxicity is rare but potentially severe. We report therapeutic dosing of metoprolol resulting in unusual pharmacokinetics and toxicity, given high-dose insulin therapy for treatment.Case details: A 90-year-old female presented with hypotension, tachycardia and severe cardiac dysfunction after commencing a rapidly increasing metoprolol dose of 250mg split daily. She was admitted to intensive care and given high-dose insulin therapy (10U/kg/h), noradrenaline, adrenaline and dobutamine for severe cardiac dysfunction (cardiac index, 0.76L/min/m(2)). She developed acute renal failure, ischaemic hepatitis and disseminated intravascular coagulopathy. Inotropes and high-dose insulin were weaned over four days with complete recovery. Metoprolol was quantified with liquid chromatography-tandem mass spectrometry and concentration-time data were analysed using MONOLIX (R) vs 4.3 (www.lixoft.com). Admission metoprolol concentration was 2.39g/mL (therapeutic reference range: 0.035-0.5g/mL). Data best fitted a one compartmental model with Michaelis-Menten kinetics and zero order elimination at high concentrations. Final parameter estimates were V, 63.4L, maximum rate [V-m], 9.57mgh(-1), Michaelis constant [K-m], 1.97mgL(-1). Predicted elimination half-life decreased from 20h over time until there was first order elimination with a half-life 9h.Conclusion: The time course of cardiac dysfunction was longer than acute overdose but consistent with prolonged zero order elimination of metoprolol, suggesting the patient was a poor CYP2D6 metaboliser. High-dose insulin euglycaemia appeared to be effective in combination with vasoconstrictors/inotropes.