title: Zero-order metoprolol pharmacokinetics after therapeutic doses: severe toxicity and cardiogenic shock.
abstract: 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.
  
  
  METHODS
  A 90-year-old female presented with hypotension, tachycardia and severe cardiac dysfunction after commencing a rapidly increasing metoprolol dose of 250 mg split daily. She was admitted to intensive care and given high-dose insulin therapy (10 U/kg/h), noradrenaline, adrenaline and dobutamine for severe cardiac dysfunction (cardiac index, 0.76 L/min/m2). 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®vs 4.3 ( www.lixoft.com ). Admission metoprolol concentration was 2.39 μg/mL (therapeutic reference range: 0.035-0.5 μg/mL). Data best fitted a one compartmental model with Michaelis-Menten kinetics and zero order elimination at high concentrations. Final parameter estimates were V, 63.4 L, maximum rate [Vm], 9.57 mg h-1, Michaelis constant [Km], 1.97 mg L-1. Predicted elimination half-life decreased from 20 h over time until there was first order elimination with a half-life 9 h.
  
  
  CONCLUSIONS
  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.
authors.affiliation: a Clinical Toxicology Research Group , University of Newcastle , New South Wales , Australia.
authors.forename: Geoffrey K
authors.initials: GK
authors.lastname: Isbister
authors.affiliation: b Department of Intensive Care , John Fawkner Private Hospital , Victoria , Australia.
authors.forename: Karyn
authors.initials: K
authors.lastname: Ang
authors.affiliation: b Department of Intensive Care , John Fawkner Private Hospital , Victoria , Australia.
authors.forename: Kieron
authors.initials: K
authors.lastname: Gorman
authors.affiliation: a Clinical Toxicology Research Group , University of Newcastle , New South Wales , Australia.
authors.forename: Joyce
authors.initials: J
authors.lastname: Cooper
authors.affiliation: c Department of Pharmaceutical Chemistry , Helwan University , Helwan , Egypt.|d Therapeutics Research Centre, School of Medicine , University of Queensland , Brisbane , Australia.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Mostafa
authors.affiliation: d Therapeutics Research Centre, School of Medicine , University of Queensland , Brisbane , Australia.|e School of Pharmacy and Medical Sciences , University of South Australia , Adelaide , Australia.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Roberts
mesh_terms: D058672:Adrenergic beta-2 Receptor Antagonists / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D000369:Aged, 80 and over; D002853:Chromatography, Liquid / Q000379:methods; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D007022:Hypotension / Q000139:chemically induced*; D007328:Insulin / Q000008:administration & dosage; D008790:Metoprolol / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D012770:Shock, Cardiogenic / Q000139:chemically induced*; D053719:Tandem Mass Spectrometry / Q000379:methods; D014662:Vasoconstrictor Agents / Q000008:administration & dosage
chemical_list: D058672:Adrenergic beta-2 Receptor Antagonists; D007328:Insulin; D014662:Vasoconstrictor Agents; D019389:Cytochrome P-450 CYP2D6; D008790:Metoprolol
keywords: Beta-blocker; Michaelis–Menten; high-dose insulin therapy; pharmacokinetics; toxicity