The Pharmacokinetics of Lignocaine and β-Adrenoceptor Antagonists in Patients with Acute Myocardial Infarction

Abstract

Lignocaine (lidocaine) and beta-adrenoceptor antagonists are widely used after acute myocardial infarction. The therapeutic value of these agents depends on the achievement and maintenance of safe and effective plasma concentrations. Lignocaine pharmacokinetics after acute myocardial infarction (MI) are controlled by a number of variables. The single most important is left ventricular function, which affects both volume of distribution and plasma clearance. Other major factors include bodyweight, age, hepatic function, the presence of obesity, and concomitant drug therapy. Lignocaine is extensively bound to alpha 1-acid glycoprotein, a plasma protein which is also an acute phase reactant. Increases in alpha 1-acid glycoprotein concentration occur after an acute MI, decreasing the free fraction of lignocaine in the plasma and consequently decreasing total plasma lignocaine clearance without altering the clearance of non-protein-bound lignocaine. Complex changes in lignocaine disposition occur with long term infusions, and therefore early discontinuation of lignocaine infusions (within 24 hours) should be undertaken whenever possible. Because the risk of ventricular tachyarrhythmia declines rapidly after the onset of an acute MI, lignocaine therapy can be rationally discontinued within 24 hours in most patients. Lignocaine has a narrow toxic/therapeutic index, so that pharmacokinetic factors are critical in dose selection. In contrast, beta-adrenoceptor antagonists' adverse effects are more related to the presence of predisposing conditions (such as asthma, heart failure, bradyarrhythmias, etc.) than to plasma concentration. The pharmacokinetics of beta-adrenoceptor antagonists are important to help assure therapeutic efficacy, to provide information about the anticipated time course of drug action, and to predict the possible role of ancillary drug effects (such as direct membrane action) and loss of cardioselectivity. Lipid solubility is the main determinant of the pharmacokinetic properties of a beta-adrenoceptor antagonist. Lipid-soluble agents like propranolol and metoprolol are well absorbed orally, and undergo rapid hepatic metabolism, with important presystemic clearance and a short plasma half-life. Water-soluble drugs like sotalol, atenolol, and nadolol are less well absorbed, and are eliminated more slowly by renal excretion. Clinical assessment of beta-adrenoceptor antagonism is more valuable than plasma concentration determinations in evaluating the adequacy of the dose of a particular beta-adrenoceptor antagonist.(ABSTRACT TRUNCATED AT 400 WORDS)

My affection for Shneior Lifson

“…Fraction bound values obtained using the 96‐well dialysis block and the Spectrum apparatus were very similar to each other and consistent with literature values21–30(Table 1). There were minor shifts in fraction bound values between successive experiments that were attributed to intersubject variations in plasma protein concentrations 31–34.…”

Brain targeting by intranasal drug delivery (INDD): a combined effect of trans-neural and para-neuronal pathway

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Intraosseous lidocaine provides effective analgesia for percutaneous vertebroplasty of osteoporotic fractures

“…14,15 In a subgroup of four patients who had a pharmacokinetic profile similar to an intravascular injection, the true peak concentrations were unknown because the first plasma levels obtained at five minutes were already falling. It was difficult for us to obtain reliable blood samples earlier because the study design required a slow and progressive (over two minutes) injection of lidocaine.…”

“…The choice of lidocaine in this study was motivated essentially by its short half-life, 14 in agreement with the duration of the procedure, and its low intrinsic toxicity compared with other amide local anesthetics. We compared IL anesthesia with iv analgesia associating NP.…”