Ww Stargel

Increased Alpha-1-Acid Glycoprotein and Lidocaine Disposition in Myocardial Infarction

In 15 patients with confirmed myocardial infarction, alpha-1-acid glycoprotein rose significantly from 117 mg/dL at admission to 140 mg/dL at 36 hours (p less than 0.01), but not in 15 age- and sex-matched patients with chest pain only. Twelve patients were given prolonged infusions of lidocaine (2 mg/min). In patients with myocardial infarction, the rise in plasma alpha 1-acid glycoprotein concentration was associated with increased lidocaine binding and a rise in total lidocaine concentrations between 12 and 48 hours (p less than 0.05). Because of the binding changes, however, the rise in free drug concentration (31.2%) was significantly less than the 56.3% rise in total drug level (p less than 0.05). No changes in alpha 1-acid glycoprotein or lidocaine disposition were seen between 12 and 48 hours in the control subjects. Our results show that the rise in alpha 1-acid glycoprotein after myocardial infarction is associated with lidocaine accumulation, but increased plasma binding attenuates the rise in free drug. This suggests that the toxicologic implications of lidocaine accumulation may have been exaggerated and therapeutic monitoring of total plasma levels may be misleading.

Relationship between α1-acid glycoprotein and lidocaine disposition in myocardial infarction

The effects of myocardial infarction (MI) on lidocaine disposition were investigated in eight patients during a constant infusion of 2 mg/min. Plasma lidocaine binding and total plasma and free lidocaine concentrations were measured 12, 24, 36, and 48 hr after beginning therapy and were related to α1‐acid glycoprotein (AAG) concentrations. By 48 hr total plasma lidocaine and AAG concentrations had risen, as had plasma lidocaine binding. Because of enhanced binding, free lidocaine concentrations did not change significantly over this time. There was a correlation between AAG and the binding ratio for lidocaine (r = 0.87) and between AAG and total plasma lidocaine concentrations (r = 0.81). The data suggest that the rise in AAG seen after MI is responsible for enhanced plasma lidocaine binding and may, at least in part, be related to lidocaine cumulation.

Clinical comparison of rapid infusion and multiple injection methods for lidocaine loading.

A rapid infusion regimen for lidocaine loading (150 mg infusion over 18 minutes following a 75 mg priming injection) was evaluated in 12 patients. This was compared with multiple injection loading method in six patients involving three 50 mg injections over 18 minutes following the same priming dose. Both loading regimens were followed by a maintenance infusion of 2 mg/min. Predictably, the multiple injection method produced wide variations in lidocaine concentrations compared to the rapid infusion method. Some evidence of lidocaine toxicity (drowsiness, tinnitus) was seen in 13 of the 18 patients after the priming injection. During multiple injection loading, all six patients experienced side effects (drowsiness, tinnitus, dysarthria, or paresthesias.) Only 1 of 12 patients experienced a side effect (drowsiness) during rapid infusion loading. The difference in incidence of adverse reactions was significantly greater with the multiple injection regimen (p less than 0.01) but was associated with measurably greater drug levels.

PHARMACOKINETIC STUDIES: THEIR ROLE IN DETERMINING THERAPEUTIC EFFICACY OF AGENTS DESIGNED TO PREVENT SUDDEN DEATH*

Ideally, drug therapy should involve ( 1 ) a knowledge of the pathophysiology of the disease to be treated, (2) drug selection on the basis of an appropriate mechanism of action to reverse that pathophysiology, and (3) individualization of the drug regimen to produce the desired effect without toxicity. Even in the absence of the perfect marriage of pathophysiology and drug action, therapeutic efficacy can often be demonstrated by clinical trial. When this involves a definable and easily measured clinical end-point, such as blood pressure, individualization of drug dosage is a simple matter. Indeed, the success of antihypertensive therapy lies as much in our ability to individualize dose as it does in the number of antihypertensive drugs available to treat high blood pressure and its disasterous sequelae. Against this background, drug trials in the secondary prevention of sudden death in normotensive patients perhaps represent the ultimate challenge in individualization of therapy. It is generally thought that the event terminaing in sudden death is ventricular fibrillation, but the precise mechanisms involved in the precipitation of this fatal arrhythmia are not at all clear. The current interest in drugs other than traditional antiarrhythmic agents (including beta-adrenergic blocking agents, antiplatelet drugs, and calcium antagonists) attests to our ignorance of mechanism and has led to the study of drugs chosen on the basis of other known actions. The choice of an appropriate drug regimen is confounded by the fact that therapy is prophylactic because sudden death itself is clearly not a clinical end-point that can be used to guide an individual’s response. Even monitoring other, related end-points may not be easy. For example, patients may not have an arrhythmia, and if they do, assessing antiarrhythmic drug efficacy is fraught with problems. It is not at all clear whether total or partial suppression of arrhythmias would suffice or whether suppression of ventricular tachycardia, leaving single ectopic beats, would be an effective approach. Measuring antiplatelet effects is technically quite difficult and not easily applicable to largescale studies. Similarly, monitoring coronary spasm is out of the question at the present time. Of all the methods being currently considered, beta-adrenergic blockade is the easiest to monitor pharmacodynamically by performing serial exercise tests. To date, however, this method has not been used in any of the many clinical trials of these drugs, presumably because of inconvenience and/or

The Use of Intravenous Antiventricular Arrhythmic Agents During Acute Myocardial Infarction

The use of intravenous antiarrhythmic drugs in the setting of acute myocardial infarction is aimed at either preventive therapy (i.e., prophylaxis of ventricular fibrillation) or the treatment of documented atrial and ventricular arrhythmias. This chapter focuses on the rationale for both prophylactic and therapeutic use of intravenous antiarrhythmic agents in the management of ventricular tachyarrhythmias occurring in this acute clinical problem.