Pa Routledge

Lidocaine plasma protein binding

The percent of unbound lidocaine in the plasma of 24 healthy subjects was measured by equilibrium dialysis after addition of 3 µg/mlC14 lidocaine hydrochloride. The percentage of unbound lidocaine varied from 19.9 to 38.8 (30.2 ± 5, mean ± SD) and was inversely related to the concentration of α1–acid glycoprotein (AAG) in the plasma (r = −0.931, p < 0.001). The binding ratio (number of moles bound divided by number of moles unbound) of lidocaine was directly related to the plasma AAG concentration (r = 0.960, p < 0.001). The binding ratio of lidocaine in solutions containing AAG but no albumin, prepared from the plasma of subjects in the study, was also directly related to the concentration of this acute‐phase protein (r=0.909, p < 0.001). Human serum albumin solution (4 gm/100 ml) bound lidocaine to the extent of 20% under the same conditions. There was no relationship between the binding ratio of lidocaine and the albumin concentration in the plasma of the 24 subjects, in 7 normal subjects variation in AAG between 2 samples collected at least 2 mo apart was associated with a concomitant change in plasma lidocaine binding (r = 0.943, p < 0.01). Thus even in normal subjects there is considerable interindividual and intraindividual variation in lidocaine binding, and measurements of AAG concentration in plasma may be a useful predictor of the extent of lidocaine plasma binding.

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.

Diazepam and lidocaine plasma protein binding in renal disease

The plasma protein binding of diazepam and lidocaine was measured in patients with renal disease (those with uremia, nephrotic syndrome, or who had received a transplant) and in age‐and sex‐matched control subjects. Percentage unbound diazepam in plasma was increased over control in all three groups of patients as follows: uremic patients 3.23%, control, 1.64% (P < 0.001), nephrotic patients, 3.55%, control, 1.63% (P < 0.001); and transplant recipients, 2.11%, control 1.50% (P < 0.001). The binding ratio (molar concentration of bound to unbound drug) in the patients was related to albumin concentration (r = 0.609, P < 0.001). Percentage of unbound lidocaine did not differ substantially from control in nephrotic patients (34.2%, control 30.8%), but was reduced in the uremic patients (20.8%, control 30.7%, P < 0.001) and transplant recipients (24.6%, control 33.7%, P < 0.005). These increases were associated with increases in α1‐acid glycoprotein (AAG) concentration (uremic patients 134.9 mg/dl, control 66.3, P < 0.001; transplant recipients 106.5, control 65.6, P < 0.001). The binding ratio of lidocaine was closely related to the AAG concentration in patients (r = 0.933, P < 0.001) and controls (r = 0.719, P < 0.001). Thus, the binding of basic drugs may be increased or decreased in patients with renal disease, depending on the relative contribution of the individual plasma proteins to the total binding and the type of disease.

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.

Diazepam and N‐desmethyldiazepam redistribution after heparin

The effects of heparin, 1,000 U intravenously, on the blood, plasma, and free concentrations of diazepam and its metabolite, N‐desmethyldiazepam, have been investigated 3 hr after oral administration of 10 mg diazepam to 5 normal subjects. The percent free diazepam and N‐desmethyldiazepam increased 15 min after heparin from 1.66 ± 0.35 to 3.99 ± 1.88 (mean ± SD; p < 0.05) in the case of diazepam and from 2.50 ± 0.65 to 5.00 ± 1.96 (p < 0.05) in the case of its metabolite. The actual free concentration of diazepam rose from 3.6 ± 1.04 to 6.9 ± 1.33 ng/ml (p < 0.05) 15 min after heparin while total blood concentration was unchanged (144 ± 54 vs 130 ± 57 ng/ml). Free concentrations of N‐desmethyldiazepam rose from 0.62 ± 0.17 to 1.01 ± 0.34 but the effect, though consistent, was not statistically significant. Blood concentrations did not change (15 ± 3.2 vs 14 ± 3.9 ng/ml). That free drug level rose without a change in blood or total plasma levels suggests that factors other than simple plasma binding displacement are involved in this drug interaction.

High-performance liquid chromatographic analysis of sulfinpyrazone and its metabolites in biological fluids

A rapid, senstivie, and specific high-performance liquid chromatographic method is described for the quantitative analysis of sulfinpyrazone and its sulfone and p-hydroxy metabolites in plasma and urine. The method uses two different procedures for sample preparation: (1) a rapid and convenient procedure using a single extraction with 1-chlorobutane and subsequent back-extraction into sodium hydroxide solution for the analysis of sulfinpyrazone and its sulfone metabolite, and (2) a more time consuming procedure using triple extraction with ethylene dichloride, a buffer wash, and back extraction into the base for the additional analysis of the p-hydroxy metabolite. The lower limit of sensitivity for fulfinpyrazone is 50 ng/ml. Concentrations of sulfinpyrazone between 0.05 and 0.1 and 50 micrograms/ml were measured with an average coefficient of variation of 3.9%, ranging from 1.5 to 6.1%.

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.