Procainamide delivery to ischemic canine myocardium following rapid intravenous administration.

Abstract

SUMMARY This study delineates the time course of procainamide accumulation in myocardium after bolus administration and its relationship to regional myocardial blood flow. The left circumflex coronary artery was ligated in 28 open-chest dogs. This was followed 40 minutes later by injection into the left atrium of labeled microspheres. 14 C-labeled procainamide, 1.5 mg/kg, was then administered as a single 1-minute infusion in 24 dogs, and four dogs were killed at each of six different times (1.5-15 minutes) after onset of drug infusion. In four additional dogs, the same dose of labeled drug was administered as a 1-minute infusion repeated every 5 minutes; after the fifth dose, the animals were killed. Myocardial sections were analyzed for regional blood flow and regional procainamide concentration. In the ischemic region, procainamide accumulated more slowly, and peak concentrations were lower than in the nonischemic region, being lowest in the most severely ischemic sections. The drug was thus distributed heterogenously through the myocardium early after bolus administration. Over time, however, this distribution became more homogenous with concentrations in nonischemic sections falling off more rapidly than in ischemic sections. Predicted steady state concentrations were achieved after 15 minutes in mildly ischemic sections (0.31-0.90 ml/min per g) but had not been reached by 25 minutes in severely ischemic sections. We conclude that ischemic myocardium, a potential site of antiarrhythmic drug action, represents a progression of pharmacokinetic compartments increasingly distal from the central compartment, depending on the severity of ischemia. CircRes 46: [789][790][791][792][793][794][795] 1980 THE HEART is generally considered to be in rapid distribution equilibrium with the central pharmacokinetic compartment because it is highly perfused (Gibaldi and Perrier, 1975;Koch-Weser, 1977). However, if the rate of drug equilibration between plasma and myocardium is related to perfusion, then ischemic areas of myocardium should behave as peripheral pharmacokinetic compartments. Depending on their blood flow, such areas might therefore be classifiable as more proximal or more distal, that is, requiring less or more time to equilibrate with the central compartment.Because ventricular premature depolarizations in patients with coronary artery disease probably originate from areas of ischemic myocardium (Waldo and Kaiser, 1973;Boineau and Cox, 1973), the sites of action of antiarrhythmic drugs may be in periph- Original manuscript received April 24, 1979; accepted for publication January 23, 1980. eral pharmacokinetic compartments. Using the R-V interval of coupled premature ventricular depolarizations as a measure of drug effect, analyzed the response of patients given repeated 1-minute infusions of procainamide every 5 minutes and observed that in most patients the drug probably continued to accumulate over the 5-minute time course. Based on those findings, they postulated that procainamide's site of action ...

Regional myocardial ajmaline concentration and antiarrhythmic activity for ischaemia‐ and reperfusion‐induced arrhythmias in rats

“…As shown in Table 4, when ajmaline was given post-occlusion, myocardial concentrations of ajmaline in the ischaemic region were lower than those in the normal region, which indicated that the coronary occlusion performed before ajmaline administration delayed the appearance of ajmaline in the ischaemic zone. Similar results were demonstrated in dogs with procainamide (Wenger et al, 1980) and lidocaine (Davis et al, 1985). Wenger et al (1980) showed a difference between normal and ischaemic myocardium with regard to the regional concentration of procainamide obtained after a single i.v.…”

“…Similar results were demonstrated in dogs with procainamide (Wenger et al, 1980) and lidocaine (Davis et al, 1985). Wenger et al (1980) showed a difference between normal and ischaemic myocardium with regard to the regional concentration of procainamide obtained after a single i.v. bolus administration and concluded that the ischaemic myocardium represents a tissue compartment whose pharmacokinetic distance from the central compartment is a function of the severity of ischaemia.…”

“…Changes in drug distribution seem to have a potential effect on the antiarrhythmic activity of the drug. However, little is known about the regional myocardial drug concentration in the ischaemic heart or its relationship with the antiarrhythmic effect (Wenger et al, 1980;Nattel et al, 1981;Curtis et al, 1984;Davis et al, 1985).…”

Approaches to the nonparametric analysis of limited longitudinal data sets

“…Alternatively, the investigator could examine the relationship of the summary response with some other factor. An example of such a treatment has been given by Wenger et al (1980), who studied the time course of procainamide accumulation in myocardium and its relationship to regional myocardial blood flow following bolus administration in dogs. Quadratic curves were used to describe the relationship of the response, that is, normalized myocardial drug concentration, versus blood flow.…”

“…After obtaining the trapezoidal areas, the investigator can address whether the magnitude of response, summarized over a series of times or dosages, appears to be associated with quantitative or semiquantitative variable using a correlational analysis such as that just described for the procainamide example of Wenger et al (1980). Another example can be drawn from the synthetic data of Table 3: Suppose the researcher wishes to assess whether the magnitude of response is related to the age of the subject.…”