VoL 266, No.2 Printed in U.SA.
ABSTRACT
ABBREVIATIONS: VERP, ventricular effective refractory period; VFRP, ventricular functional refractory period; VT, ventricular tachycardia; MPU,
myocardial procainamide uptake; MPC, myocardial procainamide content; F, coronary sinus flow; CT, ventricular conduction time.
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright C 1993 by The American Society for Pharmacology and Experimental Therapeutics
Myocardial
Uptake
and Pharmacodynamics
of Procainamide
in
Patients
with Coronary
Heart
Disease
and Sustained
Ventricular
Tachyarrhythmias1
ANNE M. GILLIS, HENRY J. DUFF, L. BRENT MITCHELL and D. GEORGE WYSE2
DWision of Cardiology, Department of Medicine, Foothills Medical Centre and the University of Calgary, Calgary, Alberta, Canada
Accepted for publication April 30, 1993
Little information is available currently regarding the time course
of myocardial accumulation and the onset of the
electrophysio-logic effects of antiarrhythmic drugs in humans. The myocardial
uptake and pharmacodynamics of the antiarrhythmic drug,
pro-cainamide, were studied during i.v. infusion in nine patients with
ventricular tachycardia undergoing electrophysiologic study.
Myocardial procainamide uptake was determined by serial
meas-urements of arterial-coronary sinus drug concentration
differ-ences and measurement of coronary sinus blood flow during a
50-mm procainamide infusion. The myocardial uptake of
procain-amide was 1 0 ± 4% (mean ± S.D.) of the total dose at 50 mm.
Coronary sinus procainamide concentrations equilibrated with
arterial concentrations within 30 mm of the start of the infusion.
However, peripheral venous procainamide concentrations did
not reach equilibrium with the arterial compartment during the
50-mm drug infusion. Changes in the QRS duration, ventricular
conduction time, QTc and ventricular refractory periods
corre-lated in a linear fashion with changes in the plasma procainamide
concentrations. The slopes of the arterial and coronary sinus
concentration-effect relationships were similar and significantly
greater than the slopes of the peripheral venous
concentration-effect relationships (P < .05). Thus, procainamide equilibrates
rapidly, but not instantaneously, in the myocardium. Short-term
electrophysiologic effects correlate best with the arterial and
coronary sinus drug concentrations. During this period, venous
procainamide concentrations do not accurately reflect the
myo-cardial concentration, effects or the eventual steady-state
rela-tionships.
It is generally assumed that drugs administered intravenously
equilibrate rapidly with the central compartment. Because the
heart is a highly perfused organ, it is often considered to be
part of the central compartment (Kates, 1984). However,
stud-ies correlating the electrophysiologic effects of drugs such as
procainamide, verapamil, bretylium or amiodarone with their
plasma concentrations have identified a dysequilibrium
be-tween the plasma and myocardial levels under nonsteady-state
conditions (Galeazzi et aL, 1976; Anderson et at., 1980; Reiter
et aL, 1982; Connolly et at., 1984). These observations suggest
that the myocardium can behave as a peripheral compartment.
In animal studies, a delay in the onset of the electrophysiologic
effects of bretylium and amiodarone has been correlated with
a delay in the accumulation of these two drugs in the
myocar-dium (Anderson et at., 1980; Connolly et at., 1984). Factors that
may determine the distribution of a drug into the heart include
the ionization and lipophilicity of a drug and regional blood
Received for publication December 14, 1992.
ISupported by the Heart and Stroke Foundation of Alberta.
2Clinical Investigator, (A.M.G.) Medical Scientist (H.J.D.) and Scholars
(L.B.M., D.G.W.) of the Alberta Heritage Foundation for Medical Research.
flow (Kates, 1984; Horowitz and Powell, 1986). The time course
of myocardial accumulation of antiarrhythmic drugs is of
po-tential clinical importance because it may be a determinant of
acute drug efficacy.
Delays in myocardial accumulation of antiarrhythmic drugs
might explain the discordant effects of oral and i.v.
administra-tion of antiarrhythmic drugs (Jackman et at., 1982; Echt et aL,
1983; Duff et aL, 1985; Interian et aL, 1991). Of course,
accu-mulation of metabolites will also contribute to this discordance
(Kates et at., 1984). Presently, little is known about the time
course of myocardial accumulation and the onset of
electro-physiologic effects of antiarrhythmic drugs in humans
(Horow-itz and Powell, 1986; Horowitz et at., 1986). Accordingly, the
present study was designed to assess the time course of
myo-cardial accumulation and the onset of electrophysiologic effects during i.v. procainamide infusions.
Methods
Study population. Nine patients undergoing a base-line electro-physiologic study to investigate ventricular tachyarrhythmias partici-pated in this study. There were eight men and one woman with a mean
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1002 Gillis et al. Vol. 266
age of 65 ± 8 (± S.D.) years All patients had documented coronary
artery disease and a prior myocardial infarction. The indications for
the electrophysiologic study were sustained VT in eight patients and
syncope with spontaneous nonsustained VT documented at another time in one patient. The mean VT cycle length was 343 ± 56 msec.
The mean left ventricular ejection fraction measured by the gated
radionuclide technique was 0.26 ± 0.11.
Electrophysiologic study. The patients underwent electrophysi-ologic evaluation in the postabsorptive state after informed written consent was obtained for their participation in this study, as approved by the local institutional review board. The electrophysiologic study protocol has been described previously (Gillis et aL, 1991). All
antiar-rhythmic drugs, including beta adrenoceptor blocking agents, were discontinued for at least five drug half-lives before the study. Two electrode catheters were positioned in the right ventricle: one at the right ventricular apex and one at the right ventricular outflow tract. One electrode catheter was inserted through an 8-French sheath into the left subclavian or right internal jugular vein and the second elec-trode catheter was inserted through a 7-French sheath positioned in the right femoral vein. A short 4-French sheath was inserted in the right femoral artery for blood pressure monitoring.
Stimuli 2 msec in duration with an intensity twice the diastolic threshold were applied to the right ventricular apex. Single, double and triple ventricular extrastimuli were administered after eight beat trains of ventricular pacing at cycle lengths of 600, 500 and 400 msec.
Thereafter, 6 and 12 beat trains of rapid ventricular pacing were
applied, beginning at a cycle length of 300 msec. The cycle length was
decreased by 10-msec intervals until 2:1 ventricular capture was
ob-served. If VT was not reproducibly induced, the stimulation protocol was repeated from the right ventricular outflow tract. The endpoint of the ventricular stimulation was completion of the protocol or induction of sustained VT. Reproducibility in the drug-free state was demon-strated by the induction of VT at least twice in all patients.
Study protocol. After base-line VT induction, the electrode
cath-eter inserted through the internal jugular or subclavian vein was
removed. An 8-French bipolar thermodilution coronary sinus flow
catheter (Webster Laboratories, Baldwin Park, CA) was introduced
and positioned in the coronary sinus with its tip approximately 4 cm
from the os. Correct placement of the coronary sinus catheter was confirmed by the characteristic electrograms and by injection of 3 to 5 ml of radiographic contrast medium. A stable coronary sinus catheter position was confirmed throughout the study. The second electrode catheter remained positioned at the right ventricular apex to determine ventricular refractory periods.
Standard definitions were used to determine electrocardiographic
intervals obtained at a paper speed of 100 mm/sec. RR, QRS and QT
intervals were measured by one investigator. Intraobserver variability
was less than 4%. The mean offive intervals measured at each sampling time was calculated. The rate corrected QT interval (QTc) was
calcu-lated from the formula QTc = QTJ1, with RR in seconds.
Ventric-ular effective and functional refractory periods were determined at a
pacing cycle length of 500 msec. The extrastimulus was progressively shortened by 10 msec until ventricular capture was lost. It was then increased again by 10 msec and progressively shortened by 2-msec intervals until ventricular capture was lost. The VERP was the longest interstimulus coupling interval that did not capture the ventricle (Jo-sephson, 1993). The VFRP was the minimal interval between ventric-ular electrograms measured during ventricular extrastimulation. Ven-tricular conduction time was measured during sinus rhythm as the interval between the right ventricular apex and coronary sinus electro-grams.
After base-line measurements were completed, procainamide was administered i.v. through the subclavian vein. Procainamide was ad-ministered in a loading dose of 10 mg/kg administered at a rate of 20 mg/mm. This was followed by a maintenance infusion of 0.075 mg kg’min’ (Wyse et aL, 1987). The mean weight of the patients was 76 ± 9 kg and the mean duration of the loading infusion was 38 ± 4 mm. The mean dose of procainamide administered was 763 ± 184 mg.
Blood samples for the measurement of procainamide were drawn simultaneously from the femoral artery and vein and the coronary sinus. Samples were drawn at base line and at 2, 4, 6, 8, 10, 12.5, 15, 17.5 and 20 mm and every 5 to 10 mm thereafter until 50 mm had elapsed during the procainamide infusion. However, the drug infusion
was continued until the VT induction protocol was completed. The
surface electrocardiograms, intracardiac electrograms, intra-arterial
pressure traces and ventricular refractory periods were also determined
at each sampling time.
Coronary sinus blood flow was measured by thermodilution using
5% dextrose at room temperature administered by means of a constant
volume infusion pump at a rate of 38 ml/min (Horowitz et at., 1986;
Ganz et al., 1971). These measurements were made in triplicate at base
line and after 20 and 40 mm of drug administration.
Drug assays. Procainamide concentrations were measured by
high-performance liquid chromatography (Annesley et at., 1986). The thresh-old sensitivities for detection of procainamide and the metabolite
N-acetyl procainamide were 10 ng/ml or 0.03 tM. The intra-amay
coef-ficient of variation for repeated measurements of procainamide at 1700 ng/ml was 6.7% (n = 24). The interassay coefficient of variation was
9.3%(n=24).
Myocardial drug uptake. The transcoronary drug concentration
(AC) was calculated as the difference between the femoral arterial and
coronary sinus procainamide concentrations (Horowitz et at., 1986; Gillis et aL, 1991). The rate of MPU was calculated over the perfusion period from the formula:
MPU = C . F
where MPU is measured in micromoles per minute.
The MPC was calculated for the region sampled by the coronary
sinus catheter from the cumulative MPU data:
MPC = MPC1 + MPU1 -f MPU2
where MPC is measured in micromoles and MPC1 is MPC at the end
of the previous sampling period, MPU1 and MPU2 are the instants-neous MPUs at the beginning and end of the current sampling periods and t is the duration of the current sampling period (Horowitz et a!.,
1986).
MPC was normalized to account for patient differences in coronary sinus flow by calculating the ratio MPC/F in micromoles per milliliter
per minute. The percent of drug extracted from the amount of drug
delivered to the myocardium was also calculated.
The myocardium was considered to be a separate compartment in
this study (Galeazzi et a!., 1976; Kates, 1984). The coronary sinus concentration-time data were fit to a one-compartment pharmacoki-netic model:
C = Co(1 - e
where C is the measured coronary sinus concentration, Co is the
estimated steady-state coronary sinus concentration and k,,,,,, is the rate constant of myocardial uptake. Because a loading and maintenance infusion protocol was used, the concentration-time data were fit only using data acquired during the initial loading phase. The T#{189}of the
accumulation of drug in the myocardium was calculated from the rate
constant.
Pharmacodynamic calculations. Drug concentration-effect
rela-tionships were determined by plotting electrophysiologic effect (e.g., QRS duration, QTc and ventricular refractory periods) versus femoral arterial and venous and coronary sinus drug concentrations. The data were fit using linear regression analysis. This is an appropriate
phar-macodynamic model because the concentration range evaluated was
small (<2 log units) and well below the concentration at which one
would observe 50% ofthe maximal effect (Holford and Schemer, 1981).
Statistical analysis. The data are presented as mean ± S.D.
Comparisons within groups were made using analysis of variance with
the Newman-Keuls test for multiple comparisons. Statistical signifi-cance was defined as a two-tailed P value less than .05.
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a 0 ARTERIAL
cs
VENOUS , . , .,____
. I -r . 0 10 20 30 40 50 1993 Procainamide Pharmacodynamice1003
Results
Coronary sinus blood flow Coronary sinus
catheteriza-tion was successful in all nine patients. Coronary sinus blood
flow could not be measured in one patient because of technical
problems. There was variability of coronary sinus blood flow
between patients (range, 34-205 mi/mm) but coronary sinus
flow did not change significantly over time within patients.
The mean coronary blood flow was 114 ± 48 ml/min, 102 ± 57
mi/mm and 105 ± 48 ml/min at 0, 20 and 40 mm, respectively
(P = N.S.).
MPU. Procainamide was detectable in the arterial, coronary
sinus and femoral venous blood by the initial 2-mm sample.
The time course of arterial, coronary sinus and femoral venous
plasma concentrations of procainamide is shown in figure 1.
The product of the coronary sinus flow and the area between
the arterial and coronary sinus procainamide
concentration-time curves represents the amount of procainamide taken up
by the myocardial bed sampled by the coronary sinus flow
catheter (Horowitz and Powell, 1986; Horowitz et at., 1986;
Hayward et at., 1983; Gillis and Keashly, 1991). Procainamide
plasma concentrations were slightly lower in the coronary sinus
samples than in the arterial samples at each sampling time for
the first 30 mm of the infusion (P < .05). In contrast, femoral
venous procainamide concentrations remained significantly
lower than the arterial and coronary sinus concentrations for
the full 50 mm of procainamide infusion (P < .01). The time
to reach peak arterial procainamide concentration was shorter
than the time to reach the peak procainamide venous
concen-tration (table 1, P < .05). The time to reach peak coronary
sinus procainamide concentration was intermediate.
The calculated MPC is shown in figure 2. The MPC reached
a plateau after 30 mm of procainamide infusion. The average
dose of procainamide delivered to the sampled myocardial bed
was 160 ± 76 mol. The average MPC was 13.8 ± 5.9 mol or
10 ± 4% ofthe dose. The regional MPU normalized for coronary
sinus flow was 0.16 ± 0.09 zmol ml’min’. The half-life of
equilibration of procainamide in the coronary sinus plasma was
12 ± 6 mm.
Electrophysiologic effects. The time course of changes in
the QRS duration and ventricular conduction time during
60 -w 40 -< z (_) 20 -0 0 0-TIME (mm)
Fig. 1. Time course of plasma procainamide concentrations. Data are
mean ± 1 S.D. for arterial (0), coronary sinus (CS) and venous (0)
concentrations.
TABLE I
Time to maximum procainamide concentration and
electrophysiologic effects 1wneto Peak ,n Drug concentrations Arterial 30 ± 8 Coronary sinus 34 ± 9 Femoral venous 36 ± 6* Electrophysiologic effects QRS 29 ± 16** VFRP 28±18 VERP 25±16** CT 26±13** QTc 34±8
* P< .01 compared with arterl& concentration. ** P< .05 compared with venous concentration.
3j
LU 0 0.3 _____________ I--- T I I 0 10 20 30 40 50 TIME (mm)Fig. 2. Time course of MPU. The MPC calculated from the differences in
arterial and coronary sinus procainamide concentrations is shown in the upper panel. The calculated MPU isexpressed relative to coronary sinus flow in the lower panel. The mean data for eight patients are shown.
procainamide infusion are shown in figure 3. Significant
in-creases in the QRS duration and ventricular conduction time
were observed during the first 20 mm of procainamide infusion
(P < .01) and these parameters did not change significantly
thereafter (P = N.S., by analysis of variance). The time course
of changes in VERP, VFRP and QTc during procainamide
infusion are shown in figure 4. VERP, VFRP and QTc increased
during the procainamide infusion (P < .01) and approached
steady state within 20 mm. The times to reach maximum
electrophysiologic effects were similar to the time to reach the
maximal arterial procainamide concentrations but were earlier
than the time to reach the maximal venous procainamide
concentrations (table 1).
Concentration-effect relationships. Linear
concentra-tion-effect relationships were observed when the
electrophysi-ologic effects were plotted versus the procainamide arterial,
coronary sinus and femoral venous plasma concentrations. The
means of the slopes of these concentration-effect relationships
are shown in table 2. The slopes describing changes in QRS
duration, ventricular conduction time, VERP, VFRP and QTc
in relation to the plasma procainamide levels of the arterial
and coronary sinus blood were similar in each instance. In
contrast, the slopes of the femoral venous concentration-effect
relationships for these electrophysiologic parameters were
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40 -20 0-15 -10 5-U 0 U, E U) 0 U 0 a, E I-C) 0-T 1 0 10 20 30 40 50
a
a
Correlation coefficient oflinear regression. p .< .05 vs. arterial and coronary sinus data. *_ P< .01vs. arterial and coronary sinus data.130 -i 0 0 0 A 100 -0 VENOUS A CS 0 ARTERIAL
1004 Gillis et al. Vol. 266
TIME (mm)
Fig. 3. Time course of change in GAS duration and CT during the
procainamide infusion in nine patients. The data are the mean ± 1 S.D.
__
50 UI
60 0 10 20 30 40 50 TIME (mm)Fig. 4. Time course of change in VERP, VFRP and QTc during
procain-amide infusion in nine patients. The data are the mean ± 1 S.D.
steeper (P < .05). Examples of these procainamide
concentra-tion-effect relationships are shown in figure 5.
VT induction. During the base-line drug-free
electrophysi-ologic study, sustained VT was induced in eight patients and
nonsustained VT (15 sec) was induced in one patient. The
mean VT cycle length in these patients was 343 ± 55 macc.
After a 50-mm procainamide infusion, sustained VT remained
inducible in six patients. No ventricular arrhythmia was
in-duced in three patients. The mean VT cycle length after
pro-TABLE 2
Concentration-effect relationships Thedataaremean±1 S.D.
Merl Coronary Sinus Femor Venous QRS Slope (msec/,M) 0.49 ± 0.48 0.49 ± 0.47 0.86 ± 0.76* A. 0.82 ± 0.12 0.84 ± 0.15 0.78 ± 0.16 CT Slope (msec/zM) 0.14 ± 0.06 0.14 ± 0.06 0.26 ± 0.15* R 0.64 ± 0.25 0.68 ± 0.22 0.66 ± 0.23 VERP Slope (msec/,M) 0.59 ± 0.33 0.64 ± 0.38 1 .31 ± 1.06* A 0.79 ± 0.09 0.82 ± 0.09 0.74 ± 0.12 VFRP Slope (msec/M) 0.57 ± 0.24 0.62 ± 0.24 1 .1 5± 0.51* A 0.72 ± 0.12 0.81 ± 0.07 0.72 ± 0.13 QTc Slope (msec/,M) 0.93 ± 0.40 1.00 ± 0.35 2.09 ± 0.70** A 0.75 ± 0.11 0.81 ± 0.07 0.83 ± 0.07 .; 120 -0 E C,, 0 110 -0 10 20 30 40 50
PROCAINAMIDE
(pM)
Fig. 5. Examples of procainamide concentration-effect relationships for
ORS duration in one patient. The lines were fitted by linear regression
analysis (CS, coronary sinus). The slopes and correlation coefficient (A)
of the analysis were 0.79 msec/,M for A = 0.96; 0.40 msec/,M for A =
0.95; and 0.40 msec/M for A = 0.97 for the femoral venous, coronary
sinus and arterial concentration-effect relationships, respectively.
cainamide was 343 ± 99 macc (n = 6), before procainamide, it
was 349 ± 67 msec (P = N.S.). The cycle length of VT induced
during procainamide infusion did not correlate with
procaina-mide plasma concentrations. Although the myocardial content
ofprocainamide was lower in drug responders (10.4 ± 4.0 imol)
compared with patients who remained inducible (18.2 ± 3.8
imol, P < .05), the procainamide content normalized for
dif-ferences in coronary sinus flow was similar in responders (0.17
± 0.15 tmol mr’min’) and drug nonresponders (0.17 ± 0.05
imol ml’min’, P = N.S.). Differences in the procainamide
concentration-effect relationships for QRS duration,
ventricu-lar conduction time, VERP, VFRP or QTc between
procaina-mide responders and nonresponders were not observed.
Discussion
In the present study, we have characterized the myocardial
accumulation and pharmacodynamics of the antiarrhythmic
drug procainamide in humans.
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Myocardial drug uptake. The procainamide concentration
in arterial blood equilibrated with that in the myocardium
within 30 mm of the start of the drug infusion. The myocardial
accumulation of procainamide (10 ± 4% of the dose) is more
extensive compared with that of lidocaine and mexiletine
ob-served by other investigators using the same technique
(Horow-itz et aL, 1986). However, Horowitz et aL studied the myocardial
accumulation of lidocaine and mexiletine after a rapid i.v. bolus
compared with the continuous i.v. infusion used in the present
study. The higher myocardial accumulation of procainamide
cannot be explained by higher lipophilicity because
procaina-mide is more hydrophilic than is lidocaine or mexiletine
(Court-ney, 1987). However, the myocardial accumulation of drugs is
inversely related to the extent of plasma protein binding (Gillis
and Kates, 1986). Because mexiletine and lidocaine, but not
procainamide, bind to plasma proteins (Bigger and Hoffman,
1990), this factor may account for the differences in the
myo-cardial accumulation of these drugs.
Although arterial procainamide concentration equilibrated
with that in the myocardium within 30 mm, a gradient persisted
between the arterial concentration and the femoral venous
concentration throughout the drug infusion period. This is
consistent with a continued distribution of procainamide in the
more peripheral compartments, including skeletal muscle.
Ho-rowitz et at. (1986) have observed a similar pattern for
mexile-tine and lidocaine. Chiou et aL (1981) have also observed higher
femoral arterial to venous concentration ratios for
procaina-mide and other antiarrhythmic drugs during acute i.v. infusion
in rabbits. This difference likely reflects a high uptake of this
drug in the leg muscle. It is possible that higher venous
concen-trations would have been measured if right atrial or pulmonary
arterial samples had been collected. However, in many clinical
and pharmacodynamic studies, peripheral venous samples have
been collected during acute drug infusions and the varying drug
concentrations can significantly influence data interpretation (Chiou, 1989a, 1989b).
The MPU, when normalized for differences in coronary sinus
flow, did not discriminate between drug responders and
non-responders. Thus, global procainamide uptake is not a critical
determinant of the antiarrhythmic response.
Pharmacodynamics of procainamide. The changes in
QRS duration, ventricular conduction time, VERP, VFRP and
QTc most closely paralleled the changes in the plasma arterial
procainamide concentrations. The times to reach maximal
dcc-trophysiologic effects were similar to the times to reach peak
arterial procainamide concentrations but significantly less than
those to reach peak venous procainamide concentrations. The
values for the coronary sinus were intermediate to those for
arterial and femoral venous blood.
All procainamide concentration-effect relationships were
un-ear. This is not surprising in view of the narrow concentration
range evaluated (Holford and Sheiner, 1981). The slopes of the
arterial and coronary sinus concentration-effect relationships
were similar. However, the slopes of the venous procainamide
concentration-effect relationships were greater than the other
two. Other investigators have also described linear plasma
venous concentration-effect relationships for procainamide
after loading and maintenance infusions similar to those used
in the present study (Morady et aL, 1988; Liem et a!., 1988).
However, several investigators have observed hysteresis, i.e.,
greater prolongation of the ventricular conduction time at a
similar plasma concentration after cessation of the
procaina-mide infusion (Scheinman et at., 1974; Galeazzi et at., 1976;
Liem et aL, 1988). Giardina and Bigger (1973) also observed such a hysteretic effect in some patients after rapid intermittent i.v. injection. We did not observe hysteresis during the
procain-amide infusion for any of the arterial, venous or coronary sinus
concentration-effect relationships. This may be explained by
the rate or the relatively short duration of the procainamide
infusion. In the latter case, sufficient time had not passed to
allow for the effects of N-acetyl procainamide to be observed.
In fact, significant accumulation of the metabolite, N-acetyl
procainamide, was not observed in the present study.
Further-more, a washout phase was not performed in the present study.
Potential limitations. Although coronary sinus
catheteri-zation is an important method for measuring the myocardial
accumulation of drugs in humans, the technique has some
limitations. The thermodilution technique may underestimate
the actual flow rates (Rossen et aL, 1992). The estimate of
myocardial drug accumulation is an assessment only of that
region being drained by the coronary sinus and the size of this
region will vary between patients as a function of vascular
anatomy, coronary lesions and the position of the coronary
sinus catheter. For example, a significant proportion of left
anterior descending artery flow is drained through routes other
than the coronary sinus (Nakazawa et a!., 1978). Furthermore,
the uptake of a drug may not be homogeneous in patients with
coronary artery disease and previous myocardial infarction
(Karagueuzian et aL, 1986). Moreover, abnormal blood flow to
the region being sampled by the coronary sinus catheter might
cause a delay in the uptake of drug in that region. For these
reasons, coronary sinus concentration-effect relationships may
not reflect global myocardial concentrations.
Clinical implications. During i.v. infusion of procainamide,
the drug accumulates rapidly but not instantaneously in the
myocardium, reaching equilibrium with the arterial
compart-ment only 20 to 30 minutes after the start of therapy. The
maximal electrophysiologic effects closely parallel the
myocar-dial accumulation time course of procainamide. Thus,
assess-ment of antiarrhythmic drug efficacy should be delayed for at
least 30 mm after the start of therapy.
Previous investigators have observed discordant effects of
antiarrhythmic drugs when comparing i.v. and oral
administra-tion. The drugs encainide and lorcainide prolong atrial and
ventricular refractory periods only after oral administration
and these effects have been attributed to accumulation of
electrophysiologically active metabolites (Jackman et aL, 1982;
Echt et at., 1983). Interian et at. (1991) recently reported
discordance of procainamide effects on the suppression of the
induction of VT in a study that compared i.v. administration
with the results of oral testing. In this series, sustained VT was
inducible during oral procainamide therapy in 65% of patients
in whom sustained VT could not be induced after i.v.
procain-amide infusion despite achieving similar plasma procainamide
levels in both studies. Duff et at. (1985) also found a similar
response when comparing i.v. and oral quinidine for the
suppression of VT. In the present study, venous procainamide
concentrations did not reach equilibrium with the arterial
compartment during more than 50 mm ofdrug infusion. During
this period, venous concentrations do not accurately reflect the
myocardial concentration, effects or the eventual steady-state
relationships. Indeed, under these conditions, venous plasma
concentrations will significantly underestimate the effective
drug concentration in drug responders. Thus, these important
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1006 GlIlis et al Vol. 266
arteriovenous concentration gradients during nonsteady-state
conditions may explain, in part, the apparent discordance in
antiarrhythmic efficacy that has been observed when others
compared similar concentrations of antiarrhythmic drugs
dur-ing acute i.v. and chronic oral administration (Duff et at., 1985;
Interian et aL, 1991).
Acknowledgments
The authors thank Leslie Masters and Marilyn Devlin for manuscript prepa-ration and the electrophysiology nursing staff of Foothills Hospital for their help with this study.
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