lACC Vol. 7. No 5 May 1986'1131-9

1131

Procainamide Pharmacokinetics in Patients With Acute Myocardial Infarction or Congestive Heart Failure

KENNETH M. KESSLER, MD, FACC, DAVID S. KAY DEN , MD, DANEIL M. ESTES, RN,

PATRICIA L. KOSLOVSKIS, PHD, RAFAEL SEQUEIRA, MD, RICHARD G. TROHMAN, MD, FACC,

ANDRES R. PALOMO, MD, ROBERT 1. MYERBURG, MD, FACC

Miami, Florida

Abnormal procainamide pharmacokinetics (prolonged half-life and decreased volume of distribution) and phar•macodynamics (decreased threshold for the suppression of premature ventricular complexes) have been sug•gested in patients with acute myocardial infarction or congestive heart failure, or both. To better define pro•cainamide kinetics, 37 patients in the acute care setting received intravenous procainamide (25 mg/min, median dose 750 mg) with peak and hourly blood samples taken over 6 hours. Compared with the 10 control patients, the 12 patients with acute myocardial infarction and the 15 patients with congestive heart failure had normal procainamide pharmacokinetics with respect to half-life (2.3 ± 1.0,2.5 ± 0.9 and 2.6 ± 0.8 hours, respectively), volume of distribution (1.9 ± 0.7, 1.8 ± 0.4 and 1.8 ± 0.5 liters/kg, respectively), clearance (11.3 ± 7.5,

Although procainamide has been widely used for the control of ventricular arrhythmias in the acllte care setting, previous studies of the pharmacokinetics of procainamide in patients with acute myocardial infarction or congestive heart failure have been scant and contradictory. Reports (1-5) suggesting impaired procainamide elimination in patients with either acute myocardial infarction or congestive heart failure were of particular interest. However, therapeutic recommenda•tions were limited by the protocol design and the small number of patients in these prior studies.

Previous pharmacodynamic information makes definition

From the Division of Cardiology. Department of Medicine, University of Miami School of Medicine, Miami. F1onda. This study was supported in part by a grant from the American Heart Association of Greater Miami and by Grant HL 28130-02 from the National Heart, Lung, and Blood Institute, National Institutes of Health. Bethesda. Maryland It was pre•sented m part at the 57th Scientific Sessions of the American Heart As•sociation, Miami Beach, Florida, 1984.

Manuscript received October 9, 1985; revised manuscript received December 23, 1985, accepted January 2. 1986.

Address for reprints: Kenneth M. Kessler, MD. Cardiology SectIOn, Department of Medicine. (IlIA), Veterans AdmmistratlOn Medical Cen•ter, 1201 N.W 16th Street, Miami. Florida 33125.

© 1986 by the Amencan COllege of Cardiology

9.3 ± 3.6 and 9.1 ± 3.5 mllmin per kg, respectively) and unbound drug fraction (6ti ± 9,66 ± 9 and 69. ± 4%, respectively). Low thresholds for greater thAn 85% premature ventricular complex suppression were con•firmed in these patients (median 4.7 "g/ml in patients with acute myocardial infarction and 3.3 "g/ml in pa•tients with congestive heart failure).

Thus, differences in the response of premature ven•tricular complexes to procainamide reflect electr~phar­macologic differences dependent on clihlca1 setting rather than pharmacokinetic abnormalities. FurthermQre, t~e reduction of procainamide dosing in patients with acute myocardial infarction or congestive heart failure, based solely on prior kinetic data, may result in iriappropriate antiarrhythmic therapy.

(J Am Coil CardioI1986;7:1l31-9)

of this kinetic data of additional importance. In a study (6) of the concentration-response relation for the treatment of premature ventricular complexes with procainamide, 85% suppression occurred at significantly lower plasma concen•trations of procainamide in patients with acute myocardial infarction than in patients with chronic ischemic heart dis•ease (5.0 ± 0.5 versus 9.3 ± 0.7 p,g/ml, p < 0.05). However, the design of that study did not permit discrim•ination of a true electropharmacologic response difference dependent on the pathophysiology of the inciting disease process, from response differences secondary to altered pharmacokinetics in different clinical settings. If the prior reports of impaired elimination of procainarnide during acute myocardial infarction were correct, a highet mean concen•tration and a decrease in the rate of decline in plasma con•centration might decrease the probability for arrhythmia es•cape such that the altered drug dynamics might be secondary to pharmacokinetic rather than electtopharmacologic dif•ferences. The current study was designed to address these kinetic/dynamic issues by the use of: 1) a prospective design, 2) larger numbers of patients, 3) uniform intravenous drug

0735-10971861$3.50

1132 KESSLER ET AL. PROCAINAMIDE IN INFARCT OR FAILURE

dosing guidelines, and 4) procainamide as the sole antiar•rhythmic agent.

Methods Patient selection and clinical features. A total of 12

patients with acute myocardial infarction and 15 patients with congestive heart failure who were admitted to the coro•nary care unit for chest pain, arrhythmia control or hemo•dynamic monitoring were studied. Inclusion criteria in•cluded: 1) a ventricular arrhythmia with intent to treat on clinical grounds; 2) no antiarrhythmic drug for the preceding 36 hours or five drug half-lives; 3) no contraindication to procainamide therapy; and 4) no life-threatening condition (for example, shock or uncontrolled pulmonary edema) in which clinical findings might change within the study time frame and for which a fixed dosing protocol would be clin•ically inappropriate. No patient was receiving an agent known to alter procainamide metabolism or elimination. Ten ad•ditional patients without acute myocardial infarction or congestive heart failure were selected as a control group. Informed consent was obtained from each participant. Each patient was carefully reviewed and their age, sex, weight, clinical diagnosis, medications, history of procainamide use and adverse reactions and the presence of liver, renal or hepatic disease were recorded. Physical examination vari•ables were confirmed with respect to the primary diagnosis and the presence or absence of jugular venous distension, rales, third heart sound and peripheral edema.

Electrocardiograms were reviewed for evidence of acute myocardial infarction and chest X-ray films for the presence of cardiomegaly, pulmonary venous congestion or pulmo•nary edema. Ejection fraction from cardiac catheterization, gated nuclear study or two-dimensional echocardiogram was charted. Serum cardiac enzymes were recorded, and our criterion for acute myocardial infarction (creatine kinase•MB > 5 IV or 5%) was used for interpretation of values. Serum albumin and creatinine levels were also recorded.

Clinical definitions. The diagnosis of acute myocardial infarction, including transmural or subendocardial infarc•tion, required at least two of the following findings: 1) prolonged precordial discomfort unrelieved by rest or ni•troglycerin, or both, 2) diagnostic abnormality of the crea•tine kinase-MB fraction, or 3) electrocardiographic criteria for acute myocardial infarction. The latter ihcluded new Q waves with classic evolutionary ST-T changes of acute transmural infarction or the ST depression and persistent T wave inversions of subendocardial myocardial infarction. Each patient from the myocardial infarction group was sub•sequently evaluated for the presence of heart failure by the criteria listed later.

Patients were categorized in relation to the presence or absence of congestive heart failure according to the follow•ing criteria: group 0 = no failure; group I = third heart sound (with history compatible with congestive heart fail-

lAce Vol 7, No 5 May 19861131-9

ure); group II = addition of rales; group III = addition of pUlmonary venous congestion on chest X-ray film; and group IV = frank pulmonary edema.

Drug dosing protocol. A Holter monitor recording was begun at least 2 hours before the dosing protocol (range 2 to 4 hours). The duration of baseline recording was limited by the acute presentation of the patients and clinically de•termined need for treatment. Thus, totally adequate baseline information for arrhythmia quantification from which to ana•lyze premature ventricular complex suppression with desir•able statistical accuracy could not be obtained in these pa•tients within the constraints of appropriate patient care. Each patient received intravenous procainamide, 25 mg/min, to one of the following end points: 1) 1,000 mg total dose, 2) adverse reaction, or 3) 100 mg past total suppression of premature ventricular complexes as monitored on-line on a coronary care unit computer with trend recording. The latter criterion was used to guarantee escape of the arrhythmia during the subsequent observation period. Such an approach is obviously limited by the spontaneous variability in pre•mature ventricular complex frequency. This probably led to underdosing in five patients; however, their results would not have affected the medians for either the acute myocardial infarction or congestive heart failure groups.

Blood samples for plasma procainamide and N-acetyl•procainamide levels were drawn before dosing, at the con•clusion of dosing (peak level) and hourly for 6 hours from the onset of dosing. Thereafter, oral procainamide (or con•tinued intravenous dosing) was administered in accordance with clinical needs.

Drug assay procedures. All blood samples were im•mediately transferred to our research laboratories where the red cells were separated and serum stored at 4°C until the time of analysis. Procainamide and N-acetylprocainamide were simultaneously quantitated by gas-liquid chromatog•raphy utilizing a nitrogen-phosphorus selective detector (Hewlett-Packard model 57IOA). The method has been re•ported previously (7), and has within-run and between-run precisions for procainamide of I and 5% and for N-acetyl•procainamide of I and 3%, respectively. Unbound procain•amide was measured by an ultrafiltration technique with a less than 5% standard error of the estimation (8).

Pharmacokinetic analysis. The hourly procainamide concentrations falling within the drug elimination phase (one compartment model) were used to calculate drug half-life by an exponential regression analysis, using the general formula y = ae- kt

, where y is the plasma concentration, a is a calculated constant, e is a mathematical constant, k is the disappearance rate constant and t is time. Half-life was calculated as 0.693/- k in hours. The volume of distribution was calculated as half-life times the clearance divided by the area under the concentration-time curve (extrapolated to infinity) divided by 0.693 in liters per kilogram. Total body clearance was calculated as drug dose divided by the area

JACC Vol 7, No 5 May 1986:1131-9

under the concentration-time curve (measured in JLg.min.ml- I)

extrapolated to infinity in milliliters per minute (9). Holter monitor analysis. Tapes were scanned on a full

disclosure system (Del-Mar Avionics, Heart Scan II) and premature ventricular complexes were quantitated. Using the 2 hour predosing period as baseline, the percent suppres•sion of premature ventricular complexes was related to pro•cain amide plasma levels whenever the absolute frequency of premature ventricular complexes at baseline allowed for this quantitative analysis (that is, 2: 10 premature ventricular complexes/h). The extrapolated procainamide concentration at which less than 85% suppression of premature ventricular complexes was noted was charted as the concentration needed for suppression.

Statistical analysis. Means and standard deviations were calculated for each variable in each of the three patient groups. The 95% confidence bands were calculated for the differences between the control and acute myocardial in•farction and congestive heart failure groups. Because of the semiquantitated nature of the arrhythmia suppression data, a normal distribution was not assumed, and range and me•dian were determined (10).

Results Clinical characteristics (Table 1). Ten control patients

were studied. There were nine men and one woman aver•aging 59 ± 14 years in age and 75 ± 12 kg in weight; they had a normal albumin concentration (3.9 ± 0.8 gllOO ml). The average creatinine concentration was normal (1.3 ± 0.4 mgllOO ml) with two patients having a mildly abnormal level of 1.9 and 2.2 mgllOO ml, respectively. These demographic criteria are similar to those of the pa•tients included in the acute myocardial infarction and congestive heart failure groups. However, the mean ejection fraction was normal in this group at 57 ± 14% with all patients having an ejection fraction of 40% or more.

Twelve patients with acute myocardial infarction were studied within 36 hours of the onset of symptoms. There were eight men and four women averaging 66 ± 9 years in age. Seven of the 12 patients had transmural myocardial infarction, 2 anterior wall and 5 inferior wall; the remaining 5 patients had subendocardial (non-Q wave) infarction. These patients averaged 72 ± 8 kg in weight and had normal serum albumin concentrations (4.2 ± 0.6 g/100 mI). The average creatinine concentration was normal (1.3 ± 0.5 mgllOO ml) with only two patients having a mildly abnormal level of 2.1 and 2.4 mgllOO ml, respectively. Of the 12 patients with myocardial infarction, 7 had no criteria for heart failure, 3 had class II and 3 had class III congestive heart failure.

Fifteen patients were included in the group with conges•tive heart failure (class I failure, 4 patients; class II, 5 patients; class III, 6 patients). The patients (14 men and I

KESSLER ET AL PROCAINAMIDE IN INFARCT OR FAILURE

1133

woman) averaged 74 ± 13 kg in weight and had normal albumin concentrations (4.0 ± 0.7 gllOO ml). The average creatinine concentration was normal (1.3 ± 0.4 mgllOO ml) with only one patient having a mildly elevated level of 2.0 mgllOO ml.

Pharmacokinetic data (Tables 2 and 3, Fig. 1). The 10 control patients received an average of 865 ± 144 mg of procainamide, which resulted in a mean peak procain•amide concentration of 8.2 ± 3.4 JLg/ml and a normalized mean peak procainamide concentration of 1.27 ± 0.55 JLg/ml.100 mg per kg. Pharmacokinetic variables included a disappearance rate constant of - 0.36 ± O. 16 with a calculated mean half-life of 2.3 ± 1.0 hours (using 5 ± 1 points; r2 = 95 ± 0.03). Clearance averaged 11.3 ± 7.5 mllmin per kg and volume of distribution 1.9 ± 0.7 li•ters/kg. The mean N-acetylprocainamide level for the 6 hour period was 1.3 ± 0.6 JLg/ml.

The 12 patients in the acute myocardial infarction group received an average of 804 ± 145 mg of procainamide, which resulted in a mean peak procainamide concentration of 7.4 ± 2.0 JLg/ml and normalized peak procainamide concentration of 1.35 ± 0.51 JLg/ml.l00 mg per kg. Phar•macokinetic variables included a disappearance rate constant of - 0.31 ± 0.11, with a calculated mean half-life of 2.5 ± 0.9 hours (using 5 ± 1 points; r2 = 0.94 ± 0.05). Clearance averaged 9.3 ± 3.6 mllmin per kg and volume of distribution 1.8 ± 0.4 liters/kg. The mean N-acetylpro•cainamide level for the 6 hour period was 1.7 ± 1.4 JLg/ml. These results did not vary significantly from values in the normal group; the 95% confidence limits were 1.9 to 3.5 hours for half-life, 2.2 to 12.2 mllmin per kg for clearance and 1.2 to 2.2 liters/kg for volume of distribution. There were no differences in kinetic variables between the five patients with and the seven patients without congestive heart failure.

The fifteen patients with congestive heart failure recei ved an average of 830 ± 168 mg of procainamide which resulted in a mean peak procainamide concentration of 9.3 ± 2.8 JLg/ml and normalized mean peak concentration of 1.60 ± 0.65 JLg/ml.l00 mg per kg. Pharmacokinetic variables in•cluded a disappearance rate constant of - 0.28 ± 0.07 with a calculated half-life of 2.6 ± 0.8 hours (utilizing 6 ± 1 points; r2 = 0.97 ± 0.02). Clearance averaged 9.1 ± 3.5 mllmin per kg and volume of distribution 1.8 ± 0.5 li•ters/kg. The mean N-acetylprocainamide level for the 6 hour period was 1.5 ± 1.2 JLg/ml. These results did not vary significantly from the normal group; the 95% confidence limits were 2.2 to 3.6 hours for half-life, 2.3 to 11.5 mllmin per kg for clearance and 1.2 to 2.2 liters/kg for volume of distribution.

Pharmacodynamic data (Table 4). In the acute myo•cardial infarction group, four patients had baseline ectopic activity of insufficient frequency to analyze. The remaining eight patients had a median baseline frequency of 59 pre-

1134 KESSLER ET AL PROCAINAMIDE IN INFARCT OR FAILURE

Table 1. Clinical Data Base

Case

2 3 4

5 6 7 8 9

10 Mean

± SD

I 2 3 4 5 6 7 8 9

10 II 12

Mean ± SO

2

3 4 5 6 7

8

9

10 II 12 13 14 15

Mean ± SD

DiagnosIs

Myocardial contusion

Unstable angina HTN,CHO Myocardial

contusion CHD HTN,CHD CHD HTN CHD CHD

IWMI IWMI IWMI SEMI IWMI IWMI SEMI SEMI ASMI SEMI SEMI AWMI

Unstable angina Ischemic

myopathy HTN,CHO CHD, VT CHD, VT Cardiomyopathy Unstable

angina, CHD Ischemic

myopathy Unstable

angina, CHD HTN, angina Cardiomyopathy Digoxin toxICity CHD,CHF CHF, diabetes HTN,CHO

Age (yr) & Sex

27M

73M 65M 54M

54M 52M 64M 57M 79M 65F 59 14

52M 70F 50M 61M 74M 70F 64M 66F 64M 80F 72M 71M 66 9

82F 69M

61M 66F 42M 61M 52M

76M

53M

60M 83M 74M 65M 64M 82M 66 12

Weight (kg)

70

59 63 77

68 101 69 81 87 74 75 12

CHF Index

(0 to 4)

Chest X-ray

CE PVC

A. Control Patients

o

o o o

o o o o o o

+

EF (%)

69

45 60 70

65 40 52 80 40 52 57 14

B. Patients With Acute Myocardial InfarctIOn

75 74 80 65 70 80 70 64 85 58 61 78 72 8

2 o o o o o o o 2 2 3 3

+ + +

+ + + +

+ +

C. Patients With Congestive Heart Failure

66 62

77 66 72 72 71

103

71

96 52 82 69 76 69 74 13

2

3 3 2

3

2

I 2 3 3 2 3

+ +

+ + + + +

+

+

+ + + + + +

+ +

+

+ +

+

70 55 75 53 NA NA 40 60 35 75 20 40 52 18

NA 22

25 30 35 NA 35

40

15

32 21 12

NA NA 60 30 13

CK-MB (IU or %)

2.2

2.3

* <5%

NA NA

<5% NA

<5%

*

28 54 93 26

101 80 6% 74 7% 7%

100 12

* *

* NA

* * *

*

*

* * * * * *

JACC Vol 7. No 5 May 1986 1131-9

Albumin (mgllOO m!)

4.1

3.2 3.9 3.8

5.2 3.4 36 5.2 4.1 2.9 3.9 0.8

4.5 4.0 4.2 4.4 3.9 4.1 4.9 5.3 4.5 NA 3.4 3.2 4.2 0.6

4.6 4.3

3.6 3.4 4.0 6.0 4.2

3.4

4.5

44 3.2 3.8 3.3 3.3 3.7 4.0 0.7

Creatinine (mg/IOO ml)

1.0

0.9 1.2 1.0

1.0 1.3 1.2 1.4 1.9 2.2 1.3 0.4

I 3 1.1 0.8 1.2 1.4 l.l 1.5 1.0 1.2 0.8 2.4 2.1 1.3 0.5

1.5 1.0

1.5 0.9 0.9 NA 1.4

0.9

15

l.l 0.8 1.4 09 1.7 2.0 1.3 0.4

*Normal creatine kinase; MB fraction not determined. ASMI = anteroseptal myocardial infarction; A WMI = anterior wall myocardial infarction; CE = cardiac enlargement; CHD = coronary heart disease; CHF = congestive heart failure; CK-MB = creatine kinase, MB fraction; EF = ejection fraction; F = female; HTN = hypertension; IWMI = inferior wall myocardial Infarction; M = male; NA = not available; PVC = pulmonary venous congestion; SEMI = subendocardial myocardial infarction; VT = ventricular tachycardia.

JACC Vol 7. No 5 May 1986'1131-9

KESSLER ET AL. PROCAINAMIDE IN INFARCT OR FAILURE

1135

Table 2. PharmacokineticlDynamlc Results of Procainamide Admmistration

Nonnahzed

Case Dose (mg)

Mean Peak Plasma Level

(p.g/ml) Peak Level

(p.g/ml·lOO mg per kg) Unbound PA (%)

Mean NAPA Level

(p.g/ml) Half-Life (hours)

Clearance (mllmin per kg)

Volume Distribution (liters/kg)

A. Control Patients

2 3 4 5 6 7 8 9

10 Mean

± SD

700 1,000 1,000

700 1,000

750 1,000

750 1,000

750 865 144

35 4.4

12.2 6.4 7.7 5.3

12.5 7.8

105 11.9 8.2 34

0.71 0.75 194 1.\9 1.13 0.52 1.81 1.28 1.21 2 15 1.27 0.55

63 60 67 57 59 70 81 60 59 80 66

9

0.5 1.9 12 08 0.7 20 1.8 0.7 1.0 1.9 1 3 0.6

J.3 3.2 2.5 12 1.\ 2.0 2.2 4.3 22 3.3 2.3 10

29.2 11.3 8.2

12.8 17.6 10.6 7.9 4.4 6.7 3.8

11.3 7.5

3.3 3.2 1.8 J.3 1.7 1.8 1.5 1.6 1.3 1.3 1.9 0.7

B. Patients WIth Acute Myocardial InfarctIOn

I 2 3 4 5 6 7 8 9

10 11 12

Mean ± SD

700 700 700 700 700 700

1,000 1,000 1,000

700 750

1.000 804 145

4.9 3.5 6.2 7.7 9.0 9.7 9.8 7.4 6.9 8.7 8.9 6.1 7.4 2.0

0.93 0.68 1.11 1.69 1.84 1.74 1.40 1.16 0.82 2.14 1.95 0.78 1.35 0.51

62 72 67 56 56 74 70 64 58 73 84 58 66 9

0.7 l.l 1.6 0.5 1.2 1.2 1.4 2.5 0.6 4.3 4.7 0.9 17 1.4

1.4 3.3 1.9 2.2 2.6 3.5 33 2.2 2.3 1.4 4.1 1.7 2.5 0.9

14.6 7.7

13.8 10.1 6.8 3.5 5.8

12.3 10.6 9.8 4.6

11.9 9.3 3.6

1.8 2.2 2.3 1.9 1.5 11 1.7 2.3 2.1 1.2 1.7 2.3 1.8 0.4

C. Pattents With Congestive Heart FaIlure

2 3 4 5 6 7 8 9

10 11 12 \3 14 15

Mean ± SD

500 700

1,000 750

1,000 800

1,000 1.000 1,000 \,000

750 900 750 700 600 830 168

5.2 14.0 14.1 10.6 86

10.1 9.0 7.7

12.6 5.5 8.8

11.3 7.4 6.9 8.3 9.3 2.8

1.58 3.23 1.83 214 1.18 1.17 1.27 0.75 1.77 0.57 2.25 1.54 1.43 130 2.00 1.60 0.65

NAPA = N-acetylprocamamide; PA = procamamlde.

mature ventricular complexes/h (range 16 to 1,221). The procainamide concentration needed for 85% or greater suppression of premature ventricular complexes was 1.6 to greater than 8.7 JLg/ml (median 4.5).

In the congestive heart failure group, one patient had inadequate baseline ectopic activity for statistical analysis.

75 74 74 68 64 69 67 69 70 67 70 63 63 68 70 69 4

06 0.7 2.1

o 1.7 1 7 2.1 2.6 5.1 0.3 0.8 1.5

0.8 1.4 1.5 1.5 1.2

3.0 2.4 I.J 1.6 2.6 33 22 2.6 2.8 3.0 2.2 3.2 1.7 22 4.3 2.6 0.8

6.0 6.7

10.6 152 9.9 5.0

10.2 73 5.3

1 J.5 11.8 7.1

14.0 12.1 34 9.1 3.5

1.6 1.4 1.0 2.1 2.2 1.4 1.9 1.7 1.3 30 2.3 2.0 2.1 2.3 1.3 1.8 0.5

Of the remaining 14 patients, the ventricular ectopic fre•quency ranged from 13 to 557 premature ventricular com•plexes/h (median 103). The procainamide concentration needed for 85% or greater suppression of premature ven•tricular complexes was 0.7 to greater than 8.6 JLg/ml (me•dian 3.3). There was no difference in the procainamide

1136 KESSLER ET AL PROCAINAMIDE IN INFARCT OR FAILURE

lACC Vol 7, No.5 May 19861131-9

Table 3. Procainamide (N-acetylprocainamide) Concentrations (J.Lg/ml)

Case Peak I Hour 2 Hours 3 Hours 4 Hours 5 Hours 6 Hours

A. Control Patients

I 3.5 (1.3) 1.8 (1.0) 1.2 (0.7) 0.6 (0.6) OA (0.5)

2 4A (0.5) 4.50.1) 3.0 (1.9) 2A (2.1) 2.1 (2.5) 1.6 (2 6) 3 12.20.1) 6.5 (1 I) 3.8 (1.0) 3.3 (I A) 2.7 (1.3) 4 6A (1.2) 4.2 (NA) 2.6 (NA) 12 (NA) 0.6 (0.1) 0.5 (NA) 5 7.7 (1.6) 5.3 (0.6) 2.6 (0.8) 1.9 (0.7) IA (0.5) 0.5 (0.5) 0.2 (OA)

6 5.3 (2.8) 3.0 (2A) 2.5 (1.8) 1.9 (1.2) 1.5 (0.9) 0.7 (OA) 0.8 (0.6) 7 12.5 (2.1) 6.9 (2.0) 3.8 (1.8) 2.6 (1.9) 2.0 (1.7) 1.7 (1.8) 1.3 (1.9) 8 7.8 (0.7) 4.6 (0 7) 3.4 (0.5) 3.2 (0.5) 2.8 (0.5) 2.2 (0.6) 2.0 (0.5) 9 10.5 (1.0) 6.6 (1.2) 4.6 (1.3) 2A (0.8) 2.1 (0.8) 1.7 (0.8) 1.3 (0.5)

10 11.9 (1.9) 7.5 (1.7) 7.0 (2.6) 5A (2.5) 4.7 (2.2) 3.1 (1.3) 2.8 (I A)

Mean 8.3 (1 A) 5.1 (1.3) 3.5 (1.3) 2.6 (1.3) 2.1 (1.1) 1.6 (1.0) IA (1.1)

:!:SD 3A (0.7) 1.8 (0.6) 1.6 (0.7) 1.3 (0.7) 1.2 (0.7) 0.9 (0.8) 0.8 (0.9)

B. Patients With Acute Myocardial InfarctIOn

I 4.9 (1.1) 3.5 (i A) 2.0 (0 9) 1.2 (0.8) 1.6(1.8) 1.1 (1.5) 0.9 (0.7) 2 3.5 (0.9) 3.6 (0.7) 2.8 (2.0) 2 I (1.9) 2.0 (2.0) 2.2 (1.8) 3 6.2 (3.1) 2A (2.2) 1.2 (I A) 0.9 (1.0) 08(1A)

4 77 (0 8) 3.9 (OA) 2A (OA) 1.8 (OA) 1.5 (0.6) 5 9.0 (I A) 4.8 (1.7) 3.2 (1.7) 2.6 (1.7) 2.1 (lA)

6 9.7 (9.8) 6.8 (0.9) 4A (0.8) 4.9 (1.3) 4.1 (1.6) 7 9.8 (1.0) 6.9 (1.2) 5.7 (1.3) 4.7 (1.8) 4.1 (1.5) 3.1 (lA) 2A (1.5)

8 7A (1.5) 4.9 (2.0) 4.1 (3.2) 3.0 (2.8) 2.3 (26) 1.5 (2.8) 1.1 (2.6) 9 6.9 (0.6) 4.1 (0.6) 3A (0.7) 26(0.6) 1.9 (0.7) 1.2 (NA)

10 8.7 (6.2) 6.9 (7.9) 3.5 (4.3) 2.9 (3.1) 1.2 (2.9) 0.5 (1.1) II 8.9 (4.6) 6.2 (4.7) 5.3 (4.8) 4.6 (4.9) 4.3 (5.3) 3.0 (4A) 2.7 (4.7) 12 6.1 (0.8) 4.2 (0.8) 3.8 (I A) 2.5 (1.0) 1.8 0.5) 1.7 (0.9) 0.6 (0.5)

Mean 7A (1.9) 4.9 (2.0) 3.5 (1.9) 2.8 (1.8) 2A(I.9) 1.9 (2.2) IA(1.9)

:!:SD 2.0 (1.8) 1.5 (2.2) 1.3 (I A) I 3 (1.3) 1.2 (1 3) 0.8 (1.2) 1.0 (1.6)

C. Patients With Congestive Heart Failure

I 5.2 (OA) 3.9 (OA) 2.6 (04) 2 14.0 (0.8) 5.5 (1.2) 3A (0.7)

3 14.1 (2.5) 7.0 (2.5) 3.9 (2.0) 4 10.6 (NA) 2.7 (NA) 1.9 (NA) 5 8.6 (2.2) 4.5 (1.8) 2.9 (1.8) 6 10.1 (1.6) 6.1 (1.6) 4.2 (1.6) 7 9.0 (2.7) 5.2 (2A) 3.3 (2.5) 8 7.7 (3.2) 4A (3.3) 2.0 (2.3) 9 12.6 (3.9) 8.5 (4.0) 6.2 (5A)

10 5.5 (0.0) 4.3 (0.3) 2.6 (OA)

11 8.8 (0.7) 4.5 (0.7) 3.1 (0.9) 12 11.3 0.5) 4.0 (1.0) 2.6 (I A)

13 7A (0.8) 3.3 (0.8) 1.8 (0.9) 14 6.9 (1.7) 2.60.1) 1.8 (1.3)

15 8.3 (1.3) 4.0 (1.5) 3.5 (I A)

Mean 9.3(1.7) 4.7 (1.6) 3.0 (1.6) :!:SD 2.8 (1.1) 1.6(1.1) 1.2(1.3)

concentration needed to suppress 85% or more of the pre•mature ventricular complexes between the acute myocardial infarction and congestive heart failure groups.

Discussion Prior studies on procainamide pharmacokinetics.

The importance of understanding procainamide pharmaco-

2.3 (0.5) 1.6 (0.3) 1.5 (0.5) 1.2 (OA) 2.5 (06) 1.8 (0.5) 1.3 (0.5) 1.2 (0.3) 3.0 (2.6) 2A (1.7) 1 5 (1.5) 1.7 (2.1) 1.0 (NA) 0.8 (NA) 2A (1.7) 1.7 (1.5) IA (1.5) 1.1 (1.5)

3.3 (1.7) 2.6 (1.7) 2A (1.8) 2.0 (1.8) 2.6 (2.0) 1.9 (1.8) 1.3 (1.6) 1.0 (1.8) 1.7 (2.8) 1.2 (2.5) 0.9 (2.3) 0.7(2.1) 57(5.6) 3.0 (3.8) 3.1 (4.3) 2.6 (4.1) 2.0 (OA) 1.6 (OA) 1.3 (0.3) 1.0 (0.5) 2.1 (1.0) IA (0.9) 1.2 (0.9) 1.0 (0.8) 2A 0.7) 1.9 (1.7) 1.6(1.7) 1.2 (I. 7) 1.3 (0.9) 0.9 (0.9) 0.7 (0.8) OA (0.6) 1.2 (1.1) 0.9 (1.1) 0.7(0.8) 0.5 (0.8) 3.1 0.2) 2 8 (1.5) 2.1 (1.3) 1.8 (2.1) 2A (1.7) 1.8 (1.5) 1.5 (I A) 1.2 (1.5) 1 I (1.3) 0.7 (0.9) 0.7 (1.0) 0.6 (1.0)

kinetics, even in normal individuals, was well demonstrated by the findings of Koch-Weser and Klein (1). Their com•prehensive study defined a normal plasma procainamide half-life of 3.5 hours and a general therapeutic range of 4 to 8 J.Lglml. These findings set a standard of practice for procainamide therapy in most patients. Since then, normal procainamide pharmacokinetics have been delineated in more detail and include an apparent volume of distribution of 1.7

lACC Vol. 7, No.5 May 1986:1131-9

Figure 1. Pharmacokinetic data. Half-life (TI/2),

total body clearance (CL) and volume of distribu•tion (VD) of procainamide ate plotted for control patients (C) and patients with acute myocardial in•farction (AMI) or congestive heart failure (CHF). The means (arrowheads) for each variable do not differ significantly from those of reported and con•current control values, (see text for 95% confidence limits).

4

3

2

1

. •• ..c

T1/2 hours

.. • ..c ... ..

•

I .. • . .... •

H.

I

C AMI CHF

KESSLER ET AL PROCAINAMIDE IN INFARCT OR FAILURE

CL mlA'nlnlKg

.. ..c .. • •• .. . • • • •

...

• • He

•• • -• •• •

3

2 .. ... t ...

1

VD UKg

••• ... ... •

1137

• , l..c II •

C AMI CHF C AMI CHF

to 2.31iters/kg (1,11,12), an elimination half-life of2.5 to 4.7 hours (1) and a clearance of 828 mllmin (13). Variations in procainamide kinetics in patients have been defined with

respect to acetylator phenotype (14), age (15) and coad•ministration of propranolol or cimetidine (16,17). Because of the major role of the kidney in procainamide elimination,

Table 4. Hourly Premature Ventricular Complexes

Mean 85% PA

85% Case - 2 Hours - 1 Hour + 1 Hour + 2 Hours + 3 Hours + 4 Hours + 5 Hours + 6 Hours Baseline Suppression Suppression

I 2 3 4 5 6 7 8 9

10 11 12

Range Median

1 2 3 4 5 6 7 8 9

10 11 12 13 14 15

Range Median

18 22

4 4

10 6

49 1

63 344

1,299 56

22 69

171 108 180 183 61

347 161 608 II

172 4

19 13

14 10 12 9

27 7

60 o

190 1,114 1,143

67

15 125 128 92

643 58 52

232 146 506

14 37 8

26 19

PA = procainamide.

2 o

2

6

46 344

19 43

9 o

12 4

269 4 3

II 12 34 o 4

15 21

1 4

6

4

366 447

33 47

13 1

22 4

211 3 o 1

20 6

10

9 3

A. Patients With Acute Myocardial Infarction

5 8

58

5

544 1,100

66 63

15 8

65

15

613 1,129

259 60

7 10

109

624 1,001

151 46

B. Patients With Congestive Heart Failure

10 27 31

7 253

18 o

13 III I7 2 8

12 5

8 13 28 16

443 31 11 19

268 III

1 25

13 8

\3 12 78

538 12 53 16

122 196

o 6

29 6

6

125

1,045 1,392

22

23 8

21

472 7

42 470 139

1 10

12

16 16 (8) (7)

19 (6)

55 (I)

127 729

1,221 62

16 to 1,221 59

18 97

150 100 412 120 57

290 154 557

13 105

(6)

23 16

13 to 557 103

3 3

1 3 1 8 0.15 19

109 183

9

3 15 23 15 62 18 9

44 23 83 2

16 1 4 3

1.6 3.2

4.0

4.4

>7.4 >8.7

4.5 >6.1

1.6 to >8.7 4.5

>5.2 3.0 3.5 0.9

>8.6 3.3 2.3 0.7 6.0 1.8 2.6 2.2

>6.9 >8.3

0.7 to >8.6 3.3

1138 KESSLER ET AL PROCAINAMIDE IN INFARCT OR FAILURE

most of the investigations of potentially altered procain•amide pharmacokinetics in disease states have focused on patients with renal dysfUnction (14,18-20). Such studies have shown a significant decrease in renal clearance re•sulting in half-life prolongation in patients with renal im•pairment. Studies of the elimination of procainamide in hepatic dysfunction have been less extensive; du Souich and Erill (21) did show a diminished capacity for procainamide hydrolysis in patients with liver disease. However, the cor•relation between the degree of liver disease and change in metabolic capacity was poor and clinical end points were not monitored.

The potential for impairment of proc&inamide elimination in patients with acute myocardial iI)fardlon or congestive heart failure is a direct application of the known changes in hepatic and renal blood flow that may accompany these disease prb~~sses. Furthermore, other antiarrhythmic agents show altere~ pharmacokinetics with infarction or heart fail•ure (8,22-25). However, prior reports with respect to pro•cainamide were scant and conflicting in their stated or im•plied conclusions. For example, Koch-Weser and Klein (l ,11 ,26) ~eported as a secondary finding a decreased vol•ume of distribution of procainamide in five patients with congestive heart failure (mean 1.51liters/kg) compared with findings in eight control patients (mean 2.01 literslkg). Collste and Karlsson (27,28) suggested the need to individualize therapy in heart failure, but their data only presented evi•dence of equivalent procainamide levels after multiple oral dosing in patients with and without acute myocardial in•farction. In 1976, Giardina et al. (2) studied the metabolic course of procainamide. Although the cardiac patients were found to have a longer mean procainamide half-life (5.5 ± 0.9 hours, n = 5 versus 2.9 ± 0.5 hours, n = 5 in normal subjects), there were significant dosing and age differences between groups. In studies of continuous infusions of pro•cainamide, a decreased clearance of procainamide in pa•tients with acute myocardial infarction and higher steady state procainamide concentrations in patients with conges•tive heart failure were found by some investigators (3,4) but not others (5). Each of these prior studies addressing procainamide pharmacokinetics in acute myocardial infarc•tion or congestive heart failure were limited by one or more of the following factors: 1) lack of prospective design, 2) lack of adequate numbers, 3) absence of or poor age cor•relation of control patients, 4) variable dosing regimens, or 5) use of patients in whom treatment with lidocaine was unsuccessful and many of whom were still receiving lido•caine at the time of study. The current study was designed to overcome these problems.

Present study. Our findings refute the prior concept of impaired procainamide pharmacokinetics in patients with acute myocardial infarction or congestive heart failure. The longest procainamide half-life was 4.1 hours in the acute myocardial infarction group and 4.3 hours in the congestive

lACC Vol 7. No 5 May 1986.1131-9

heart failure group; thus the extreme values and 95% con•fidence limits were within the range noted in prior (1,29) and concurrent control subjects. Unlike quinidine, procain•amide binding does not seem to vary during the course of acute myocardial infarction (8). To confirm this observation, unbound procainamide was measured by ultrafiltration tech•niques and was found to be comparably normal (7). The low concentrations of N-acetylprocainamide were probably related to the acute dosing format and were clearly below the range commonly accepted for antiarrhythmic efficacy. Thus, procainamide pharmacokinetics in patients with acute myocardial infarction or congestive heart failure were nor•mal. This finding was evident at serum creatinine levels up to 2.5 mgllOO ml, and suggests that downward adjustment of procainamide dosing, based on limited prior studies, can•not be justified. However, normal kinetics cannot be inferred for patients with overt shock, unresponsive pulmonary edema or significant degrees of renal insufficiency; in such patients, careful individualization of therapy is required.

Although limited by the short baseline observation period in these acutely ill patients, the dynamic information again suggests the relative sensitivity of ventricular ectopic activ•ity to procainamide in this setting (6). The median minimal procainarnide concentration needed to maintain 85% or more suppression of ventricular ectopic complexes was 4.5 /Lg/ml in patients with acute infarction and 3.2/Lg/ml in those with congestive heart failure, values that are actually below the median of the usually accepted therapeutic range of 4 to 8 /Lg/ml but similar to our prior findings in patients with acute myocardial infarction (6).

Conclusions. Procainamide pharmacokinetics are nor•mal in patients with acute myocardial infarction or conges•tive heart failure. This suggests that 1) differences in the sensitivity of ventricular ectopic responses to procainamide reflect a true electropharmacologic difference, dependent on clinical setting as an independent variable, and 2) decreased procainamide dosage based on prior kinetic data may result in inappropriate antiarrhythmic therapy.

We thank Manna Lopez for technical assistance, Diana Gomez, Janet Fossum and Suzanne Smith for secretanal assistance and Kimberly Kessler and Paula Wozniak for data analYSIS.

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JACC V"I 7, No 5 May 1986 1131-9

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1139

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