Effects of sustained intravenous diltiazem infusion in healthy persons

NOVEMBER 151988

The American

Journal

of CARDIOLOGY” VOLUME 58 NUMBER 11

CARDIOVASCULAR PHARMACOLOGY

Effectsof SustainedIntravenous DiltiazemInfusionin HealthyPersons KENNETH A. ELLENBOGEN, MD, STEVEN F. ROARK, MD, MARK S. SMITH, MD, ELIZABETH A. MCCARTHY, RN, THORIR D. BJORNSSON, MD, and EDWARD L.C. PRITCHETT, MD A 3-stage infusion of diltiazem was tested in 8 subjects for up to 48 hours: a bolus injection (10 mg over 3 minutes), a rapid loading infusion (20 mg over 30 minutes) and a maintenance infusion (10 mg/hour to the end of the study). This regimen produced stable median plasma diltiazem concentrations of approximately 150 @ml. The median halflife of elimination for diltiazem was 208 minutes (range 144 to 452) and median total clearance was 980 ml/min (range 665 to 1,907). The PR interval lengthened IO to 18 % during the maintenance infusion in 7 subjects; in 1 subject atrioventricular nodal Wenckebach conduction was recorded during the

rapid loading infusion. Systolic blood pressure decreased from 124 f 7 mm Hg (mean f standard deviation) during the control period to 121 f 8 mm Hg during the rapid loading infusion (p = 0.03 compared with control) and to 117 f 7 mm Hg (p = 0.04 compared with control) during the maintenance infusion. Heart rate did not change. PR interval and blood pressure returned to control levels within 4 hours after the infusion was stopped. Loading and maintenance infusion may be an attractive method of administering diltiazem when stable drug concentrations are required for prolonged periods. (Am J Cardiol 1986;58:1055-1060)

D

Methods

From the Department of Medicine, Division of Cardiology, Duke University Medical Center, Durham, North Carolina. This study was supported in part by grant RR-30 from the General Clinical Research Centers Program, Division of Research Resources and by grants HL17670 and HL24920 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland. Manuscript received April 11,1986; revised manuscript received June 9,1986, accepted June 11,1986. Address for reprints: Edward L.C. Pritchett, MD, Box 3477, Duke University Medical Center, Durham, North Carolina 27710.

The subjects for this study were 12 male volunteers, aged 18 to 29 years, who had no evidence of heart disease by history, physical examination or electrocardiogram. No subject had abnormal kidney, liver or bone marrow function detected by clinical findings or laboratory examination. Volunteers were admitted to the Clinical Research Unit the day before the study. They were given nothing by mouth and were kept at complete bed rest for 6 hours before the study. In each subject a Teflon@ cannula (Quick Cath ZN114, Travenol Laboratories] was inserted into a superficial forearm vein and the vein was occluded with a sterile obturator between drawing blood samples. Another cannula was inserted into the opposite arm and connected to an infusion of 5% dextrose solution. A modified electrocardiographic lead II (left shoulder negative, cardiac apex positive] was displayed continuously and electrocardiographic rhythm strips were recorded at a paper speed of 100 mm/s on an Elema Mingograf recorder. Blood pressure was measured using a sphygmomanometer.

iltiazem hydrochloride, a calcium channel blocking drug, is a potent vasodilator.lJ It slows conduction in the atrioventricular (AV) node and it may be useful for treatment of supraventricular tachycardias.3z4The effects of diltiazem are brief after an intravenous bolus injection because of rapid drug distribution and elimination In some situations it may be desirable to maintain an antianginal or antiarrhythmic effect for several hours with a continuous intravenous infusion. We describe our experience with a loading and maintenance infusion of intravenous diltiazem that was designed to maintain stable plasma diltiazem concentrations.

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INFUSION

Infusion protocol: Two infusion regimens were designed using pharmacokinetic variables from previous studies.5*6Both regimens used 3 stages: a bolus injection, a rapid loading infusion and a maintenance infusion. Our “low-dose regimen” was intended to maintain a plasma diltiazem concentration of approximately 175 rig/ml. A bolus of 10 mg was injected over 3 minutes; a rapid loading infusion of 20 mg over 30 minutes; and maintenance infusion of 10 mg/hour was given indefinitely. Our “high-dose regimen” was designed to maintain a plasma diltiazem concentration of approximately 260 rig/ml. A bolus of 15 mg was injected over 3 minutes; a rapid loading infusion of 45 mg over 60 minutes; and a maintenance infusion of 15 mg/hour was given indefinitely. Blood pressure was measured and an electrocardiogram recorded every 15 minutes during a l-hour control period before the diltiazem infusion began. Each subject received a bolus and loading infusion. With each subsequent subject the maintenance infusion was progressively lengthened. In this way the infusion was extended to 48 hours as confidence in the safety of the regimen developed. The infusion was stopped if AV Wenckebach conduction was recorded. Blood pressure was measured, the electrocardiogram was recorded, and blood samples were drawn 3, 5, 7, 10, 15, 30, 45, 60, 120, 180 and 240 minutes after drug administration was begun and then every 4 hours until the infusion was stopped. These variables were measured again 3,5,7,10,15,20,45 and 60 minutes and 2, 4 and 8 hours after the infusion ended. Diltiazem assay: Blood samples were placed in heparinized glass tubes and immediately centrifuged, Plasma was then separated, frozen and stored at -20°C until assay. Plasma diltiazem and deacetyldil-

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tiazem were measured using high-pressure liquid chromatographic assay.7 The average coefficient of variation was 13% for diltiazem and 12.6% for deacetyldiltiazem. The detection limit for these assays was 10 rig/ml. Electrocardiographic variables: The PR interval and cardiac cycle length were measured using a Graf/ pen@sonic x-y digitizer and an interactive computer program. The mean of 10 consecutive cardiac cycles (rounded to the nearest millisecond) was calculated at each observation time. The electrocardiographic intervals for the control period.were calculated as the mean of the intervals measured every 15 minutes during the l-hour control period. Calculation of pharmacokinetic parameters: Terminal half-life, total clearance and apparent volume of distribution (Vd,,,,) were calculated using standard methods. Terminal half-life was calculated using the concentration vs time data points on the terminal linear phase after the drug infusion was stopped. Total diltiazem clearance was computed using 2 independent methods. First, clearance was calculated as the total dose administered divided by the total area under the concentration vs time curve. The latter was computed using the trapezoidal rule over the range of observed data points and was extrapolated to infinity using the terminal rate constant and the last data point. Second, clearance was calculated as the maintenance infusion rate, 10 mg/hour, divided by the average steady-state drug concentration. The latter was obtained by averaging the last 3 to 5 measured concentrations before cessation of the infusion. Vd,,,, was computed using the clearance estimate obtained by the first method and the terminal rate constant. Statistical methods: Changes in PR interval, sinus cycle length and blood pressure were tested for signifi-

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TIME (minutes) FIGURE 1. Median plasma diltiarem concentrations for subjects receiving the lowdose regimen. Shaded area represents levels at each time. The number of patients for whom data were available at each ttme point is shown in parentheses.

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cance with the Wilcoxon signed rank order test, Changes in the diltiazem level were correlated with changes in PR interval using the Spearman rank correlation coefficient. Values are reported as median or mean f standard deviation.

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Results Low-dose regimen: The low-dose regimen was tested in 8 subjects. Data were collected for all 8 subjects through 15 minutes, for 7 subjects through 4 hours, for 6 subjects through 8 hours, for 5 subjects through 16 hours, for 4 subjects through 24 hours and for 2 subjects through 48 hours. The median plasma diltiazem level produced by the bolus was 104 rig/ml (range 34 to 274) [Fig. 1). The median diltiazem level at the end of the rapid loading infusion was 141 rig/ml (range 55 to 212). The median nadir between the bolus and rapid loading infusion [measured 5 to 15 minutes after the start of the infusion) was 62 rig/ml (range 21 to 144). Median plasma diltiazem concentration remained relatively stable near 150 rig/ml during the maintenance infusion. The highest diltiazem levels were achieved after the bolus in 1 subject, at the end of the rapid loading infusion in 2 subjects, and during the maintenance infusion in 5 subjects (Fig. 2). Deacetyldiltiazem reached measurable plasma levels 30 minutes after the start of diltiazem infusion in 5 subjects, after 60 minutes in 1 subject and after 8 hours in 1 subject [Fig. 3). Deacetyldiltiazem gradually accumulated during the infusion, and peak levels were measured within 15 minutes of ending the infusion. The deacetyldiltiazem concentration for the 2 subjects with 48-hour infusions was 60 and 170 rig/ml when the infusion was terminated. The median PR interval measured during the control period was 152 ms [range 138 to 200). Lengthening of the PR interval was apparent in all subjects immediately after the bolus injection, but maximal lengthening was not observed until the end of the rapid loading infusion [Fig. 4 and 5). Among all subjects the median peak PR interval was 18% longer than the control PR interval. PR-interval prolongation was sustained for the duration of the infusion (range 10 to 18% greater than control) and returned to normal within 4 hours after the end of the infusion. In 1 subject AV nodal Wenckebach conduction developed after 11 minutes of the rapid loading infusion. Peak PR interval prolongation of 41% above control was recorded before Wenckebach block was observed. The peak diltiazem level after the bolus was 123 rig/ml and the plasma diltiazem level at the time of Wenckebach block was 131 rig/ml. Blood pressure did not significantly change after the bolus injection. However, mean systolic blood pressure decreased from 124 f 7 mm Hg during the control period to 121 f 8 mm Hg during the rapid loading infusion (p = 0.03 compared with control) and to 117 f 7 mm Hg (p = 0.04 compared with control) during the maintenance infusion. Blood pressure returned to control levels within 1 hour after the infusion ended. Heart rate was not affected by any stage of the infusion.

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O= AV NODAL WENCKEBACH FIGURE 2. Peak plasma diltiazem concentrations (.4) and peak PRinterval prolongation (6) produced by the highdose and low-dose infusion regimens. In patients in whom atrioventricular nodal Wenckebach conduction developed during infusion (open circles), peak PR prolongation before Wenckebach conduction is shown.

Pharmacokinetic variables for the 7 subjects who underwent the sustained intravenous diltiazem infusion without development of Wenckebach block are shown in Table I. The terminal half-life and total clearance showed 2- to s-fold variability. The mean elimination half-life was 253 f 105 minutes and mean clearance was 1,124 f 398 ml/min. The clearance estimates by the 2 independent methods yielded almost identical values. Vd,,,, was 380 f 120 liters. High-dose regimen: The high-dose regimen was tested in 4 subjects. In 2 of the 4 AV nodal Wenckebath conduction developed during the loading infusion; 1 of the other 2 subjects received a l-hour infusion and the other received a &hour infusion. The

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TIME

(minutes)

FIGURE 3. Median plasma deacetyldiltiazem concentrations for subjects receiving the low-dose regimen. Shaded area represents range of levels at each time. The number of patients for whom data were available at each time point is shown in parentheses.

median plasma diltiazem level produced by the bolus in all 4 subjects was 492 rig/ml (range 226 to 628). None of the 4 subjects showed important changes in blood pressure during any phase of the infusion. Diltiazem levels and PR-interval prolongation: Subjects receiving the high-dose regimen had higher plasma diltiazem levels, as expected, and appeared to have greater PR-interval prolongation than subjects receiving the low-dose regimen (Fig. 2). The diltiazem level correlated with PR prolongation during the drug washout period (r = 0.7) in individual patients, but did not correlate with PR prolongation at the end of the bolus, at the end of the loading infusion or during maintenance infusion. Side effects: Except for development of AV nodal Wenckebach conduction in 3 subjects (1 receiving the

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low-dose regimen and 2 receiving the high-dose regimen], no important bradycardia, tachycardia or hypotension was observed.

Discussion Our low-dose regimen appeared to be suitable for testing in clinical settings. Diltiazem is known to slow AV nodal conduction,8 and our low-dose regimen slowed AV conduction (measured as prolongation of the PR interval) by 10 to 18% for periods up to 48 hours. The regimen may therefore be useful for management of atria1 fibrillation and other supraventricular tachycardias. Diltiazem is also a vasodilator, and our regimen may warrant testing in patients with vasospastic angina and other acute syndromes of coronary artery disease.

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TIME (minutes) FIGURE 4. Median PR-interval prolongation (expressed as percent increase compared with control PR interval) low-dose regimen. The number of patients with data available at each time point is shown in parentheses.

for 7 subjects receiving the

November

FIGURE 5. PR-interval prolongation (fop) and plasma diltiazem and deacetyldiltiazem concentrations (bottom) from a subject who received the low-dose regimen for 24 hours. The PR interval returned to control value within 6 hours after the infusion was terminated.

2OOr

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TIME (hours)

The 3 stages of the infusion were designed with several specific objectives. The bolus injection rapidly achieved high plasma drug concentrations. The rapid loading infusion prevented the sharp dip in drug concentration caused by drug distribution. The maintenance phase provided stable plasma drug concentrations of approximately 150 rig/ml for up to 48 hours. For ease of delivery in clinical settings, the maintenance infusion rate was selected to be a simple multiple of the rapid loading infusion rate. The maintenance infusion produced stable median plasma diltiazem concentrations of about 150 rig/ml for up to 48 hours. However, the method of separate exponentials (used to devise these infusion regimens] predicts that other diltiazem plasma concentrations can be achieved easily by multiplying the bolus injection dose, the rapid loading infusion rate, and the maintenance infusion rate by the desired fractional increase in maintenance plasma diltiazem concentration.6 Deacetyldiltiazem appeared to accumulate gradually during infusion in our subjects. Deacetyldiltiazem and other metabolic products of deacetylation or Ndemethylation are converted to glucuronides or sulphates and excreted primarily in the urine.gJ0 The elimination half-life of deacetyldiltiazem appears to be considerably longer than that of diltiazem, and accumulation has been reported with repeated dosing.lO The role of deacetyldiltiazem in the efficacy of diltiazem is unclear.

Many studies show that diltiazem slows AV nodal conduction, which can be measured on the surface electrocardiogram as lengthening of the PR interval. In a study of diltiazem given by rapid intravenous injection, peak PR interval prolongation was recorded several minutes after peak plasma diltiazem concentrations were observed.5J* This observation explains why AV nodal Wenckebach conduction was not observed in our 3 subjects until 11 to 17 minutes after the

TABLE I Sustained

Pharmacokinetic Infusion

Measurements

of Diltiazem

After

Subject

Dose (ms)

f’h (min)

Cl’ (ml/min)

w (mbmin)

Wea (liters)

1 2 3 4 5 6 7

505 505 265 265 185 105 65

333 452 189 249 206 144 199

665 959 956 1,063 980 1,907 1,338

646 921 1,004 1,134 1,104 1,773 1,462

320 626 261 382 291 396 385

258 181 166 147 151 94 114

Median Mean SD

265 271 177

206 253 105

980 1,124 398

1,104 1,149 369

382 380 120

151 159 53

C*, (Wml)

*Calculated as total dose divided by total AUC. tCalculated as infusion rate of maintenance Lv. infusion (10 mg/hour) divided by the average steady-state concentration. C, = average steady-state concentration of diltiazem; Cl = total clearance; SD = standard deviation; Vd,., = apparent volume of distribution.

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addition, such a regimen may have ‘value in clinical bolus injection. At the time Wenckebach conduction settings where stable plasma drug concentrations are was recorded in the 2 subjects who received the highdose regimen, plasma diltiazem concentrations were needed to establish pharmacologic effects. lower than peak levels observed several minutes earlier when AV conduction was normal. References Previous investigators have reported a significant decrease in heart rate at rest in subjects taking 120 to 1. Pepine CJ, Feldman RL, Whittle J, Curry C, Conti CR. Effect of diltiazem in with variant angina: a randomized double-blind trial. Am Heart J 360 mg of diltiazem compared with placebo.12 Our patients i981;101:719-725. study and that of Joyal et alI1 show that diltiazem may 2. Hossack KF, Bruce RA. Improved exercise performance in persons with stable angina pectoris receiving diltiazem. Am J Cardiol 1981;47:95-101. be administered without resulting in significant brady3. Mitchell LB, Jutzy KR, Lewis SJ, Schroeder JS, Mason JW. Intracardiac cardia. The divergence between these studies has 2 electrophysiofogic study of intravenous diltiazem and combined diltiazempossible explanations. Our study group was composed digoxin in patients. Am Heart r 1982;103:57-66. of healthy, male volunteers, many of whom spent con- 4. Rozanski JJ,Zaman L, Castellanos A. Electrophysiologic effects of diltiazem hydrochloride on supraventricular tachycardia. Am J Cardiol 1982;49:621siderable time exercising,- as reflected by their low 628. heart rates at rest. This may partially explain the high 5. Smith MS, Verghese CP, Shand DG, Pritchett ELC. Pharmacokinetic and pharmacodynamic effects of diltiazem. Am J Cardiol 1983;51:1369-1374. incidence of Wenckebach conduction during the high6. Shand DG, Desjardins RE, Bjornsson TD, HammiII SC, Pritcheff ELC. The dose regimen. An explanation for the lack of bradycarmethod of separate exponentials: a simple aid to devising intravenous drugdia during intravenous diltiazem infusion may be re- loading regimens. Clin Pharmacol Ther 1981;29:542-547. Verghese C, Smith MS, Aanonsen L, Pritchett ELC, Shand DG. High lated to the subject’s normal cardiac function. In these 7. performance liquid chromatographic analysis of diltiazem and its metabolite subjects, the direct effect of diltiazem on the sinus in plasma. f Chromatogr 1983;272:149-155. 8. Mitchell LB, Schroeder JS,Mason JW. Comparative clinical electrophysionode may be counterbalanced by the reflex tachycarlogic effects of diltiazem, veropamil and nifedipine: a review. Am J Cordiol dia caused by its vasodilatation of arterioles. 1982;49:629-635. The pharmacokinetic variables derived from this 9. Morselli PL, Rovei V, Mitchard M. Durand A, Gomeni R, Larriband J. study are similar to those reported for diltiazem.10~13-16 Pharmacokinetics and metabolism of diltiazem in man (observations on healthy volunteers and angina pectoris patients). In: Bing RI, ed. New Drug Long-term oral administration of drugs such as diltiaTherapy with a Calcium Antagonist. Amsterdam: Excerpta Medica. 1979; zem having a high first-pass metabolism may lead to 152-168. Kates RE. Calcium antagonists: pharmacokinetic properties. Drugs unexpected accumulation due to a decrease in clear- 10. 1983;25:113-124. ance.10,17,18 This phenomenon was not observed in our 11. Joyal M, Pieper J, Cremer K, Feldman RL, Pepine CJ. Pharmacodynomic aspects of intravenous diltiazem administration. Am Heart J 1986;111:54-61. study when diltiazem was given as a long-term intraBala Subramanian V, Khurmi NS, Bowles MJ, O’Hara M, Raftery EB. venous infusion, as the 2 clearance estimates were al- 12. Objective evaluation of three dose levels of diltiazem in patients with chronic most the same (i.e., when clearance was determined stable angina. rACC 1983;1:1144-1153. 13. Zelis RF, Kinney EL. The pharmacokinetics of diltiazem in healthy Amerfrom drug concentrations over the entire drug adminmen. Am J Cardiol 1982;49:529-532. istration period and when it was based on the last few ican 14. Ocbs HR, Knuchel M. Pharmacokinetics and absolute bioavailability of drug concentrations before drug administration was diltiazem in humans. Klin Wochenschr 1984;62:303-306. 15. Hermann P, Rodger SD, Remones G, Thenot JP,London DR, Morselli PL. stopped]. Pharmacokinetics of diltiazem after intravenous and oral administration. Eur Clinical implications: Potential uses for intraveJ Clin Pharmacol 1983;24:349-352. 16. Chaffman M, Brogden RN. Diltiazem: a review of its pharmacological nous diltiazem include acute treatment of supravenand therapeutic efficacy. Drugs 1985;29:387-454. tricular tachycardias, vasospastic angina, unstable an- properties 17. Shand DG, Hammill SC, Aanonsen L, Pritchett ELC. Reduced verapamil gina, postoperative ischemia and vasospasm after clearance during long-term oral administration. Clin Pharmacol Ther 1981; angioplasty.l6 Since the effect of an intravenous bolus 30:701-703. 18.Evans GE, Shand DG. Disposition of propranolol. V. Drug accumulation injection of diltiazem is transient, a sustained infusion and steady-state concentrations during chronic oral administration in man. of intravenous diltiazem may be of clinical value. In Clin Phormacol Ther 1973;14:487-493.