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Pharmacokinetic-hemodynamic studies of nitroglycerin ointment in congestive heart failure
Pharmacokinetic-Hemodynamic Studies of Nitroglycerin Ointment in Congestive Heart Failure
PAUL
W.
ARMSTRONG,
MD,
FACC”
JOYCE A. ARMSTRONG, MSc GERALD S. MARKS, DPhil
with the technical assistance of JAMES
McKlNVEN
SUSAN
SLAUGHTER
Kingston, Ontario, Canada
From the Departments of Medicine (Cardiology) and Pharmacology, Queen’s University, Kingston, Ontario, Canada. This study was supported in part by a grant from the Ontario Heart Foundation, Toronto, Ontario, Canada. Manuscript received January 9, 1980; revised manuscript received April 21, 1980, accepted Aprit 29, 1980. ‘Recipient of a Senior Research Fellowship from the Ontario Heart Foundation, Toronto, Ontario, Canada. Address for reprints: Paul W. Armstrong, MD. Department of Medicine (Cardiology), Queen’s University, Kingston, Ontario, K7L 3N6 Canada.
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The aim of this study was to determine the bioavailability of nitroglycerin after application of nitroglycerin ointment in patients with heart failure and to examine whether a correlation exists between plasma nitroglycerin and its hemodynamio, effects. The dose of nitroglycerin ointment selected was based on the prior hemodynamlc response of individual patients to an intravenous infusion of nitroglycerin. Nine patients received 1 to 2 Inches of nitroglycerin olntment on a single skin site (small dose group) and five patients received 4 inches (2 inches to two separate skin sites, large dose group). There was good correlation between the dose of nitroglycerin ointment and bloavallabllity (area under the plasma concentration time curve from 0 to 240 minutes) (r = 0.81, p
Nitroglycerin applied to the skin in ointment form enters the circulation in a manner that bypasses the gastrointestinal tract and portal circulation. Since 1944, nitroglycerin has been adminstered percutaneously in ointment form for the therapy of peripheral circulatory disorders.’ In 1955, Davis et a1.2 reported that this agent had favorable effects in patients with angina pectoris. This finding was later confirmed by Reichek et a1.3 who demonstrated at least a 3 hour increase in exercise capacity in patients with angina pectoris. Studies@ from our own institution and elsewhere in patients with angina pectoris, myocardial infarction and congestive heart failure have demonstrated that the hemodynamic effects of nitroglycerin ointment are maximal between 60 to 90 minutes after its application and persist for at least 4 to 6 hours. Expansion of the indications for the use of nitrate therapy has generated a need for and the development of preparations with a Ionger duration of action than the conventional sublingual form.7 One such preparation is oral isosorbide dinitrate, which has been demonstrated to produce hemodynamic effects for approximately 6 hours after adminstrati0n.s Although this agent is effective, in some clinical situations
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the oral route of drug a.dministration may be unsatisfactory, for example, when the oral route is precluded by nasogastric suction or paralytic ileus or the absorption of oral agents is co:mpromised by a malabsorption syndrome. In such patients, the percutaneous route may constitute an effective alternative. Another circumstance in which the absorption of oral medications may be both variable and incomplete is congestive heart failure.g Whether the percutaneous route is preferable in this setting is as yet unknown. In previous studies of patients with heart failure a subset who did not respond to nitroglycerin ointment was identified with hemodynamic monitoring.l’JJi Because plasma levels of nitroglycerin were unavailable, the possibility existed that this lack of response resulted from an inability to achieve adequate plasma concentrations of nitroglycerin. Accordingly, we undertook a pharmokinetic-hemodynamic study of nitroglycerin ointment administered percutaneously to patients with congestive heart failure. Our objectives were (1) to determine the bioavailability of nitroglycerin after application of nitroglycerin ointment in patients with heart failure; and (2) to examine whether a correlation exists between the concentration of nitroglycerin in plasma and its hemodynamic effects, both afl;er application of nitroglycerin ointment and after its removal. Methods Patients: Fourteen patients with congestive heart failure formed the study group: There were 11 men and 3 women with a mean age of 53 years (range 38 to 67). Three had cardiomyopathy, seven had chronic arteriosclerotic heart disease and four were studied within l month of a myocardial infarction; these patients were all in New York Heart Association functional class III or IV12 and refractory to conventional therapy including administration of digoxin and furosemide. Four patients with diabetes were insulin-dependent. Five had received isosorbide dinitrate for at least 3 weeks before this study. All drugs except digoxin and insulin were withheld for at least 24 hours before onset of the study. Hemodynamic studies: After informed consent was obtained, the patients were fitted with instruments for hemodynamic monitoring in a istandard fashion. This included the placement of a triple lumen thermodilution Swan-Ganz catheter in the pulmonary artery and a Teflon@ cannula in the radial artery. Right atrial, pulmonary arterial and pulmonary capillary wedge pressures (obtained by balloon occlusion) and systemic arterial pressure were monitored. The cardiac output was measured, at least in duplicde, with the thermodilution technique (injection of 10 ml of ice-cold 5 percent dextrose in water into the right atrium).‘” Intravenous nitroglycerin: Nitroglycerin was prepared for intravenous use as a 6.5 percent solution in ethanol. A 9.5 percent lactose mixture (Parke-Davis Company, Brockville, Ontario, Canada) (6.3 g) was added to ethyl alcohol (99 percent) to a total volume of 120 ml. The alcoholic supernatant was decanted and passed through a 0.22 Millexe millipore filter. The solution was assayed using a spectrophotometric technique before being reassayed using our gas-liquid chromatographic method.14 Immediately before use, the nitroglycerin solution was added to 5 percent dextrose in water and contained in glass bottles to produce a concentration of 100 /.&ml.
STUDIES OF NITROGLYCERIN OINTMENT-ARMSTRONG
ET AL.
I.0 -
0.8 -
rr
0.w
pso*)l
2.0
4.0 I.V. GTN ug/kg/min
6.0
8.0
FIGURE 1. Relation between dose of nitroglycerin ointment (NGO) and peak intravenous nitroglycerin (I.V.GTN) infusion rate. p = probability; r = correlation coefficient.
After a control period of 30 minutes, during which the hemodynamic measurements were demonstrated to be reproducible, intravenous nitroglycerin was infused at an initial rate of 15 to 20 pg/min. The aim was to reduce pulmonary capillary wedge pressure by at least 25 percent, and the infusion was increased in stepwise fashion (50 percent increments of prior rate) every 10 to 15 minutes until either the desired hemodynamic end point was achieved or a greater than lo-fold increment in the initial infusion rate had been reached. The final infusion rate was maintained until a hemodynamic steady state was achieved, which required approximately 15 to 20 minutes. The infusion was then discontinued and monitoring performed for at least an additional 30 to 60 minutes until return to control hemodynamic values had been demonstrated. Nitroglycerin ointment groups: We15J6 have previously found that the hemodynamic response to intravenous nitroglycerin is useful in establishing the response to and selecting the dose of other forms of nitrate therapy.15J6 In this study, patients in whom the hemodynamic end point was reached at an intravenous nitroglycerin infusion rate of 2.5 pglkg per min or less received 2 inches (5 cm) or less of nitroglycerin ointment. The nine patients in this group had mean (i standard deviation) intravenous nitroglycerin infusion rate of 1.2 f 0.8 pg/kg per min. Patients who received more than 2.5 gg/kg per min of intravenous nitroglycerin received 4 inches (10 cm) of nitroglycerin ointment. Among the five patients in this group, the hemodynamic end point was reached in only one, and the average intravenous nitroglycerin infusion rate was 6.3 f 1.9 pg/kg per min. The relation between the dose of intravenous nitroglycerin and nitroglycerin ointment is shown in Figure 1. Detailed examination of the pharmacokinetichemodynamic response to intravenous nitroglycerin in nine of our patients has been reported separately.uj Nitroglycerin ointment (Nitrol@ 2 percent, Kremers-Urban Company, Milwaukee, Wisconsin) was applied to the chest or flank over a 3 by 3 inch (7.6 by 7.6 cm) square area. AS indicated, the dose selected was based on the patient’s response to prior intravenous administration of nitroglycerin (Fig. 1). When more than 2 inches was applied, a second 3 by 3 inch site was utilized. After application of nitroglycerin ointment, hemodynamic monitoring was performed at frequent intervals through 240 minutes: In selected instances the period of monitoring was prolonged to 480 minutes. The occlusive dressing was then removed, the residual ointment scraped from the skin and the skin site washed with alcohol. Arterial blood samples were withdrawn during the control period before the administration of intravenous nitroglycerin
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TABLE I Summary of Hemodynamic Response to Nitroglycerin Ointment (n = 14) Time Period (mm)
HR
PCW
C 30 60 90 120 240 P
93f 16 93f 15 93f 15 92f 15 92f 15 91 f 15 NS
28 f 7 24 f 8 24 f 8 24 f 8 23 f 8 24 f 9 <0.0005
MAP
Cl
SI
93 f 20 90f 17 90 f 20 89 f 21 90 f 20 86f 18 NS
2.2 f 0.7 2.3 f 0.6 2.3 f 0.6 2.3 f 0.5 2.3 f 0.5 2.4 f 0.7 <0.05
23.9 f 8.3 25.5 f 6.5 24.9 f 6.8 25.1 f 4.0 25.0 f 6.8 27.6 f 9.3 <0.02
RAP 14f 7 12f6 11 f6 12f7 11 f6 12f8 <0.0005
TPR 22.3 20.4 20.7 20.6 21.0 19.9
f 10.4 f 8.6 f 8.2 f 9.5 f 8.6 f 9.7 NS
All summary values represent mean f standard deviation; p values represent a linear regression analysis performed on average percent from control value (r = 0) against time. C = control value; Cl = cardiac in&x (liters/min per m*; HP = heart rate (beats/min); MAP = mean arterial pressure (mm Hg); NS = not significant; PCW = oulmonarv capillarv wedqe pressure (mm Hg); RAP = right atrial pressure (mm Hg); SI = stroke index (ml/beat per m*); TPR = total peripheral resistance (units& ’ . -.
as well as just before the application of nitroglycerin ointment and at 60,90 and 240 minutes after the application of ointment. In some instances, additional samples were available up to and including 480 minutes as well as 30 minutes after the removal of nitroglycerin ointment. Blood samples were immediately centrifuged at Y’ C and the decanted plasma was frozen at -20” C. Subsequent analysis was performed using a gas-liquid chromatograph with isosorbide dinitrate or dinitrobenzene as the internal standard (14).
paired observations used when appropriate. The correlations and their significance were tested using Fisher’s F test. The area under the plasma concentration time curve (from 0 to 240 minutes and from 0 to 480 minutes) was determined with trapezoidal integration using discrete points.
Results
Analysis of data: Derived calculations were performed using the formulas SI = &I/HR and TPR = MAP-RAP/CO, where SI = stroke index in ml/beat per m2,CI = cardiac index in liters/min per m2, TPR = total peripheral resistance in units, MAP = mean arterial pressure in mm Hg, CO = cardiac output in liters/min and RAP = right atria1 pressure in mm Hg. Statistical comparisons of measurements were made using regression analysis and Student’s t test with paired and un-
0
60
120
180
240
MINUTES AFTER APPLICATION
FIGURE 2. Plot of the relation between plasma nitroglycerin (glyceryl trinitrate) (GTN) concentration (solld lines) and percent decrease in pulmn-rary capilfaty wedge pesslre (PCW) (dashed lines) for the goups receiving small dose (2 inches or less) and large dose (4 inches) of nitroglycerin ointment. Standard deviations for plasma nitroglycerin and percent reduction in pulmonary capillary wedge pressure are equal to or less than f4.3 ng/ml and f 11.5 percent, respectively, in the large dose group and equal to or less than f3.1 ng/ml and f9.5 percent in the small dose group.
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The relation between the dose of nitroglycerin ointment selected and the peak nitroglycerin infusion rate (that is the dose that either produced a 25 percent reduction in pulmonary capillary wedge pressure or was greater than 10 times the initial infusion rate) is illustrated in Figure 1. A regression analysis performed between the doses of the two modes of nitroglycerin adminstration demonstrates a good correlation (r = 0.96, probability [p]
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TABLE II
Relation Between Bioavailability of Nitroglycerin Ointment and Peak Hemodynamic Effect Peak Hemodynamic Effect Dose of NGO Case
(inches)
(mglkg)
Nitroglycerin Bioavailability
Control PCW
AUCO_240(ngmin/ml)
(mm Hg)
Decrease in PCW
Control RAP
(%)
(mm Hg)
Decrease in PCW (%)
Small Dose Group (n = 9) 1 3’
1.0 1.5 1.25
0.17 0.215 0.19
325 684 233
::
::
4 5
::“5 1.5
0.:!5 0.2!9 0.2!7
905 970 525
Z? 24 28
3: 29
33 8 t ;: 63 : ::
7 9” Mean SD
1.5 ;::
0.30 0.37 0.:!7 0.67
263 1752 490 683 480
40 2: 26 7
:: 2253 31’ 11
:: :2’ 13 7
8: 32 37’ 15
9
16
25
:z 14
14 16
42;
:z 25
;J 7
1:+ 5
;“o 18 4
2:+ 17
24” 13
15 7
24’ 19
Large Dose Group (n = 5) 10
4.0
0.59
1467
:: 13 14 Mean SD
4.0 t ::
0.75 0.60 0.76 0.86 0.71 O.ll
2901 1452 2483 1424 1945 698
z5
Both Groups (n = 14) Mean SD
0.43 0.23
1134 828
28 7
Statistical significance: Paired t test (percent decrease in pulmonary capillary wedge and right atrial pressures): p < 0.001; t p < 0.025. Unpaired t test (small dose versus large dose group) for area under the concentration-time curve, control value and percent decrease in pulmonary capillary wedge pressure and control value and percent decrease in right atrial pressure: p < 0.005, < 0.005, < 0.005, NS and NS, respectively. AUC = area under concelntration-time curve: NGO = nitroalvcerin ointment: NS = not significant; PCW = pulmonary capillary wedge pressure: - . RAP = right atrial pressure: SD = standard deviation. l
have arbitrarily divided the data into two subsets based on the dose of nitroglycerin ointment applied. The small dose group (n =9) received 1 to 2 inches or 12.5 to 25 mg of nitroglycerin ointment on a single skin site. The large dose group (n = 5) received 4 inches or 50 mg of nitroglycerin ointment (2 inches applied to two separate skin sites). The control value of pulmonary capillary wedge pressure was higher in the large than in the small dose group, (33 versus 26 mm Hg, p <0.005). After application of nitroglycerin ointment there was a greater decrease in pulmonary capillary wedge pressure in the small (31 percent) than in the large dose group (13 percent, p cO.005). There was no significant difference in the control value (or in the changes in right atria1 pressure between the two groups. The area under the plasma concentrationtime curve from 0 to 240 minutes was significantly less in the small than in the large dose group (p X0.005). Changes in pulmonary capillary pressure correlated with plasma nitroglycerin concentration: In Figure 2, the percent changes from the control value of pulmonary capillary wedge pressure are displayed over the 240 minute period after application of nitroglycerin ointment to allow for comparison with plasma nitroglycerin concentration data in the large and small dose groups. In the s:mall dose group, pulmonary capillary wedge pressure decreased substantially at 30
minutes, reaching its maximal reduction of 23 percent at 120 minutes and remaining depressed through 240 minutes. Plasma nitroglycerin concentration in this group increased to 3.1 f 3.0 (standard deviation) ng/ml at 60 minutes and remained at that level throughout the remainder of the sampling period. In the large dose group a plasma nitroglycerin level of 8.9 f 4.0 ng/ml was achieved at 60 minutes and was sustained throughout the 240 minute sampling period. Despite this plasma nitroglycerin concentration there was little decline in pulmonary capillary wedge pressure. We analyzed the decrease in pulmonary capillary wedge pressure produced by nitroglycerin ointment as a function of resting pulmonary capillary wedge pressure, cardiac index and total peripheral resistance and found that none of these indexes were of value in predicting the change in pulmonary capillary wedge pressure after application of nitroglycerin ointment (r 50.53, in all instances). In four patients (Cases 4, 10, 11 and 14), hemodynamic and plasma nitroglycerin data were available for 480 minutes after application of nitroglycerin ointment (Fig. 3). There was a modest early reduction in right atria1 pressure that was sustained through 360 minutes and returned toward the control value at 480 minutes. There was a small and sustained reduction in pulmonary capillary wedge pressure. The plasma nitroglycerin
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T
0 60
90
240
MO
480
Z
r3
MIMTES AFTER APPLICATION NGO
FIGURE 3. Hemcdynamic and plasma nitroglycerin data in four patients studied for 480 minutes after application of nitroglycerin ointment (NO). All data represent mean values f standard deviations. CONC = concentration; PCW = pulmonary capillary wedge pressure; RAP = right atrial pressure.
levels were elevated to nearly 5 ng/ml at 60 minutes and remained elevated through the balance of the sampling period. In four patients in the large dose group and in seven in the small dose group, we analyzed the effects of removing nitroglycerin ointment. Six patients were studied to 240 minutes, two to 360 minutes and three to 480 minutes (Fig. 4). There was little change in either
4000
‘,L
ONNGO 30’ OFF Nu)
FIGURE 4. Influence of removal of nitroglycerin ointment (NGO) in 11 patients. “On NGO” indicates the last observation before removal. Seven patients are in the small dose group (solid lines) and four in the large dose group (dashed lines). Significant changes occurred in pulmonary capillary wedge pressure (PCW) in the small dose group (18 to 23 mm Hg, p cO.025) and in nitroglycerin (GTN) plasma concentration (p CO.05 for both groups). The plasma concentration data in the small dose group are based on values in three patients.
right atria1 or pulmonary capillary wedge pressure in the large dose group 30 minutes after removal of nitroglycerin despite a substantial decrease in plasma nitroglycerin. By contrast, in the small dose group there was a slight rise in right atria1 pressure and a significant increment in pulmonary capillary wedge pressure 30 minutes after removal of nitroglycerin. Plasma nitroglycerin, available in three patients in the small dose group, showed a sharp decrease similar to that noted in the large dose group. The relation between plasma nitroglycerin concentration and the dose of nitroglycerin ointment applied was testing using a linear regression analysis. In all patients the relation between peak plasma nitroglycerin and dose of nitroglycerin ointment in mglkg was r = 0.89 (p
1
3000
E
e P f4 2000 2 u
rS0.81 P
Discussion 0.8
1.0
1.2
DOSE mglkg
FIGURE 5. Linear regression analysis of relation between the area under the plasma concentration-time curve from 0 to 240 minutes (AU&-s& and dose of nitroglycerin ointment for the total study group (r = 0.81; p
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Bioavailability of nitroglycerin ointment: This study documents the bioavailability of nitroglycerin when delivered percutaneously to patients with congestive heart failure. There was in general a good relation between the area under the plasma concentration-time curve from 0 to 240 minutes and the dose of nitroglycerin ointment (Fig. 5). This relation improved
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when it was examined in the four patients who were observed for 480 minutes after application of nitroglycerin ointment (Fig. 3). The previously demonstrated short half-life of nitroglycerin of 1.9 minutes coupled with the observation o:f sustained plasma nitroglycerin levels 480 minutes afl;er application of nitroglycerin ointment indicates that absorption of nitroglycerin must have continued throughout the entire period of application.16 This suggests that “flip-flop” kinetics are operative when nitrogl.ycerin ointment is applied; that is, the plasma concentration over the study period is directly dependent on continuing absorption.17 Despite the good relation between dose of nitroglycerin ointment and area under the plasma concentration-time curve from 0 to 240 minutes, some interpatient variability occurrled. There are a variety of reasons why interpatient differences in bioavailability might be expected after application of similar doses of nitroglycerin ointment. Thlese differences relate in part to variations in percutaneous absorption as modulated by skin perfusion, perme,ability and thickness. Moreover, differences in both systemic perfusion and venous congestion in these patients with heart failure would be expected to alter volume of distribution, rate of hepatic metabolism and, therefore, clearance of nitroglycerin-l8 The interpatient variability would probably have been diminished had all patients been evaluated throughout the complete time cou.rse of absorption, which is as yet unknown. Examining our data in the light of the experimental studies of Horhota and Funglg is of considerable interest. These investigators studied the effects of topical application of nitroglycerin ointment to the abdominal skin surface of rats; they demonstrated a wide variation in the nitroglycerin pllasma concentration-time curve among individual rats despite similar doses. They also found that the concentration of blood nitroglycerin remained elevated throughout the duration of the 4 hour study period. Analysis of surface sections after the 4 hour absorption experiments revealed that nearly 60 percent of the applied drug could be recovered, indicating that significant quantities of the drug were still available for absorption. Although in the current study we found that plasma nitroglycerin decreased substantially after removal of nitroglycerin ointment, it was still detectable 30 minutes thereafter. This finding was unexpected in view of the short half-life of nitroglycerin of 1.9 minutes and it suggests that a depot for nitroglycerin exists in the :skin of human subjects, as it does in rats, after percutaneous application.‘” Beneficial hemodynamic effects of nitroglycerin ointment: This study confirms that nitroglycerin ointment provides prompt and sustained hemodynamic benefit in selected patients with congestive heart failure. The patients in the slmall dose group who were characterized as sensitive to nitroglycerin by prior intravenous nitroglycerin infusion demonstrated hemodynamic benefit concomitant with the appearance of approximately 3 ng/ml of nii;roglycerin in plasma. The hemodynamic effects were already clearly evident 30 minutes after application of nitroglycerin ointment at a time
STUDIES OF NITROGLYCERIN OINTMENT-ARMSTRONG
ET AL.
when the plasma level was probably less than 3 ng/ml (Fig. 2). This concentration of nitroglycerin is within the therapeutic range of 1.2 to 11.1 ng/ml defined in our previous study of 16 patients with congestive heart failure who received intravenous nitroglycerin.16 Although there appeared to be a good correlation between plasma nitroglycerin and its hemodynamic effects in the small dose group, a subset of patients has again been identified who demonstrate minimal response to nitroglycerin despite achieving plasma concentrations of 9 ng/ml. These findings were anticipated from the patients’ prior attenuated response to intravenous nitroglycerin. The attenuated response in these patients is also demonstrated by the lack of hemodynamic alteration after removal of nitroglycerin ointment despite a substantial decrease in plasma nitroglycerin. We16 have previously shown that some patients with heart failure may respond to nitroglycerin with a reduction in right atria1 pressure, but little change in left ventricular filling pressure.“j This appeared to be the case in Patients lo,12 and 13 and may be partly related to asymmetric distribution of cardiac disease expressed by differing compliance characteristics of the two ventricles.20 Factors influencing response to nitroglycerin: A variety of factors may have influenced the response to nitroglycerin in this study. Nitrate responsiveness could not be predicted from the value of the resting cardiac index, total peripheral resistance or pulmonary capillary wedge pressures.21 Three of the five patients in the large dose group had diabetes, and two of these three were insulin-dependent; small vessel disease secondary to the diabetes could have modified the hemodynamic response in these patients. Prior nitrate therapy did not appear to be a predictor of response to nitroglycerin ointment because only two of the five patients who received prior nitrate therapy were in the large dose group.22 The amount of circulating catecholamines and angiotensin is known to be increased in some patients with heart failure; variations in the levels of these substances would also be expected to alter the response of the peripheral circulation to pharmacologic therapy.2”v24 Because the concentration of nitroglycerin in plasma was in the therapeutic range in the patients who did not respond, absorption of the drug from ointment was confirmed. Lack of response was not due to failure of drug delivery but probably represented target organ resistance in peripheral arterioles and veins. This resistance cannot be predicted from control hemodynamic indexes, but it can be anticipated by prior intravenous nitroglycerin infusion and is best detected by hemodynamic monitoring. Clinical implications: From these data we conclude that nitroglycerin ointment provides therapeutic levels of nitroglycerin that are associated with substantial hemodynamic benefit in selected patients with heart failure. Therapeutic plasma concentrations of nitroglycerin are demonstrable through at least 480 minutes and probably persist for a longer period. In those cases in which an attenuated response is found during intra-
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STUDIES OF NITROGLYCERINOINTMENT-ARMSTRONG ET AL.
Acknowledgment
venous infusion of nitroglycerin, large doses of nitroglycerin ointment (4 inches) are also unlikely to be of benefit. Further investigation is required to (1) document the complete time course of nitroglycerin bioavailability and hemodynamics after application of nitroglycerin ointment, (2) explore the mechanism of resistance of nitroglycerin, and (3) determine whether tolerance
occurs in responsive
We acknowledge the capable assistance of Sheila Dee, RN, Marlene Adam, BNSc, the nurses of the Coronary Care Unit of the Kingston General Hospital, and the assistance of Assil Bassili, BPharm in the preparation and spectrophotometric analysis of the intravenous nitroglycerin, the statistical advice of Donald G. Watts, PhD, and the secretarial assistance of Anne Baron and Jeanine MacRow.
patients.
References 1. Lund F. Percutaneous nitroglycerin treatment in cases of peripheral circulatory disorders, especially Raynaud’s disease. Acta Med Stand [Suppl] 1948;206:196-206. 2. Davis JA, Wieesi BH, EPstein SE. The treatment of angina pectoris with nitroglycerin ointment. Am J Med Sci 1955;230:259-63. 3. Reichek N, Goldstein RE, Redwood DR, et al. Sustained effects of nitroglycerin ointment in patients with angina pectoris. Circulation 1974;50:348-52. 4. Parker JO, Augustine RJ, Burton JR, West RO, Armstrong PN. The effect of nitroglycerin ointment on the clinical and hemodynamic response to exercise. Am J Cardiol 1976;38:162-6. 5. Armstrong PW, Mathew MT, Boroomand K, Parker JO. Nitroglycerin ointment in acute myocardial infarction. Am J Cardiol 1976:38:74-a. 6. Taylor WR, Forrester JS, Magnusson P, Takano T, Chatlerjee K, Swan HJC. Hemodynamic effects of nitroglycerin ointment in congestive heart failure. Am J Cardiof 1976;38:469-73. 7. Gold HK, Lefnbach RC, Sanders CA. Use of sublingualnitroglycerin in congestive failure following acute myocardial infarction. Circulation 1972;46:839-45. 8. Gray R, Chatterjee K, Vyden JK, Ganz W, Forrester JS, Swan HJC. Hemodynamic and metabolic effects of isosorbide dinitrate in chronic congestive heart failure. Am Heart J 1975;90:34652. 9. Benowitz NL, Meister W. Pharmacokinetics in patients with cardiac failure. Clin Pharmacokinet 1976;1:389-405. 10. Kiausner S, Chatterjee K, Parmiey WW. Therapy of chronic heart failure with nitroglycerin ointment: the necessity for measuring hemodynamics to determine non-responders (abstr). Circulation 1976;53:ll-66. 11. Armstrong PW, Leach AJ, Brown JE. Oiowoyeye JO. Comparative vasodilator studies in congestive cardiac failure (abstr). Clin Res 7978;26:830A. 12. Criteria Committee of the New York Heart Association. Nomen-
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13.
14. 15.
16.
17. 18. 19. 20.
21. 22.
23.
24.
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clature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 8th ed. Boston:Fittle, Brown, 1979290. Forrester JS, Ganz W, Diamond G, McHugh T, Chonette OW, Swan HJC. Thermodilution cardiac output determination with a single flow directed catheter. Am Heart J 1972;83:306-11. Armstrong PW, Armstrong JA, Marks GS. Blood levels after sublingual nitroglycerin. Circulation 1979;59:585-8. Armstrong PW, Parker JO. Intravenous nitroglycerin and congestive failure in acute myocardial infarction (abstr). Ann Coll Can 1977;10:34. Armstrong PW, Armstrong JA, Marks GS. Pharmacokinetichemodynamic studies of intravenous nitroglycerin in congestive cardiac failure. Circulation 1980;62:160-6. Gibaidi M, Perrier D. Pharmacokinetics. New York: Dekker, 1975;35. Hepner GW, Veseii EA, Tantum KR. Reduced drug elimination in congestive heart failure. Am J Med 1978;65:271-6. Horhota ST, Fung HL. Percutaneous nitroglycerin absorption in rats. J Pharm Sci 1979;68:608-12. Ludbrook PA, Byrne JD, Kurnik PV, McKnight RC. Influence of reduction of preload and afterload by nitroglycerin on left ventricular diastolic pressure volume relations and relaxation in man. Circulation 1977;56:937-43. Goldberg S, Mann T, Grossman W. Nitrate therapy of heart failure in valvular heart disease. Am J Med 1978;65:161-6. Kiock JC. Nonocclusive coronary disease after chronic exposure to nitrates: evidence for physiologic nitrate dependence. Am Heart J 1975;89:510-3. Curtiss C, Cohn JN, Vrobei T, Franciosa JA. Role of the reninangiotensin system in systemic vasoconstriction of chronic congestive heart failure. Circulation 1979;58:763-70. Chidsey CA, Harrison DC, Braunwaid E. Augmentation of the plasma norepinephrine response to exercise in patients with congestive heart failure. N Engl J Med 1962;267:650-4.
PAUL
W.
ARMSTRONG,
MD,
FACC”
JOYCE A. ARMSTRONG, MSc GERALD S. MARKS, DPhil
with the technical assistance of JAMES
McKlNVEN
SUSAN
SLAUGHTER
Kingston, Ontario, Canada
From the Departments of Medicine (Cardiology) and Pharmacology, Queen’s University, Kingston, Ontario, Canada. This study was supported in part by a grant from the Ontario Heart Foundation, Toronto, Ontario, Canada. Manuscript received January 9, 1980; revised manuscript received April 21, 1980, accepted Aprit 29, 1980. ‘Recipient of a Senior Research Fellowship from the Ontario Heart Foundation, Toronto, Ontario, Canada. Address for reprints: Paul W. Armstrong, MD. Department of Medicine (Cardiology), Queen’s University, Kingston, Ontario, K7L 3N6 Canada.
670
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The aim of this study was to determine the bioavailability of nitroglycerin after application of nitroglycerin ointment in patients with heart failure and to examine whether a correlation exists between plasma nitroglycerin and its hemodynamio, effects. The dose of nitroglycerin ointment selected was based on the prior hemodynamlc response of individual patients to an intravenous infusion of nitroglycerin. Nine patients received 1 to 2 Inches of nitroglycerin olntment on a single skin site (small dose group) and five patients received 4 inches (2 inches to two separate skin sites, large dose group). There was good correlation between the dose of nitroglycerin ointment and bloavallabllity (area under the plasma concentration time curve from 0 to 240 minutes) (r = 0.81, p
Nitroglycerin applied to the skin in ointment form enters the circulation in a manner that bypasses the gastrointestinal tract and portal circulation. Since 1944, nitroglycerin has been adminstered percutaneously in ointment form for the therapy of peripheral circulatory disorders.’ In 1955, Davis et a1.2 reported that this agent had favorable effects in patients with angina pectoris. This finding was later confirmed by Reichek et a1.3 who demonstrated at least a 3 hour increase in exercise capacity in patients with angina pectoris. Studies@ from our own institution and elsewhere in patients with angina pectoris, myocardial infarction and congestive heart failure have demonstrated that the hemodynamic effects of nitroglycerin ointment are maximal between 60 to 90 minutes after its application and persist for at least 4 to 6 hours. Expansion of the indications for the use of nitrate therapy has generated a need for and the development of preparations with a Ionger duration of action than the conventional sublingual form.7 One such preparation is oral isosorbide dinitrate, which has been demonstrated to produce hemodynamic effects for approximately 6 hours after adminstrati0n.s Although this agent is effective, in some clinical situations
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the oral route of drug a.dministration may be unsatisfactory, for example, when the oral route is precluded by nasogastric suction or paralytic ileus or the absorption of oral agents is co:mpromised by a malabsorption syndrome. In such patients, the percutaneous route may constitute an effective alternative. Another circumstance in which the absorption of oral medications may be both variable and incomplete is congestive heart failure.g Whether the percutaneous route is preferable in this setting is as yet unknown. In previous studies of patients with heart failure a subset who did not respond to nitroglycerin ointment was identified with hemodynamic monitoring.l’JJi Because plasma levels of nitroglycerin were unavailable, the possibility existed that this lack of response resulted from an inability to achieve adequate plasma concentrations of nitroglycerin. Accordingly, we undertook a pharmokinetic-hemodynamic study of nitroglycerin ointment administered percutaneously to patients with congestive heart failure. Our objectives were (1) to determine the bioavailability of nitroglycerin after application of nitroglycerin ointment in patients with heart failure; and (2) to examine whether a correlation exists between the concentration of nitroglycerin in plasma and its hemodynamic effects, both afl;er application of nitroglycerin ointment and after its removal. Methods Patients: Fourteen patients with congestive heart failure formed the study group: There were 11 men and 3 women with a mean age of 53 years (range 38 to 67). Three had cardiomyopathy, seven had chronic arteriosclerotic heart disease and four were studied within l month of a myocardial infarction; these patients were all in New York Heart Association functional class III or IV12 and refractory to conventional therapy including administration of digoxin and furosemide. Four patients with diabetes were insulin-dependent. Five had received isosorbide dinitrate for at least 3 weeks before this study. All drugs except digoxin and insulin were withheld for at least 24 hours before onset of the study. Hemodynamic studies: After informed consent was obtained, the patients were fitted with instruments for hemodynamic monitoring in a istandard fashion. This included the placement of a triple lumen thermodilution Swan-Ganz catheter in the pulmonary artery and a Teflon@ cannula in the radial artery. Right atrial, pulmonary arterial and pulmonary capillary wedge pressures (obtained by balloon occlusion) and systemic arterial pressure were monitored. The cardiac output was measured, at least in duplicde, with the thermodilution technique (injection of 10 ml of ice-cold 5 percent dextrose in water into the right atrium).‘” Intravenous nitroglycerin: Nitroglycerin was prepared for intravenous use as a 6.5 percent solution in ethanol. A 9.5 percent lactose mixture (Parke-Davis Company, Brockville, Ontario, Canada) (6.3 g) was added to ethyl alcohol (99 percent) to a total volume of 120 ml. The alcoholic supernatant was decanted and passed through a 0.22 Millexe millipore filter. The solution was assayed using a spectrophotometric technique before being reassayed using our gas-liquid chromatographic method.14 Immediately before use, the nitroglycerin solution was added to 5 percent dextrose in water and contained in glass bottles to produce a concentration of 100 /.&ml.
STUDIES OF NITROGLYCERIN OINTMENT-ARMSTRONG
ET AL.
I.0 -
0.8 -
rr
0.w
pso*)l
2.0
4.0 I.V. GTN ug/kg/min
6.0
8.0
FIGURE 1. Relation between dose of nitroglycerin ointment (NGO) and peak intravenous nitroglycerin (I.V.GTN) infusion rate. p = probability; r = correlation coefficient.
After a control period of 30 minutes, during which the hemodynamic measurements were demonstrated to be reproducible, intravenous nitroglycerin was infused at an initial rate of 15 to 20 pg/min. The aim was to reduce pulmonary capillary wedge pressure by at least 25 percent, and the infusion was increased in stepwise fashion (50 percent increments of prior rate) every 10 to 15 minutes until either the desired hemodynamic end point was achieved or a greater than lo-fold increment in the initial infusion rate had been reached. The final infusion rate was maintained until a hemodynamic steady state was achieved, which required approximately 15 to 20 minutes. The infusion was then discontinued and monitoring performed for at least an additional 30 to 60 minutes until return to control hemodynamic values had been demonstrated. Nitroglycerin ointment groups: We15J6 have previously found that the hemodynamic response to intravenous nitroglycerin is useful in establishing the response to and selecting the dose of other forms of nitrate therapy.15J6 In this study, patients in whom the hemodynamic end point was reached at an intravenous nitroglycerin infusion rate of 2.5 pglkg per min or less received 2 inches (5 cm) or less of nitroglycerin ointment. The nine patients in this group had mean (i standard deviation) intravenous nitroglycerin infusion rate of 1.2 f 0.8 pg/kg per min. Patients who received more than 2.5 gg/kg per min of intravenous nitroglycerin received 4 inches (10 cm) of nitroglycerin ointment. Among the five patients in this group, the hemodynamic end point was reached in only one, and the average intravenous nitroglycerin infusion rate was 6.3 f 1.9 pg/kg per min. The relation between the dose of intravenous nitroglycerin and nitroglycerin ointment is shown in Figure 1. Detailed examination of the pharmacokinetichemodynamic response to intravenous nitroglycerin in nine of our patients has been reported separately.uj Nitroglycerin ointment (Nitrol@ 2 percent, Kremers-Urban Company, Milwaukee, Wisconsin) was applied to the chest or flank over a 3 by 3 inch (7.6 by 7.6 cm) square area. AS indicated, the dose selected was based on the patient’s response to prior intravenous administration of nitroglycerin (Fig. 1). When more than 2 inches was applied, a second 3 by 3 inch site was utilized. After application of nitroglycerin ointment, hemodynamic monitoring was performed at frequent intervals through 240 minutes: In selected instances the period of monitoring was prolonged to 480 minutes. The occlusive dressing was then removed, the residual ointment scraped from the skin and the skin site washed with alcohol. Arterial blood samples were withdrawn during the control period before the administration of intravenous nitroglycerin
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TABLE I Summary of Hemodynamic Response to Nitroglycerin Ointment (n = 14) Time Period (mm)
HR
PCW
C 30 60 90 120 240 P
93f 16 93f 15 93f 15 92f 15 92f 15 91 f 15 NS
28 f 7 24 f 8 24 f 8 24 f 8 23 f 8 24 f 9 <0.0005
MAP
Cl
SI
93 f 20 90f 17 90 f 20 89 f 21 90 f 20 86f 18 NS
2.2 f 0.7 2.3 f 0.6 2.3 f 0.6 2.3 f 0.5 2.3 f 0.5 2.4 f 0.7 <0.05
23.9 f 8.3 25.5 f 6.5 24.9 f 6.8 25.1 f 4.0 25.0 f 6.8 27.6 f 9.3 <0.02
RAP 14f 7 12f6 11 f6 12f7 11 f6 12f8 <0.0005
TPR 22.3 20.4 20.7 20.6 21.0 19.9
f 10.4 f 8.6 f 8.2 f 9.5 f 8.6 f 9.7 NS
All summary values represent mean f standard deviation; p values represent a linear regression analysis performed on average percent from control value (r = 0) against time. C = control value; Cl = cardiac in&x (liters/min per m*; HP = heart rate (beats/min); MAP = mean arterial pressure (mm Hg); NS = not significant; PCW = oulmonarv capillarv wedqe pressure (mm Hg); RAP = right atrial pressure (mm Hg); SI = stroke index (ml/beat per m*); TPR = total peripheral resistance (units& ’ . -.
as well as just before the application of nitroglycerin ointment and at 60,90 and 240 minutes after the application of ointment. In some instances, additional samples were available up to and including 480 minutes as well as 30 minutes after the removal of nitroglycerin ointment. Blood samples were immediately centrifuged at Y’ C and the decanted plasma was frozen at -20” C. Subsequent analysis was performed using a gas-liquid chromatograph with isosorbide dinitrate or dinitrobenzene as the internal standard (14).
paired observations used when appropriate. The correlations and their significance were tested using Fisher’s F test. The area under the plasma concentration time curve (from 0 to 240 minutes and from 0 to 480 minutes) was determined with trapezoidal integration using discrete points.
Results
Analysis of data: Derived calculations were performed using the formulas SI = &I/HR and TPR = MAP-RAP/CO, where SI = stroke index in ml/beat per m2,CI = cardiac index in liters/min per m2, TPR = total peripheral resistance in units, MAP = mean arterial pressure in mm Hg, CO = cardiac output in liters/min and RAP = right atria1 pressure in mm Hg. Statistical comparisons of measurements were made using regression analysis and Student’s t test with paired and un-
0
60
120
180
240
MINUTES AFTER APPLICATION
FIGURE 2. Plot of the relation between plasma nitroglycerin (glyceryl trinitrate) (GTN) concentration (solld lines) and percent decrease in pulmn-rary capilfaty wedge pesslre (PCW) (dashed lines) for the goups receiving small dose (2 inches or less) and large dose (4 inches) of nitroglycerin ointment. Standard deviations for plasma nitroglycerin and percent reduction in pulmonary capillary wedge pressure are equal to or less than f4.3 ng/ml and f 11.5 percent, respectively, in the large dose group and equal to or less than f3.1 ng/ml and f9.5 percent in the small dose group.
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The relation between the dose of nitroglycerin ointment selected and the peak nitroglycerin infusion rate (that is the dose that either produced a 25 percent reduction in pulmonary capillary wedge pressure or was greater than 10 times the initial infusion rate) is illustrated in Figure 1. A regression analysis performed between the doses of the two modes of nitroglycerin adminstration demonstrates a good correlation (r = 0.96, probability [p]
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TABLE II
Relation Between Bioavailability of Nitroglycerin Ointment and Peak Hemodynamic Effect Peak Hemodynamic Effect Dose of NGO Case
(inches)
(mglkg)
Nitroglycerin Bioavailability
Control PCW
AUCO_240(ngmin/ml)
(mm Hg)
Decrease in PCW
Control RAP
(%)
(mm Hg)
Decrease in PCW (%)
Small Dose Group (n = 9) 1 3’
1.0 1.5 1.25
0.17 0.215 0.19
325 684 233
::
::
4 5
::“5 1.5
0.:!5 0.2!9 0.2!7
905 970 525
Z? 24 28
3: 29
33 8 t ;: 63 : ::
7 9” Mean SD
1.5 ;::
0.30 0.37 0.:!7 0.67
263 1752 490 683 480
40 2: 26 7
:: 2253 31’ 11
:: :2’ 13 7
8: 32 37’ 15
9
16
25
:z 14
14 16
42;
:z 25
;J 7
1:+ 5
;“o 18 4
2:+ 17
24” 13
15 7
24’ 19
Large Dose Group (n = 5) 10
4.0
0.59
1467
:: 13 14 Mean SD
4.0 t ::
0.75 0.60 0.76 0.86 0.71 O.ll
2901 1452 2483 1424 1945 698
z5
Both Groups (n = 14) Mean SD
0.43 0.23
1134 828
28 7
Statistical significance: Paired t test (percent decrease in pulmonary capillary wedge and right atrial pressures): p < 0.001; t p < 0.025. Unpaired t test (small dose versus large dose group) for area under the concentration-time curve, control value and percent decrease in pulmonary capillary wedge pressure and control value and percent decrease in right atrial pressure: p < 0.005, < 0.005, < 0.005, NS and NS, respectively. AUC = area under concelntration-time curve: NGO = nitroalvcerin ointment: NS = not significant; PCW = pulmonary capillary wedge pressure: - . RAP = right atrial pressure: SD = standard deviation. l
have arbitrarily divided the data into two subsets based on the dose of nitroglycerin ointment applied. The small dose group (n =9) received 1 to 2 inches or 12.5 to 25 mg of nitroglycerin ointment on a single skin site. The large dose group (n = 5) received 4 inches or 50 mg of nitroglycerin ointment (2 inches applied to two separate skin sites). The control value of pulmonary capillary wedge pressure was higher in the large than in the small dose group, (33 versus 26 mm Hg, p <0.005). After application of nitroglycerin ointment there was a greater decrease in pulmonary capillary wedge pressure in the small (31 percent) than in the large dose group (13 percent, p cO.005). There was no significant difference in the control value (or in the changes in right atria1 pressure between the two groups. The area under the plasma concentrationtime curve from 0 to 240 minutes was significantly less in the small than in the large dose group (p X0.005). Changes in pulmonary capillary pressure correlated with plasma nitroglycerin concentration: In Figure 2, the percent changes from the control value of pulmonary capillary wedge pressure are displayed over the 240 minute period after application of nitroglycerin ointment to allow for comparison with plasma nitroglycerin concentration data in the large and small dose groups. In the s:mall dose group, pulmonary capillary wedge pressure decreased substantially at 30
minutes, reaching its maximal reduction of 23 percent at 120 minutes and remaining depressed through 240 minutes. Plasma nitroglycerin concentration in this group increased to 3.1 f 3.0 (standard deviation) ng/ml at 60 minutes and remained at that level throughout the remainder of the sampling period. In the large dose group a plasma nitroglycerin level of 8.9 f 4.0 ng/ml was achieved at 60 minutes and was sustained throughout the 240 minute sampling period. Despite this plasma nitroglycerin concentration there was little decline in pulmonary capillary wedge pressure. We analyzed the decrease in pulmonary capillary wedge pressure produced by nitroglycerin ointment as a function of resting pulmonary capillary wedge pressure, cardiac index and total peripheral resistance and found that none of these indexes were of value in predicting the change in pulmonary capillary wedge pressure after application of nitroglycerin ointment (r 50.53, in all instances). In four patients (Cases 4, 10, 11 and 14), hemodynamic and plasma nitroglycerin data were available for 480 minutes after application of nitroglycerin ointment (Fig. 3). There was a modest early reduction in right atria1 pressure that was sustained through 360 minutes and returned toward the control value at 480 minutes. There was a small and sustained reduction in pulmonary capillary wedge pressure. The plasma nitroglycerin
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T
0 60
90
240
MO
480
Z
r3
MIMTES AFTER APPLICATION NGO
FIGURE 3. Hemcdynamic and plasma nitroglycerin data in four patients studied for 480 minutes after application of nitroglycerin ointment (NO). All data represent mean values f standard deviations. CONC = concentration; PCW = pulmonary capillary wedge pressure; RAP = right atrial pressure.
levels were elevated to nearly 5 ng/ml at 60 minutes and remained elevated through the balance of the sampling period. In four patients in the large dose group and in seven in the small dose group, we analyzed the effects of removing nitroglycerin ointment. Six patients were studied to 240 minutes, two to 360 minutes and three to 480 minutes (Fig. 4). There was little change in either
4000
‘,L
ONNGO 30’ OFF Nu)
FIGURE 4. Influence of removal of nitroglycerin ointment (NGO) in 11 patients. “On NGO” indicates the last observation before removal. Seven patients are in the small dose group (solid lines) and four in the large dose group (dashed lines). Significant changes occurred in pulmonary capillary wedge pressure (PCW) in the small dose group (18 to 23 mm Hg, p cO.025) and in nitroglycerin (GTN) plasma concentration (p CO.05 for both groups). The plasma concentration data in the small dose group are based on values in three patients.
right atria1 or pulmonary capillary wedge pressure in the large dose group 30 minutes after removal of nitroglycerin despite a substantial decrease in plasma nitroglycerin. By contrast, in the small dose group there was a slight rise in right atria1 pressure and a significant increment in pulmonary capillary wedge pressure 30 minutes after removal of nitroglycerin. Plasma nitroglycerin, available in three patients in the small dose group, showed a sharp decrease similar to that noted in the large dose group. The relation between plasma nitroglycerin concentration and the dose of nitroglycerin ointment applied was testing using a linear regression analysis. In all patients the relation between peak plasma nitroglycerin and dose of nitroglycerin ointment in mglkg was r = 0.89 (p
1
3000
E
e P f4 2000 2 u
rS0.81 P
Discussion 0.8
1.0
1.2
DOSE mglkg
FIGURE 5. Linear regression analysis of relation between the area under the plasma concentration-time curve from 0 to 240 minutes (AU&-s& and dose of nitroglycerin ointment for the total study group (r = 0.81; p
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Bioavailability of nitroglycerin ointment: This study documents the bioavailability of nitroglycerin when delivered percutaneously to patients with congestive heart failure. There was in general a good relation between the area under the plasma concentration-time curve from 0 to 240 minutes and the dose of nitroglycerin ointment (Fig. 5). This relation improved
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when it was examined in the four patients who were observed for 480 minutes after application of nitroglycerin ointment (Fig. 3). The previously demonstrated short half-life of nitroglycerin of 1.9 minutes coupled with the observation o:f sustained plasma nitroglycerin levels 480 minutes afl;er application of nitroglycerin ointment indicates that absorption of nitroglycerin must have continued throughout the entire period of application.16 This suggests that “flip-flop” kinetics are operative when nitrogl.ycerin ointment is applied; that is, the plasma concentration over the study period is directly dependent on continuing absorption.17 Despite the good relation between dose of nitroglycerin ointment and area under the plasma concentration-time curve from 0 to 240 minutes, some interpatient variability occurrled. There are a variety of reasons why interpatient differences in bioavailability might be expected after application of similar doses of nitroglycerin ointment. Thlese differences relate in part to variations in percutaneous absorption as modulated by skin perfusion, perme,ability and thickness. Moreover, differences in both systemic perfusion and venous congestion in these patients with heart failure would be expected to alter volume of distribution, rate of hepatic metabolism and, therefore, clearance of nitroglycerin-l8 The interpatient variability would probably have been diminished had all patients been evaluated throughout the complete time cou.rse of absorption, which is as yet unknown. Examining our data in the light of the experimental studies of Horhota and Funglg is of considerable interest. These investigators studied the effects of topical application of nitroglycerin ointment to the abdominal skin surface of rats; they demonstrated a wide variation in the nitroglycerin pllasma concentration-time curve among individual rats despite similar doses. They also found that the concentration of blood nitroglycerin remained elevated throughout the duration of the 4 hour study period. Analysis of surface sections after the 4 hour absorption experiments revealed that nearly 60 percent of the applied drug could be recovered, indicating that significant quantities of the drug were still available for absorption. Although in the current study we found that plasma nitroglycerin decreased substantially after removal of nitroglycerin ointment, it was still detectable 30 minutes thereafter. This finding was unexpected in view of the short half-life of nitroglycerin of 1.9 minutes and it suggests that a depot for nitroglycerin exists in the :skin of human subjects, as it does in rats, after percutaneous application.‘” Beneficial hemodynamic effects of nitroglycerin ointment: This study confirms that nitroglycerin ointment provides prompt and sustained hemodynamic benefit in selected patients with congestive heart failure. The patients in the slmall dose group who were characterized as sensitive to nitroglycerin by prior intravenous nitroglycerin infusion demonstrated hemodynamic benefit concomitant with the appearance of approximately 3 ng/ml of nii;roglycerin in plasma. The hemodynamic effects were already clearly evident 30 minutes after application of nitroglycerin ointment at a time
STUDIES OF NITROGLYCERIN OINTMENT-ARMSTRONG
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when the plasma level was probably less than 3 ng/ml (Fig. 2). This concentration of nitroglycerin is within the therapeutic range of 1.2 to 11.1 ng/ml defined in our previous study of 16 patients with congestive heart failure who received intravenous nitroglycerin.16 Although there appeared to be a good correlation between plasma nitroglycerin and its hemodynamic effects in the small dose group, a subset of patients has again been identified who demonstrate minimal response to nitroglycerin despite achieving plasma concentrations of 9 ng/ml. These findings were anticipated from the patients’ prior attenuated response to intravenous nitroglycerin. The attenuated response in these patients is also demonstrated by the lack of hemodynamic alteration after removal of nitroglycerin ointment despite a substantial decrease in plasma nitroglycerin. We16 have previously shown that some patients with heart failure may respond to nitroglycerin with a reduction in right atria1 pressure, but little change in left ventricular filling pressure.“j This appeared to be the case in Patients lo,12 and 13 and may be partly related to asymmetric distribution of cardiac disease expressed by differing compliance characteristics of the two ventricles.20 Factors influencing response to nitroglycerin: A variety of factors may have influenced the response to nitroglycerin in this study. Nitrate responsiveness could not be predicted from the value of the resting cardiac index, total peripheral resistance or pulmonary capillary wedge pressures.21 Three of the five patients in the large dose group had diabetes, and two of these three were insulin-dependent; small vessel disease secondary to the diabetes could have modified the hemodynamic response in these patients. Prior nitrate therapy did not appear to be a predictor of response to nitroglycerin ointment because only two of the five patients who received prior nitrate therapy were in the large dose group.22 The amount of circulating catecholamines and angiotensin is known to be increased in some patients with heart failure; variations in the levels of these substances would also be expected to alter the response of the peripheral circulation to pharmacologic therapy.2”v24 Because the concentration of nitroglycerin in plasma was in the therapeutic range in the patients who did not respond, absorption of the drug from ointment was confirmed. Lack of response was not due to failure of drug delivery but probably represented target organ resistance in peripheral arterioles and veins. This resistance cannot be predicted from control hemodynamic indexes, but it can be anticipated by prior intravenous nitroglycerin infusion and is best detected by hemodynamic monitoring. Clinical implications: From these data we conclude that nitroglycerin ointment provides therapeutic levels of nitroglycerin that are associated with substantial hemodynamic benefit in selected patients with heart failure. Therapeutic plasma concentrations of nitroglycerin are demonstrable through at least 480 minutes and probably persist for a longer period. In those cases in which an attenuated response is found during intra-
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Acknowledgment
venous infusion of nitroglycerin, large doses of nitroglycerin ointment (4 inches) are also unlikely to be of benefit. Further investigation is required to (1) document the complete time course of nitroglycerin bioavailability and hemodynamics after application of nitroglycerin ointment, (2) explore the mechanism of resistance of nitroglycerin, and (3) determine whether tolerance
occurs in responsive
We acknowledge the capable assistance of Sheila Dee, RN, Marlene Adam, BNSc, the nurses of the Coronary Care Unit of the Kingston General Hospital, and the assistance of Assil Bassili, BPharm in the preparation and spectrophotometric analysis of the intravenous nitroglycerin, the statistical advice of Donald G. Watts, PhD, and the secretarial assistance of Anne Baron and Jeanine MacRow.
patients.
References 1. Lund F. Percutaneous nitroglycerin treatment in cases of peripheral circulatory disorders, especially Raynaud’s disease. Acta Med Stand [Suppl] 1948;206:196-206. 2. Davis JA, Wieesi BH, EPstein SE. The treatment of angina pectoris with nitroglycerin ointment. Am J Med Sci 1955;230:259-63. 3. Reichek N, Goldstein RE, Redwood DR, et al. Sustained effects of nitroglycerin ointment in patients with angina pectoris. Circulation 1974;50:348-52. 4. Parker JO, Augustine RJ, Burton JR, West RO, Armstrong PN. The effect of nitroglycerin ointment on the clinical and hemodynamic response to exercise. Am J Cardiol 1976;38:162-6. 5. Armstrong PW, Mathew MT, Boroomand K, Parker JO. Nitroglycerin ointment in acute myocardial infarction. Am J Cardiol 1976:38:74-a. 6. Taylor WR, Forrester JS, Magnusson P, Takano T, Chatlerjee K, Swan HJC. Hemodynamic effects of nitroglycerin ointment in congestive heart failure. Am J Cardiof 1976;38:469-73. 7. Gold HK, Lefnbach RC, Sanders CA. Use of sublingualnitroglycerin in congestive failure following acute myocardial infarction. Circulation 1972;46:839-45. 8. Gray R, Chatterjee K, Vyden JK, Ganz W, Forrester JS, Swan HJC. Hemodynamic and metabolic effects of isosorbide dinitrate in chronic congestive heart failure. Am Heart J 1975;90:34652. 9. Benowitz NL, Meister W. Pharmacokinetics in patients with cardiac failure. Clin Pharmacokinet 1976;1:389-405. 10. Kiausner S, Chatterjee K, Parmiey WW. Therapy of chronic heart failure with nitroglycerin ointment: the necessity for measuring hemodynamics to determine non-responders (abstr). Circulation 1976;53:ll-66. 11. Armstrong PW, Leach AJ, Brown JE. Oiowoyeye JO. Comparative vasodilator studies in congestive cardiac failure (abstr). Clin Res 7978;26:830A. 12. Criteria Committee of the New York Heart Association. Nomen-
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13.
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21. 22.
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24.
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clature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 8th ed. Boston:Fittle, Brown, 1979290. Forrester JS, Ganz W, Diamond G, McHugh T, Chonette OW, Swan HJC. Thermodilution cardiac output determination with a single flow directed catheter. Am Heart J 1972;83:306-11. Armstrong PW, Armstrong JA, Marks GS. Blood levels after sublingual nitroglycerin. Circulation 1979;59:585-8. Armstrong PW, Parker JO. Intravenous nitroglycerin and congestive failure in acute myocardial infarction (abstr). Ann Coll Can 1977;10:34. Armstrong PW, Armstrong JA, Marks GS. Pharmacokinetichemodynamic studies of intravenous nitroglycerin in congestive cardiac failure. Circulation 1980;62:160-6. Gibaidi M, Perrier D. Pharmacokinetics. New York: Dekker, 1975;35. Hepner GW, Veseii EA, Tantum KR. Reduced drug elimination in congestive heart failure. Am J Med 1978;65:271-6. Horhota ST, Fung HL. Percutaneous nitroglycerin absorption in rats. J Pharm Sci 1979;68:608-12. Ludbrook PA, Byrne JD, Kurnik PV, McKnight RC. Influence of reduction of preload and afterload by nitroglycerin on left ventricular diastolic pressure volume relations and relaxation in man. Circulation 1977;56:937-43. Goldberg S, Mann T, Grossman W. Nitrate therapy of heart failure in valvular heart disease. Am J Med 1978;65:161-6. Kiock JC. Nonocclusive coronary disease after chronic exposure to nitrates: evidence for physiologic nitrate dependence. Am Heart J 1975;89:510-3. Curtiss C, Cohn JN, Vrobei T, Franciosa JA. Role of the reninangiotensin system in systemic vasoconstriction of chronic congestive heart failure. Circulation 1979;58:763-70. Chidsey CA, Harrison DC, Braunwaid E. Augmentation of the plasma norepinephrine response to exercise in patients with congestive heart failure. N Engl J Med 1962;267:650-4.