Hemodynarnic effects of different H,-receptor antagonists In a randomized, placebo-controlled, double-blind study, 10 healthy volunteers were treated orally once a day for 1week each with placebo, 800 mg cimetidine, 300 mg ranitidine, and 40 mg famotidine. On the seventh treatment day, heart rate, blood pressure, systolic time intervals, and impedance cardiography were measured before the morning dose and at 2, 6, 12, and 24 hours after the morning dose. Heart rate and blood pressure were not markedly altered by any of the Hz-receptor antagonists compared with the findings for placebo. Cimetidine and ranitidine did not markedly alter parameters of systolic time interval and impedance cardiography compared with placebo in contrast to famotidine, which significantly decreased stroke volume, cardiac output, and the Heather Index in impedance cardiography (p < 0.05) and also significantly increased the ratio of the preejection period to the left ventricular ejection time in systolic time interval (p < 0.05) 2 hours after the morning dose. Six hours after administration, most of these alterations could no longer be detected. The observed changes in hemodynamic parameters confirm that famotidine exerts negative effects on cardiac performance, whereas such iduences could not be THER1990;48:302-8.) shown for cimetidine and ranitidine. (CLINPHARMACOL
Holger Hinrichsen, MD, Atef Halabi, MD, and Wilhelrn Kirch, MD Kzel, West Germany It is well established that histamine exerts various effects on cardiac performance in humans'" that are mediated in the heart by HI- and H,-re~eptors.~-~ The positive inotropic effects of histamine, which mainly involve the H,-re~eptors,~-~ are antagonized by cimetidine in ~ i t r o . ~By ,'~ contrast, Hz-agonists such as impromidine or dimaprit have been shown to exert positive inotropic effects in vitro and in vivo in catecholamineinsensitive congestive heart fail~re.".'~ Thus the question arose regarding whether Hz-receptor antagonists might exert negative effects on cardiac performance. Indeed, the occurrence of bradycardia and atrioventricular conduction disturbances have been described in some case reports after rapid intravenous injection of cimetidine or ranitidine.'3-'8 In vitro experiments have also indicated negative inotropic properties for some Hz-receptorantagonists.l9 Recently, the novel Hzreceptor antagonist famotidine was found to exert negative effects on cardiac performance in healthy adults, as assessed by impedance cardiography and mechanocardiographyz0-methods that have been shown to be From the I. Medical Department, Christian-Albrechts-Universitat. Received for publication April 18, 1990; accepted June 6, 1990. Reprint requests: Wilhelm Kuch, MD, I. Medizinische Klinik, Christian-Albrechts-Universitat, Schittenhelmstrasse 12, D-2300 Kiel, West Germany. 13/1/23008
suitable for characterizing cardiovascular drug effects in clinical pharmacology.21-24 Therefore the aim of the present study was to compare the effects of three Hzantagonists-cimetidine, ranitidine, and famotidineon hemodynamic parameters on long-term treatment in healthy subjects.
METHODS Clinical protocol. The study protocol was approved by the Ethics Committee of the First Medical Hospital of the University of Kiel. Ten healthy volunteers (six men and 4 women) were included in this placebocontrolled, randomized, double-blind study. All subjects were in good health on the basis of histories, physical examinations, urinalyses, and blood chemistries. None had a history of cardiovascular, renal, hepatic, gastrointestinal, respiratory, hematologic, or other disease that could affect the absorption, distribution, metabolism, or excretion of the study drugs. Their mean ( + SD) age was 26.5 + 2.3 years and body weight was 67.8 + 9.5 kg. Each subject received oral doses of either 800 mg cimetidine, 300 mg ranitidine, 40 mg famotidine, or placebo once daily for 1 week. These doses were chosen according to the usual clinical recommendations for once daily dosage of the three Hzantagonists. Subjects were then randomly crossed over to the next of the three subsequent treatment regimens after 7-day therapy-free washout intervals.
VOLUME 48 NUMBER 3
Hemodynamic efects ofH,-antagonists 303 PLACEBO 0-2h
0-6h
ClMETlDlNE (Mh
0-6h
RANITIDINE (Mh
(Mh
FAMOTIDINE 0-2h
0-6h
Fig. 1. Median ( + SEM) changes in cardiac output from baseline measured at 2 and 6 hours in healthy subjects successively treated for 1 week each with placebo, cimetidine, ranitidine, and famotidine. Star, Significant with p < 0.05 compared with placebo; solid circle, significant with p < 0.05 compared with ranitidine.
On the seventh day of each treatment week, the final dose of the Hz-antagonist or placebo was given in the morning. Heart rate, blood pressure, systolic time intervals, and impedance cardiographic parameters were then determined under standardized conditions before and 2, 6, 12, and 24 hours after administration. The volunteers observed detailed restrictions concerning food, drink, and physical activity during the study days, and each subject rested for 30 minutes in the supine position before the measurements were made. Written informed consent was obtained from all participants after the purpose, procedures, and risks of the study were explained. Noninvasive hemodynamic measurements. The heart rate was calculated from 20 RR intervals in the ECG at a paper speed of 10 mm per second; blood pressure was determined by use of the Riva-Rocci method. The calculation of systolic time intervals was based on the simultaneous recordings of the ECG, phonocardiogram, and carotid pulse tracing in the supine position after a 30-minute rest period. Measurements were made from five consecutive heart beats at a paper speed of 100 rnm per second,
repeated three times, and the results then a ~ e r a g e d . , ~ . ~ ~ Total QS, (electromechanical systole) was measured according to Weissler et al." from the beginning of the QRS complex in the ECG to the beginning of the highfrequency vibrations of the second heart sound in the phonocardiogram. The left ventricular ejection time (LVET) was measured from the start of the carotid pulse tracing upstroke to its dicrotic notch. The preejection period (PEP) was calculated from the difference between QS, and LVET (PEP = QSz - LVET). The ratio of PEP to LVET was also determined. Heart rate corrections (QS,,, LVET,, PEP,) were made in accordance with Weissler et al.," and as applied by others .29'30 Impedance cardiography was performed by the simultaneous registration of an ECG, a phonocardiogram, and the changes in transthoracic electrical impedance. The latter were detected by a Kardio-Dynagraph (Diefenbach GmbH, Frankfurt am Main, West Germany). Four bands of self-adhesive electrodes were placed around the patient's body: two around the neck, the third at the level of the xiphisternum, and the fourth at 5 to 10 cm below the xiphisternum. The two outer
CLIN PHARMACOL THER SEMEMBER 1990
304 Hindsen, Halabz, and Kzrch PLACEBO
ClMETlDlNE
RANITIDINE
FAMOTlDINE
Fig. 2. Median ( ? SEM) changes in stroke volume from baseline measured at 2 and 6 hours in healthy subjects successively treated for 1 week each with placebo, cimetidine, ranitidine, and famotidine. Stars, Significant with p < 0.05 compared with placebo; solid circle, significant with p < 0.05 compared with ranitidine; solid triangle, significant with p < 0.05 compared with cimetidine.
electrodes transmitted a constant sinusoidal alternating current (40 kHz) through the thorax, and the changes in thoracic impedance were detected by the two inner electrodes. Measurements were carried out with the patient in the supine position and holding his or her breath at end-expiration. Stroke volume was calculated by use of the equation described by Kubicek et al.31: In this equation, AV is the stroke volume in centimeters; p represents the resistivity of the blood, which can, according to Quail and Tra~gott,~' be assumed to be a constant with a value of 135 R cm; L is the average distance between the inner electrodes in centimeters; Z, is the mean thoracic impedance between these same electrodes in R ; (dzldt),, is the maximum amplitude of the dz / dt curve; and t (in seconds) is the time interval between the zero crossing of the dz/dt curve just before the maximal peak and the beginning of the second heart sound. Cardiac output (CO, in liters per minute) was calculated as CO = AV X Heart rate/ 1000. Another impedance cardiographic parameter used in the present study was the Heather Index, a measure of cardiac performance that correlates with the
PEPILVET ratio, stroke volume, and cardiac output. The Heather Index (HI, Wsec-') was evaluated as In this equation, RZ is the time HI = (dz/dt),/RZ. interval between the "R" deflection in the ECG and the maximum amplitude of the dz/dt curve in the carotid pulse tracing. Statistical analysis of the hemodynamic data obtained was performed by use of the Friedman rank variance analysis and the Wilcoxon-Wilcox tests.33Results were expressed as median values + standard error of the median.
RESULTS Changes in cardiac output from baseline at 2 and 6 hours after administration of the test substances are shown in Fig. 1. Two hours after famotidine ingestion, cardiac output was reduced by - 0.61 + 0.29 Llmin. This decrease (which was found in each individual subject investigated) was significant (p < 0.05) when compared with increases of 0.28 + 0.16 and 0.06 + 0.23 L/min for subjects receiving placebo and ranitidine, respectively. Analogous changes in stroke volume were also observed 2 hours after dosing (Fig. 1). Famotidine significantly (p < 0.05) reduced base-
VOLUME 48 NUMBER 3
PLACEBO 0-Zh
0-6h
ClMETlDlNE
RANITIDINE
FAMOTlDlNE
0-2h
0-2h
0-Zh
0-6h
0-6h
0-8h
Fig. 3. Median ( ? SEM) changes in rate of preejection period to left ventricular ejection time from baseline measured at 2 and 6 hours in healthy subjects successively treated for 1 week each with placebo, cimetidine, ranitidine, and famotidine. Star, Significant with p < 0.05 compared with placebo; solid triangle, significant with p < 0.05 compared with cimetidine.
line stroke volume by - 8.8 + 3.5 cm3compared with changes for placebo ( 5.5 + 3.1 cm3) and ranitidine (+4.3 + 1.2 cm3). A decrease in stroke volume after famotidine administration was observed in all but one subject. The Heather Index was significantly altered in a parallel manner. Famotidine decreased the index by - 1.56 + 0.72 fl/sec2 from baseline 2 hours after the morning dose, whereas the same parameter was increased by 0.45 + 0.57 and 0.04 + 0.34 n/secZ 120 minutes after intake of placebo and ranitidine, respectively (both p < 0.05 versus famotidine; Fig 2). The PEPJLVET ratio was the sole mechanocardiographic parameter to be significantly altered. Two hours after famotidine administration, the ratio was increased from baseline by 0.19 + 0.006 (Fig. 3). In contrast, slight decreases of - 0.003 + 0.003 and - 0.001 -+ 0.006 were recorded 2 hours after intake for placebo and cimetidine, respectively (both p < 0.05 versus famotidine; Fig. 3). Six hours after the test substances were received, significant intergroup differences were solely observed in terms of stroke volume (Fig. 2). The decrease in stroke volume from baseline values induced by famotidine (-4.4 + 2.7 cm3) contrasted with increases of 2.0 2 4.9 cm3for placebo and + 5.0 + 3.3 cm3for
+
+
cimetidine (both p < 0.05 versus famotidine). When values were compared for placebo and Hz-antagonists at 12 hours, no further differences in impedance cardiographic or mechanocardiographic parameters could be demonstrated. During the entire investigational period, no significant differences emerged between placebo and either cimetidine or ranitidine. Finally, as seen in Table I, no significant differences in heart rate or blood pressure were observed either before or 2 and 6 hours after administration of famotidine, ranitidine, or cimetidine compared with placebo values.
DISCUSSION The findings of the present study indicate that the H,-receptor antagonist famotidine exerts negative effects on cardiac performance. The decreases in impedance cardiographic parameters (stroke volume, cardiac output, and Heather Index) and the increase in the mechanographically derived PEP/ LVET ratio contrasted significantly with changes in placebo values, thereby confirming our previous observation^.^^ These effects appear to be mediated by cardiac Hz-receptors. However, blood pressure and heart rate were not altered by famotidine. In contrast to the changes induced by famotidine,
CLIN PHARMACOL THER SEPTEMBER 1990
306 Winrichsen, Halabi, and Kim3
Table I. Blood pressure and heart rate at baseline and at 2 and 6 hours after successive 1-week administration of placebo, cimetidine, ranitidine, and famotidine* Test substance
Baseline
Value after 2 hr
Value after 6 hr
Placebo Blood pressure (mrn Hg) Systolic Diastolic Heart rate (beatslmin)
115.0 2 6 72.5 + 6 62.5 k 7
117.5 2 6 70.0 + 4 61.5 k 5
122.5 + 3 75.0 k 3 67.0 + 5
Cimetidine Blood pressure (mm Hg) Systolic Diastolic Heart rate (beats1min)
117.5 5 6 70.0 + 6 65.0 +- 2
122.5 72.5 62.5
+9 +6 +4
120.0 +- 6 75.0 + 4 67.5 5 4
Ranitidine Blood pressure (mm Hg) Systolic Diastolic Heart rate (beatslmin)
117.5 +- 4 67.5 + 4 61.0 + 4
112.5 70.0 58.0
+4 +4 +4
122.5 70.0 60.5
Farnotidine Blood pressure (mm Hg) Systolic Diastolic Heart rate (beatslmin)
117.5 72.5 59.0
+9 +6
115.0 70.0 59.0
+
122.5 ? 4 70.0 + 4 64.5 + 4
+3
7
+6 +3
+7 +4 +
3
*All values are median k SEM.
negative effects on cardiac performance could not be demonstrated after oral doses of the older Hz-receptor antagonists cimetidine and ranitidine. Such findings are in accord with data from postmarketing surveillance and other safety assessments of these widely used drugs that have failed to detect any evidence of associated cardiac dec~mpensation.~~"~ The significant differences in hemodynamic data that emerged between famotidine and both cimetidine and ranitidine point to famotidine as being the only Hz-receptor antagonist of the three that had negative effects on cardiac performance. Nevertheless, data from in vitro experiments have indicated that some H2-receptor antagonists may exert negative inotropic effects in the human atria.lg Although such hemodynamic effects have never 'been consistently demonstrated in vivo in animals and human^,^'-^^ isolated case reports show evidence of sinus bradycardia and atrioventricular conduction disturbances with cimetidine and ranitidine.I3-l8Thus these substances appear to influence cardiac chronotropism and dromotropism, but not myocardial contractility. To our knowledge, two studies with famotidine have been conducted thus far to investigate hernodynamic effects measured by invasive techniques after a single intravenous dose of the d r ~ g . ~In~ both , ~ ' studies, pa-
tients at an intensive care unit who were under concomitant therapy with positive inotropic substances (such as catecholamines) were investigated; no cardiodepressant effects of famotidine were observed. These data contrasted with the findings of our previous investigation-performed with use of noninvasive methods in healthy subjects who were not on concurrent drug treatment-indicating negative effects by famotidine on cardiac performance." The divergent findings obtained with the various H2receptor antagonists concerning their cardiovascular effects may be explained by their varying chemical structures, resulting in differences in receptor affinity and sensitivity. Cimetidine is an imidazole derivative, whereas ranitidine contains a furan ring. Receptor affinity of ranitidine is higher than that of cimetidine such that an equivalent dose of ranitidine need only be one fourth as large as that of cimetidine. As for the more recent Hz-antagonistfamotidine, this guanidinethiazole derivative has the highest affinity for Hz-receptorsfound thus far.42In addition, farnotidine showed an unsurmountable antagonism to Hz-receptors at higher concentrations, which has not been reported for cimetidine or ranitidine. Famotidine affinity for H2-receptorswas also highly resistant to washout.43These pharmacologic
VOLUME 48 NUMBER 3
differences between the Hz-receptor antagonists may explain their varying pharmacodynamic properties, specifically with regard to their cardiovascular effects. More recently, an Hz-receptor antagonist has been introduced (nizatidine) that exerts consistent and marked negative chronotropic effects after oral a d m i n i ~ t r a t i o n . ~ ~ In conclusion, the findings of the present study indicate that the older Hz-receptor antagonists cimetidine and ranitidine fail to exert negative inotropic effects, whereas famotidine does exert these effects, thereby confirming data from a previous studyz0 that showed negative influences on cardiac performance. These effects are not only demonstrable when comparing hemodynamic measurements on famotidine with those on placebo but when comparing data on famotidine with those on cimetidine and ranitidine as well. In addition, the findings of this study should be confirmed when investigating patients with coronary disease o r congestive heart failure. This manuscript represents part of the doctoral thesis of Mrs. G. Hiibner, Department of Internal Medicine, ChristianAlbrechts-Universitat, Kiel, West Germany.
References Levi R, Owen DAA, Trzeciakowski J. Actions of histamine on the heart and vasculature. In: Ganellin CR, Parsons M, eds. Pharmacology of histamine receptors. London: J Wright & Sons, 1982:236-97. Wolff AA, Levi R. Histamine and cardiac arrhythmias. Circ Res 1986;58:1-16. Baller D, Huchzermeyer H. Cardiovascular effects of histamine with special reference to cardiac side effects of Hz-receptor antagonists. Klin Wochenschr 1989;67: 743-55. Black JW, Duncan WAM, Durant CJ, Ganellin CR, Parsons EM. Definition and antagonism of histamine Hzreceptors. Nature 1972;236:385-90. Ginsburg R, Bristow MR, Stinson EB, Harrison DC. Histamine receptors in the human heart. Life Sci 1980;26:2245-9. Levi R, Capurro N, Lee CH. Pharmacological characterization of cardiac histamine receptors: sensitivity to H,- and Hz-receptoragonists and antagonists. Eur J Pharmacol 1975;30:328-35. Baumann G, Felix SB, Schrader CD, et al. Cardiac contractile and metabolic effects mediated via the myocardial Hz-receptoradenylate cyclase system: characterization of two new specific H,-receptor-agonists, impromidine and dimaprit, in the guinea pig and human myocardium. Res Exp Med (Berl) 1981;179:81-98. Baumann G, Schrader J, Gerlach E. Inhibitory action of adenosine on histamine- and dopamine-stimulated cardiac contractility and adenylate cyclase in guinea pigs. Circ Res 1981;48:259-66.
Baumann G, Loher U, Felix SB, et al. Deleterious effects of cimetidine in the presence of histamine on coronary circulation. Possible clinical implications in anaphylactic states in individuals with coronary heart disease. Res Exp Med (Berl) 1982;180:209-13. Eckel L, Gristwood RW, Nawrath H, Owen DA, Satter P. Inotropic and electrophysiologicaleffects of histamine on human ventricular heart muscle. J Physiol (Lond) 1982;330:112-3. Baumann G, Felix SB, Heidecke CD, et al. Apparent superiority of Hz-receptor stimulation and simultaneous P-blockade over conventional treatment with Psympathomimetic drugs in post-acute myocardial infarction: cardiac effects of imprornidine-a new specific Hz-receptor agonist-in the surviving catecholamineinsensitive myocardium. Agents Actions 1984;15:21628. Baumann G, Permanetter B, Wirzfeld A. Possible value of Hz-receptor agonists for treatment of catecholamineinsensitive congestive heart failure. Pharmacol Ther 1984;24:165-77. Camarri E, Chirone E, Fanteria G, Zocchi M. Ranitidine induced bradycardia [Letter]. Lancet 1982;2:160. Jeffreys DB, Vale JA. Cimetidine and bradycardia [Letter]. Lancet 1978;2:828. Mehta AB, Goldman JM. Cimetidine and cardiac dysrhythmias [Letter]. Ann Intern Med 1982;97:283. Nikolic G, Singh JB. Cimetidine, vasopressin and chronotropic incompetence. Med J Aust 1982;2:435-6. Tordjman T, Korzets A, Kotas R, Manor J. Klajman A. Complete atrioventricularblock and long-term cimetidine therapy [Letter]. Arch Intern Med 1984;144:861. Stirnrnese B, Daoudal P, Neidhardt A, Ory JP. Bradycardie au cours d'un traitement par cimktidine [Letter]. Nouv Press Med 1978;7:4233. Coruzzi G, Poli E, Fesani F, Medici D, Bertaccini G. Negative inotropic effect of some Hz-receptor antagonists on the isolated human atria. Experientia 1983;39: 1284-6. Kirch W, Halabi A, Linde M, Santos SR, Ohnhaus EE. Negative effects of famotidine on cardiac performance assessed by noninvasive hernodynamic measurements. Gastroenterology 1989;96:1388-92. Weissler AM. Noninvasive methods for assessing left ventricular performance in man. Am J Cardiol 1974; 34:111-4. Belz GG, Doering E, Munkes R, Matthews J. Interaction between digoxin and calcium antagonists and antiarrhythmic drugs. CLINPHARMACOL THER1983;33:410-7. Linde M, Ohnhaus EE, Kirch W. Mechano- und impedanz-kardiographische Parameter bei Patienten mit Herzinsuffizienz unter Gabe eines CalciumAntagonisten. Die Bedeutung des Heather-Index. Z Kardiol 1989;78:181-6. Spodick DH, Yoshinori LD, Bishop RL, Hashimoto T. Systolic time intervals reconsidered. Reevaluation of the
CLIN PHARMACOL THER SElTEMBER 1990
308 Hinrichsen, Halabi, and Kirch preejection period: absence of relation to heart rate. Am J Cardiol l984;53: 1667-70. 25. Erbel R, Belz GG. Untersuchungen zur Messmethode der systolischen Zeitintervalle. Z Kardiol 1977;66: 433-5. 26. Kuhn H, Loogen F. Die Bestimmung der systolischen Zeitintervalle. Dtsch Med Wochenschr 1980;105:214-8. 27. Weissler AM, Harris WS, Schoenfeld CD. Bedside technics for the evaluation of ventricular function in man. Am J Cardiol 1969;23:577-603. 28. Weissler AM, Harris WS, Schoenfeld CD. Systolic time intervals in heart failure in man. Circulation 1968;37: 149-56. 29. Staffeld HF, Mertens HM, Gleichmann U. Der Einfluss von dynamischer Belastung und Korperlichem Training auf die systolischen Zeitintervalle bei Gesunden und Patienten mit koronarer Herzkrankheit. Z Kardiol 1978;67: 305-16. 30. Lewis RP, Rittgers MS, Forester WF, Boudoulas H. A critical review of the systolic time intervals. Circulation lW7;56: 146-58. 31. Kubicek WG, Karnegis JN, Patterson RP, Witsoe DA, Mattson RM. Development and evaluation of an impedance cardiac output system. Aerospace Med 1966;37: 1208-12. 32. Quail AW, Traugott FM. Effects of changing haematocrit, ventricular rate and myocardial inotropy on the accuracy of impedance cardiography. Clin Exp Pharmacol Physiol 1981;8:335-43. 33. Sachs L. Applied statistics. 2nd ed. New York: SpringerVerlag , 1984. 34. Humphries TJ, Meyerson RM, Gifford LM, et al. A unique postmarket outpatient surveillance program of cimetidine: report on phase I1 and final summary. Am J Gastroenterol 1984;79:593-6. 35. Zimmerman TW, Schenker S. A comparative evaluation
36.
37.
38.
39.
40.
41.
42.
43.
44.
of cimetidine and ranitidine. Ration Drug Ther 1985;19: 1-7. Penston J, Wormsley KG. Adverse reactions and interactions with Hz-receptorantagonists. Med Toxic01 1986; 1:192-216. Chow JS, Wang RY, Wong PH, Chen WW. Lai CL. Intravenous ranitidine has no hemodynamic effects in subjects with normal lung function and patients with chronic obstructive airway disease. Aust N Z J Med 1983;13:261-3. Toettermann K, Kupaari M, Paakkari I, Nieminen MS. Acute effects of intravenous cimetidine. Acta Med Scand 1985;217:277-80. Breuer HW, Meschig R, Breuer J, Goehlich G, Arnold G. Hemodynamic studies on cimetidine and ranitidine in anesthetized dogs. Res Exp Med (Berl) 1984;184:265-8. Matsukawa S, Hoshi K, Kaise A, Sasaki I, Hashimoto Y, Amaha K. The cardiovascular effect of famotidine in intensive care patients. J Intensive Care Med 1986;lO: 763-7. Omote K, Namiki A, Sumita S, Takahashi T, Ujike Y, Hagiwara T. Comparative studies on hemodynarnic effects of intravenous cimetidine, ranitidine, and famotidine in intensive care unit patients. Jpn J Anesthesiol 1987;36:940-7. Bertaccini G, Coruzzi G, Poli E. Adarni M. Pharmacology of the novel Hz-antagonist famotidine: in vitro studies. Agents Actions 1986;19:180-7. Pendleton RG, Torchiana ML, Chung C, Cook P, Wiese S, Clineschmidt BV. Studies on MK-208 (YM-11170) a new slowly dissociable Hz-receptorantagonist. Arch Int Pharmacodyn Ther 1983;266:4-16. Kirch W, Halabi A. Nizatidine significantly decreases THER1990;47: heart rate [Abstract]. CLIN PHARMACOL 202.
Holger Hinrichsen, MD, Atef Halabi, MD, and Wilhelrn Kirch, MD Kzel, West Germany It is well established that histamine exerts various effects on cardiac performance in humans'" that are mediated in the heart by HI- and H,-re~eptors.~-~ The positive inotropic effects of histamine, which mainly involve the H,-re~eptors,~-~ are antagonized by cimetidine in ~ i t r o . ~By ,'~ contrast, Hz-agonists such as impromidine or dimaprit have been shown to exert positive inotropic effects in vitro and in vivo in catecholamineinsensitive congestive heart fail~re.".'~ Thus the question arose regarding whether Hz-receptor antagonists might exert negative effects on cardiac performance. Indeed, the occurrence of bradycardia and atrioventricular conduction disturbances have been described in some case reports after rapid intravenous injection of cimetidine or ranitidine.'3-'8 In vitro experiments have also indicated negative inotropic properties for some Hz-receptorantagonists.l9 Recently, the novel Hzreceptor antagonist famotidine was found to exert negative effects on cardiac performance in healthy adults, as assessed by impedance cardiography and mechanocardiographyz0-methods that have been shown to be From the I. Medical Department, Christian-Albrechts-Universitat. Received for publication April 18, 1990; accepted June 6, 1990. Reprint requests: Wilhelm Kuch, MD, I. Medizinische Klinik, Christian-Albrechts-Universitat, Schittenhelmstrasse 12, D-2300 Kiel, West Germany. 13/1/23008
suitable for characterizing cardiovascular drug effects in clinical pharmacology.21-24 Therefore the aim of the present study was to compare the effects of three Hzantagonists-cimetidine, ranitidine, and famotidineon hemodynamic parameters on long-term treatment in healthy subjects.
METHODS Clinical protocol. The study protocol was approved by the Ethics Committee of the First Medical Hospital of the University of Kiel. Ten healthy volunteers (six men and 4 women) were included in this placebocontrolled, randomized, double-blind study. All subjects were in good health on the basis of histories, physical examinations, urinalyses, and blood chemistries. None had a history of cardiovascular, renal, hepatic, gastrointestinal, respiratory, hematologic, or other disease that could affect the absorption, distribution, metabolism, or excretion of the study drugs. Their mean ( + SD) age was 26.5 + 2.3 years and body weight was 67.8 + 9.5 kg. Each subject received oral doses of either 800 mg cimetidine, 300 mg ranitidine, 40 mg famotidine, or placebo once daily for 1 week. These doses were chosen according to the usual clinical recommendations for once daily dosage of the three Hzantagonists. Subjects were then randomly crossed over to the next of the three subsequent treatment regimens after 7-day therapy-free washout intervals.
VOLUME 48 NUMBER 3
Hemodynamic efects ofH,-antagonists 303 PLACEBO 0-2h
0-6h
ClMETlDlNE (Mh
0-6h
RANITIDINE (Mh
(Mh
FAMOTIDINE 0-2h
0-6h
Fig. 1. Median ( + SEM) changes in cardiac output from baseline measured at 2 and 6 hours in healthy subjects successively treated for 1 week each with placebo, cimetidine, ranitidine, and famotidine. Star, Significant with p < 0.05 compared with placebo; solid circle, significant with p < 0.05 compared with ranitidine.
On the seventh day of each treatment week, the final dose of the Hz-antagonist or placebo was given in the morning. Heart rate, blood pressure, systolic time intervals, and impedance cardiographic parameters were then determined under standardized conditions before and 2, 6, 12, and 24 hours after administration. The volunteers observed detailed restrictions concerning food, drink, and physical activity during the study days, and each subject rested for 30 minutes in the supine position before the measurements were made. Written informed consent was obtained from all participants after the purpose, procedures, and risks of the study were explained. Noninvasive hemodynamic measurements. The heart rate was calculated from 20 RR intervals in the ECG at a paper speed of 10 mm per second; blood pressure was determined by use of the Riva-Rocci method. The calculation of systolic time intervals was based on the simultaneous recordings of the ECG, phonocardiogram, and carotid pulse tracing in the supine position after a 30-minute rest period. Measurements were made from five consecutive heart beats at a paper speed of 100 rnm per second,
repeated three times, and the results then a ~ e r a g e d . , ~ . ~ ~ Total QS, (electromechanical systole) was measured according to Weissler et al." from the beginning of the QRS complex in the ECG to the beginning of the highfrequency vibrations of the second heart sound in the phonocardiogram. The left ventricular ejection time (LVET) was measured from the start of the carotid pulse tracing upstroke to its dicrotic notch. The preejection period (PEP) was calculated from the difference between QS, and LVET (PEP = QSz - LVET). The ratio of PEP to LVET was also determined. Heart rate corrections (QS,,, LVET,, PEP,) were made in accordance with Weissler et al.," and as applied by others .29'30 Impedance cardiography was performed by the simultaneous registration of an ECG, a phonocardiogram, and the changes in transthoracic electrical impedance. The latter were detected by a Kardio-Dynagraph (Diefenbach GmbH, Frankfurt am Main, West Germany). Four bands of self-adhesive electrodes were placed around the patient's body: two around the neck, the third at the level of the xiphisternum, and the fourth at 5 to 10 cm below the xiphisternum. The two outer
CLIN PHARMACOL THER SEMEMBER 1990
304 Hindsen, Halabz, and Kzrch PLACEBO
ClMETlDlNE
RANITIDINE
FAMOTlDINE
Fig. 2. Median ( ? SEM) changes in stroke volume from baseline measured at 2 and 6 hours in healthy subjects successively treated for 1 week each with placebo, cimetidine, ranitidine, and famotidine. Stars, Significant with p < 0.05 compared with placebo; solid circle, significant with p < 0.05 compared with ranitidine; solid triangle, significant with p < 0.05 compared with cimetidine.
electrodes transmitted a constant sinusoidal alternating current (40 kHz) through the thorax, and the changes in thoracic impedance were detected by the two inner electrodes. Measurements were carried out with the patient in the supine position and holding his or her breath at end-expiration. Stroke volume was calculated by use of the equation described by Kubicek et al.31: In this equation, AV is the stroke volume in centimeters; p represents the resistivity of the blood, which can, according to Quail and Tra~gott,~' be assumed to be a constant with a value of 135 R cm; L is the average distance between the inner electrodes in centimeters; Z, is the mean thoracic impedance between these same electrodes in R ; (dzldt),, is the maximum amplitude of the dz / dt curve; and t (in seconds) is the time interval between the zero crossing of the dz/dt curve just before the maximal peak and the beginning of the second heart sound. Cardiac output (CO, in liters per minute) was calculated as CO = AV X Heart rate/ 1000. Another impedance cardiographic parameter used in the present study was the Heather Index, a measure of cardiac performance that correlates with the
PEPILVET ratio, stroke volume, and cardiac output. The Heather Index (HI, Wsec-') was evaluated as In this equation, RZ is the time HI = (dz/dt),/RZ. interval between the "R" deflection in the ECG and the maximum amplitude of the dz/dt curve in the carotid pulse tracing. Statistical analysis of the hemodynamic data obtained was performed by use of the Friedman rank variance analysis and the Wilcoxon-Wilcox tests.33Results were expressed as median values + standard error of the median.
RESULTS Changes in cardiac output from baseline at 2 and 6 hours after administration of the test substances are shown in Fig. 1. Two hours after famotidine ingestion, cardiac output was reduced by - 0.61 + 0.29 Llmin. This decrease (which was found in each individual subject investigated) was significant (p < 0.05) when compared with increases of 0.28 + 0.16 and 0.06 + 0.23 L/min for subjects receiving placebo and ranitidine, respectively. Analogous changes in stroke volume were also observed 2 hours after dosing (Fig. 1). Famotidine significantly (p < 0.05) reduced base-
VOLUME 48 NUMBER 3
PLACEBO 0-Zh
0-6h
ClMETlDlNE
RANITIDINE
FAMOTlDlNE
0-2h
0-2h
0-Zh
0-6h
0-6h
0-8h
Fig. 3. Median ( ? SEM) changes in rate of preejection period to left ventricular ejection time from baseline measured at 2 and 6 hours in healthy subjects successively treated for 1 week each with placebo, cimetidine, ranitidine, and famotidine. Star, Significant with p < 0.05 compared with placebo; solid triangle, significant with p < 0.05 compared with cimetidine.
line stroke volume by - 8.8 + 3.5 cm3compared with changes for placebo ( 5.5 + 3.1 cm3) and ranitidine (+4.3 + 1.2 cm3). A decrease in stroke volume after famotidine administration was observed in all but one subject. The Heather Index was significantly altered in a parallel manner. Famotidine decreased the index by - 1.56 + 0.72 fl/sec2 from baseline 2 hours after the morning dose, whereas the same parameter was increased by 0.45 + 0.57 and 0.04 + 0.34 n/secZ 120 minutes after intake of placebo and ranitidine, respectively (both p < 0.05 versus famotidine; Fig 2). The PEPJLVET ratio was the sole mechanocardiographic parameter to be significantly altered. Two hours after famotidine administration, the ratio was increased from baseline by 0.19 + 0.006 (Fig. 3). In contrast, slight decreases of - 0.003 + 0.003 and - 0.001 -+ 0.006 were recorded 2 hours after intake for placebo and cimetidine, respectively (both p < 0.05 versus famotidine; Fig. 3). Six hours after the test substances were received, significant intergroup differences were solely observed in terms of stroke volume (Fig. 2). The decrease in stroke volume from baseline values induced by famotidine (-4.4 + 2.7 cm3) contrasted with increases of 2.0 2 4.9 cm3for placebo and + 5.0 + 3.3 cm3for
+
+
cimetidine (both p < 0.05 versus famotidine). When values were compared for placebo and Hz-antagonists at 12 hours, no further differences in impedance cardiographic or mechanocardiographic parameters could be demonstrated. During the entire investigational period, no significant differences emerged between placebo and either cimetidine or ranitidine. Finally, as seen in Table I, no significant differences in heart rate or blood pressure were observed either before or 2 and 6 hours after administration of famotidine, ranitidine, or cimetidine compared with placebo values.
DISCUSSION The findings of the present study indicate that the H,-receptor antagonist famotidine exerts negative effects on cardiac performance. The decreases in impedance cardiographic parameters (stroke volume, cardiac output, and Heather Index) and the increase in the mechanographically derived PEP/ LVET ratio contrasted significantly with changes in placebo values, thereby confirming our previous observation^.^^ These effects appear to be mediated by cardiac Hz-receptors. However, blood pressure and heart rate were not altered by famotidine. In contrast to the changes induced by famotidine,
CLIN PHARMACOL THER SEPTEMBER 1990
306 Winrichsen, Halabi, and Kim3
Table I. Blood pressure and heart rate at baseline and at 2 and 6 hours after successive 1-week administration of placebo, cimetidine, ranitidine, and famotidine* Test substance
Baseline
Value after 2 hr
Value after 6 hr
Placebo Blood pressure (mrn Hg) Systolic Diastolic Heart rate (beatslmin)
115.0 2 6 72.5 + 6 62.5 k 7
117.5 2 6 70.0 + 4 61.5 k 5
122.5 + 3 75.0 k 3 67.0 + 5
Cimetidine Blood pressure (mm Hg) Systolic Diastolic Heart rate (beats1min)
117.5 5 6 70.0 + 6 65.0 +- 2
122.5 72.5 62.5
+9 +6 +4
120.0 +- 6 75.0 + 4 67.5 5 4
Ranitidine Blood pressure (mm Hg) Systolic Diastolic Heart rate (beatslmin)
117.5 +- 4 67.5 + 4 61.0 + 4
112.5 70.0 58.0
+4 +4 +4
122.5 70.0 60.5
Farnotidine Blood pressure (mm Hg) Systolic Diastolic Heart rate (beatslmin)
117.5 72.5 59.0
+9 +6
115.0 70.0 59.0
+
122.5 ? 4 70.0 + 4 64.5 + 4
+3
7
+6 +3
+7 +4 +
3
*All values are median k SEM.
negative effects on cardiac performance could not be demonstrated after oral doses of the older Hz-receptor antagonists cimetidine and ranitidine. Such findings are in accord with data from postmarketing surveillance and other safety assessments of these widely used drugs that have failed to detect any evidence of associated cardiac dec~mpensation.~~"~ The significant differences in hemodynamic data that emerged between famotidine and both cimetidine and ranitidine point to famotidine as being the only Hz-receptor antagonist of the three that had negative effects on cardiac performance. Nevertheless, data from in vitro experiments have indicated that some H2-receptor antagonists may exert negative inotropic effects in the human atria.lg Although such hemodynamic effects have never 'been consistently demonstrated in vivo in animals and human^,^'-^^ isolated case reports show evidence of sinus bradycardia and atrioventricular conduction disturbances with cimetidine and ranitidine.I3-l8Thus these substances appear to influence cardiac chronotropism and dromotropism, but not myocardial contractility. To our knowledge, two studies with famotidine have been conducted thus far to investigate hernodynamic effects measured by invasive techniques after a single intravenous dose of the d r ~ g . ~In~ both , ~ ' studies, pa-
tients at an intensive care unit who were under concomitant therapy with positive inotropic substances (such as catecholamines) were investigated; no cardiodepressant effects of famotidine were observed. These data contrasted with the findings of our previous investigation-performed with use of noninvasive methods in healthy subjects who were not on concurrent drug treatment-indicating negative effects by famotidine on cardiac performance." The divergent findings obtained with the various H2receptor antagonists concerning their cardiovascular effects may be explained by their varying chemical structures, resulting in differences in receptor affinity and sensitivity. Cimetidine is an imidazole derivative, whereas ranitidine contains a furan ring. Receptor affinity of ranitidine is higher than that of cimetidine such that an equivalent dose of ranitidine need only be one fourth as large as that of cimetidine. As for the more recent Hz-antagonistfamotidine, this guanidinethiazole derivative has the highest affinity for Hz-receptorsfound thus far.42In addition, farnotidine showed an unsurmountable antagonism to Hz-receptors at higher concentrations, which has not been reported for cimetidine or ranitidine. Famotidine affinity for H2-receptorswas also highly resistant to washout.43These pharmacologic
VOLUME 48 NUMBER 3
differences between the Hz-receptor antagonists may explain their varying pharmacodynamic properties, specifically with regard to their cardiovascular effects. More recently, an Hz-receptor antagonist has been introduced (nizatidine) that exerts consistent and marked negative chronotropic effects after oral a d m i n i ~ t r a t i o n . ~ ~ In conclusion, the findings of the present study indicate that the older Hz-receptor antagonists cimetidine and ranitidine fail to exert negative inotropic effects, whereas famotidine does exert these effects, thereby confirming data from a previous studyz0 that showed negative influences on cardiac performance. These effects are not only demonstrable when comparing hemodynamic measurements on famotidine with those on placebo but when comparing data on famotidine with those on cimetidine and ranitidine as well. In addition, the findings of this study should be confirmed when investigating patients with coronary disease o r congestive heart failure. This manuscript represents part of the doctoral thesis of Mrs. G. Hiibner, Department of Internal Medicine, ChristianAlbrechts-Universitat, Kiel, West Germany.
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