European Journal of Clinical Investigation ( 1992) 22, 9- 18
REVIEW
Haemodynamic effects of H2-receptorantagonists
H . HINRICHSEN, A. HALABI & W. KIRCH, 1st Medical Clinic, Christian Albrechts University, Kiel, Germany
Received 19 November 1990 and in revised form 23 May 1991; accepted 27 May 1991
Introduction H2-receptor antagonists are among the most frequently prescribed and thoroughly documented class of drugs in use today. Their ability to inhibit the secretion of gastric acid in hypersecretory states makes them effective in the treatment of peptic ulcer disease, the Zollinger-Ellison syndrome, and other conditions such as the prevention of stress ulcers in severely ill or burned patients [I]. The safety and tolerability of the older H2 blockers has been confirmed by large postmarketing surveillance studies [2- 121. When considering the most important studies, the incidence of cardiovascular adverse reactions has been shown to vary between I .8 cases per 100 000 patients and 6 cases per 791 1 patients, during treatment with different H2 blockers [4,5]. It is well known that histamine exerts effects on the cardiovascular system in man [ 13-2 I] which are mediated by H I as well as by H2 receptors. As new and more powerful H2 blockers are being developed and marketed, this review attempts to summarize the information known concerning the haemodynamic effects of Hz-receptor antagonists. The considerable number of reports ofcardiovascular drug reactions has necessitated the selection of only the most relevant ones. Histamine-mediated cardiac effects Eighty years ago, Dale & Laidlaw first described the stimulation of the mammalian heart by histamine [22]. Since then, numerous studies have been undertaken to investigate the role of histamine in the human heart. Administration of histamine enhances the force of ventricular contraction (positive inotropism), increases the sinus rate (positive chronotropism), slows atrioventricular conduction (negative dromotropism), and causes ventricular arrhythmias (positive bathmotropism) [ 13-2 1,23-261. Whereas catecholamines also Correspondence: Professor Dr Dr W. Kirch. 1. Medizinische Klinik, SchittenhelmstraDe 12, D-2300 Kiel, Germany.
exert positive inotropic, chronotropic, and bathmotropic effects, histamine acts independently of the adrenergic system [ 15- I7,27-291. After the existence of two distinct subclasses of histamine receptors became apparent, it was soon demonstrated that the cardiac effects of histamine were mediated by both H I and H2 receptor types, albeit differently. As seen in Table I , histamine exerts positive inotropic effects via H2 receptors, while stimulation of H I receptors leads to reduced myocardial contractility [16,17,19,30]. The positive inotropic effect of histamine mediated by the H2 receptor usually predominates over the negative inotropism caused by the stimulation of H I receptors. Histamine receptors have been detected in the human heart and coronary arteries [31-331, but the autocoid’s role under physiological conditions has yet to be clarified. By contrast, the triggering effect of histamine in anaphylaxis is well documented [34-391. The vasodilating properties of histamine caused afterload reduction and reflex tachycardia-haemodynamic alterations which are not primarily due to cardiac effects of histamine, but represent reactive changes due to vascular influences. Histamine may alter the tone of the coronary vessels as well, thereby leading to changes in cardiac function [31,321. In the following sections, only direct effects of histamine on the myocardium, on impulse formation, and the conduction system are considered. Table 1. Effects of histamine on the human heart as mediated by the different histamine receptors Histamine receptors Cardiac effect
HI
Hz
Sinus rate Atrial and ventricular contractility Atrial and ventricular automaticity Atrioventricular conduction time Ventricular fibrillation threshold
-
f T
1 -
T 1
T -
1
9
10
H. HINRTCHSEN et al.
I
C
S-CHz-CH2-NH-
II ........ .'""
C N i
C IMETlDlNE
I
H2-S-CH2-CH2-NH-C
II
H3C,
5H
N-CH H,C
RANITIDINE
NO2
C t+- S- C t+ H2N>=N H2 N
-C H2- F,NH2
FAMOTIDINE
"S02-Nt+
Figure 1. Chemical structures of different H2-receptor antagonists (cimetidine, ranitidine. farnotidine, nizatidine).
Pharmacological aspects of various Hz-receptor antagonists Chemical structure und eflects q f HZuntugonists Since the publication of the classical study by Black et ul. [ 181 in which the first Hz-receptor antagonist burimamide was characterized, a considerable number of new compounds in this drug class have been developed [40,41]. Burimamide was the first competitive antagonist of histamine able to both inhibit gastric hydrochloric acid secretion and stimulate heart rate and myocardial contractility in the guinea-pig atrium [ 181. As an imidazole derivative, burimamide closely resembed histamine. Later compounds also retained the imidazole ring of histamine. Cimetidine (Fig. I), the first Hz blocker to be approved for general clinical use, has now been prescribed for more then 12 years. By contrast, ranitidine (Fig. I ) is a furan derivative which is four times more potent than cimetidine in terms of its Hz-receptor-mediated inhibition of hista-. minergic effects. Ranitidine also shows competitive antagonism for the Hz receptor [40]. In addition to these types of actions, Hz-receptor antagonists might also exert non-specific effects in which they may differ from one another. Bertaccini & Coruzzi [42,43] reported cholinergic-like effects of ranitidine on the gastrointestinal tract. However, it is uncertain whether this effect is due to stimulation of muscarinergic receptors, increased release of acetylcholine, or inhibition of acetylcholinesterase. Support for this notion was provided by results indicating that
an inhibition of cholinesterase by ranitidine might occur [44]. In isolated heart preparations, no cholinergic effects could be observed [45]. For cimetidine or the newer Hz-receptor antagonists, no data are available concerning cholinergic effects on the heart. In recent years, new compounds (famotidine and nizatidine) have been introduced which contain a thiazole ring as their main chemical backbone (Fig. I ) . Famotidine has been shown to be 30 times more potent than cimetidine, while nizatidine possesses the same potency as ranitidine [40]. Like other recently devcloped Hl-receptor antagonists, famotidine shows an unsurmountable non-competitive antagonism in iitro for the H2 receptor at higher concentrations [46]. This was not the case for the older drugs cimetidine and ranitidine [40,47,48]. Substances such as loxtidine. tiotidine, or lupitidine, which also exerted an unsurmountable non-competitive H2-receptor antagonism or a long duration of action, could not he distributed commercially as they were found to cause gastric tumours [40]. Finally, another recently developed Hl blocker, roxatidine, is a piperidinylniethylphenoxy derivative [49]. This substance showed similar characteristics to ranitidine with regard to the inhibition of histaminergic effects [49]. Roxatidine is also a competitive antagonist for HZ receptors. Meanwhile, there are several newer H2-receptor antagonists under clinical investigation. The present review restricts itself to providing information about the haemodynamic effects of those Hz blockers which are in widespread clinical use.
HAEMODYNAMIC EFFECTS OF Hz BLOCKERS
11
Table 2. Adverse cardiovascular reactions during treatment with cimetidine reported in the literature
Dosage 400 mg i.v. 200 mg i.v
300 mg i.v. 200 mg i.v. bolus I g i.v.
200 mg i.v. 800 mg i.v. 1200 mg i.v.
300 mg i.v. 300 mg i.v. 200 mg i.v. I g/day p.o
I giday p a 400 mg/day p.0. Suicide with diazepam and cimetidinc I giday p.0. 200 mg/day p.0.
Adverse reactions
Therapy/outcome
Underlying cardiac disease
Age (years)
Sex (m/f)
Reference
Sinus arrest Cardiac arrest Atrial fibrillation Ventricular extrasystoles Ventricular tachycardia Ventricular fibrillation Sinus arrest
Resuscitation
None
56
m
61
Defibrillation
None
50
m
60
Spontaneous recovery
m
62
Spontaneous recovery Spontaneous recovery
Not reported None Daunorubicine therapy in acute leukaemia
20
Atrial fibrillation Tachycardia
34 13
m m
69 58
Sinus bradycardia Sinus bradycardia Sinus bradycardia
Spontaneous recovery Spontaneous recovery Spontaneous recovery
62 71 78
m m m
59 63 64
Sinus bradycardia Sinus bradycardia 1 atrioventricular blockade Tachycardia Sinus bradycardia
Spontaneous recovery Death by bradyarrhythmia
None Coronary heart disease
35 59
m m
65 66
Verapamil Spontaneous recover)
Left bundle branch block Daunorubicine therapy in acute leukaemia
85 24
f m
54 58
Sinus bradycardia
Spontaneous recovery
3 atrioventricular blockade 3 atrivoentricular blockade
Spontaneous recovery
None None None
39 70
59 67
38
m m f
None None
49 42
m m
53
3 atrioventricular blockade Atropine I atrioventricular blockade Spontaneous recovery
1st degree atrioventricular blockade
68
57
i.v.. intravenously: p.0.. per 0s.
In vitro and anitnal experiments on cardioiuscular effects of' HI-receptor antagonists
As already mentioned, histamine plays an important role as an autocoid in the cardiovascular system; its effects are mediated by HI and HI receptors. It is well known that the positive chronotropic and inotropic effects of histamine may not be altered by H I receptor agonists as well as by antagonists [ 181. Therefore, after the discovery of H? receptors and the development of Hz-receptor antagonists, it was not long before the cardiovascular effects of these drugs were investigated in in t'itro studies and animal experiments. Black et al. [I 81 described the haemodynamic properties of the first Hz-receptor antagonist burimamide in cats. The H? blocker was found to completely antagonize the fall in blood pressure after histamine infusion. Thereupon, it became necessary to investigate the cardiovacular effects of all new Hz-receptor antagonists. In each case, they antagonized histamine-mediated cardiac effects [40,46-491. Cimetidine and ranitidine were found to be competitive antagonists for the positive inotropic effect of histamine, also at higher concentrations [40,47,48]. whereas other drugs such as oxmetadine,
tiotidine, or farnotidine showed an unsurmountable non-competitive antagonism at their higher concentrations [40,46-481. In addition, the very potent Hzreceptor antagonist tiodidine exerted a negative inotropic effect in the absence of histamine [48]. Thus, H2-receptor antagonists vary in the degree of their cardiovascular effects. Although the negative inotropic and chronotropic effects of the Hz antagonists are mediated by the same Hz receptor, it was surprising that not all parameters of cardiac function were altered by an identical H l antagonist in the same way during H2 receptor stimulation. Tiotidine, for example, showed a non-competitive antagonism for the positive inotropic effect of histamine mediated by Hl receptors [48]. On the other hand, the positive chronotropic effect of histamine also mediated by these receptors was competitively antagonized by tiotidine [48]. Those H? antagonists with the highest affinity for Hz receptors exerted non-competitive antagonism [40,48]. The only Hz antagonist currently on the market reported to exert unsurmountable non-competitive antagonism is famotidine [48]. Bradycardia and atrioventricular conduction disturbances are the most common cardiovascular adverse
12
H. HINRICHSEN et al. Table 3. Adverse cardiovascular reactions during treatment with ranitidine reported in the literature
Dosage 100 mg i.v. 2 times/day 100 mg i.v.
50 rng i.v. 50 mg i.v 150 mg p.0. 2 times/day
Adverse reactions
Therapy/outcome
Underlying cardiac disease
(years)
Sinus bradycardia Sinus bradycardia Bradycardia Cardiac arrest Bradycardia
Atropine Atropine Atropine resuscitation Resuscitation Spontaneous recovery
None Atrial premature contractions None None Ischaemic heart disease
59 82 13 47 71
Age
Sex (m/f)
f
Reference
f rn
55 55 70
m
71
f
56
i.v.. intravenously; p.0.. per 0s.
reactions during H2-receptor antagonist treatment. In animal experiments, dose-dependent prolongation of atrioventricular conduction time with cimetidine and ranitidine has been demonstrated [50]. Furthermore, the antagonistic effect of cimetidine on histamineinduced abnormal automaticity was observed in the guinea-pig ventricle and in the anaesthetized rat [51,52]. Thus, through in vitro studies and animal experiments, various cardiovascular effects of the H2receptor antagonists have been confirmed. Clinical observations of adverse haemodynamic reactions with H2-receptor antagonists
Case reports concerning adverse cardiovascular reactions associated with administration of H2 blockers have been published since 1977 and have mostly involved dysrhythmias [53]. As seen in Tables 2 and 3, numerous cases were characterized by bradycardia or atrioventricular conduction disturbances. In this context, it must be mentioned that the patients involved were often being treated with several drugs concurrently and were suffering from various concomitant diseases. Therefore, it was often difficult to decide whether the reactions were unequivocally caused by the H2 blockers. Nevertheless, the presence of H2 receptors in the human heart led the investigators to conclude that this was probably the case. Moreover, in some cases involving discontinuation of cimetidine or ranitidine due to the occurrence of serious dysrhythmias, the cardiac symptoms were observed to reoccur upon continuation of treatment with the H2 blocker [54-591. In one noteworthy case, a patient on cimetidine developed bradycardia necessitating therapeutic withdrawal; upon resuming treatment with ranitidine years later, the symptom reoccurred again [56]! However, in addition to the use of the H2 blocker, clinical circumstances involving many of these case reports (e.g., underlying hepatic and/or renal disease, drug interactions, etc.) must be considered as a potential contributory hctor for the development of dysrhythmias [53,56,58,60]. Most reports of bradycardia and atrioventricular conduction disturbances have been described for cimetidine, the oldest H2-receptor antagonist. These reac-
tions were noted after intravenous and oral administration as well as after single dose and long-term treatment with this drug and have included cases involving sinus or cardiac arrest [6 1,621, sinus bradycardia [58,59,63-661, all degrees of atrioventricular blockade [53,57,66-681, atrial fibrillation [60,69], ventricular extrasystoles [60,69], tachycardia [54,58,60,69], and ventricular fibrillation [60,69]. Sinus bradycardia accompanied by the development of cardiac decompensation has been the most frequent adverse reaction described. In some cases the dysrhythmia spontaneously disappeared [54,57,59,64,67,69], while in others, patients required atropine or other drugs [53,54,60,61]. In several of these patients, underlying cardiovascular disease (Table 2) was present [54,58,64,66]. As ranitidine has been available o n the market for a shorter period of time, fewer haemodynamic side effects have been reported with this drug (Table 3). Like cimetidine, they were observed following intravenous, oral, single dose or long term administration [55,56,70,71]. The types of adverse effects with ranitidine were similar to those ascribed to cimetidine, with bradycardia [55,56,70] and cardiac arrest [7 I] occurring most frequently. To our knowledge, similar case reports have not yet been published for the more recent H2 blockers famotidine, nizatidine, and roxatidine. This is understandable since these newer drugs have not yet been as widely prescribed as the older ones, and also because the incidence of dysrhythmias with cimetidine or ranitidine only varies between 1.6 and 3.6 per 10million prescriptions [72]. Despite the fact that the possibility of adverse cardiovascular effects of H2 blockers is mentioned in the package labelling for these drugs, physicians may not be sufficiently alerted to their occasional occurrence. Recently, Tanner & Arrowsmith [72] pointed out that physicians should be more aware of these reactions and not fail to report such reactions to their local health authorities so that the medical community and general public can benefit from current information about drug safety. Although numerous reports of cardiac dysrhythmias are to be found in the literature, there is scant mention concerning the influence of H2 blockers on
HAEMODYNAMIC EFFECTS OF H? BLOCKERS
13
Table 4. Overview of the clinical investigations on haemodynamic effects of Hz-receptor antagonists
Drug
Dosage
Subjects studied
Haemodynamic parameters
Reference
Cimetidine
300 mg i.v single dose 400 mg i.v. single dose 1600 mg p.0. 7 days 3.5 mg/kg body weight single dose 1.5 mg/kg body weight single dose 200, 400, 800 mg i.v. single dose 400 mg i.v. bolus injection 400 mg i.v. short infusion 400 mg i.v. single dose 400 mg i.v. single dose 200 mg i.v. single dose 200 mg i.v. single dose 200 mg i.v. single dose 50 rng i.v. single dose 200 mg i.v. single dose 50 mg i.v. single dose 20 mg i.v. single dose 20 mg i.v. single dose 50 mg i.v. single dose 200 mg i.v. single dose 40 mg p.0. 7 days 40 mg p.0. 7 days 300 mg p.0. 7 days 1200 mg p.0. 7 days 30 mg p.0. 7 days
10 cardiac patients
HR, SNF
74
10 ICU patients
BP, HR, CVP,C O
75
6 healthy subjects
HR, BP, STI
76
6 healthy subjects
HR. BP. STI
76
6 healthy subjects
HR, BP, STI
76
6 healthy subjects
HR, BP, STI
77
6 healthy subjects
HR, BP, STI, C O
77
6 healthy subjects
HR. BP, STI, C O
77
8 healthy subjects
HR, BP, C O
78
16 A D patients
HR, BP, CO
78
10 cardiac patients
BP
79
10 healthy subjects
BP, STI, M M E
80
50 ICU patients
HR, BP
81
50 ICU patients
HR, BP
81
68 ICU patients
HR. BP
82
26 ICU patients
HR, BP. CO
83
10 ICU patients
HR, BP. C O
84
30 ICU patients
HR, BP. C O
85
30 ICU patients
HR. BP. C O
85
30 ICU patients
HR, BP, C O
85
12 healthy subjects
HR. BP, CO, STI
86
12 healthy subjects
HR, BP. CO. STI
87
12 healthy subjects
HR. BP. CO. STI
87
12 healthy subjects
HR, BP. CO. STI
87
12 healthy subjects
HR. BP. C O
88
Ranitidine Cimetidine
Cimetidine
Ranitidine Cimetidine Ranitidine Farnotidine
Ranitidine Cimetidine Famotidine
Ranitidine Cimetidine Nizatidine
AD, airway disease; BP. blood pressure; CO, cardiac output; CVP, central venous pressure; ICU, intensive care unit; i.v., intravenously; MME. M-mode echography; P.o., per 0s; SNF. sinus node function; STI. systolic time intervals.
myocardial contractility. There is one report concerning this issue alleging a more frequent incidence of pneumonia (congested lung?) in intensive care unit patients treated with Hr blockers [73]. However, in that
report, the development of pneumonia was thought to be due to another mechanism of action [73]. Until now, no-one has questioned the possible influence of Hzreceptor antagonists on cardiac decompensation, but
14
H. HINRICHSEN et al.
1
6
Cirnetidine
1001
1 HE
I
m
II
*
20
j
I V
0
4
I
8
12
16
20
24
Time, rnin
Figure 2. Time course and magnitude of cimetidine-induced hypotension in a patient with acute anterior myocardial infarction who required dopamine for circulatory support. Note unchanged heart rate and pulmonary artery pressure despite marked blood pressure decrease (after Kiowski & Frei [82]).
it is certainly more difficult to confirm such a connection than to detect an arrhythmia using the electrocardiogram.
Clinical investigations on haemodynamic effects of receptor antagonists
H2-
Description of investigations perjormed To date, relatively few clinical studies have been performed to characterize cardiovascular effects of different Hz-receptor antagonists. The key results of the most important studies are chronologically summarized in Table 4. Following the initial case reports of bradycardia due to cimetidine treatment, Engel & Luck [74] investigated the influence of cimetidine on sinus nose function in patients undergoing electrophysiological testing. In the patients studied, heart rate and sinus node function were not altered. Samuel & Dundee [75] reported a fall in blood pressure (20 mmHg systolic) and cardiac output (30%) using the Hamilton-Steward dye dilution method 5 min after administration of cimetidine in one of 10 patients tested. Barbat & Warrington [76] noted a reduction in heart rate following oral cimetidine treatment whereas ECG, systolic time intervals (STI), and blood pressure were unaffected. After intravenous administration none of the cardiovascular parameters measured were altered in that study. However, Boyce [77] found a dose-dependent increase in heart rate and a decrease of the pre-ejection period in STI with cimetidine. After rapid intravenous injection these effects were more pronounced, but cardiac output and stroke volume
remained unchanged. Lee et al. [78] demonstrated a fall in blood pressure and an increase in heart rate with cimetidine, whereas cardiac output (direct Fick principle) was unaffected. Jost et a/. [79] and Tottermann et al. [80] confirmed the fall in blood pressure; neither M-mode echocardiographic parameters nor those of STI were altered. Three other studies [81-831 reported a fall in blood pressure and a possibly reactive rise in heart rate following intravenous administration of cimetidine while ranitidine did not produce these changes. As an example, a fall in blood pressure without occurrence of reflex tachycardia [82] is shown in Fig. 2. Concerning the more recent H?-receptor antagonist famotidine, no alterations in heart rate, blood pressure and cardiac output (thermodilution method) were observed after intravenous administration [84,85], whereas cimetidine led to a fall in mean arterial pressure in one of these studies [85]; however. Kirch rt al. [86] reported a decrease in cardiac output and stroke volume (impedance cardiography) and comparable results for STI after oral administration of famotidine. Hinrichsen el a/. [87] confirmed the results obtained by Kirch et al. [86] for famotidine, whereas cardiovascular parameters were unaffected by cimetidine and ranitidine (Fig. 3). Finally, a marked negative chronotropic effect was determined with the more recent H2 blocker nizatidine in the study by Halabi & Kirch [88] (Fig. 4). Cardiac output (impedance cardiography) decreased on nizatidine due to the heart rate reducing effect of this Hz antagonist. The heart rate reducing effect of nizatidine was even more pronounced upon concurrent treatment with the beta
HAEMODYNAMIC EFFECTS OF H2 BLOCKERS PLACEBO O-Zh
ClMETlDlNE
0-8h
M h
RANIflDlNE
M h
06h
FAMOTlDlNE
O-zh
Wh
15
0-8h
0.4-
'
0.5-
-
0.6 0.7
-
0.80.9
,
Figure 3. Median (kSEM) changes in cardiac output from baseline measured at 2 and 6 h in 10 healthy subjects, each successively treated for I week with placebo, cimetidine, ranitidine, and famotidine. *, significant with P
REVIEW
Haemodynamic effects of H2-receptorantagonists
H . HINRICHSEN, A. HALABI & W. KIRCH, 1st Medical Clinic, Christian Albrechts University, Kiel, Germany
Received 19 November 1990 and in revised form 23 May 1991; accepted 27 May 1991
Introduction H2-receptor antagonists are among the most frequently prescribed and thoroughly documented class of drugs in use today. Their ability to inhibit the secretion of gastric acid in hypersecretory states makes them effective in the treatment of peptic ulcer disease, the Zollinger-Ellison syndrome, and other conditions such as the prevention of stress ulcers in severely ill or burned patients [I]. The safety and tolerability of the older H2 blockers has been confirmed by large postmarketing surveillance studies [2- 121. When considering the most important studies, the incidence of cardiovascular adverse reactions has been shown to vary between I .8 cases per 100 000 patients and 6 cases per 791 1 patients, during treatment with different H2 blockers [4,5]. It is well known that histamine exerts effects on the cardiovascular system in man [ 13-2 I] which are mediated by H I as well as by H2 receptors. As new and more powerful H2 blockers are being developed and marketed, this review attempts to summarize the information known concerning the haemodynamic effects of Hz-receptor antagonists. The considerable number of reports ofcardiovascular drug reactions has necessitated the selection of only the most relevant ones. Histamine-mediated cardiac effects Eighty years ago, Dale & Laidlaw first described the stimulation of the mammalian heart by histamine [22]. Since then, numerous studies have been undertaken to investigate the role of histamine in the human heart. Administration of histamine enhances the force of ventricular contraction (positive inotropism), increases the sinus rate (positive chronotropism), slows atrioventricular conduction (negative dromotropism), and causes ventricular arrhythmias (positive bathmotropism) [ 13-2 1,23-261. Whereas catecholamines also Correspondence: Professor Dr Dr W. Kirch. 1. Medizinische Klinik, SchittenhelmstraDe 12, D-2300 Kiel, Germany.
exert positive inotropic, chronotropic, and bathmotropic effects, histamine acts independently of the adrenergic system [ 15- I7,27-291. After the existence of two distinct subclasses of histamine receptors became apparent, it was soon demonstrated that the cardiac effects of histamine were mediated by both H I and H2 receptor types, albeit differently. As seen in Table I , histamine exerts positive inotropic effects via H2 receptors, while stimulation of H I receptors leads to reduced myocardial contractility [16,17,19,30]. The positive inotropic effect of histamine mediated by the H2 receptor usually predominates over the negative inotropism caused by the stimulation of H I receptors. Histamine receptors have been detected in the human heart and coronary arteries [31-331, but the autocoid’s role under physiological conditions has yet to be clarified. By contrast, the triggering effect of histamine in anaphylaxis is well documented [34-391. The vasodilating properties of histamine caused afterload reduction and reflex tachycardia-haemodynamic alterations which are not primarily due to cardiac effects of histamine, but represent reactive changes due to vascular influences. Histamine may alter the tone of the coronary vessels as well, thereby leading to changes in cardiac function [31,321. In the following sections, only direct effects of histamine on the myocardium, on impulse formation, and the conduction system are considered. Table 1. Effects of histamine on the human heart as mediated by the different histamine receptors Histamine receptors Cardiac effect
HI
Hz
Sinus rate Atrial and ventricular contractility Atrial and ventricular automaticity Atrioventricular conduction time Ventricular fibrillation threshold
-
f T
1 -
T 1
T -
1
9
10
H. HINRTCHSEN et al.
I
C
S-CHz-CH2-NH-
II ........ .'""
C N i
C IMETlDlNE
I
H2-S-CH2-CH2-NH-C
II
H3C,
5H
N-CH H,C
RANITIDINE
NO2
C t+- S- C t+ H2N>=N H2 N
-C H2- F,NH2
FAMOTIDINE
"S02-Nt+
Figure 1. Chemical structures of different H2-receptor antagonists (cimetidine, ranitidine. farnotidine, nizatidine).
Pharmacological aspects of various Hz-receptor antagonists Chemical structure und eflects q f HZuntugonists Since the publication of the classical study by Black et ul. [ 181 in which the first Hz-receptor antagonist burimamide was characterized, a considerable number of new compounds in this drug class have been developed [40,41]. Burimamide was the first competitive antagonist of histamine able to both inhibit gastric hydrochloric acid secretion and stimulate heart rate and myocardial contractility in the guinea-pig atrium [ 181. As an imidazole derivative, burimamide closely resembed histamine. Later compounds also retained the imidazole ring of histamine. Cimetidine (Fig. I), the first Hz blocker to be approved for general clinical use, has now been prescribed for more then 12 years. By contrast, ranitidine (Fig. I ) is a furan derivative which is four times more potent than cimetidine in terms of its Hz-receptor-mediated inhibition of hista-. minergic effects. Ranitidine also shows competitive antagonism for the Hz receptor [40]. In addition to these types of actions, Hz-receptor antagonists might also exert non-specific effects in which they may differ from one another. Bertaccini & Coruzzi [42,43] reported cholinergic-like effects of ranitidine on the gastrointestinal tract. However, it is uncertain whether this effect is due to stimulation of muscarinergic receptors, increased release of acetylcholine, or inhibition of acetylcholinesterase. Support for this notion was provided by results indicating that
an inhibition of cholinesterase by ranitidine might occur [44]. In isolated heart preparations, no cholinergic effects could be observed [45]. For cimetidine or the newer Hz-receptor antagonists, no data are available concerning cholinergic effects on the heart. In recent years, new compounds (famotidine and nizatidine) have been introduced which contain a thiazole ring as their main chemical backbone (Fig. I ) . Famotidine has been shown to be 30 times more potent than cimetidine, while nizatidine possesses the same potency as ranitidine [40]. Like other recently devcloped Hl-receptor antagonists, famotidine shows an unsurmountable non-competitive antagonism in iitro for the H2 receptor at higher concentrations [46]. This was not the case for the older drugs cimetidine and ranitidine [40,47,48]. Substances such as loxtidine. tiotidine, or lupitidine, which also exerted an unsurmountable non-competitive H2-receptor antagonism or a long duration of action, could not he distributed commercially as they were found to cause gastric tumours [40]. Finally, another recently developed Hl blocker, roxatidine, is a piperidinylniethylphenoxy derivative [49]. This substance showed similar characteristics to ranitidine with regard to the inhibition of histaminergic effects [49]. Roxatidine is also a competitive antagonist for HZ receptors. Meanwhile, there are several newer H2-receptor antagonists under clinical investigation. The present review restricts itself to providing information about the haemodynamic effects of those Hz blockers which are in widespread clinical use.
HAEMODYNAMIC EFFECTS OF Hz BLOCKERS
11
Table 2. Adverse cardiovascular reactions during treatment with cimetidine reported in the literature
Dosage 400 mg i.v. 200 mg i.v
300 mg i.v. 200 mg i.v. bolus I g i.v.
200 mg i.v. 800 mg i.v. 1200 mg i.v.
300 mg i.v. 300 mg i.v. 200 mg i.v. I g/day p.o
I giday p a 400 mg/day p.0. Suicide with diazepam and cimetidinc I giday p.0. 200 mg/day p.0.
Adverse reactions
Therapy/outcome
Underlying cardiac disease
Age (years)
Sex (m/f)
Reference
Sinus arrest Cardiac arrest Atrial fibrillation Ventricular extrasystoles Ventricular tachycardia Ventricular fibrillation Sinus arrest
Resuscitation
None
56
m
61
Defibrillation
None
50
m
60
Spontaneous recovery
m
62
Spontaneous recovery Spontaneous recovery
Not reported None Daunorubicine therapy in acute leukaemia
20
Atrial fibrillation Tachycardia
34 13
m m
69 58
Sinus bradycardia Sinus bradycardia Sinus bradycardia
Spontaneous recovery Spontaneous recovery Spontaneous recovery
62 71 78
m m m
59 63 64
Sinus bradycardia Sinus bradycardia 1 atrioventricular blockade Tachycardia Sinus bradycardia
Spontaneous recovery Death by bradyarrhythmia
None Coronary heart disease
35 59
m m
65 66
Verapamil Spontaneous recover)
Left bundle branch block Daunorubicine therapy in acute leukaemia
85 24
f m
54 58
Sinus bradycardia
Spontaneous recovery
3 atrioventricular blockade 3 atrivoentricular blockade
Spontaneous recovery
None None None
39 70
59 67
38
m m f
None None
49 42
m m
53
3 atrioventricular blockade Atropine I atrioventricular blockade Spontaneous recovery
1st degree atrioventricular blockade
68
57
i.v.. intravenously: p.0.. per 0s.
In vitro and anitnal experiments on cardioiuscular effects of' HI-receptor antagonists
As already mentioned, histamine plays an important role as an autocoid in the cardiovascular system; its effects are mediated by HI and HI receptors. It is well known that the positive chronotropic and inotropic effects of histamine may not be altered by H I receptor agonists as well as by antagonists [ 181. Therefore, after the discovery of H? receptors and the development of Hz-receptor antagonists, it was not long before the cardiovascular effects of these drugs were investigated in in t'itro studies and animal experiments. Black et al. [I 81 described the haemodynamic properties of the first Hz-receptor antagonist burimamide in cats. The H? blocker was found to completely antagonize the fall in blood pressure after histamine infusion. Thereupon, it became necessary to investigate the cardiovacular effects of all new Hz-receptor antagonists. In each case, they antagonized histamine-mediated cardiac effects [40,46-491. Cimetidine and ranitidine were found to be competitive antagonists for the positive inotropic effect of histamine, also at higher concentrations [40,47,48]. whereas other drugs such as oxmetadine,
tiotidine, or farnotidine showed an unsurmountable non-competitive antagonism at their higher concentrations [40,46-481. In addition, the very potent Hzreceptor antagonist tiodidine exerted a negative inotropic effect in the absence of histamine [48]. Thus, H2-receptor antagonists vary in the degree of their cardiovascular effects. Although the negative inotropic and chronotropic effects of the Hz antagonists are mediated by the same Hz receptor, it was surprising that not all parameters of cardiac function were altered by an identical H l antagonist in the same way during H2 receptor stimulation. Tiotidine, for example, showed a non-competitive antagonism for the positive inotropic effect of histamine mediated by Hl receptors [48]. On the other hand, the positive chronotropic effect of histamine also mediated by these receptors was competitively antagonized by tiotidine [48]. Those H? antagonists with the highest affinity for Hz receptors exerted non-competitive antagonism [40,48]. The only Hz antagonist currently on the market reported to exert unsurmountable non-competitive antagonism is famotidine [48]. Bradycardia and atrioventricular conduction disturbances are the most common cardiovascular adverse
12
H. HINRICHSEN et al. Table 3. Adverse cardiovascular reactions during treatment with ranitidine reported in the literature
Dosage 100 mg i.v. 2 times/day 100 mg i.v.
50 rng i.v. 50 mg i.v 150 mg p.0. 2 times/day
Adverse reactions
Therapy/outcome
Underlying cardiac disease
(years)
Sinus bradycardia Sinus bradycardia Bradycardia Cardiac arrest Bradycardia
Atropine Atropine Atropine resuscitation Resuscitation Spontaneous recovery
None Atrial premature contractions None None Ischaemic heart disease
59 82 13 47 71
Age
Sex (m/f)
f
Reference
f rn
55 55 70
m
71
f
56
i.v.. intravenously; p.0.. per 0s.
reactions during H2-receptor antagonist treatment. In animal experiments, dose-dependent prolongation of atrioventricular conduction time with cimetidine and ranitidine has been demonstrated [50]. Furthermore, the antagonistic effect of cimetidine on histamineinduced abnormal automaticity was observed in the guinea-pig ventricle and in the anaesthetized rat [51,52]. Thus, through in vitro studies and animal experiments, various cardiovascular effects of the H2receptor antagonists have been confirmed. Clinical observations of adverse haemodynamic reactions with H2-receptor antagonists
Case reports concerning adverse cardiovascular reactions associated with administration of H2 blockers have been published since 1977 and have mostly involved dysrhythmias [53]. As seen in Tables 2 and 3, numerous cases were characterized by bradycardia or atrioventricular conduction disturbances. In this context, it must be mentioned that the patients involved were often being treated with several drugs concurrently and were suffering from various concomitant diseases. Therefore, it was often difficult to decide whether the reactions were unequivocally caused by the H2 blockers. Nevertheless, the presence of H2 receptors in the human heart led the investigators to conclude that this was probably the case. Moreover, in some cases involving discontinuation of cimetidine or ranitidine due to the occurrence of serious dysrhythmias, the cardiac symptoms were observed to reoccur upon continuation of treatment with the H2 blocker [54-591. In one noteworthy case, a patient on cimetidine developed bradycardia necessitating therapeutic withdrawal; upon resuming treatment with ranitidine years later, the symptom reoccurred again [56]! However, in addition to the use of the H2 blocker, clinical circumstances involving many of these case reports (e.g., underlying hepatic and/or renal disease, drug interactions, etc.) must be considered as a potential contributory hctor for the development of dysrhythmias [53,56,58,60]. Most reports of bradycardia and atrioventricular conduction disturbances have been described for cimetidine, the oldest H2-receptor antagonist. These reac-
tions were noted after intravenous and oral administration as well as after single dose and long-term treatment with this drug and have included cases involving sinus or cardiac arrest [6 1,621, sinus bradycardia [58,59,63-661, all degrees of atrioventricular blockade [53,57,66-681, atrial fibrillation [60,69], ventricular extrasystoles [60,69], tachycardia [54,58,60,69], and ventricular fibrillation [60,69]. Sinus bradycardia accompanied by the development of cardiac decompensation has been the most frequent adverse reaction described. In some cases the dysrhythmia spontaneously disappeared [54,57,59,64,67,69], while in others, patients required atropine or other drugs [53,54,60,61]. In several of these patients, underlying cardiovascular disease (Table 2) was present [54,58,64,66]. As ranitidine has been available o n the market for a shorter period of time, fewer haemodynamic side effects have been reported with this drug (Table 3). Like cimetidine, they were observed following intravenous, oral, single dose or long term administration [55,56,70,71]. The types of adverse effects with ranitidine were similar to those ascribed to cimetidine, with bradycardia [55,56,70] and cardiac arrest [7 I] occurring most frequently. To our knowledge, similar case reports have not yet been published for the more recent H2 blockers famotidine, nizatidine, and roxatidine. This is understandable since these newer drugs have not yet been as widely prescribed as the older ones, and also because the incidence of dysrhythmias with cimetidine or ranitidine only varies between 1.6 and 3.6 per 10million prescriptions [72]. Despite the fact that the possibility of adverse cardiovascular effects of H2 blockers is mentioned in the package labelling for these drugs, physicians may not be sufficiently alerted to their occasional occurrence. Recently, Tanner & Arrowsmith [72] pointed out that physicians should be more aware of these reactions and not fail to report such reactions to their local health authorities so that the medical community and general public can benefit from current information about drug safety. Although numerous reports of cardiac dysrhythmias are to be found in the literature, there is scant mention concerning the influence of H2 blockers on
HAEMODYNAMIC EFFECTS OF H? BLOCKERS
13
Table 4. Overview of the clinical investigations on haemodynamic effects of Hz-receptor antagonists
Drug
Dosage
Subjects studied
Haemodynamic parameters
Reference
Cimetidine
300 mg i.v single dose 400 mg i.v. single dose 1600 mg p.0. 7 days 3.5 mg/kg body weight single dose 1.5 mg/kg body weight single dose 200, 400, 800 mg i.v. single dose 400 mg i.v. bolus injection 400 mg i.v. short infusion 400 mg i.v. single dose 400 mg i.v. single dose 200 mg i.v. single dose 200 mg i.v. single dose 200 mg i.v. single dose 50 rng i.v. single dose 200 mg i.v. single dose 50 mg i.v. single dose 20 mg i.v. single dose 20 mg i.v. single dose 50 mg i.v. single dose 200 mg i.v. single dose 40 mg p.0. 7 days 40 mg p.0. 7 days 300 mg p.0. 7 days 1200 mg p.0. 7 days 30 mg p.0. 7 days
10 cardiac patients
HR, SNF
74
10 ICU patients
BP, HR, CVP,C O
75
6 healthy subjects
HR, BP, STI
76
6 healthy subjects
HR. BP. STI
76
6 healthy subjects
HR, BP, STI
76
6 healthy subjects
HR, BP, STI
77
6 healthy subjects
HR, BP, STI, C O
77
6 healthy subjects
HR. BP, STI, C O
77
8 healthy subjects
HR, BP, C O
78
16 A D patients
HR, BP, CO
78
10 cardiac patients
BP
79
10 healthy subjects
BP, STI, M M E
80
50 ICU patients
HR, BP
81
50 ICU patients
HR, BP
81
68 ICU patients
HR. BP
82
26 ICU patients
HR, BP. CO
83
10 ICU patients
HR, BP. C O
84
30 ICU patients
HR, BP. C O
85
30 ICU patients
HR. BP. C O
85
30 ICU patients
HR, BP, C O
85
12 healthy subjects
HR. BP, CO, STI
86
12 healthy subjects
HR, BP. CO. STI
87
12 healthy subjects
HR. BP. CO. STI
87
12 healthy subjects
HR, BP. CO. STI
87
12 healthy subjects
HR. BP. C O
88
Ranitidine Cimetidine
Cimetidine
Ranitidine Cimetidine Ranitidine Farnotidine
Ranitidine Cimetidine Famotidine
Ranitidine Cimetidine Nizatidine
AD, airway disease; BP. blood pressure; CO, cardiac output; CVP, central venous pressure; ICU, intensive care unit; i.v., intravenously; MME. M-mode echography; P.o., per 0s; SNF. sinus node function; STI. systolic time intervals.
myocardial contractility. There is one report concerning this issue alleging a more frequent incidence of pneumonia (congested lung?) in intensive care unit patients treated with Hr blockers [73]. However, in that
report, the development of pneumonia was thought to be due to another mechanism of action [73]. Until now, no-one has questioned the possible influence of Hzreceptor antagonists on cardiac decompensation, but
14
H. HINRICHSEN et al.
1
6
Cirnetidine
1001
1 HE
I
m
II
*
20
j
I V
0
4
I
8
12
16
20
24
Time, rnin
Figure 2. Time course and magnitude of cimetidine-induced hypotension in a patient with acute anterior myocardial infarction who required dopamine for circulatory support. Note unchanged heart rate and pulmonary artery pressure despite marked blood pressure decrease (after Kiowski & Frei [82]).
it is certainly more difficult to confirm such a connection than to detect an arrhythmia using the electrocardiogram.
Clinical investigations on haemodynamic effects of receptor antagonists
H2-
Description of investigations perjormed To date, relatively few clinical studies have been performed to characterize cardiovascular effects of different Hz-receptor antagonists. The key results of the most important studies are chronologically summarized in Table 4. Following the initial case reports of bradycardia due to cimetidine treatment, Engel & Luck [74] investigated the influence of cimetidine on sinus nose function in patients undergoing electrophysiological testing. In the patients studied, heart rate and sinus node function were not altered. Samuel & Dundee [75] reported a fall in blood pressure (20 mmHg systolic) and cardiac output (30%) using the Hamilton-Steward dye dilution method 5 min after administration of cimetidine in one of 10 patients tested. Barbat & Warrington [76] noted a reduction in heart rate following oral cimetidine treatment whereas ECG, systolic time intervals (STI), and blood pressure were unaffected. After intravenous administration none of the cardiovascular parameters measured were altered in that study. However, Boyce [77] found a dose-dependent increase in heart rate and a decrease of the pre-ejection period in STI with cimetidine. After rapid intravenous injection these effects were more pronounced, but cardiac output and stroke volume
remained unchanged. Lee et al. [78] demonstrated a fall in blood pressure and an increase in heart rate with cimetidine, whereas cardiac output (direct Fick principle) was unaffected. Jost et a/. [79] and Tottermann et al. [80] confirmed the fall in blood pressure; neither M-mode echocardiographic parameters nor those of STI were altered. Three other studies [81-831 reported a fall in blood pressure and a possibly reactive rise in heart rate following intravenous administration of cimetidine while ranitidine did not produce these changes. As an example, a fall in blood pressure without occurrence of reflex tachycardia [82] is shown in Fig. 2. Concerning the more recent H?-receptor antagonist famotidine, no alterations in heart rate, blood pressure and cardiac output (thermodilution method) were observed after intravenous administration [84,85], whereas cimetidine led to a fall in mean arterial pressure in one of these studies [85]; however. Kirch rt al. [86] reported a decrease in cardiac output and stroke volume (impedance cardiography) and comparable results for STI after oral administration of famotidine. Hinrichsen el a/. [87] confirmed the results obtained by Kirch et al. [86] for famotidine, whereas cardiovascular parameters were unaffected by cimetidine and ranitidine (Fig. 3). Finally, a marked negative chronotropic effect was determined with the more recent H2 blocker nizatidine in the study by Halabi & Kirch [88] (Fig. 4). Cardiac output (impedance cardiography) decreased on nizatidine due to the heart rate reducing effect of this Hz antagonist. The heart rate reducing effect of nizatidine was even more pronounced upon concurrent treatment with the beta
HAEMODYNAMIC EFFECTS OF H2 BLOCKERS PLACEBO O-Zh
ClMETlDlNE
0-8h
M h
RANIflDlNE
M h
06h
FAMOTlDlNE
O-zh
Wh
15
0-8h
0.4-
'
0.5-
-
0.6 0.7
-
0.80.9
,
Figure 3. Median (kSEM) changes in cardiac output from baseline measured at 2 and 6 h in 10 healthy subjects, each successively treated for I week with placebo, cimetidine, ranitidine, and famotidine. *, significant with P
