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Comparative study of the antihypertensive effect of verapamil and atenolol
ComparativeStudy of the AntihypertensiveEffect of Verapamiland Atenolol JORGE ESCUDERO,
MD, HECTOR HERNANDEZ,
MD, and FROYLAN
MARTINEZ, MD
A clinical trial in 24 patients with essential arterial hypertension (14 women and 10 men; mean age 47.5) was conducted on a double-blind basis using a placebo, 240~mg verapamil and lOO-mg atenolol daily. The total duration of the trial was 12 weeks: a 2-week washout period on placebo, a 4-week period on one of the trial drugs,’ a second 2-week weaning period and’s further 4-week treatment period on the other trial drug. Stabilization of the hypertension was obtained in 80% of the patients on verapamil and 71’% ‘of the patients on atenolol both
in the supine and upright positions; there was no significant difference between the 2 drugs. A moderate decrease in heart rate was obtained. Sinus bradycardia was observed in 3 patients on verapamil and 4 patients on atenolol. No instances of atrioventricular block were observed on electrocardiogram. No adverse effects were reported with verapamil and in ,only 1 patjent taking atenolol. Adequate stabilization of hypertension appears possible in most patients with both verapamil and atenolol; (Am J Cardiol 1989;57i54D-58D)
I
Methods
n 1964, Fleckensteinl reported the discovery of a new family of chemical compounds that he named the “calcium antagonists.” Verapamil (Lu-isopropyl-a-(N,methyl-N-homoveratriI)-yTaminopropyl-3, +dimethoxyphenylacetonitrile hydrochloride] was the first of these compounds to undergo experimental trials. This drug inhibits the influx of calcium ions through the cell membrane; mainly in the myocardium, in the smooth muscle cells of the coronary arteries and peripheral blood vessels and in the atrioventricular’node? As a result of its biochemical and pharmacologic characteristics, verapamil has been widely used as an antianginal and antiarrhythmic agent. In recent years it has also been used as an antihypertensive, an effect initially described’by Wette et al3 in 1966 and subsequently by others. 4-10Because arterial hypertension is a multifactorial disease that continues to be a serious public health problem, there is always room for new antihypertensive agents with different modes of action and properties, for administration on their own or in combination with other drugs. Like atenolol, a selective blocking agent of the ,&adrenergic receptors, verapamil is an effective antihypertensive agent. We therefore undertook a comparative clinical trial of verapamil and the P-blocking agent atenolol.
Twenty-four hypertensive outpatients* (14 women and 10 men, aged between 29 and 73 years, mean age of 47.5) entered the trial. Six of these patients were suffering from’stage I and Y8 patients from stage II hypertension according to the World Health Organization classification (160/95 mm Hg and 160/95 mm Hg plus left ventricular hypertrophy, respectively). Patients with secondary or malignant arterial hypertension, advanced liver or kidney diseases, myocardial infarct or cerebrovascular accident within the past 3 months, cardiac insufficiency, pronounced bradycardia, atrioventricular block, pathologic mammary syndrome, bronchial asthma, chronic bronchitis, bronchial spasm, pulmonary emphysema or respiratory insufficiency were excluded from the trial. Women who were pregnant, lactating or liable to become pregnant during the trial and patients requiring multiple therapy were also excluded. .’ The trial was carried out on a double-blind basis, using placebo, 240-mg verapamil (120 mg, 2 times a day) and 100-mg atenolol (50 mg, 2 times a day) in capsules of identical appearance. The total duration of the trial was 12 weeks, divided into 4 periods: an initial *The patients were from the Cardiology and Pneumology Hospital of the IMSS National Medical Center, the 20th of November Hospital of the ISSSTE and the Western Medical Center of Guadalajara, Jal.
From the Hospital de Cardiologia y Neumologia, Centro Medico National, I.M.S.S., Mexico City, Mexico. Address for reprints: Jorge Escudero, MD, Fuego 618, 01900 Mexico DF, Mexico. 54D
February 26, 1986
Z-week weaning period from previous medications during which the patients received a placebo, a second 4-week period during which half the patients received verapamil and half received atenolol, a further weaning period on placebo and then administration of the other trial product for the remaining 4 weeks. Each patient underwent 8 outpatient examinations; they were carried out weekly during the initial placebo period and fortnightly during the remainder of the trial. The arterial blood pressure was determined with a mercury sphygmomanometer by the same physician while the patient was in the supine and upright positions (3 times in each position); from these the mean reading was selected. The diastolic pressure was determined in phase 5 of the Korotkow sc&le. Any adverse effects were noted at each examination. Laboratory analyses, electrocardiograms (ECGs) and Z-dimensional echocardiograms were performed on 3 occasions: at the end of the first weaning period, at the end of the 4-week period on the first drug and at the end of the 4-week period on the second drug. The following laboratory analyses were performed: blood counts, urea, uric acid, creatinine, glucose, bilirubin, pyruvic glutamic transaminase, alkaline phosphatase, cholesterol, triglycerides, sodium, potassium, creatinine clearance and urine analysis.
THE AMERICAN
JOURNAL
OF CARDIOLOGY
Volume 57
The ventricular function and the ejection and contraction fractions were measured on the echocardiogram, in order to assess the pumping and muscular functions of the heart. At the conclusion of the trial, the results were subjected to statistical analysis by the x2 test and analysis of variance.
Results Arterial blood pressure: A significant decrease in both systolic and diastolic arterial pressures in comparison with the baseline values was observed both with verapamil and atenolol (Fig. 1 and 2). During verapamil treatment, the systolic pressure in the upright position fell from 154 f 19 to 135 f 19 mm Hg and in the supine position from 154 f 19 to 140 f 19 mm Hg; the diastolic pressure in the upright position fell from 105 f 9 to 87 f 10 mm Hg and in the supine position from 103 f 9 to 88 f 12 mm Hg (p <0.05). During atenolol treatment, the systolic pressure in the upright position fell from 154 f 16 to 134 f 16 mm Hg and in the supine position from 154 f 19 to 142 f 19 mm Hg, while the diastolic pressure in the upright position fell from 105 f 9 to 87 f 10 mm Hg and in the supine position from 103 f 9 to 90 f 14 mm Hg (p <0.05).
114.13 110
FIGURE 1. Left, systolic arterial pressure in the upright position (mean [x] f standard deviation [SD]). Right, diastolic arterial pressure in the upright position. A = atenolol; P = placebo; V = verapamil.
104.67
100
J
90 8a ,. 60
P-z 0.05
Systolic arterial pressure (in the upright position) (X + SD)
55D
Diastolic arterial pressure (in the upright position)
56D
A SYMPOSIUM:
CALCIUM
ANTAGONISTS
IN HYPERTENSION-FOCUS
No statistically significant difference could be found between the results obtained with the 2 drugs. Figures 3 to 6 show the antihypertensive effect of both drugs in the supine and upright positions in each of the patients treated. Heart rate: The mean heart rate under baseline conditions was 71 f 9 beats/min. The heart rate fell to 67 f 7 beats/min during verapamil treatment and to 65 f 12 beats/min during atenolol; only the latter difference was statistically significant (p = 0.03). A more pronounced decrease in heart rate was noted in 3 patients on verapamil and in 4 patients on atenolol but did not represent a serious problem; it was never necessary to interrupt the trial. Adverse effects: Only 1 patient exhibited unwanted adverse effects [while on atenolol) in the form of nausea, asthenia and weakness of the lower limbs. The symptoms were sufficiently serious to necessitate suspension of treatment. Electrocardiograms: The results of ECGs were normal in 10 patients. The most frequent abnormalities were a systolic overload of the left ventricle in 7 patients (29.1%), left ventricular hypertrophy in 6 patients (25%) and ventricular repolarization disorders
ON VERAPAMIL
in 6 patients (25%). No significant changes occurred in the ECGs during the trial. Echocardiograms: The ejection and contraction fractions and the circumferential contraction rate were normal both in the initial and subsequent examinations. The recorded changes were minimal and not statistically significant. The baseline ejection fraction was 69.06 f 7; it was 69.5 f 8 in the verapamil group and 69.05 f 8 in the atenolol group. The baseline contraction fraction was 32.79 f 6; it was 32.53 f 6 in the verapamil group and 32.98 f 6 in the atenolol group. Laboratory indexes: No changes were observed in the laboratory indexes during the trial.
Discussion A reduction in the arterial blood pressure was obtained as a result of the peripheral vasodilator effect of verapamil, which not only neutralizes a number of vasoconstrictor substances but also reduces the sensitivity of the systemic arteries and arterioles to mechanical stimuli, such as extension of the vascular wall, by increasing the intraluminal pressure (the Bayliss effect). This type of calcium antagonist can therefore suppress the automatic regulation of vasoconstriction
150WO130 120111.74
IlO-,
103 ,oo-
T 100.4
FIGURE 2. Left, systolic arterial pressure in the supine position (mean [$ f standard deviation [SD]). Right, diastolic arterial pressure in the supine position. A = atenolol; P = placebo; V = verapamil.
94.26 OO-
66.13
oo75.66 IO6050‘to302010.
P
Systolic
arterial
pressure
(X + SD)
Diastolic
arterial
pressure
February 26, 1986
based on calcium, reducing the increase in the secondary blood pressure accompanying an increase in the peripheral resistance .ll By reducing the aortic resistance and the peripheral vascular resistance in general, it is possible to reduce the arterial blood pressure in proportion to the patient’s age, initial arterial pressure and plasma renin levels9 without stimulating the sympathetic nervous system responsible for the initial tachycardia or the renin-angiotensin-aldosterone system.lO In the present trial, satisfactory stabilization of the hypertension was achieved in 19 patients with verapamiI(80%) and in 17 patients with atenolol(71%), with no statistically significant difference between the z drugs. In the 5 patients in whom arterial pressure values returned to normal, no correlation was found with age, although the ages varied from 41 to 61 years with a mean age of 49.4. A slight reduction in heart rate, which was not statistically significant, was obtained with verapamil; as was to be expected, the bradycardia obtained with
B
T
arterial
Volume 57
578
atenolol was slightly greater (p = 0.03). No widening of the PR interval on the ECC was obtained in any of the patients on verapamil, as described in other studies.2J2Js In some hemodynamic and electrophysiological studies, verapamil has been found to decrease inotropism.5,6a7 It has also been reported that the oral administration of a single large dose of verapamil caused changes on the echocardiogram-e.g., decrease in the ejection time, in the diastolic diameter of the left ventricle, in the contraction rate of the circumferential fibers and of the rear wall, in the final diastolic volume of the left ventricle and in the ejection fraction and heart output-accompanied by an increase in the preejection period, left ventricular ejection time ratio and in the final systolic volume.14 These findings could not be confirmed in the present trial; the changes in the ejection and contraction fractions and in the circumferential contraction rate on the echocardiogram were minimal and not statistically significant. In previous clinical trials only 182 out of 4,352 patients have reported 1 or more adverse effects; bradycardia, hypotension, first-degree atrioventricular
pressure
in the supine position.
B =
‘$6
f8
T ATENOLOL
VERAPAMIL
FIGURE 5. Systolic basal; T = terminal.
arterial
pressure
In the upright position.
B=
1140
140 1
0-i
OF CARDIOLOGY
ATENOLOL
VERAPAMIL
FIGURE 3. Systolic basal; T = terminal.
JOURNAL
00 1
T
8
THE AMERICAN
0
T
FIGURE 4. Diastolic basal; 1 = terminal.
arterial
T
B
c
o
ATENOLOL
VERAPAMIL
pressure
in the supine position.
“3
El
T
B =
FIGURE 6. Diastolic basal; T = terminal.
arterial
T
s ATENOLOL
VERAPAMIL
pressure
In the upright position.
B =
58D
A SYMPOSIUM:
CALCIUM
ANTAGONISTS
IN HYPERTENSION-FOCUS
block, cardiac insufficiency, constipation, nausea and vomiting were the most frequent. A feeling of sickness, headache, asthenia, pruritus and flushing in the facial area have also been reported. In the present trial moderate bradycardia was caused by verapamil in only 3 patients and by atenolol in 4 patients. One patient complained of nausea, asthenia and weakness of the lower limbs while taking atenolol.
References 1. Fleckenstein A. Die Bedeutung der energiereichen phosphate fur kontraktilitat und tonus des myokards. Verh Dtsch Ges Inn Med 1964;70: suppI:&91.
2. Nayler WG. Calcium antagonism: a new approach. Clin Exp Pharmacol PhysioJ 1382;suppI 6:~ 3. Wette K, Heimsoth V, Jansen FK. lnfluencia del iproveratril sobre Jas modificaciones electrocardiograficas en 10shipertensos con angina pectoris. Munch Med Wsch 1966;108:1238.(Spanish ed: 1967;109:44.) 4. Pichardo FA, Molina CA, Pedrero NL. Valoracion clinica de 10sefectos antihipertensivos del clorhidrato de isoptin. Rev MBd ISSSTE M8x 1973;8:145-155. 5. Lewis BS, Mitha AS, Gotsman MS. Intermediate haemodynamic effects of verapomil in man. Cardiology 1975;60:366-376.
ON VERAPAMIL
6. Singh BN, Roche AHG. Effects of intravenous verapamil on hemodynamics in patients with heart disease. Am Heart J 1977;94:593-599. 7. Mangiardie LM. Hariman RJ. McAllister RG Jr, Bhargava V, Surawicz B, Shabetai R. Electrophysiologic and hemodynamic effects of verapamil. Correlation with plasma drug concentrations. Circulation 1978;57:366372. 8. Kabela E. Los antagonistas de1calcio en la fisiologia deJ miocardio y de1 musculo Iiso. Relation con su utihdad terapeutica. Arch Inst Cardiol Mex 1980;50:533-534. 9. Biihler FR, Hulten UL, Kiowski W, Mtiller FB, Bolli P. The place of the calcium antagonist verapamil in antihypertensive therapy. J Cardiovasc Pharmacol 1982;4:suppf3:350-357. 10. Leonetti G, Cuspidi C, Sampieri L, Terzoli L, Zanchetti A. Comparison of cardiovascular, renal and humoral effects of acute administration of two calcium channel blockers in normotensive and hypertensive subjects. J Cardiovosc Pharmacol 2982;4:suupJ3:319-324. 11. Fleckenstein A, Fleckenstein-Grtin G, Frey M. Efecto antiespastico arterial, antihipertensivo y anticalcinotico de 10santagonistas de1 calcio. Resumenes del Simposio “Calcio-antagonistas en la hipertension: enfoque sobre verapamil” [abstr). Mexico D F 15-17 November 1984;l. 12. Midtbo K. Verapamil regular y de liberation prolongada en el tratamiento de la hipertension arterial esencial. In Ref 11: 12. 13. Dargie HJ, McInnes GT, Findlay IN, Cleland JGF. Respuestascardiovasculares al verapamil y propranolol en pacientes con hipertension esencial. In Ref 11: 16. 14. Ortiz J. Funcion de1ventricuio izquierdo despues de una sola dosis alta de verapamil. In Ref 11: 6.
MD, HECTOR HERNANDEZ,
MD, and FROYLAN
MARTINEZ, MD
A clinical trial in 24 patients with essential arterial hypertension (14 women and 10 men; mean age 47.5) was conducted on a double-blind basis using a placebo, 240~mg verapamil and lOO-mg atenolol daily. The total duration of the trial was 12 weeks: a 2-week washout period on placebo, a 4-week period on one of the trial drugs,’ a second 2-week weaning period and’s further 4-week treatment period on the other trial drug. Stabilization of the hypertension was obtained in 80% of the patients on verapamil and 71’% ‘of the patients on atenolol both
in the supine and upright positions; there was no significant difference between the 2 drugs. A moderate decrease in heart rate was obtained. Sinus bradycardia was observed in 3 patients on verapamil and 4 patients on atenolol. No instances of atrioventricular block were observed on electrocardiogram. No adverse effects were reported with verapamil and in ,only 1 patjent taking atenolol. Adequate stabilization of hypertension appears possible in most patients with both verapamil and atenolol; (Am J Cardiol 1989;57i54D-58D)
I
Methods
n 1964, Fleckensteinl reported the discovery of a new family of chemical compounds that he named the “calcium antagonists.” Verapamil (Lu-isopropyl-a-(N,methyl-N-homoveratriI)-yTaminopropyl-3, +dimethoxyphenylacetonitrile hydrochloride] was the first of these compounds to undergo experimental trials. This drug inhibits the influx of calcium ions through the cell membrane; mainly in the myocardium, in the smooth muscle cells of the coronary arteries and peripheral blood vessels and in the atrioventricular’node? As a result of its biochemical and pharmacologic characteristics, verapamil has been widely used as an antianginal and antiarrhythmic agent. In recent years it has also been used as an antihypertensive, an effect initially described’by Wette et al3 in 1966 and subsequently by others. 4-10Because arterial hypertension is a multifactorial disease that continues to be a serious public health problem, there is always room for new antihypertensive agents with different modes of action and properties, for administration on their own or in combination with other drugs. Like atenolol, a selective blocking agent of the ,&adrenergic receptors, verapamil is an effective antihypertensive agent. We therefore undertook a comparative clinical trial of verapamil and the P-blocking agent atenolol.
Twenty-four hypertensive outpatients* (14 women and 10 men, aged between 29 and 73 years, mean age of 47.5) entered the trial. Six of these patients were suffering from’stage I and Y8 patients from stage II hypertension according to the World Health Organization classification (160/95 mm Hg and 160/95 mm Hg plus left ventricular hypertrophy, respectively). Patients with secondary or malignant arterial hypertension, advanced liver or kidney diseases, myocardial infarct or cerebrovascular accident within the past 3 months, cardiac insufficiency, pronounced bradycardia, atrioventricular block, pathologic mammary syndrome, bronchial asthma, chronic bronchitis, bronchial spasm, pulmonary emphysema or respiratory insufficiency were excluded from the trial. Women who were pregnant, lactating or liable to become pregnant during the trial and patients requiring multiple therapy were also excluded. .’ The trial was carried out on a double-blind basis, using placebo, 240-mg verapamil (120 mg, 2 times a day) and 100-mg atenolol (50 mg, 2 times a day) in capsules of identical appearance. The total duration of the trial was 12 weeks, divided into 4 periods: an initial *The patients were from the Cardiology and Pneumology Hospital of the IMSS National Medical Center, the 20th of November Hospital of the ISSSTE and the Western Medical Center of Guadalajara, Jal.
From the Hospital de Cardiologia y Neumologia, Centro Medico National, I.M.S.S., Mexico City, Mexico. Address for reprints: Jorge Escudero, MD, Fuego 618, 01900 Mexico DF, Mexico. 54D
February 26, 1986
Z-week weaning period from previous medications during which the patients received a placebo, a second 4-week period during which half the patients received verapamil and half received atenolol, a further weaning period on placebo and then administration of the other trial product for the remaining 4 weeks. Each patient underwent 8 outpatient examinations; they were carried out weekly during the initial placebo period and fortnightly during the remainder of the trial. The arterial blood pressure was determined with a mercury sphygmomanometer by the same physician while the patient was in the supine and upright positions (3 times in each position); from these the mean reading was selected. The diastolic pressure was determined in phase 5 of the Korotkow sc&le. Any adverse effects were noted at each examination. Laboratory analyses, electrocardiograms (ECGs) and Z-dimensional echocardiograms were performed on 3 occasions: at the end of the first weaning period, at the end of the 4-week period on the first drug and at the end of the 4-week period on the second drug. The following laboratory analyses were performed: blood counts, urea, uric acid, creatinine, glucose, bilirubin, pyruvic glutamic transaminase, alkaline phosphatase, cholesterol, triglycerides, sodium, potassium, creatinine clearance and urine analysis.
THE AMERICAN
JOURNAL
OF CARDIOLOGY
Volume 57
The ventricular function and the ejection and contraction fractions were measured on the echocardiogram, in order to assess the pumping and muscular functions of the heart. At the conclusion of the trial, the results were subjected to statistical analysis by the x2 test and analysis of variance.
Results Arterial blood pressure: A significant decrease in both systolic and diastolic arterial pressures in comparison with the baseline values was observed both with verapamil and atenolol (Fig. 1 and 2). During verapamil treatment, the systolic pressure in the upright position fell from 154 f 19 to 135 f 19 mm Hg and in the supine position from 154 f 19 to 140 f 19 mm Hg; the diastolic pressure in the upright position fell from 105 f 9 to 87 f 10 mm Hg and in the supine position from 103 f 9 to 88 f 12 mm Hg (p <0.05). During atenolol treatment, the systolic pressure in the upright position fell from 154 f 16 to 134 f 16 mm Hg and in the supine position from 154 f 19 to 142 f 19 mm Hg, while the diastolic pressure in the upright position fell from 105 f 9 to 87 f 10 mm Hg and in the supine position from 103 f 9 to 90 f 14 mm Hg (p <0.05).
114.13 110
FIGURE 1. Left, systolic arterial pressure in the upright position (mean [x] f standard deviation [SD]). Right, diastolic arterial pressure in the upright position. A = atenolol; P = placebo; V = verapamil.
104.67
100
J
90 8a ,. 60
P-z 0.05
Systolic arterial pressure (in the upright position) (X + SD)
55D
Diastolic arterial pressure (in the upright position)
56D
A SYMPOSIUM:
CALCIUM
ANTAGONISTS
IN HYPERTENSION-FOCUS
No statistically significant difference could be found between the results obtained with the 2 drugs. Figures 3 to 6 show the antihypertensive effect of both drugs in the supine and upright positions in each of the patients treated. Heart rate: The mean heart rate under baseline conditions was 71 f 9 beats/min. The heart rate fell to 67 f 7 beats/min during verapamil treatment and to 65 f 12 beats/min during atenolol; only the latter difference was statistically significant (p = 0.03). A more pronounced decrease in heart rate was noted in 3 patients on verapamil and in 4 patients on atenolol but did not represent a serious problem; it was never necessary to interrupt the trial. Adverse effects: Only 1 patient exhibited unwanted adverse effects [while on atenolol) in the form of nausea, asthenia and weakness of the lower limbs. The symptoms were sufficiently serious to necessitate suspension of treatment. Electrocardiograms: The results of ECGs were normal in 10 patients. The most frequent abnormalities were a systolic overload of the left ventricle in 7 patients (29.1%), left ventricular hypertrophy in 6 patients (25%) and ventricular repolarization disorders
ON VERAPAMIL
in 6 patients (25%). No significant changes occurred in the ECGs during the trial. Echocardiograms: The ejection and contraction fractions and the circumferential contraction rate were normal both in the initial and subsequent examinations. The recorded changes were minimal and not statistically significant. The baseline ejection fraction was 69.06 f 7; it was 69.5 f 8 in the verapamil group and 69.05 f 8 in the atenolol group. The baseline contraction fraction was 32.79 f 6; it was 32.53 f 6 in the verapamil group and 32.98 f 6 in the atenolol group. Laboratory indexes: No changes were observed in the laboratory indexes during the trial.
Discussion A reduction in the arterial blood pressure was obtained as a result of the peripheral vasodilator effect of verapamil, which not only neutralizes a number of vasoconstrictor substances but also reduces the sensitivity of the systemic arteries and arterioles to mechanical stimuli, such as extension of the vascular wall, by increasing the intraluminal pressure (the Bayliss effect). This type of calcium antagonist can therefore suppress the automatic regulation of vasoconstriction
150WO130 120111.74
IlO-,
103 ,oo-
T 100.4
FIGURE 2. Left, systolic arterial pressure in the supine position (mean [$ f standard deviation [SD]). Right, diastolic arterial pressure in the supine position. A = atenolol; P = placebo; V = verapamil.
94.26 OO-
66.13
oo75.66 IO6050‘to302010.
P
Systolic
arterial
pressure
(X + SD)
Diastolic
arterial
pressure
February 26, 1986
based on calcium, reducing the increase in the secondary blood pressure accompanying an increase in the peripheral resistance .ll By reducing the aortic resistance and the peripheral vascular resistance in general, it is possible to reduce the arterial blood pressure in proportion to the patient’s age, initial arterial pressure and plasma renin levels9 without stimulating the sympathetic nervous system responsible for the initial tachycardia or the renin-angiotensin-aldosterone system.lO In the present trial, satisfactory stabilization of the hypertension was achieved in 19 patients with verapamiI(80%) and in 17 patients with atenolol(71%), with no statistically significant difference between the z drugs. In the 5 patients in whom arterial pressure values returned to normal, no correlation was found with age, although the ages varied from 41 to 61 years with a mean age of 49.4. A slight reduction in heart rate, which was not statistically significant, was obtained with verapamil; as was to be expected, the bradycardia obtained with
B
T
arterial
Volume 57
578
atenolol was slightly greater (p = 0.03). No widening of the PR interval on the ECC was obtained in any of the patients on verapamil, as described in other studies.2J2Js In some hemodynamic and electrophysiological studies, verapamil has been found to decrease inotropism.5,6a7 It has also been reported that the oral administration of a single large dose of verapamil caused changes on the echocardiogram-e.g., decrease in the ejection time, in the diastolic diameter of the left ventricle, in the contraction rate of the circumferential fibers and of the rear wall, in the final diastolic volume of the left ventricle and in the ejection fraction and heart output-accompanied by an increase in the preejection period, left ventricular ejection time ratio and in the final systolic volume.14 These findings could not be confirmed in the present trial; the changes in the ejection and contraction fractions and in the circumferential contraction rate on the echocardiogram were minimal and not statistically significant. In previous clinical trials only 182 out of 4,352 patients have reported 1 or more adverse effects; bradycardia, hypotension, first-degree atrioventricular
pressure
in the supine position.
B =
‘$6
f8
T ATENOLOL
VERAPAMIL
FIGURE 5. Systolic basal; T = terminal.
arterial
pressure
In the upright position.
B=
1140
140 1
0-i
OF CARDIOLOGY
ATENOLOL
VERAPAMIL
FIGURE 3. Systolic basal; T = terminal.
JOURNAL
00 1
T
8
THE AMERICAN
0
T
FIGURE 4. Diastolic basal; 1 = terminal.
arterial
T
B
c
o
ATENOLOL
VERAPAMIL
pressure
in the supine position.
“3
El
T
B =
FIGURE 6. Diastolic basal; T = terminal.
arterial
T
s ATENOLOL
VERAPAMIL
pressure
In the upright position.
B =
58D
A SYMPOSIUM:
CALCIUM
ANTAGONISTS
IN HYPERTENSION-FOCUS
block, cardiac insufficiency, constipation, nausea and vomiting were the most frequent. A feeling of sickness, headache, asthenia, pruritus and flushing in the facial area have also been reported. In the present trial moderate bradycardia was caused by verapamil in only 3 patients and by atenolol in 4 patients. One patient complained of nausea, asthenia and weakness of the lower limbs while taking atenolol.
References 1. Fleckenstein A. Die Bedeutung der energiereichen phosphate fur kontraktilitat und tonus des myokards. Verh Dtsch Ges Inn Med 1964;70: suppI:&91.
2. Nayler WG. Calcium antagonism: a new approach. Clin Exp Pharmacol PhysioJ 1382;suppI 6:~ 3. Wette K, Heimsoth V, Jansen FK. lnfluencia del iproveratril sobre Jas modificaciones electrocardiograficas en 10shipertensos con angina pectoris. Munch Med Wsch 1966;108:1238.(Spanish ed: 1967;109:44.) 4. Pichardo FA, Molina CA, Pedrero NL. Valoracion clinica de 10sefectos antihipertensivos del clorhidrato de isoptin. Rev MBd ISSSTE M8x 1973;8:145-155. 5. Lewis BS, Mitha AS, Gotsman MS. Intermediate haemodynamic effects of verapomil in man. Cardiology 1975;60:366-376.
ON VERAPAMIL
6. Singh BN, Roche AHG. Effects of intravenous verapamil on hemodynamics in patients with heart disease. Am Heart J 1977;94:593-599. 7. Mangiardie LM. Hariman RJ. McAllister RG Jr, Bhargava V, Surawicz B, Shabetai R. Electrophysiologic and hemodynamic effects of verapamil. Correlation with plasma drug concentrations. Circulation 1978;57:366372. 8. Kabela E. Los antagonistas de1calcio en la fisiologia deJ miocardio y de1 musculo Iiso. Relation con su utihdad terapeutica. Arch Inst Cardiol Mex 1980;50:533-534. 9. Biihler FR, Hulten UL, Kiowski W, Mtiller FB, Bolli P. The place of the calcium antagonist verapamil in antihypertensive therapy. J Cardiovasc Pharmacol 1982;4:suppf3:350-357. 10. Leonetti G, Cuspidi C, Sampieri L, Terzoli L, Zanchetti A. Comparison of cardiovascular, renal and humoral effects of acute administration of two calcium channel blockers in normotensive and hypertensive subjects. J Cardiovosc Pharmacol 2982;4:suupJ3:319-324. 11. Fleckenstein A, Fleckenstein-Grtin G, Frey M. Efecto antiespastico arterial, antihipertensivo y anticalcinotico de 10santagonistas de1 calcio. Resumenes del Simposio “Calcio-antagonistas en la hipertension: enfoque sobre verapamil” [abstr). Mexico D F 15-17 November 1984;l. 12. Midtbo K. Verapamil regular y de liberation prolongada en el tratamiento de la hipertension arterial esencial. In Ref 11: 12. 13. Dargie HJ, McInnes GT, Findlay IN, Cleland JGF. Respuestascardiovasculares al verapamil y propranolol en pacientes con hipertension esencial. In Ref 11: 16. 14. Ortiz J. Funcion de1ventricuio izquierdo despues de una sola dosis alta de verapamil. In Ref 11: 6.