- Email: [email protected]
Amlodipine in the treatment of mild-to-moderate essential hypertension
CURRENT THERAPEUTIC RESEARCH VOL. 55, NO. 9, SEPTEMBER 1994
AMLODIPINE IN THE TREATMENT OF MILD-TO-MODERATE ESSENTIAL HYPERTENSION R. A. ESIN, O. E. ESSIEN, AND J. ANDY
Department of Medicine, College of Medical Sciences, University of Calabar, Calabar, Nigeria
ABSTRACT To evaluate the a n t i h y p e r t e n s i v e effect and safety of amlodipine, the drug was a d m i n i s t e r e d for 8 to 12 weeks to 21 Nigerian patients with mild-to-moderate hypertension. After a washout period of 1 week, amlodipine was a d m i n i s t e r e d at a dose of 5 mg once daily for 2 weeks and increased to 10 mg once daily if the patient's diastolic blood pressure did n o t fall to ~<90 m m Hg. Heart rate, blood pressure, a n d adverse drug reactions were monitored at 2-week intervals. Compliance was assessed by pill count. Nineteen patients completed the study. Systolic and diastolic blood pressures were significantly reduced i n all patients. Amlodipine m o n o t h e r a p y achieved effective r e d u c t i o n of diastolic blood pressure to ~<90 m m Hg in 95% of the cases. Heart rate did not change. Adverse events were generally mild a n d i n c l u d e d increased micturition or p o l y u r i a , headache, dizziness, p i t t i n g leg edema, and a b d o m i n a l discomfort with mild diarrhea. We conclude that monotherapy with amlodipine 5 to 10 mg/day is well tolerated a n d effective in c o n t r o l l i n g mild-to-moderate essential hypertension. INTRODUCTION
Calcium antagonists have assumed an important role in the management of angina pectoris and hypertension. 1'2 These drugs generally have a greater affinity for the calcium channels of vascular smooth muscles, especially those of the coronary arteries, than to those of the heart muscle itself, and they have virtually no affinity for the calcium channels in skeletal muscles. 1 Available calcium antagonists such as verapamil, diltiazem, and nifedipine have a short half-life and a low oral bioavailability, due to rapid elimination after oral administration) Unlike nifedipine, amlodipine has been reported to have a very slow rate of association and dissociation with the calcium channel receptors, and intra-arterial blood pressure monitoring has shown that once-daily oral administration of amlodipine is effective for 24-hour control of blood pressure. 3'4 Therefore, it was of interest to Address correspondenceto: J. Andy, Department of Medicine,Collegeof Medical Sciences,University of Calabar, Calabar, Nigeria. Received for publication on September 1, 1992. Printed in the U.S.A. Reproductionin whole or part is not permitted. 1112
0011-393X/94/$3.50
R. A. ESIN ET AL.
study the efficacy and safety of amlodipine in Nigerian hypertensive patients. P A T I E N T S AND M E T H O D S
Twenty-one patients (4 men, 17 women), ages 32 to 72 years (mean age, 47.7 years) with uncomplicated essential hypertension (World Health Organization stages I to II), were recruited for the study from the medical outpatient clinics of the University of Calabar Teaching Hospital, Calabar, Nigeria. Sixteen patients had been previously diagnosed and were receiving various other antihypertensive agents, and five patients were newly diagnosed. Only patients with essential hypertension and a diastolic blood pressure ranging from 95 to 115 mm Hg were eligible for the study. Patients with clinical heart failure, serious arrhythmias, hepatic dysfunction, renal decompensation, or mental disorders were excluded from the trial. Pregnant or lactating women and those taking oral contraceptives, as well as alcoholic patients, were also excluded. None of the patients included in the study had a concomitant illness. At entry, all patients gave informed consent. They provided a medical history and underwent a physical examination; laboratory tests included a complete blood count, electrolytes, urea, creatinine, and fasting blood sugar. Liver function studies, routine urinalysis, chest roentgenogram, and electrocardiogram were also performed. All antihypertensive medications were stopped during a 1-week washout period. If the sitting diastolic blood pressure was within the prescribed range (95 to 115 mm Hg) after the washout period, the patient was included in the study. Oral amlodipine 5 mg/day was then given for 2 weeks. If the diastolic blood pressure was >90 mm Hg at the end of 2 weeks, the dose was increased to 10 mg/day for another 2 weeks. After 4 weeks of therapy, patients who did not achieve the target diastolic blood pressure (~<90 mmHg) or who showed clinically significant adverse reactions were excluded from the study. Patients with acceptable blood pressure control and no serious adverse reactions were then followed up at 2-week intervals for an additional 8 weeks. Blood pressure (sitting and standing), heart rate, and weight were recorded at each visit. A pill count was also made at each visit to assess compliance, and the patient was questioned about side effects of the drugs. Data are expressed as the mean -+ standard error of the mean. Student's t test was used to compare data between the two groups. RESULTS
Nineteen patients (2 men, 17 women) completed 8 weeks of therapy; 13 of 1113
AMLODIPINEFOR HYPERTENSION
these patients remained in the study for 12 weeks. Two patients voluntarily withdrew from the study after 2 weeks and were not included in the data analysis. Eleven patients required 5 mg/day and eight patients required 10 mg/day of amlodipine to achieve acceptable blood pressure control. Patient compliance was excellent (100%). By week 4, both the systolic and diastolic blood pressures were significantly reduced (P < 0.005), and this reduction was maintained throughout the trial (figure). Diastolic blood pressure decreased to ~<90 mmHg in 18 (95%) of the 19 patients. In the remaining patient, the baseline blood pressure of 180/110 mmHg dropped to 180/90 mmHg and 170/90 mmHg at 4 and 6 weeks, respectively, but was 200/100 mmHg at 8 weeks of therapy, despite regular treatment with amlodipine 10 mg. This patient was removed from the trial at 8 weeks. There were no significant changes between sitting and standing blood pressures throughout the study. The mean heart rate was 87 + 13.2, 87 -+ 11.6, 83 -+ 13.2, 84 -+ 12.7 beats/rain at baseline, 4 weeks, 8 weeks, and 12 weeks, respectively. The heart rate did not significantly change during the study. Nine patients complained of increased micturition and polyuria, which was mild in eight but associated with increasing weakness in one. ioo
I90~
.'!" "i
80
170
E 60
,~150
u.I I,-
uJ 150 n"
~
~HR
r
I
I
I
T
n" I-rr
40
'
=
J.
•
SBP
o'~ u) I.U
20 ~ ,,o
"I-
T
a 0 0
0
~
90
1
~
j.
~
|
DSP
I
70
50"
30
6 n19
~,
e
n19 DURATION
12
hi9 OF
THERAPY
hi3 (WEEKS)
Figure. Mean change in h e a r t rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) in response to therapy with amlodipine 5 to 10 mg/day. *P < 0.05 compared with baseline; **P < 0.01 compared with week 4. 1114
R.A. ESIN ET AL.
However, electrolyte and urea levels remained normal in all nine patients. Seven patients admitted to improved appetite during therapy, but fasting blood sugar was normal and urine sugar was negative in all of them. Two patients complained of headache, which was intense in one; the headache occurred 1 to 2 hours after the drug was administered and disappeared with continuation of therapy. Two male patients discontinued the medication for a few days, complaining of weakness at coitus. Three patients complained of dizziness, two of pitting leg edema, and one of abdominal discomfort with mild diarrhea. Except for severe headache in one patient and polyuria with weakness in another, these side effects were considered mild. The complete blood count, liver and renal function studies, fasting blood sugar, radiologic and electrocardiographic studies remained essentially unchanged throughout the study. DISCUSSION
In this study, 95% of patients with mild-to-moderate hypertension achieved good blood pressure control with a once-daily dose of amlodipine, without significant alterations in heart rate or liver and renal functions and without associated postural hypotension. Blood pressure control was maintained throughout the trial. Side effects were generally mild, except for severe headache in one patient and polyuria with weakness in another. Polyuria, a complaint in nine of our patients, has been previously reported with amlodipine therapy. 5 Amlodipine, like diltiazem, has been found to cause marked and sustained increases in sodium excretion and urine volume in experimental animals. ~ The sustained natriuretic and diuretic properties of amlodipine may be useful in offsetting the normal tendency of vasodilation to induce fluid retention; these properties may also contribute to the drug's antihypertensive efficacy.3'5 Amlodipine's gradual onset of action may explain its effectiveness without associated tachycardia, since reflex control mechanisms responsible for maintenance of homeostasis have a longer time to adjust. ~ In conclusion, this study shows that amlodipine 5 to 10 mg once daily is effective in controlling mild-to-moderate hypertension. The drug is well tolerated, and the tachycardia, headache, and flushing associated with other vasodilators are less severe and less common with amlodipine. The once-daily dosing regimen makes amlodipine a convenient agent for the monotherapy of mild-to-moderate essential hypertension.
Acknowledgment We thank Dr. S. B. Olupitan, of Pfizer Products (Nigeria) PLC, Ikeja, La1115
AMLODIPINEFORHYPERTENSION
gos, Nigeria, for initiating and supporting the trial and providing the study drugs. References:
1. Swartz A, Van Zwieten PA, Matlib MA, Millard RW. Pharmacology and therapeutic considerations of amlodipine, a new 1,4-dihydropyridine calcium antagonist. A m J Cardiol 1989; 64:1I-2I. 2. Swartz A. Calcium antagonists: Review and perspective on mechanism of action. A m J Cardiol 1989; 64:6I-9I. 3. Burges RA, Dodd MG, Gardiner DG. Pharmacologic profile of amlodipine. A m J Cardiol 1989; 64:101-20I. 4. Raftery EB, Heber ME, Erigden G, A1 Khawaja I. 24-hour control of blood pressure with the new once daily calcium antagonist amlodipine. In: Poole-Wilson PA, ed. 24-hour protection and control: A new era o f calcium antagonists. 1989:19-20. 5. Carter AJ, Gardiner DG, Burges RA. Natriuretic activity of amlodipine, diltiazem and nitrendipine in saline-loading anaesthetized dogs. J Cardiovasc P h a r m a c o l 1988; 12(Suppl 7):534-538.
1116
AMLODIPINE IN THE TREATMENT OF MILD-TO-MODERATE ESSENTIAL HYPERTENSION R. A. ESIN, O. E. ESSIEN, AND J. ANDY
Department of Medicine, College of Medical Sciences, University of Calabar, Calabar, Nigeria
ABSTRACT To evaluate the a n t i h y p e r t e n s i v e effect and safety of amlodipine, the drug was a d m i n i s t e r e d for 8 to 12 weeks to 21 Nigerian patients with mild-to-moderate hypertension. After a washout period of 1 week, amlodipine was a d m i n i s t e r e d at a dose of 5 mg once daily for 2 weeks and increased to 10 mg once daily if the patient's diastolic blood pressure did n o t fall to ~<90 m m Hg. Heart rate, blood pressure, a n d adverse drug reactions were monitored at 2-week intervals. Compliance was assessed by pill count. Nineteen patients completed the study. Systolic and diastolic blood pressures were significantly reduced i n all patients. Amlodipine m o n o t h e r a p y achieved effective r e d u c t i o n of diastolic blood pressure to ~<90 m m Hg in 95% of the cases. Heart rate did not change. Adverse events were generally mild a n d i n c l u d e d increased micturition or p o l y u r i a , headache, dizziness, p i t t i n g leg edema, and a b d o m i n a l discomfort with mild diarrhea. We conclude that monotherapy with amlodipine 5 to 10 mg/day is well tolerated a n d effective in c o n t r o l l i n g mild-to-moderate essential hypertension. INTRODUCTION
Calcium antagonists have assumed an important role in the management of angina pectoris and hypertension. 1'2 These drugs generally have a greater affinity for the calcium channels of vascular smooth muscles, especially those of the coronary arteries, than to those of the heart muscle itself, and they have virtually no affinity for the calcium channels in skeletal muscles. 1 Available calcium antagonists such as verapamil, diltiazem, and nifedipine have a short half-life and a low oral bioavailability, due to rapid elimination after oral administration) Unlike nifedipine, amlodipine has been reported to have a very slow rate of association and dissociation with the calcium channel receptors, and intra-arterial blood pressure monitoring has shown that once-daily oral administration of amlodipine is effective for 24-hour control of blood pressure. 3'4 Therefore, it was of interest to Address correspondenceto: J. Andy, Department of Medicine,Collegeof Medical Sciences,University of Calabar, Calabar, Nigeria. Received for publication on September 1, 1992. Printed in the U.S.A. Reproductionin whole or part is not permitted. 1112
0011-393X/94/$3.50
R. A. ESIN ET AL.
study the efficacy and safety of amlodipine in Nigerian hypertensive patients. P A T I E N T S AND M E T H O D S
Twenty-one patients (4 men, 17 women), ages 32 to 72 years (mean age, 47.7 years) with uncomplicated essential hypertension (World Health Organization stages I to II), were recruited for the study from the medical outpatient clinics of the University of Calabar Teaching Hospital, Calabar, Nigeria. Sixteen patients had been previously diagnosed and were receiving various other antihypertensive agents, and five patients were newly diagnosed. Only patients with essential hypertension and a diastolic blood pressure ranging from 95 to 115 mm Hg were eligible for the study. Patients with clinical heart failure, serious arrhythmias, hepatic dysfunction, renal decompensation, or mental disorders were excluded from the trial. Pregnant or lactating women and those taking oral contraceptives, as well as alcoholic patients, were also excluded. None of the patients included in the study had a concomitant illness. At entry, all patients gave informed consent. They provided a medical history and underwent a physical examination; laboratory tests included a complete blood count, electrolytes, urea, creatinine, and fasting blood sugar. Liver function studies, routine urinalysis, chest roentgenogram, and electrocardiogram were also performed. All antihypertensive medications were stopped during a 1-week washout period. If the sitting diastolic blood pressure was within the prescribed range (95 to 115 mm Hg) after the washout period, the patient was included in the study. Oral amlodipine 5 mg/day was then given for 2 weeks. If the diastolic blood pressure was >90 mm Hg at the end of 2 weeks, the dose was increased to 10 mg/day for another 2 weeks. After 4 weeks of therapy, patients who did not achieve the target diastolic blood pressure (~<90 mmHg) or who showed clinically significant adverse reactions were excluded from the study. Patients with acceptable blood pressure control and no serious adverse reactions were then followed up at 2-week intervals for an additional 8 weeks. Blood pressure (sitting and standing), heart rate, and weight were recorded at each visit. A pill count was also made at each visit to assess compliance, and the patient was questioned about side effects of the drugs. Data are expressed as the mean -+ standard error of the mean. Student's t test was used to compare data between the two groups. RESULTS
Nineteen patients (2 men, 17 women) completed 8 weeks of therapy; 13 of 1113
AMLODIPINEFOR HYPERTENSION
these patients remained in the study for 12 weeks. Two patients voluntarily withdrew from the study after 2 weeks and were not included in the data analysis. Eleven patients required 5 mg/day and eight patients required 10 mg/day of amlodipine to achieve acceptable blood pressure control. Patient compliance was excellent (100%). By week 4, both the systolic and diastolic blood pressures were significantly reduced (P < 0.005), and this reduction was maintained throughout the trial (figure). Diastolic blood pressure decreased to ~<90 mmHg in 18 (95%) of the 19 patients. In the remaining patient, the baseline blood pressure of 180/110 mmHg dropped to 180/90 mmHg and 170/90 mmHg at 4 and 6 weeks, respectively, but was 200/100 mmHg at 8 weeks of therapy, despite regular treatment with amlodipine 10 mg. This patient was removed from the trial at 8 weeks. There were no significant changes between sitting and standing blood pressures throughout the study. The mean heart rate was 87 + 13.2, 87 -+ 11.6, 83 -+ 13.2, 84 -+ 12.7 beats/rain at baseline, 4 weeks, 8 weeks, and 12 weeks, respectively. The heart rate did not significantly change during the study. Nine patients complained of increased micturition and polyuria, which was mild in eight but associated with increasing weakness in one. ioo
I90~
.'!" "i
80
170
E 60
,~150
u.I I,-
uJ 150 n"
~
~HR
r
I
I
I
T
n" I-rr
40
'
=
J.
•
SBP
o'~ u) I.U
20 ~ ,,o
"I-
T
a 0 0
0
~
90
1
~
j.
~
|
DSP
I
70
50"
30
6 n19
~,
e
n19 DURATION
12
hi9 OF
THERAPY
hi3 (WEEKS)
Figure. Mean change in h e a r t rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) in response to therapy with amlodipine 5 to 10 mg/day. *P < 0.05 compared with baseline; **P < 0.01 compared with week 4. 1114
R.A. ESIN ET AL.
However, electrolyte and urea levels remained normal in all nine patients. Seven patients admitted to improved appetite during therapy, but fasting blood sugar was normal and urine sugar was negative in all of them. Two patients complained of headache, which was intense in one; the headache occurred 1 to 2 hours after the drug was administered and disappeared with continuation of therapy. Two male patients discontinued the medication for a few days, complaining of weakness at coitus. Three patients complained of dizziness, two of pitting leg edema, and one of abdominal discomfort with mild diarrhea. Except for severe headache in one patient and polyuria with weakness in another, these side effects were considered mild. The complete blood count, liver and renal function studies, fasting blood sugar, radiologic and electrocardiographic studies remained essentially unchanged throughout the study. DISCUSSION
In this study, 95% of patients with mild-to-moderate hypertension achieved good blood pressure control with a once-daily dose of amlodipine, without significant alterations in heart rate or liver and renal functions and without associated postural hypotension. Blood pressure control was maintained throughout the trial. Side effects were generally mild, except for severe headache in one patient and polyuria with weakness in another. Polyuria, a complaint in nine of our patients, has been previously reported with amlodipine therapy. 5 Amlodipine, like diltiazem, has been found to cause marked and sustained increases in sodium excretion and urine volume in experimental animals. ~ The sustained natriuretic and diuretic properties of amlodipine may be useful in offsetting the normal tendency of vasodilation to induce fluid retention; these properties may also contribute to the drug's antihypertensive efficacy.3'5 Amlodipine's gradual onset of action may explain its effectiveness without associated tachycardia, since reflex control mechanisms responsible for maintenance of homeostasis have a longer time to adjust. ~ In conclusion, this study shows that amlodipine 5 to 10 mg once daily is effective in controlling mild-to-moderate hypertension. The drug is well tolerated, and the tachycardia, headache, and flushing associated with other vasodilators are less severe and less common with amlodipine. The once-daily dosing regimen makes amlodipine a convenient agent for the monotherapy of mild-to-moderate essential hypertension.
Acknowledgment We thank Dr. S. B. Olupitan, of Pfizer Products (Nigeria) PLC, Ikeja, La1115
AMLODIPINEFORHYPERTENSION
gos, Nigeria, for initiating and supporting the trial and providing the study drugs. References:
1. Swartz A, Van Zwieten PA, Matlib MA, Millard RW. Pharmacology and therapeutic considerations of amlodipine, a new 1,4-dihydropyridine calcium antagonist. A m J Cardiol 1989; 64:1I-2I. 2. Swartz A. Calcium antagonists: Review and perspective on mechanism of action. A m J Cardiol 1989; 64:6I-9I. 3. Burges RA, Dodd MG, Gardiner DG. Pharmacologic profile of amlodipine. A m J Cardiol 1989; 64:101-20I. 4. Raftery EB, Heber ME, Erigden G, A1 Khawaja I. 24-hour control of blood pressure with the new once daily calcium antagonist amlodipine. In: Poole-Wilson PA, ed. 24-hour protection and control: A new era o f calcium antagonists. 1989:19-20. 5. Carter AJ, Gardiner DG, Burges RA. Natriuretic activity of amlodipine, diltiazem and nitrendipine in saline-loading anaesthetized dogs. J Cardiovasc P h a r m a c o l 1988; 12(Suppl 7):534-538.
1116