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Therapy Versus Monotherapy In Reducing

Blood Pressure - A Focus On Safety And
E cacy (AbstractView.aspx?PID=2020-13-
6-85)
Author(s): Diksha Sharma (search.aspx?key=Diksha Sharma), Dinesh Kumar Mehta (search.aspx?key=Dinesh
Kumar Mehta), Karun Bhatti (search.aspx?key=Karun Bhatti), Rina Das (search.aspx?key=Rina Das), Ram Mohan
Chidurala (search.aspx?key=Ram Mohan Chidurala)

Email(s): rinammu@gmail.com (mailto:rinammu@gmail.com)

DOI: 10.5958/0974-360X.2020.00532.6 (https://doi.org/10.5958/0974-360X.2020.00532.6)

Address: Diksha Sharma1, Dinesh Kumar Mehta1, Karun Bhatti2, Rina Das1*, Ram Mohan Chidurala3
1M.M.College of Pharmacy, Maharishi Markandeshwar (Deemed to be) University, Mullana, Ambala, HR, India.
2Department of Medicine, M.M. Institute of Medical Sciences and Research, Maharishi Markandeshwar (Deemed
to be) University, Mullana, Ambala, HR, India.
3Hospitalist medicine physicians of Ohio, Mount Carmel East Hospital, 6001 E.broad street, Columbus, Ohio,
USA.
*Corresponding Author

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2/3/2021 RJPT - Amlodipine And Atenolol: Combination Therapy Versus Monotherapy In Reducing Blood Pressure - A Focus On Safety And Efficacy

Published In:   Volume - 13,      Issue - 6,     Year - 2020 (Issues.aspx?VID=13&IID=6)

Keywords: Amlodipine () Atenolol () Combination therapy () Hypertension () Monotherapy. ()

Cite this article:

Diksha Sharma, Dinesh Kumar Mehta, Karun Bhatti, Rina Das, Ram Mohan Chidurala.
Amlodipine And Atenolol: Combination Therapy Versus Monotherapy In Reducing Blood
Pressure - A Focus On Safety And Ef cacy. Research J. Pharm. and Tech 2020; 13(6): 3007-
3013. doi: 10.5958/0974-360X.2020.00532.6

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Amlodipine And Atenolol: Combination Therapy

Versus Monotherapy In Reducing Blood Pressure
- A Focus On Safety And Efficacy
Diksha Sharma1, Dinesh Kumar Mehta1, Karun Bhatti2, Rina Das1*, Ram
Mohan Chidurala3
1M.M.College of Pharmacy, Maharishi Markandeshwar (Deemed to be) University, Mullana, Ambala, HR, India
2Department of Medicine, M.M. Institute of Medical Sciences and Research, Maharishi Markandeshwar (Deemed to be)
University, Mullana, Ambala, HR, India
3Hospitalist medicine physicians of Ohio, Mount Carmel East Hospital, 6001 E.broad street,
Columbus, Ohio, USA.
*Corresponding Author E-mail: rinammu@gmail.com

ABSTRACT:
Cardiovascular diseases are major public health challenge. Hypertension is among the most important modifiable risk-factors for
cardiovascular diseases. Many placebo-controlled trials and meta-analysis study of antihypertensive medication have shown that
such treatment can prevent and postpone myocardial infarction and stroke. Amlodipine and atenolol are widely used in the
treatment of high blood pressure. Combining multiple classes of antihypertensive drugs together is one important practice for
achieving blood pressure control in most hypertensive patients. Most of the benefits of combination therapy in comparison with
monotherapy includes: a synergistic effect of each drug’s therapeutic effects and reduction of side effects due to lower dose of
each drug. Amlodipine with atenolol might bestow a good option for combining these two classes of agents with proven
cardiovascular benefits for better blood pressure control. In this study we have reviewed the effect of combination of atenolol and
amlodipine over monotherapy of amlodipine and atenolol in patients with mild-to-moderate hypertension.

KEYWORDS: Amlodipine, Atenolol, Combination therapy, Hypertension, Monotherapy.

INTRODUCTION:
Hypertension is the major and one of the strongest risk factors for almost all different cardiovascular diseases acquired during
life, including coronary disease, left ventricular hypertrophy and valvular heart diseases, cardiac arrhythmias including atrial
fibrillation, cerebral stroke and renal failure[1]. Moreover, untreated hypertension can adversely affect brain, heart, blood vessels,
kidneys and other parts of the body. Damage to these organs may cause heart disease, a heart attack, heart failure, stroke, kidney
failure loss of vision and other problems [2] To prevent cardio vascular diseases (CVD) it is important to improve lifestyle and
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failure, loss of vision, and other problems [2]. To prevent cardio vascular diseases (CVD), it is important to improve lifestyle and
reduce cardiovascular risk factors in the early stage [3].

Many anti-hypertensive drugs are currently available in the market for treatment of hypertension. They can be used as
monotherapy or in combination form [4]. Taking medication, making lifestyle changes help to control blood pressure. Daily life
style changes which include eating a diet that is low in fat and salt, maintaining a healthy weight, exercising at least 30 minutes
most days, not smoking, and using alcohol in moderation [5-6]. A satisfactory blood pressure control is rarely reached with
monotherapy alone. Most of the patients those are having problem related to high BP will need a combination drug therapy to
achieve the therapeutic goals [7]. The benefits of combination therapy compared with monotherapy include: a synergistic
enhancement of each drug’s hypertensive effects and a potential reduction of side effects if each drug is used at lower dose [8].

Although long-acting dihydropyridine calcium channel blockers and Beta-blockers are a good fit for combination therapy,
because of the risk of atrioventricular block and bradycardia, the combination of verapamil and beta blockers is not advised.
Amlodipine and atenolol are wide employed in the treatment of high blood pressure and appears different in this regard and
provides an opportunity for combining these two classes of agents with proven cardiovascular benefits for better blood pressure
control. The aim of the present study was to analyze the effect of amlodipine and atenolol alone as monotherapy and in
combination in lowering and stabilizing blood pressure and reducing other cardiovascular risks. This article will also address the
side effects associated with monotherapy of these drugs and will analyze if those side effects could be lessen or eradicated with
the combination of the two drugs to achieve a better and safer therapeutic lowering of blood pressure.

Amlodipine monotherapy:
Amlodipine, a calcium channel blocker (CCB) is indicated for the treatment of high blood pressure heart attacks, and chest pain
(angina). Randomized trials have ascertained its utility in angina pectoris [4]. Amlodipine significantly decreases the blood
pressure while causing little or no aggravation of renal dysfunction in hypertensive patients with renal impairment [9-10]. It has
also shown robust reductions on CV end points (especially stroke). Its abilities to prevent activation of counter-regulatory
mechanisms, to slow the progression of atherosclerosis, to confer antioxidant properties and to enhance NO production are all
unique actions. Amlodipine is a superior option in the treatment of hypertension, not only for controlling BP but also for safely
improving patient outcomes [11-12].

Amlodipine is usually dosed on a once daily basis because of its long half-life, which is favorable for patient compliance [13].
Adverse effect can be minimised if the drug is given at bedtime and if lower doses (2.5 or 5 mg/day) are used [14]. Joseph TF et
al. administered amlodipine to 55 children with hypertension, 49 of whom (89%) had secondary hypertension and found that
there was an inverse relationship between patient age and amlodipine dose. Adverse effects reported such as dizziness, fatigue,
flushing, and leg edema improved with dose reduction. Authors also concluded that young children require higher doses per
kilogram of body weight than older children [15]. The occurrence of leg edema due to amlodipine was also confirmed by a study
done by Rabah F and co-workers. Resolution of the edema took place with stoppage of amlodipine which confirmed amlodipine
as the cause of the edema [16]. In a study performed on hypertensive patients, not controlled by beta-blockers (BB) and
angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB), either conventional amlodipine or (S)-
amlodipine was administered, while continuing their previous anti-hypertensive medications. They concluded that in
hypertensive patients not controlled on prior BB and ACEI/ARB therapy, addition of (S)-amlodipine besylate at half the dose of
conventional amlodipine provides better tolerability with reduced incidence of peripheral edema, and equal antihypertensive
efficacy compared to amlodipine given at usual doses [17].

Monotherapy with amlodipine 5 to 10 mg/day is well tolerated and effective in controlling mild-to-moderate essential
hypertension as evident by clinical trial carried out by Esin RA and co-workers [18]. In another placebo-controlled, double-blind
trial conducted by Mehta JL et al concluded that amlodipine is effective in the 24-hour control of blood pressure in patients with
mild to moderate hypertension with the once daily dose and has lesser side effect if given once a day [19]. In a similar study
conducted on patients having mild-to-moderate essential hypertension, amlodipine significantly lower blood pressure compared
with placebo after 4 weeks of treatment[20]. Y. Valcarcel et al. concluded that amlodipine was well tolerated and effective drug,
and achieved the therapeutic goal in a higher proportion of patients at specialised-care centres compared with those in primary
care, and in those receiving combination therapy compared with monotherapy [21]. Wang JG et al. conducted a BP variability
(BPV) study in which they assessed whether patients receiving amlodipine vs other antihypertensive agents had lower BPV after
≥12 weeks of treatment. They concluded that amlodipine is effective for minimizing BPV [22].

Lee SA et al. conducted a meta-analysis study to compare the effects of amlodipine besylate, with other non-calcium channel
blocker and concluded that amlodipine reduced the risk of total cardiovascular events as well as all-cause mortality compared
with non-calcium channel blocker [23]. Similar study was conducted by Hamada T and co-workers where they concluded that
use of the drug amlodipine did not inhibit the increase in sympathetic nerve activity in essential hypertensive patients during the
chronic period, other beneficial effects on essential hypertension can be expected after its long-term administration [24].
Amlodipine can be safely combined with other antihypertensive drug classes, including diuretics [25-26].

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Atenolol monotherapy:
Beta-blockers are effective and safe antihypertensive drugs and are recommended as first-line therapy in most uncomplicated
hypertensive patients, used either alone or in combination with other drugs [27]. The new guidelines of JNC VII and the
European Society of Hypertension / European Society of Cardiolog listed conditions favouring the use of beta-blockers when
hypertension occurs together with angina pectoris, post-myocardial infarction, congestive heart failure, pregnancy or
tachyarrhythmia’s, but they also listed possible and compelling contraindications against the use of beta-blockers in hypertension
[28-29]. β-blockers are also indicated for patients at risk of stroke [30]. Study conducted by Asheesh K and co-workers concluded
that beta-blockers are more effective in long term secondary prevention after myocardial infarction and give life saving benefits
in most of the different types of patients. They found not to be effective for primary prevention of cardiovascular disease [31, 32].
Atenolol is a relatively long-acting (24 hours) beta-blocker [33]. It is recommended in myocardial infarction (MI), many other
types of arrhythmias, control of atrial fibrillation rate [34], chronic heart failure, hyper-adrenergic states such as a thyrotoxicosis,
migraines [35], or as a form of cardio protection in patients with anthracycline-induced cardiotoxicity [36]. Endothelial
dysfunction can also improve by atenolol [37]. Atenolol was found to produce maximum hypotensive effect at the 100mg dosage
and plasma level of atenolol and its hypotensive action were not related [38].

Studies also revealed that atenolol is an effective hypotensive agent in a once-daily dose [39] and has advantages over other beta-
adrenergic blocking agents [40]. Douglas-jones AP et al. reported that atenolol effectively decreased lying and standing blood
pressures, and there was no difference between the effects of the three doses. It was very effective in long-term treatment of high
blood pressure [41]. Atenolol reduced peripheral blood pressure but had different effects on central systolic wave reflections [42].
Drug showed reduction of BP when atenolol was given in doses of 100 and 200 mg once, plasma renin activity (PRA) was
decreased and there was no correlation between atenolol and stimulated pretreatment renin level [43]. Wilcox RG et al. conducted
a trial where atenolol and bendrofluazide was given once in a daily as effective in reducing blood pressure as the same
combination given twice daily. Drug atenolol reduced plasma renin and urate concentrations but increased plasma potassium
levels [44].

Jackson G et al. involved patients with stable angina pectoris and atenolol was given once daily. The research concluded atenolol
was an effective antianginal agent and suppressed resting and exercise-stressed heart rate for 24 hours after ingestion when given
in a 100-mg or 200-mg dose once daily[45].
But many research trials are evident that beta blockers including atenolol should not remain first choice in the treatment of
primary hypertension. A study involved follow up for a mean of four to six years which showed higher mortality rate
cardiovascular diseases with atenolol treatment than with other antihypertensive treatment. Chances of stroke were also more
frequent with atenolol treatment [46].

Eriksson S et al. suggested possible secondary prophylactic effect of atenolol in secondary prophylaxis after stroke and TIA [47].
In another study, Lindholm LH et al. found that relative risk of stroke was 16% higher for beta blockers than for other drugs.
They believe that beta blockers should not remain first choice in the treatment of primary hypertension [48]. Atenolol was found
to cause relatively weak blood pressure-lowering effect and the blood pressure instability [49-50]. Meta-analysis has suggested
the demerits of atenolol in the management of hypertension [51-52].

Amlodipine Vs Atenolol:
It was found that combination of long-acting dihydropyridine calcium channel blockers and β-blockers are a good fit for
combination therapy, because of the risk of atrioventricular block and bradycardia, the combination of verapamil and β-blockers
is not advised. Combination of higher-dose diltiazem and β-blockers is also not advised. Beta-blockers and diuretic agents as
initial lone combination therapy are not the preferred combination to be used in uncomplicated hypertension. Drugs ACE
inhibitor as initial combination therapy with most β-blockers is not recommended because of a lack of antihypertensive efficacy
[53]. Wald DS et al. concluded that blood pressure reduction from combining drugs have additive effects and the extra blood
pressure reduction from combining drugs from two different classes is approximately 5 times greater than doubling the dose of
one drug [54].

Anthony J B et al. concluded from their study that those patients who received amlodipine had better echocardiographic which
indicates better diastolic function at both time points when compared with atenolol [55]. Robyn JT et al. conducted study and
involved 1006 participants in HACVD (Hypertension Associated Cardiovascular Disease) substudy of ASCOT and concluded
that patients who received treatment with an amlodipine-based regimen had better diastolic function than patients treated with the
atenolol-based regimen [56].

In Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA), Collier DJ and co-workers
involved 9257 patients of age above 65 years and younger than 65 years and randomly assigned amlodipine or atenolol-based
antihypertensive therapy to both age groups. They concluded that amlodipine-based regimen is more effective than atenolol based
regimen in cardiovascular diseases for both older and younger patients [57]. It was also reported that treatment with amlodipine
corrected and improved endothelial function in essential hypertensive patients, as compared to the drug atenolol [58]. Based on a
computerized autospiror analysis it was concluded that atenolol treatment resulted in significant decline of forced vital capacity
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p p y g p y
(FVC), % forced vital capacity (%FVC), and forced expiratory volume in first second (FEV1) whereas amlodipine did not show
any significant change on various pulmonary parameters [59].

Rothwell PM et al. conducted a randomized trials in which the Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure
Lowering Arm (ASCOT-BPLA) compared amlodipine-atenolol based regimens hypertensive patients and found there was lower
risk of stroke in the amlodipine group and also the reduced risk of vascular events in SBP were increased in the atenolol group
compared with the placebo- diuretic group [60]. In a study of the Anglo-Scandinavian Cardiac Outcome Trial, Charlotte HM et
al. measured right carotid artery of 259 patients for finding out differences in wave reflection patterns when amlodipine- atenolol
based therapies were administered to hypertensive patients. Amlodipine regimen had lower carotid blood pressure when it
compared with atenolol. This difference is attributable to a lesser magnitude of wave reflection in patients randomized to the
amlodipine-based regimen[61].

Amlodipine and Atenolol: Combination therapy:

Importance of combination medical care has been well recognized within the treatment of high blood pressure. All of these
presumably novel approaches offer useful options for treatment in the otherwise difficult-to-control hypertensive patient [62].

Drugs which lower the blood pressure have some effects and may help to reduce each other's adverse effects. These combination
therapies have synergistic effect or their mechanisms of action include beta blocker and diuretic [63], ARB and diuretic [64-65]
ACE inhibitor and diuretic [63], CCB and ACE inhibitor [66-68], CCB and diuretic [69] and a thiazide diuretic plus and
potassium-sparing diuretic [63]. Both amlodipine and atenolol were found to reduce mean arterial pressure when assessed by a
non-imaging Echo-Doppler cardiac output device, over 3 months in 24 patients with essential hypertension [70].

Research suggests that the amlodipine has a gradual onset of action [71-73] and prolonged half-life [74] that causes little or no
reflex tachycardia [75]. These properties may improve its efficacy in suppressing ischemia, both alone and in combination with a
beta-blocker [76-77]. Johnson BF et al. found that once-daily administration of amlodipine or atenolol was well-tolerated and
provided adequate blood pressure control [78]. Pehrsson SK et al. found drug atenolol was more effective than amlodipine
regarding total time and number of ST-depression episodes. They conclude that if any alone drug given is more effective than
combination of a beta blocker with a calcium antagonist[79]. A 12-week concluded that superior antihypertensive efficacy is
offered by once daily treatment with atenolol/amlodipine fixed-dose combination over atenolol monotherapy in patients [80].
Mettimano M et al. found that when added to atenolol showed reduction of blood pressure values compared with placebo in
patients whose blood pressure was not controlled by atenolol alone. Blood pressure circadian rhythm remained same. Side-effects
were found to be reduced by adding amlodipine to a beta-blocker which confirms the effectiveness of this combination [81].

Lekha S et al. concluded in a study that the relative risk of developing constipation is 4 times more in patients who are taking
amlodipine alone as compared to those patients who are on combination of amlodipine and atenolol [82-83].

The basic principle for successful management of chronic conditions is medication compliance. Fixed drug combinations (FDC)
are formulated to simplify the medication regimens and thereby help in improving the drug compliance. The FDC therapy of
amlodipine and atenolol is widely accepted for managing [84] hypertension and chronic stable angina.

DISCUSSION:
Many anti-hypertensive drugs are currently available in the market for treatment of hypertension. They can be used as
monotherapy or in combination form. Amlodipine, a calcium channel blocker, proved to be highly effective for the treatment of
hypertension and stable angina as evidenced by the fewer hospitalizations for unstable angina and revascularization in
randomized controlled trials. It is effective for minimizing BP variability (BPV). But it was found that there is development of
edema in patients treated with amlodipine. Atenolol like beta-blockers are effective and safe antihypertensive drugs and are
recommended as first-line therapy in most uncomplicated hypertensive patients, used either alone or in combination with other
drugs. But many research trials are evident that beta blockers including atenolol should not remain first choice in the treatment of
primary hypertension. A four to six years follow up study showed higher mortality rate cardiovascular diseases with atenolol
treatment than with other antihypertensive treatment. Chances of stroke were also more frequent with atenolol treatment.

Amlodipine-based regimen was found to be more effective than atenolol based regimen in cardiovascular diseases for both older
and younger patients. Also patients who received treatment with an amlodipine-based regimen reported to have better diastolic
function than patients treated with the atenolol-based regimen. Amlodipine had better echocardiographic which indicates better
diastolic function when compared with atenolol. Amlodipine corrected and improved endothelial function in essential
hypertensive patients, as compared to the drug atenolol. But in essential hypertensive patients treatment with atenolol resulted in
significant decline of FVC, % FVC, and FEV1 whereas amlodipine did not show any significant change on various pulmonary
parameters. Also drug atenolol was more effective than amlodipine regarding total time and number of ST-depression episodes in
patients having stable angina pectoris and ST depression.

Fixed dose drug combination (FDC) of amlodipine and atenolol are being prescribed extensively for the management of
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g ( ) p g p y g
hypertension and chronic stable angina. By combining two drugs with different mechanisms of action, an antihypertensive effect
of two to five times greater than that obtained by monotherapy is possible[85]. Increasing the dose of monotherapy reduces
coronary events by 29% and cerebrovascular events by 40%, while combining two antihypertensive agents with a different
mechanism of action which help to reduces coronary events by 40% and cerebrovascular events by 54% [86]. Thus, the use of
combination therapy provides greater protection to a target organ than increasing the dose of monotherapy.

Combination therapy utilizing amlodipine and atenolol looks like a better option than increasing the dose as ischemia can be
more effectively suppressed by combination of these two than either single drug and the relative risk of developing constipation is
4 times more in patients who are taking amlodipine alone as compared to those patients who are on combination of amlodipine
and atenolol.

CONCLUSION:
A satisfactory blood pressure response is rarely reached with monotherapy alone. To combat the major side effects of a single
drug, combination therapy can be of substantial use. As development of edema, constipation etc with amlodipine results in poor
adherence, poor BP control and necessitate switching therapy, using beta-blockers like atenolol is likely to result in better
tolerance and BP control. FDC therapy of amlodipine and atenolol is widely accepted for managing hypertension and chronic
stable angina. The use of combination therapy provides greater protection to a target organ than increasing the dose of
monotherapy.

ACKNOWLEDGEMENTS:
The authors wish to thank M.M. College of Pharmacy, Maharishi Markandeshwar (Deemed to be) University, Mullana, India for
all necessary facilities.

DISCLOSURES:
The authors declare that there is no conflict of interest.

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