A Project Report on

CLINICAL MANAGEMENT OF ANTIHYPERTENSIVE DRUGS

This project is submitted to

Dr. APJ Abdul Kalam Technical University, Lucknow (UP)

For the award degree of

Bachelor of Pharmacy

By

Himanshu Sharma

Roll no.: 1909080500035

Under the guidance of

Ms. Sakshi Sharma

Assistant Professor

NOIDA INSTITUTE OF ENGINEERING & TECHNOLOGY PHARMACY INSTITUTE,

GREATER NOIDA

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 CERTIFICATE

The project, “CLINICAL MANAGEMENTOF ANTIHYPERTENSIVE DRUGS” was

successfully carried out by Himanshu Sharma under my supervision. I certify that this is his
authentic work. The work described is original and has not been submitted to any other
university for any other degree.

Date:

Place: Greater Noida, UP

Project guide Ms. Sakshi Sharma (Assistant Professor)

Forwarded to: Dr.Avijit Mazumder

(Director, NIET, Pharmacy Institute)

---------------------------- ___________________

Internal Examiner External Examiner

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 STATEMENT BY THE CANDIDATE

As required by university regulation, I wish to state that this work embodied in this report titled
“CLINICAL MANAGEMENTOF ANTIHYPERTENSIVE DRUGS " forms my own
contribution to the research work carried out under the guidance of MS. SAKSHI SHARMA ,
Assistant Professor, Noida Institute of Engineering and Technology (Pharmacy Institute). This
work has not been submitted for any other degree of this or any other university. Whenever
references have been made to provious work of others, it has been clearly indicated as such and
included in the bibliography.

3
 DECLARATION

As required by University regulations, Himanshu Sharma, state that this work embodied in the
title “CLINICAL MANAGEMENT OF ANTIHYPERTENSIVE DRUGS” forms my own
contribution of the research work carried out under the guidance of Ms. Sakshi Sharma This
work has been submitted to Dr. APJ Abdul Kalam Technical University, Lucknow. The
information and data given in the report is authentic to the best of my knowledge and any
references of previous work of others has been mentioned in bibliography at the end of this
project. This work has not been submitted for any other degree or any other University.

Forwarded:

Ms. Sakshi Sharma (Assistant Professor)

NIET, Pharmacy Institute
Greater Noida

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 ACKNOWLEGMENT

This project on “CLINICAL MANAGEMENT OF ANTIHYPERTENSIVE DRUGS” would

not have been possible without the encouragement and support of my guide, Ms. Sakshi Sharma.
I extend my gratitude and respect to my guide who has been very supportive and has motivated
me. I am thankful to her that she invested her precious time to give her valuable suggestions and
guidance. I would also like to thank Dr. Avijit Mazumder (Director, NIET, Pharmacy Institute)
for his support and encouragement throughout the project. Apart from that, I would like to
extend my gratitude to my family and friends who did the best they could to help me do this
project successfully. This would not be possible without their love and support.

Himanshu Sharma 8thsem

Bachelor of Pharmacy NIET, (Pharmacy Institute)
Roll no.: 1909080500035

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 CONTENTS

S.NO CHAPTER PAGE NUMBER

1 Introduction 6-16
2 17-18
Literature review
3 Aim and objectives 19-20
4 21-22
Research methodology
5 Result and discussion 23-26
6 Conclusion 27-28

7 Reference 29-32

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 LIST OF FIGURES
Figure Number Figure Name
Figure 1.1 Causes of hypertension
Figure 1.2 Blood pressure
Figure 1.3 Antihypertension drug
Figure 1.1 Mechanism

LIST OF GRAPH
Graph number Graph Name
Graph 5.1 Antihypertensive drug related to age
Graph 5.2 Antihypertensive drug related to gender
Graph 5.3 Location
Graph 5.4 Do you have hypertension
Graph 5.5 Common medication physician/doctor
prescribed
Graph 5.6 Frequency of medication
Graph 5.7 Adverse drug reaction
Graph 5.8 Any other adverse effect

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 ABSTRACT
Successful treatment of hypertension is possible with limited side effects given the availability of
multiple antihypertensive drug classes. This review describes the various pharmacological
classes of antihypertensive drugs, under two major aspects: their mechanisms of action and side
effects. The mechanism of action is analysed through a pharmacological approach, i.e. the
molecular receptor targets, the various sites along the arterial system, and the extra-arterial sites
of action, in order to better understand in which type of hypertension a given pharmacological
class of antihypertensive drug is most indicated. In addition, side effects are described and
explained through their pharmacological mechanisms, in order to better understand their
mechanism of occurrence and in which patients drugs are contra-indicated. This review does not
address the effectiveness of monotherapies in large randomized clinical trials and combination
therapies, since these are the matters of other articles of the present issue. Five major
pharmacological classes of antihypertensive drugs are detailed here: beta-
blockers, diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists,
and calcium channel blockers. Four additional pharmacological classes are described in a shorter
manner: renin inhibitors, alpha-adrenergic receptor blockers, centrally acting agents, and direct
acting vasodilators.

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Chapter I: Introduction

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 INTRODUCTION: HYPERTENSION

1.1 Hypertension is a global disease considered as the leading risk factor for cardiovascular
diseases with significant health burden and accounts for 9.4 million deaths as well as 7.0%
disability-adjusted life years (DALYs) of global DALYs in 2010.(1) The prevalence in Nigeria
is estimated at over 28.9%.(2) It is associated with a high morbidity and mortality, from
increased risks of stroke, ischemic heart disease, renal failure, congestive heart failure as well
hypertensive heart diseases and the observation that it is worse in people of black
ancestry.(1,3,4,5)
1.2 The use of medicines and other forms of nonpharmacological therapy in treating
hypertension has been shown to reduce this morbidity and mortality.(6,7)There has been a
considerable increase in the arsenal of antihypertensive medicines in the past few decades, and
their use may be associated with the development of adverse reactions which is likely to result
in nonadherence to therapy, increased morbidity and mortality as well as economic
consequences.(8,9) It has also led to the withdrawal of some of these medicines from use.(10)
1.3 Adverse reactions in outpatient care have been estimated to occur in about 25% of
patients(11) and factors that have been associated with increased frequency of adverse
reactions include, number of medicines taken by the patient's genetic disposition, age,
pregnancy, and exogenous factors such as food and interactions with other
medicines.(12)Identification of adverse reactions using different methods has also been
advocated to limit the poor prognosis that is associated with adverse reactions.(11) The profile
of adverse reactions to antihypertensive medicines in our environment has not been properly
characterized given the antihypertensive armamentarium in use in this setting. There is a need
to properly characterize the tolerability profile of these medicines in this environment.

1.4 Few randomized clinical trials have considered the safety and efficacy of antihypertensive
medication reduction.
1.5 In routine clinical practice reduction. This trial examined a structured approach to
antihypertensive medication reduction in older patients with multimorbidity and controlled
systolic hypertension prescribed 2 or more antihypertensives.

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1.6 Antihypertensive drugs comprise several classes of compound with the therapeutic intention
of preventing, controlling, or treating hypertension. The classes of antihypertensive drug differ
both structurally and functionally. They are important in anesthetic practice because they are
commonly prescribed to the general population, with the overall prevalence of hypertension
being 31% in the UK [defined by the National Institute for Health and Care Excellence (NICE)
as a measurement of 140/90 mm Hg or higher in clinic, with subsequent ambulatory or home
measurement of 135/85 mm Hg or higher].(1) Antihypertensive drugs are used frequently in
other unrelated conditions, for example, β-blockers in thyrotoxicosis and anxiety, or angiotensin-
converting enzyme inhibitors (ACEIs) in heart failure. Hence both the drug and its indication are
relevant to the conduct of anesthesia.
1.7 This article focuses on the applied pharmacology of agents commonly encountered in UK
clinical practice, their therapeutic and side-effects, drug interactions, and implications for
anesthesia and surgery. The causes of hypertension are summarized in figure 1.

Figure 1.1 CAUSES OF HYPERTENSION

1.8 The majority of hypertensive patients have primary (or essential) hypertension, that is,
hypertension in which secondary causes are not present. Management aims to control arterial
pressure, prevent end-organ damage (cerebrovascular, cardiovascular, and renal), and reduce the
risk of premature death. (1) Arterial pressure may be lowered by reducing cardiac output,

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systemic vascular resistance (SVR), or both (Fig. 1). Drugs manipulating SVR may also bring
about clinical improvement through modification of vascular compliance and reactivity. For
example, the β-blockers carvedilol and atenolol reduce arterial pressure similarly at rest, but
carvedilol is associated with improved vascular compliance.
Drugs may be classified by mechanism or site of action. (2) Within each class, there are multiple
drugs with structural and pharmacological variations resulting in differing therapeutic and side-
effects (Fig 2). Many agents do not have a ‘clean’ mechanism of action, but act on multiple
pathways.

Figure 1.2 BLOOD PRESSURE

1.9 CLASSIFICATION OF HYPERTENSION

Classes and subclasses of antihypertensive medications with common examples:

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Figure 1.3 ANTIHYPERTENSION DRUGS

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1.9.1 Antihypertensives may be divided into two broad groups, (3) the first group being those
which directly or indirectly block the renin–angiotensin system (RAS), for example, ACEIs,
angiotensin receptor antagonists (ARAs), direct renin inhibitors (DRIs), and to a lesser extent
β-blockers. While these drugs have multiple mechanisms of action, their predominant effect
is to cause vasodilatation. The second group of drugs works by increasing water and sodium
excretion, thereby reducing intravascular volume, or by causing vasodilatation through non-
RAS pathways, for example, diuretics and calcium channel blockers (CCBs). The actions of
this second group increase RAS activity through negative feedback, a result of which is that
they can potentiate the activity of drugs which target and inhibit the RAS. The appropriate
choice of antihypertensive drug depends on which groups of drugs are most likely to be
effective both in controlling arterial pressure and in preventing complications such as end-
organ damage. Current NICE guidance recommends that patients under the age of 55 be
initiated on drugs which target the RAS as first-line therapy. Patients aged over 55 and black
people of African or Caribbean family origin are initially treated with drugs which act
through non-RAS mechanisms, as these latter patient groups typically have low-renin
hypertension. Additionally, there may be compelling individual indications or
contraindications for the use of a particular drug class. (1) Three drug classes directly target
points of the RAS pathway. They act to reduce production of the peptide hormone
angiotensin II, or reduce its receptor binding (Fig. 2). Angiotensin II has high affinity for
AT1 Gprotein-coupled receptors, activation of which causes increased arteriolar tone and
SVR. It also causes sympathetic nervous system activation, increased pituitary secretion of
antidiuretic and adrenocortocotrophic hormones, and increased adrenocortical secretion of
aldosterone. (4) By antagonizing the RAS pathway, SVR and arterial pressure are reduced.
This effect is potentiated by a reduction in aldosterone secretion with resultant reduction in
renal sodium and water retention. Negative feedback results in increased renin release by the
juxtaglomerular apparatus.
1.10 SYMPTOMS OF HYPERTENSION
• severe headaches.
• chest pain.
• dizziness.
• difficulty breathing.
• nausea.
• vomiting.
• blurred vision or other vision changes.
• anxiety.

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 Figure 1.4 SYMPTOMS

1.11 MECHANISM OF ANTIHYPERTENSION DRUGS

Figure 1.5 MECHANISM

1.11.1 Thiazide and Thiazide like diuretics: mechanism of action for thiazide-type diuretics
is not fully understood. Thiazides inhibit sodium transport in the distal tubule by blocking the
Na/Cl channels. Thiazides can have a small effect on the proximal tube by impairing sodium
transport, but the main action is on the distal tubule. Thiazides cause initial volume depletion
associated with decreased cardiac output, which recovers within 6 to 8 weeks of starting the
treatment in a reverse autoregulation mechanism while the blood pressure remains controlled;
thiazide diuretics can acutely activate the renin-angiotensin system and cause systemic
vascular resistance, which prevents a good response to the diuretic treatment, this increase in
renin-angiotensin activity may resolve with chronic thiazide treatment, the addition of an

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ACE inhibitor or ARB can enhance the blood pressure control. Also, the thiazide-type
diuretics have a modest vasodilation effect, although the mechanism is still unclear.

1.11.2 Calcium channel blockers: The mechanism of action of CCBs is related to the
inhibition of Ca2+ entry to the cells; this occurs by binding to the L-type voltage-gated
calcium channels located in the heart muscle. This effect can cause peripheral vasodilation,
which is seen mainly in dihydropyridines, or a negative inotropic effect on the heart muscle
in non-dihydropyridines, inhibiting the sinoatrial and atrioventricular nodes leading to slow
cardiac contractility and conduction.

1.11.3 ACE inhibitors decrease the blood pressure by inhibiting the angiotensin-converting
enzyme; this causes a decline in the production of angiotensin II and increases the bradykinin
level by inhibiting its degeneration, which leads to vasodilation.

1.11.4 ARBs work by blocking the binding of angiotensin II to the angiotensin 1 AT1
receptors, which inhibit the angiotensin II effect. In contrast to ACE inhibitors, ARBs do not
affect the kinin levels.

1.11.5 Beta-blockers work by inhibiting the catecholamines from binding to the Beta 1, 2,
and 3 receptors. Beta-1 receptors are found primarily in the heart muscle, beta-2 receptors are
located in the bronchial and peripheral vascular smooth muscles, and beta-3 receptors appear
in adipose tissue of the heart. Cardio-selective beta-blockers (e.g., metoprolol succinate,
metoprolol tartrate, atenolol, betaxolol, and acebutolol) inhibit only beta-1 receptors, causing
fewer bronchospasms. By inhibiting the catecholamines binding to the beta receptors, the
beta-blockers have a negative inotropic effect, which results in vasodilation of coronary and
peripheral arteries and decreases the heart rate, which helps to reduce the oxygen
consumption.

1.11.6 Loop diuretics work by increasing the sodium exertion at the level of the medullary
and cortical aspects of the thick ascending limb. This action causes a decrease in volume,
which leads to decreased blood pressure.

1.11.7 Potassium Sparing Diuretics: Act on the principal cells in the late distal tubule and
the collecting duct; they inhibit the sodium reabsorption at this level in association with
decreased excretion of potassium and hydrogen ions. Spironolactone and eplerenone are
considered mineralocorticoid receptor antagonists, inhibiting the mineralocorticoid receptor.

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1.11.8 Hydralazine is an arteriolar vasodilator; it inhibits Ca2+ release in the smooth
muscles of the vessels by decreasing its cytoplasmic concentration.

1.11.9 Clonidine: stimulates alpha-2 receptors located in the rostral ventrolateral medulla,
which reduces the sympathetic outflow from the central nervous system and decreases plasma
norepinephrine levels leading to decreased cardiac output.

1.11.10 Minoxidil is an arteriolar vasodilator; it opens the adenosine triphosphate-sensitive

potassium channels located in the smooth muscles of the vessels.

1.11.11 Alpha-blockers act by inhibiting alpha-1 receptors, which decrease vascular smooth
muscle contractions, leading to vasodilation.

1.12 ADVERSE EFFECT

1.12.1 Thiazides Side Effects

Thiazide and thiazide-like diuretics are associated with multiple side effects. Most of these
side effects are directly related to the diuretic dose; hypokalemia and hyponatremia are the
most common metabolic effects, followed by hyperuricemia, hypomagnesemia,
hyperlipidemia, and increased glucose levels.

Chlorthalidone was found in a study to have an increased risk of hospitalization due to severe
hypokalemia in the elderly. Other non-dose-related side effects are sexual dysfunction and
sleep disturbance.

1.12.2 CCB Side Effects

The treatment with dihydropyridine CCBs is often associated with peripheral edema. Long-
acting nifedipine is associated with a higher incidence of edema when compared to
amlodipine; the edema is related to the dose of the CCB. It is not related to sodium or fluid
retention or developing heart failure. Since CCBs induced edema is not a result of volume
increase, it does not improve with diuretics therapy; on the other hand, the combination of
CCBs with ACE inhibitors or ARBs to a lesser effect showed decreased risk of developing
peripheral edema. Dihydropyridines can cause lightheadedness, flushing, headaches, and
gingival hyperplasia.

Non-dihydropyridines are associated with bradycardia and can cause constipation in 25% of
patients.

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CCBs inhibit platelet aggregation and are associated with an increased risk of gastrointestinal
bleeding; caution is necessary when prescribing these agents to older patients and patients
with a high risk of bleeding.

1.12.3 ACE Is and ARBs Side Effects

The most common side effects related to ACE inhibitors are cough, hypotension, fatigue, and
azotemia; reversible renal impairment is a common side effect, especially if the patient
develops volume depletion due to diarrhea or vomiting.

Cough can occur in up to 20% of patients on ACE inhibitors. It takes up to 14 to 28 days after
discontinuation for the cough to resolve. The incidence of cough is less common with ARB
treatment; comparing losartan with hydrochlorothiazide showed a similar incidence of cough
in both medications. ARBs are safe to use in asthma patients; candesartan did not correlate
with an increase in the incidence of cough in patients with asthma compared to CCBs.
Ramipril demonstrated a higher rate of cough incidence compared to telmisartan.

ACE inhibitor treatment is commonly associated with mild hyperkalemia. Even in patients
with normal renal function, the risk of hyperkalemia increases in patients with renal failure,
diabetes, or CHF. Ramipril and telmisartan are similar in rates of developing hyperkalemia,
acute kidney injury, and syncope. but telmisartan is associated with more incidence of
symptomatic hypotension.

Angioedema is a rare side effect of ACE inhibitors; it appears in 0.3 % of patients on

ramipril; ARBs are less associated with angioedema than ACE inhibitors.

In Black patients, ARBs correlated with less incidence of both cough and angioedema.

1.12.4 Beta-blockers: Common side effects of beta-blockers are bradycardia, constipation,

depression, fatigue, and sexual dysfunction. Additionally, they are associated with
bronchospasm and worsening symptoms of peripheral vascular disease. They can cause a
flare-up of Raynaud syndrome.

1.12.5 Loop diuretics: are associated with electrolyte imbalance, mainly hypokalemia,
hyponatremia, hypomagnesemia, and hypochloremia. Other metabolic adverse reactions are
dehydration, hyperuricemia, and hyperlipidemia. Ototoxicity and deafness may occur with
loop diuretics treatment.

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1.12.6 Side effects of the Mineralocorticoid receptor antagonists: Hyperkalemia is the
major side effect of this group of medications. They can cause metabolic acidosis due to
decreased exertion of hydrogen ions. Erectile dysfunction and gynecomastia in men and
irregular menstrual periods in women can also occur.

1.12.7 Hydralazine: can cause headaches, flushing, palpitations, dizziness, hypotension

symptoms, and dizziness due to the sympathetic system stimulation. It is associated with
drug-induced lupus erythematosus, hemolytic anemia, and other immune phenomena.

1.12.8 Clonidine's common side effects are drowsiness, headache, dizziness, irritability,
nausea and vomiting, constipation, upper abdominal pain, and bradycardia, but other serious
side effects can occur as angioedema, atrioventricular block, and severe hypotension.

1.12.9 Minoxidil is associated with hirsutism.

1.12.10 Alpha-blockers are associated with tachycardia and orthostatic hypotension as a

result of venous dilation.

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Chapter II: Literature Review

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 LITERATURE REVIEW
1.Simon B. Dimmitt et al (2019): Efficacy and toxicity of antihypertensive pharmacotherapy
relative to effective dose 50

2.Tariq M Alhawassi et al (2018): Antihypertensive-related adverse drug reactions among

older hospitalized adults

3Sarah E McDowell et al (2013): A practical guide to monitoring for adverse drug reactions
during antihypertensive drug therapy

4.L J Veehof et al (2010): Adverse drug reactions and polypharmacy in the elderly in general
practice

5.Widya N Insani et al (2021): Prevalence of adverse drug reactions in the primary care
setting: A systematic review and meta-analysis

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Chapter III: Aim and Objectives

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 AIM AND OBJECTIVES
The aim of the present study was to monitor adverse drug reactions associated with
antihypertensive drugs. The study was conducted in Delhi-NCR. The study was conducted by
way of one-to-one patient interview by using a questionnaire based Adverse Drug Reaction
Monitoring Form drafted according to the World Health Organization Monitoring Guidelines
using google forms. The objectives of my study are:

• To find out categorized age group suffering from hypertension.

• General anti hypertensives prescribed by doctors.

• Adverse reactions of prescribed anti hypertensives.

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Chapter IV: Research Methodology

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 RESEARCH METHODOLOGY
There is only one technique which is used for the data collection of market survey of calcium
channel blocker drugs, data collection technique. Data collection Techniques: there are
following sub classes of data collection technique which are applied to collect the data in
about the calcium channel blocker drugs

• open (objective) data collection

• closed (objective) data collection

• primary data collection technique

• secondary data collection technique

• Questionnaire

1. Open (objective) data collection: The process in which data relating to the patient’s
problem are elicited from a Patient’s family the data are retrieved from the patient’s
description of an event rather than from a physical examination which provide object data.
The interviewer encourages a full description of the onset, the course and the character of the
problem of any factors that aggravate or ameliorate it

2. Closed (objective) data collection technique. The process in which the objective type of
data relating to the patient’s problem are formed and used to the elicit the patients problem
called as the closed data collection techniques.

3. Primary data collection technique: The data which are observed or collected from first
hand experiences is called as primary data collection technique

4. Secondary data collection techniques The data which are published and the data collected
from the past or other pales like Internet

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Chapter V: Result And Discussion

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RESULT AND DISCUSSION

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21
22
Chapter VI: Conclusion

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 CONCLUSION
In all, there is a relatively high prevalence of adverse reactions experienced by patients on
antihypertensive therapy resulting in a high rate of discontinuations as seen in this study.
Notable reactions experienced by the patients include dry cough to ACEIs, excessive
micturition to diuretics, and frequent micturition in patients on CCBs. Utilization of a
medicine induced symptom checklist revealed symptoms which were not reported on direct
questioning such as reduced libido and erectile dysfunction.

Some knowledge of the profile of antihypertensive medicines in use by the physicians will
aid the management of hypertension. Further studies are required to characterize this
problem.

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Chapter VII: Reference

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