Literature Review On Cardiovascular Disease

A Literature Review on Modern and Herbal Pharmacological Approaches to
the Treatment of Cardiovascular Diseases
A dissertation submitted to the Department of Pharmacy, East West University, in partial

fulfillment of the requirements for the Degree of Bachelor of Pharmacy
Submitted by:
Name: Shaherin Islam Tuba
ID: 2018-1-70-008
B. Pharm, Department of Pharmacy
East West University, Dhaka, Bangladesh
Submitted to:
Mst. Marium Begum
Senior Lecturer
Department of Pharmacy
East West University, Dhaka, Bangladesh
In the name of ALLAH
The most Graceful
The most Merciful
Declaration by the Research Candidate
I declare that this is a true copy of my research paper, including any final revisions, as approved
by my research supervisor.
Review Paper Title “A Literature Review on Modern and Herbal Pharmacological

Approaches to the Treatment of Cardiovascular Diseases”. I do hereby declare that the whole
research work presented as a research paper has been submitted in partial fulfillment of the
requirement for the Degree of B. Pharm under the supervision and guidance of Mst. Marium
Begum, Senior Lecturer, Department of Pharmacy, East West University, Dhaka. The work
presented in this research paper has not been submitted previously for any kind of degree at any
educational institution. I certify that, to the best of my knowledge, my research paper does not
infringe upon anyone’s copyright nor violate any proprietary rights and that any ideas, techniques,
quotations, or any other material from the work of other people included in my research paper,
published or otherwise, are fully acknowledged following the standard referencing practices.
________________________________
Shaherin Islam Tuba

ID: 2018-1-70-008
Department of Pharmacy,
East West University.
Certificate by the Supervisor
A Literature Review on Modern and Herbal Pharmacological Approaches to the Treatment of

Cardiovascular Diseases submitted to the Department of Pharmacy, East West University for the
partial fulfillment of the requirement for the award of the degree Bachelor of Pharmacy is a
bonafide record of original and genuine research work carried out by Shaherin Islam Tuba, ID
No.: 2018-1-70-008 in 2021 of her research in Department of Pharmacy, East West University,
under the supervision and guidance of me.
__________________________________
Mst. Marium Begum

Senior Lecturer
Certificate by the Chairperson
This is to certify that the research paper entitled “A Literature Review on Modern and Herbal
Pharmacological Approaches to the Treatment of Cardiovascular Diseases”. East West
University for the partial fulfilment of the requirement for the award of the degree Bachelor of
Pharmacy is a bonafide record of original and genuine research work carried out by Shaherin
Islam Tuba, ID No.: 2018-1-70-008 in 2021 of her research in the Department of Pharmacy, East
West University, under the supervision and guidance of me.
________________________________
Dr. Chowdhury Faiz Hossain

Professor and Chairperson
Acknowledgment
To begin with, all praises go to the Almighty, the most lenient, most liberal and bounteous to every
human being and living creature and their activities.
I would like to express my deepest gratitude to my research supervisor, Mst. Marium Begum,
Senior Lecturer, Department of Pharmacy, East West University, who had always been optimistic
and full of passion and ideas. Her generous advice, constant supervision, intense support,
enthusiastic encouragement and reminders during the research work not only helped to shape this
study but also helped me to be a better researcher. Her in-depth thinking, motivation, timely advice
and encouragement have made it possible for me to complete this research. It is her guided
supervision that brought about effective fulfillment and submission of the research paper.
During this research work, a lot of experience I have received which is of inestimable value for
my life.
I
Abstract
The majority of the population worldwide suffers from cardiovascular diseases (CVDs). Ischemic
heart disease is a number 1 cause of death that takes approximately 18 million lives each year
globally. If any defect occurs in cardiac impulse formation, it causes the alternation of impulse
conduction that leads to several types of disturbances in cardiac rhythm. As the treatment of a
cardiac patient is very costly, death occurs to patients who are left untreated. A huge number of
medicines are available in the market for cardiac patients and many medicines are in clinical trials
for the treatment of CVDs. This article represents the traditional and pharmacological medications
used in healthcare for the treatment of various CVDs. The information on the medications effective
against CVDs published in scientific journals, books, websites and reports were compiled from
different electronic databases using specific keywords. In total, more than 170 relevant papers,
journals, books and websites were reviewed for preparing this article. In this study, cardiovascular
medicines were found to be the most effective medication for the patients followed by lifestyle
modification and surgical means. The most effective and frequently used medicines for cardiac
patients are β-blockers, ACE inhibitors, ARBs, organic nitrates, renin inhibitors, diuretics, calcium
channel blockers, vasodilators, vasopressors, anticholinergic chronotropic agents and
antihypertensive combinations against CVDs within the flora of modern treatment.
Keywords: Cardiovascular Diseases • Pharmacology • Pharmacokinetic Properties • Medicines •

Contributing Factors
II
Index
Contents Page Number
Acknowledgment I
Abstract II
Table of Contents IV
List of Tables VI
List of Graphs and Charts VI
List of Figures VII
List of Abbreviations VIII
III
Table of Contents
Chapters Contents Page
Number
Chapter 1: Introduction 1
1.1 An overview of Cardiovascular Disease 2
1.2 Types of Cardiovascular Disease 3
1.3 Global Burden of Cardiovascular Disease 4
1.4 Prevalence of Cardiovascular Disease in Bangladesh 8
1.5 Contributing Factors of Cardiovascular Disease Complications 11
Chapter 2: The Heart and Heart Function 13
2.1 The Heart 14
2.2 Physiology of Cardiac Function: Cardiac Rhythm 17
2.3 Distribution of Cardiac Rhythm 17
2.4 Physiology of Cardiac Function: Cardiac Contraction 19
2.4.1 Myocardial Contractility and Viability 19
2.4.2 Myocardial Oxygen Consumption and Coronary Blood Flow 19
2.5 Drugs that affect Cardiac Function 20
Chapter 3: Methodology 21
3.1 Search Strategy 22
3.2 Study Selection and Data Extraction 22
Chapter 4: Pharmacological Approaches for Cardiovascular Disease: 23
Modern Heart Medications
4.1 An Overview of Heart Disease Drugs 24
4.2 Angiotensin-Converting Enzymes (ACE) Inhibitors 26
4.3 Angiotensin Receptor Blockers (ARBs) 29
4.4 Antianginal Drugs 32
4.5 Organic Nitrates 32
4.6 Ca2+ Channel Blockers 34
4.7 β-Adrenergic Receptor Antagonists (β-Blockers) 37
4.8 Antiarrhythmic Drugs 40
IV
Table of contents
Chapters Contents Page
Numbers
Chapter 4: Pharmacological Approaches for Cardiovascular Disease: Modern Heart
Medications
4.9 Diuretics 47
4.10 Renin Inhibitor 54
4.11 Vasodilators 56
4.12 Vasopressors and Inotropic Agents 57
4.13 Anticholinergic Chronotropic Agents 58
4.14 Antihypertensive Combinations 58
Chapter 5: Pharmacological Approaches for Cardiovascular Disease: 63
Herbal Heart Medications
5.1 Herbal Medications against Cardiovascular Disease 64
Conclusion 68
Bibliography 69
V
List of Tables
Serial Contents Page
Number Number
1.2.1 Types of Cardiovascular Diseases (CVDs) 3
1.5.1 Contributing Factors of Cardiovascular Diseases 11
4.1.1 Types of Cardiovascular Drugs 24
4.2.1 ACE Inhibitors 26
4.2.2 Pharmacokinetic Properties of ACE Inhibitors 27
4.3.1 Pharmacokinetic Properties of ARBs 30
4.5.1 Pharmacokinetic Properties of Organic Nitrates 33
4.6.1 Pharmacokinetic Properties of Ca2+ Channel Blockers 35
4.7.1 Pharmacokinetic Properties of β-Blockers 38
4.8.1 Antiarrhythmic Drugs 40
4.8.2 Summary of Antiarrhythmic Drugs 41
4.9.1 Types, Location, Mechanism of Action and Examples of Diuretics 48
4.13.1 A Short Description of Anticholinergic Chronotropic Agents 58
4.14.1 Description of Antihypertensive Combinations 59
List of Graphs and Charts

Number Number
Graph A Heart Disease Mortality between 1990 and 2020 in Male 5
Graph B Heart Disease Mortality between 1990 and 2020 in Female 6
Graph C Cardiac patient according to the demographic viewpoint. 8
Graph D Different medical conditions observed among patients. 9
Graph E Therapeutic classes prescribed to patients. 9
Graph F Therapeutic combinations prescribed by physicians. 10
Chart A CVD mortality in Developed Countries per 100,000 (Male) 7
Chart B CVD mortality in Developed Countries per 100,000 (Female) 7
VI
List of Figures
Number Number
2.1.1 Longitudinal Diagram of Human Heart 15
2.1.2 Cross-sectional Diagram of Human Heart 16
4.2.1 Chemical Structure of ACE Inhibitors 28
4.3.1 Chemical Structure of ARBs 30
4.5.1 Chemical Structure of Organic Nitrates 34
4.6.1 Chemical Structure of Ca2+ Channel Blockers 36
4.7.1 Chemical Structure of β-Blockers 39
4.8.1 Chemical Structure of Class Ia Antiarrhythmics 44
4.8.2 Chemical Structure of Class Ib Antiarrhythmics 44
4.8.3 Chemical Structure of Class Ic Antiarrhythmics 45
4.8.4 Chemical Structure of Class II Antiarrhythmics 45
4.8.5 Chemical Structure of Class III Antiarrhythmics 46
4.8.6 Chemical Structure of Class IV Antiarrhythmics 46
4.8.7 Chemical Structure of Miscellaneous Antiarrhythmics 47
4.9.1 Chemical Structure of Osmotic Diuretics 52
4.9.2 Chemical Structure of Carbonic Anhydrase Inhibitor 52
4.9.3 Chemical Structure of Loop Diuretics 53
4.9.4 Chemical Structure of K+ Sparing Diuretics 53
4.9.5 Chemical Structure of Thiazide Diuretics 54
4.10.1 Chemical Structure of Renin Inhibitors 55
4.11.1 Chemical Structure of Vasodilators 56
4.12.1 Chemical Structure of Vasopressors 57
VII
List of Abbreviations
CVDs: Cardiovascular Diseases
ACE: Angiotensin Converting Enzyme
ARB: Angiotensin Receptor Blockers
NO: Nitric Oxide
cGMP: Cyclic guanosine monophosphate
PPAR: Peroxisome Proliferator-Activated Receptor
RAAS: Renin-angiotensin-aldosterone system
FDA: Food and Drug Administration
WHO: World Health Organization
NHANES: National Health and Nutrition Examination Survey
VIII
Chapter 1: Introduction
1
1.1. An Overview of Cardiovascular Disease
The cardiovascular system, as an integral part of the organ systems, is associated with the
distribution of blood to all parts of the body. This system plays a major role in blood circulation
throughout the body, thus allowing it to survive. Blood contains several essential nutrients like
oxygen, electrolytes, etc. The body takes those essential nutrients and releases waste products like
carbon dioxide. The cardiovascular system also functions in regulating body temperature and
immune response. Cardiovascular diseases (CVDs) or heart diseases refer to several classes of
diseases in which the heart, arteries & veins that supply oxygen to the body are altered due to
abnormalities or dysfunction. As a result, cells, tissues, organs and the heart cannot get enough
blood supply. If oxygen supply is not enough according to the cells, tissues and organs’ needs,
they will die. In severe cases, the heart stops functioning. In recent years, these diseases are rising
due to the increase of life expectancy, smoking, inactivity, obesity, high blood pressure, diabetes,
high cholesterol and/or family history of CVDs. A new report from the World Health Organization
(WHO) shows that about 523 million people were suffering from various kinds of heart diseases
worldwide (in 2019), among them 18.6 million deaths [1].
In the first stage, lifestyle modification (maintaining a healthy diet and light exercises, low intake
of fat, quitting smoke) helps to prevent or control heart disease. If lifestyle modification doesn’t
work, medicine supplements play an important role in the treatment of cardiovascular diseases
without or with limited side effects. For the treatment of cardiovascular disease, traditional and
synthetic medicines are prescribed to the patients based on their body’s physiology.
Anticoagulants, angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, calcium-channel
blockers, digitalis glycoside, diuretics, cholesterol-lowering medications are some popular and
widely used medications in the treatment of these diseases. If lifestyle modification and medicine
intake don’t work, then surgery is needed for critical patients according to their heart condition.
Thus, the knowledge of pharmacology and ethnobotany is important to provide valuable
approaches for the medications and treatment of cardiac illness [2].
The aim of this review paper is to provide a brief overview of current updates on modern and
herbal pharmacological approaches for cardiovascular disease management.
2
1.2. Types of Cardiovascular Disease
As cardiovascular disease is a major worldwide concern, it is important to know about its
classification and symptoms to prevent this disease. If a patient has proper knowledge, he can
easily manage his medications and maintain a healthy life. There are several types of CVDs
identified by the healthcare professionals and scientists listed below [3, 4, 5, 6, 7]:
Table 1.2.1: Types of Cardiovascular Diseases (CVDs) [3]

Name of the Disease Cause(s)
Abnormal Heart Rhythms or Arrhythmias Uneven, irregular or abnormal heartbeat
(either too slow or too fast) than the normal
range (60-100 times per minute).
Aorta Disease and Marfan Syndrome Hardening of arteries, high blood pressure,
connective tissue disorders and injury.
Congenital Heart Disease Genetic disorder, viral infections, alcohol.
Coronary Artery Disease Build-up of plaque, narrowing of the arteries.
Deep Brain Thrombosis and Pulmonary Clotting of blood in veins (usually legs),
Embolism genetic disorder, long time bed rest,
pregnancy, birth control pills, and hormone
replacement.
Heart Attack Death of cardiac tissue due to very poor blood
supply [4].
Heart Failure The heart stops functioning.
Cardiomyopathy Thicker, stiffer or enlargement of heart muscle
[5].
Heart Valve Disease Narrowing of aortic valve, poor blood flow.
Pericardial Disease Inflammation on the lining of the heart.
Peripheral Vascular Disease Blockage, spasms or narrower blood vessels
including arteries and veins of the heart [6].
Rheumatic Heart Disease Damaging of heart valves (Inflammation).
Stroke Blockage of blood flow to the brain.
Vascular Disease (Blood Vessel Disease) Stretching of the network of blood vessels [7].
3
1.3. Global Burden of Cardiovascular Disease
The treatment of cardiovascular disease is very costly. So, it is a challenging issue not only for
developing countries but also for many developed countries like America, China, and Japan. The
disease profile and health status of a patient are economically linked to each other. With
civilization and industrialization, the death and disability of people have also increased because of
man-made pollutants, accidents, violence and infectious diseases [8].
In advanced societies, there are deficiencies of nutritional foods, laziness and meals containing
high cholesterol are the several factors that influence CVDs. Nowadays, different countries in the
world have different stages of epidemiologic transition and these transitions are causing many
degenerative diseases like CVD, cancer and diabetes [9].
A statistical view is presented on graph A and B where we can see the increase of percentage of
heart disease mortality in different Asian, European and American regions (both male and female)
between the years of 1990 and 2020 [10].
In developing countries, high burdens of CVD are increasing day by day due to urbanization and
contributing factors like obesity, dyslipidemia, hypertension, diabetes etc. and these factors can
arise at a very early age in both males and females [11]. Percentage (%) of increase in cardiac
mortality are quite higher in males than females in each region. So, males are always at greater
risk of suffering from CVD.
Another two pie charts show CVD mortality per 100,000 people [12]. In the 8 countries mentioned
in the pie chart, low cardiac mortality rates were observed in Japan and in Ukraine, the cardiac
mortality is much higher in both males and females. These differences were caused due to the
variations in diet, serum cholesterol and blood pressure among people.
A recent report of the World Health Organization (WHO) demonstrates that men are in 10-fold
greater risk of affecting cardiovascular mortality than women [13].
4
An Estimate of Ischemic Heart Disease Mortality (Thousand) According
to the Regional Viewpoint Between 1990 and 2020 in Male
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
1990 2020 % of Increase
Graph A: Heart Disease Mortality between 1990 and 2020 in Male [13]
5
An Estimate of Ischemic Heart Disease Mortality (Thousands) According
to the Regional Viewpoint Between 1990 and 2020 in Female
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
1990 2020 % of Increase
Graph B: Heart Disease Mortality between 1990 and 2020 in Female [13]
6
CVD Mortality in Develpoed Countries per 100,000 (Male)
60 43
103
474
138
240
390
262
Ukraine Russia Hungary Czech Republic

Canada Brazil France Japan
Chart A: CVD mortality in Developed Countries per 100,000 (Male) [12]
CVD Mortality in Developed Countries per 100,000 (Female)
24 22
63
62 279
129
142 193
Ukarine Russia Hungary Czech Republic

Canada Brazil France Japan
Chart B: CVD mortality in Developed Countries per 100,000 (Female) [12]
7
1.4. Prevalence of Cardiovascular Diseases in Bangladesh
A descriptive study was carried out in July 2016 and continued for three months to observe the
prevalence of cardiovascular disease among 853 Bangladeshi patients in both males and females.
The study ended in September 2016. The ratio of male and female patients was 5.8:4.2 and most
patients came from urban areas. Among them, more than 48% patients were suffering from lipid
level disorder, 30% were reported hypertension, 28.5% were suffering from heart failure, 20.9%
were suffering from myocardial infarction, 19.9% patient had ischemic heart disease, 17.1% had
stroke and 11% were suffering from angina pectoris. Four graphical methods are presented here
sequentially to view the prevalence of cardiovascular disease and their treatment strategy in
Bangladesh [14].
Percentage of Cardiac Patient According to the Demographic Viewpoint

600
500
Percentages (%)
400
300
200
100
0
Male Female
Percentages % 57.8 42.2
Number of Patients 493 360
Graph C: Cardiac patient according to the demographic viewpoint [14].
8
Different Medical Conditions Observed Among Patients
Angina 11
94
Stroke 17.1
146
Ischemic Heart Disease 19.9

170
Myocardial Infraction 20.9

179
Heart Failure 28.5

243
Hypertension 30
256
Lipid Level Disorder 48.7

415
0 50 100 150 200 250 300 350 400 450
Percentage (%) Number of Patients
Graph D: Different medical conditions observed among patients [14].
Therapeutic Classes Prescribed to those Patients
Calcium Channel Blockers 111

13
ARBs 131
15.4
ACE Inhibitors 276

32.4
Diuretics 334
39.2
Beta Blockers 444

52.1
Others 531
62.3
Lipid Lowering Drugs 659

77.3
Antianginal 673
78.9
Antiatherogenic 702
82.3
Anxiolytics 710
83.2
0 100 200 300 400 500 600 700 800
Number of Patients Percentage (%)
Graph E: Therapeutic classes prescribed to patients [14].
9
% of Therapeutic Combination Prescribed by Physician
Angiotensin II Receptor Antagonist+ACE Inhibitor+ 2.7

Antihyperlipidemic 23
ACE Inhibitor+Beta Blocker+Antianginal 2.7

23
Antianginal+ACE Inhibitor+Coronary Vasodilator 27.5

235
Beta Blocker+Antihyperlipidemic+ACE Inhibitor 10.8

92
ACE Inhibitor+Antianginal+Antihyperlipidemic 5.5

47
Antianginal+Coronary Vasodilator 2.7

23
Antihyperlipidemic+Beta Blocker 5.5

47
ACE Inhibitor+Diuretics 2.7

23
Antihyperlipidemic+Coronary Vasodilator 2.7

23
Antihyperlipidemic+Angiotensin II Receptor Antagonist 2.7

23
Beta Blocker+Antianginal 10.8

92
ACE Inhibitor+Antianginal 10.8

92
ACE Inhibitor+Antihyperlipidemic 10.8

92
Beta Blocker+Antihyperlipidemic 21.3

182
Antianginal+Antihyperlipidemic 5.5
47
Beta Blocker+ARBs 5.5

47
ACE Inhibitor+Beta Blocker 5.5

47
0 50 100 150 200 250
Percentages (%) Number of Patients
Graph F: Therapeutic combinations prescribed by physicians [14].
10
1.5. Contributing Factors of Cardiovascular Disease Complications
The exact cause of the cardiovascular disease is unclear. But there are a lot of factors that can
increase the risk of getting it. These factors are known as “contributing factors” or “risk factors”.
So, a person should be aware of the risk factors of CVDs to prevent it. The main risk factors that
develop CVDs are listed below [15]:
Table 1.5.1: Contributing Factors of Cardiovascular Diseases [15]

Categories Risk Factors Cause(s)
Health Conditions Elevated Blood Pressure High pressure of blood to the arteries and
veins causes abnormal heart rhythm.
High Cholesterol Level Cholesterol is a waxy substance that builds
up on the walls of arteries of the heart and
reduces or restricts the blood flow within it.
Diabetes Mellitus High levels of sugar build up in the blood
that reduces the flow of blood into the heart.
Obesity Excess body fat linked with Low Density
Lipoprotein cholesterol (bad cholesterol)
causes elevated blood pressure and diabetes
mellitus. Thus develops CVDs.
Behaviour Eating highly saturated Cholesterol is a waxy substance that builds
fat and cholesterol up on the walls of arteries of the heart and
reduces or restricts the blood flow within it
whereas saturated fat contains excess sodium
that causes elevated blood pressure.
Laziness Body cannot disburse enough energy
provided by the foods as a result, builds up
other risk factors like high blood pressure,
diabetes, obesity, high cholesterol levels and
develops CVDs.
11
Contributing Factors of Cardiovascular Diseases
Categories Risk Factors Cause(s)
Behaviour Drinking Alcohol Alcohol increases fat and cholesterol level in
the blood as a result, blood vessels become
too fatty and stiffer. Fatty blood vessels
restrict blood flow to the heart. All these
conditions build up CVDs and high blood
pressure.
Smoking Smoking damages the heart and blood
vessels, reduces blood flow to the heart thus
reduces heart function, raises blood pressure
and reduces oxygen level in the blood. All
these complexes together cause severe
symptoms of CVDs.
Family History Heredity If diseased traits are passed from previous
[Transmission of traits generation to the next generation, the
(genetic information) members of the next generation can be at
from one generation to high risk of developing CVDs as the
the next generation is environments, lifestyle and diets of the
called heredity.] generations are quite common.
Other Age & Sex CVDs can happen at any age, but older
persons are at higher risk of developing
CVDs than younger ones. Men are more
susceptible to heart disease than women.
Race & Ethnicity For some racial and ethnic groups, CVDs are
more crucial and death occurs more
frequently to those ethnics include the
United States, African Americans, American
Indians and Alaska Natives, and white
people. Asian Americans, Pacific Islanders
and Hispanics are highly susceptible.
12
Chapter 2: The Heart and Heart Functions
13
2.1. The Heart
The heart is a muscular organ. It acts as a pumping machine to circulate blood throughout the body
through arteries and veins. A healthy human heart beats about 2600 million times on average and
clears 155 million liters (1.5 million tons) of blood from each ventricle during his lifetime. The
weight of the heart is approximately 300 grams in males and 200 grams in females. A healthy heart
beats 60-100 times per minute.
Location: The heart is located above the diaphragm, between two lungs, just behind and slightly
left of the breastbone.
Shape: The shape of the heart is triangle. The upper part of the heart is wider and the bottom part
is very narrower which locates in between the 5th and 6th ribs.
The heart is protected with a thin membrane consisting of two layers, known as pericardium. The
outermost layer of pericardium is called parietal pericardium and the innermost layer is called
visceral pericardium. Pericardial fluid is located between the two layers. Its main function is to
control the contraction and relaxation of the heart.
The cardiac muscle or heart muscle consists of three layers:
Epicardium: It is the outer layer. Scattered fat molecules are adhered on this layer.
Myocardium: It is the middle layer. It helps in contraction and relaxation of the heart muscle.
Endocardium: It is the inner layer. It makes up the lining of the valves, serving as a barrier
between the cardiac muscles and bloodstream. This layer contains necessary blood vessels [16].
Human heart is divided into four parts. Two upper parts are known as right and left atrium and two
bottom parts are known as right and left ventricles. The right atrium receives blood from the veins
and pumps it to the right ventricle.
The right ventricle receives blood from the right atrium and pumps it to the lungs, where it is
loaded with oxygen. When contraction occurs, the left atrium receives oxygenated blood from the
lungs and pumps it to the left ventricle. The left ventricle (considered as the strongest chamber)
pumps oxygen-rich blood throughout the body. The pressure of the left ventricle regulates blood
pressure. The coronary arteries run along the surface of the heart and provide oxygen-rich blood
to the heart muscle [17].
14
Figure 2.1.1: Longitudinal Diagram of Human Heart [18]
15
Figure 2.1.2: Cross-sectional Diagram of Human Heart [19]
16
2.2. Physiology of Cardiac Function: Cardiac Rhythm
The heart chambers are normally arranged in a coordinated manner to pump the blood efficiently
by the valves. Systole is the phase of heartbeat when heart muscle contracts and pumps the blood
from the chamber into the arteries. Diastole is exactly the opposite phase, when the heart muscle
relaxes and allows the chamber to fill with blood. Each systole and each diastole, together, is called
a heartbeat. Cardiac rhythm is the pattern of electrical impulses that allows the heart to squeeze
and pump blood, controlled by sinoatrial (SA) node, atrioventricular (AV) node, bundle of His,
Purkinje fibres and ventricles [20]. Electrical impulses transfer by the nerves to voltage gated ion
channels which are selective for various ions, such as, Na+, K+ and Ca2+. Electrical impulses
conduct the heartbeat. There are several features that distinct the electrophysiology of cardiac cells
from other cells such as:
● Activity of pacemaker
● Absence of fast electrical input of SA and AV nodes
● Long action potential
● Slow electrical impulse of Ca2+ ion channels.
To initiate a healthy cardiac rhythm, normal electrical impulses of voltage-dependent Ca2+

channels are very important. In adults, the L-type Ca2+ channel is very prominent because it is
specialized in the conduction of myocardium.
The cardiac rhythm follows an orderly pattern that can be disturbed by several factors such as heart
disease, unwanted action of drugs or by the action of circulating hormones. The abnormal cardiac
rhythm can be restored to a normal cardiac rhythm by the intake of therapeutic cardiovascular
drugs. The most common causes of abnormal cardiac rhythm are ischemic heart disease,
myocardial infarction and heart attack which take millions of lives globally.
2.3. Disturbances of Cardiac Rhythm
Disturbance of cardiac rhythm is called “Dysrhythmias”. Dysrhythmias are classified by several

factors, such as: Abnormal heartbeat (increased in tachycardia or decreased in bradycardia),
arterial, junctional, or ventricular abnormality. These factors are responsible for causing
palpitations or unconsciousness of patients. These patients are diagnosed with electrocardiograms
17
and medicines are needed to retain cardiac rhythm to normal. Four basic phenomena are
responsible to initiate the abnormality of cardiac rhythm:
1) Delayed after-depolarisation
2) Re-entry
3) Ectopic activity of pacemaker and
4) Heart block
1) Delayed after-depolarization:
[Ca2+] ion rises abnormally and activates Na+/Ca2+ exchange. Thus excess Ca2+ initiates abnormal
action potential. Transfer of one Ca2+ ion out of the cell and entrance of three Na+ ions results in a
net influx of one positive charge and membrane depolarization occurs. Ca2+ also opens non-
selective cation channels in the plasma membrane. As a result, entry of Ca2+ rises gradually
(Hypercalcemia) that promotes depolarization [21].
2) Re-entry:
It is a critical situation in which a cardiac impulse re-excites the myocardial regions after it has
activated the ventricles. As a result, continuous circulation of the action potential occurs. Electrical
impulses die when two impulses meet at any point due to continuous circulation. This situation
causes severe myocardial damage and propagates anatomical anomalies, dysrhythmia and damage
to atria, ventricles or nodal tissue.
3) Ectopic activity of Pacemaker
In the SA node of the right atrium, the physiological pacemaker resides. Cardiac tissues play an
important role in pacemaker activity. The activity of the pacemaker is a safety mechanism when
the SA node fails to initiate electrical impulses, which sometimes can also be fatal. Ectopic activity
of the pacemaker propagates the heart to beat outside the SA node in a spontaneous rhythm
resulting in severe pain and myocardial infarction.
4) Heart Block:
Heart block refers to the situation in which damage of atrioventricular (AV) nodes occurs, the
ventricles can beat in a slow rate causing unconsciousness of the patient. This situation can be
treated by inserting an artificial pacemaker into the patient’s heart.
18
2.4. Physiology of Cardiac Function: Cardiac Contraction
Cardiac contraction occurs by several intrinsic factors such as [Ca2+] and ATP. These factors are
sensitive to various drugs and pathological conditions. Some extrinsic factors also cause cardiac
contraction like elasticity and contractility of arteries and veins and blood volume and viscosity.
2.4.1. Myocardial Contractility and Viability
Myocardial contractility depends on the activity of myocardial striated muscle and voluntary
striated muscle. Their activity is quite similar. Both involve [Ca2+] ion binding to troponin C,
forming troponin complex, permitting cross binding of myosin to actin and finally initiating the
contraction of cardiac muscle. A drug named “Levosimendan” is widely used for treating heart
failure. This drug acts by increasing the contractility of the heart muscle by binding of Ca 2+ to
troponin C [22].
2.4.2. Myocardial Oxygen Consumption and Coronary Blood Flow
In normal conditions, coronary blood flow relates to myocardial O2 consumption. A healthy heart
changes the condition of rest and maximum exercise over nearly 10-fold range. There are many
drugs that influence cardiac metabolism directly by influencing and initiating coronary blood flow.
The name of one of these drugs is “Trimetazidine” which acts by improving myocardial glucose
utilisation through the inhibition of metabolism of fatty acids.
Some factors are responsible for regulating coronary blood flow to the poorly perfused tissues.
Such as:
1) Physical factor
2) Vascular control
3) Neural and humoral control
1) Physical factor:
Myocardial pressure on vessels is exerted during systole. This pressure is equal to perfusion
pressure or sometimes exceeds the perfusion pressure. As a result, coronary blood flow occurs
during diastole. When heartbeat increases (tachycardia), diastole phase becomes shortened and
19
reduces myocardial perfusion. In contrast, when heartbeat decreases (bradycardia), diastole phase
becomes longer than systole thus increases myocardial perfusion.
2) Vascular Control:
Coronary blood flow is regulated by vascular control in the presence of metabolites. This factor is
very important for efficient blood flow to the cardiac tissues. A reduction in partial arterial pressure
of O2 (PO2) results in increased vasodilation of coronary vessels in the presence of metabolites.
3) Neural and humoral control:
Large, dense coronary vessels initiate α-adrenoreceptors to regulate vasoconstriction. Smaller

coronary vessels initiate β-adrenoreceptors to regulate vasodilation. These mechanisms can be
altered by mechanical and metabolic activity during exercise & several pathological conditions
and may decrease neural & humoral effects.
2.5. Drugs that affect Cardiac Function
There are several drugs that affect cardiac function which sometimes can be fatal to a patient. So,
a person should never intake those medicines without a physician's advice. The drugs that have
major action on the heart are classified into three groups:
1) Drugs affect myocardial cells directly. Such as:
i. Autonomic neurotransmitters
ii. Cardiac glycosides
iii. Inotropic drugs
iv. Antidysrhythmic drugs
v. Miscellaneous drugs
2) Drugs affect myocardial cells indirectly. Such as:
i. Antianginal drugs
ii. Diuretics
iii. Angiotensin converting enzyme (ACE) inhibitors
3) Drugs act as calcium antagonists. Such as:
i. Calcium channel blockers [23]

20
Chapter 3: Methodology
21
3.1. Search Strategy
Comprehensive literature studies published in journals, reports, websites, articles, research papers
and books were performed to get a systematic overview about the medicines used against
cardiovascular diseases in Bangladesh and global perspective. Various electronic databases
including Cambridge University Press, Oxford University Press, Springer Nature, Academia,
Routledge, Elsevier, Peter Lang, Thomson Reuters, Blackwell, Sage, MDPI, Frontiers, Online
Willy, PolseOne, ResearchGate, Drugs.com and Google Scholar were searched.
3.2. Study Selection and Data Extraction
The publications dealing with cardiovascular medicines have been identified from all the possible
sources until the end of June 2021. All the updated information is taken for this study. The search
was limited to literature published in English. The names of the cardiovascular agents along with
their class of drugs are listed in this literature. Informations including clinical, pre-clinical, in-vivo
and ex-vivo presented on the articles available online are taken for the pharmacological evidence.
The history of each class of drug, their pharmacological properties along with mechanism of action
are searched and included from the most authentic web sources and books. The pharmacological
properties of each drug including therapeutic dose(s), bioavailability, peak plasma concentration
and elimination half-life are listed on the tables.
Several graphical data are presented in this literature study to show a comparative analysis of heart
disease mortality in past and recent years in the developed and developing countries. All the
graphical data are extracted from primary data sources that were published online.
The views in this literature do not necessarily reflect and should not be interpreted as being the
official position of any agency or institution.
22
Chapter 4: Pharmacological Approaches for
Cardiovascular Disease: Modern Heart Medications
23
4.1. An Overview of Heart Disease Drugs
In the previous chapter, it is shown that cardiovascular diseases (CVDs) are classified into several
types [Chapter 1.2]. There are many types and combinations of drugs available in the market for
each type of CVD. A physician prescribes specific types of medicines to a patient based on his
health condition. Cardiovascular drugs are also known as cardiovascular agents, cardiovascular
medicines and heart medicines.
This chapter summarizes the pharmacology, pharmacokinetics and mechanism of action of the
most common types of cardiovascular drugs that are used in modern treatment.
Table 4.1.1: Types of Cardiovascular Drugs [24]

● Agents for Hypertensive Emergencies
● Agents for Pulmonary Hypertension
● Aldosterone Receptor Antagonists
● Angiotensin Converting Enzyme (ACE) Inhibitors
● Angiotensin Receptor Blockers (ARBs)
● Antiadrenergic Agents (acts as centrally)
● Antiadrenergic Agents (acts as peripherally)
● Antianginal Drugs
● Antiarrhythmic Agents
▪ Group I Antiarrhythmics
▪ Group II Antiarrhythmics
▪ Group III Antiarrhythmics
▪ Group IV Antiarrhythmics
● Anticholinergic Chronotropic Agents
● Antihypertensive Combinations
▪ ACE Inhibitors with Calcium Channel Blocking Agents
▪ ACE Inhibitors with Thiazides
▪ Angiotensin II Inhibitors with Calcium Channel Blockers
▪ Angiotensin II Inhibitors with Thiazides
▪ Antiadrenergic Agents (central) with Thiazides
▪ Antiadrenergic Agents (peripheral) with Thiazides
24
▪ Beta Blockers with Thiazides
▪ Miscellaneous Antihypertensive Combinations
▪ Potassium Sparing Diuretics with Thiazides
● β-Adrenergic Blocking Agents
▪ Cardioselective β-Blockers
▪ Non-cardioselective β-Blockers
● Calcium Channel Blocking Agents
● Catecholamines
● Diuretics
▪ Carbonic Anhydrase Inhibitors
▪ Loop Diuretics
▪ Miscellaneous Diuretics
▪ Potassium-sparing Diuretics
▪ Thiazide Diuretics
● Inotropic Agents
● Miscellaneous Cardiovascular Agents
● Peripheral Vasodilators
● Renin Inhibitors
● Sclerosing Agents
● Vasodilators
● Vasopressin Antagonists
▪ Vasopressors
25
4.2. Angiotensin Converting Enzymes (ACE) Inhibitors:
History:
In the 1960s, some scientists found that venom of pit vipers contained some enzymes that showed
an increased response to bradykinin. It was thought that these enzymes are made of peptides that
inhibit kininase II, an enzyme that inactivates bradykinin. Later on, scientists proved that
angiotensin converting enzyme (ACE) and kininase II are the same enzyme that inactivate and
destroy bradykinin and catalyse the synthesis of angiotensin II. Research continued to discover an
inhibitor which would be effective against ACE to treat those patients who are suffering from heart
diseases. Teprotide was the first ACE inhibitor to be effective for patients with heart failure, by
lowering blood pressure. But this inhibitor was not orally active. Intravenous infusion of this
inhibitor showed several adverse effects. So, there was a need for an orally active ACE inhibitor.
The research was continued for the development of orally active drugs. Captopril was the first
orally active ACE inhibitor to be marketed for the treatment of heart disease [25].
Pharmacology:
There are many ACE inhibitors available in the market. ACE inhibitors are classified into three
major groups:
Table 4.2.1: ACE Inhibitors [26]

Class I Sulfhydryl-containing ACE Inhibitor Fentiapril, Pivalopril, Zofenopril,
and Alacepril
Class II Di-carboxyl-containing ACE Inhibitor Lisinopril, Benazepril, Quinapril,
Moexipril, Ramipril,
Trandolapril, Spirapril,
Perindopril,
Pentopril, and Cilazapril
Class III Phosphorus-containing ACE Inhibitor Fosinopril
All ACE inhibitors effectively block the conversion of angiotensin I to angiotensin II. They all are
highly selective drugs, increase the level of bradykinin [26], restrict the production of ACE,
26
increase renin release, thus increase the rate of formation of angiotensin I. ACE inhibitors have
little effect on systemic blood pressure when given orally [27].
Pharmacokinetic Properties:
Pharmacokinetic properties of ACE inhibitors vary according to the variation of functional groups
(sulfhydryl, carboxyl or phosphinyl) in different classes of drugs and allow possible safety
margins. Pharmacokinetics of some of the widely used ACE inhibitors are listed below [28]:
Table 4.2.2: Pharmacokinetic Properties of ACE Inhibitors [28]

ACE Inhibitors Therapeutic Bioavailability Peak Plasma Elimination
Oral Dose (mg) (%) Concentration Half-Life (h)
(h)
Captopril 6.25-150 75 1 2
Enalapril 2.5-5 60 1 1.3
Lisinopril 5-40 30 7 12
Benazepril 5-80 37 0.5-1 10-11
Fosinopril 10-80 36 2-3 11.5
Quinapril 5-80 60 2 2-25
Ramipril 1.25-20 50-60 3 2-4,
9-18,
>50
Mechanism of Action:
Renin-angiotensin-aldosterone system (RAAS) is a complex system of the human body,

responsible for regulating blood pressure. ACE inhibitors interfere with the RAAS to inhibit ACE
formation.
The kidneys release renin, an enzyme responsible for lowering blood salt concentration (low Na +
and high K+). This enzyme also interrupts the circulating angiotensinogen that forms angiotensin
I. ACE then converts angiotensin I to angiotensin II (active form). The conversion results in
contraction of cardiac muscles, increase of blood pressure, stimulation of aldosterone release and
water & sodium reabsorption. Thus increases blood pressure. ACE inhibitors cause dilation of
27
blood vessels by restricting the production of angiotensin II. By doing so, ACE inhibitors decrease
cardiac output and reduce the possibility of stroke. Body’s major organs such as: brain, blood
vessels, kidneys, heart and adrenal glands are affected by ACE inhibitors [29].
Figure 4.2.1: Chemical Structure of ACE Inhibitors
28
4.3. Angiotensin Receptor Blockers (ARBs)
History:
In the 1898s, a physiologist named Robert Tigerstedt, injected some kidney extracts to the rabbit’s
body for his experiment to determine if there is any substance present in the extracts that are
responsible for altering blood pressure. He found that kidneys produce a protein, renin, that is
responsible for increasing blood pressure. Later on in 1930s, a scientist experimented with dogs
and found that, kidneys secrete a chemical that causes vasoconstriction. 9 years later, scientists
proved that, renin doesn’t increase blood pressure, but an enzyme, angiotensin I is responsible for
increasing blood pressure [30]. In the 1970s, researchers and scientists observed that the active
form of angiotensin I, which is called angiotensin II, harms the heart, kidneys and causes fatal
adverse effects to the patients with myocardial infarction and stroke [31]. In the 1970s, after the
introduction of ACE inhibitors, it was observed that angiotensin II played an important role in
increasing blood pressure [32]. This theory gave rise to the discovery of the first orally active ARB,
Losartan that inhibits angiotensin II formation more effectively than ACE inhibitors [33, 34].
Pharmacology:
The ARBs are highly selective, potentially exerts its pharmacological effects by:
● initiating rapid responses of drugs

● stimulating peripheral nervous system
● increasing vasopressin release
● secreting aldosterone
● stimulating the effects of angiotensin II on the kidneys and
● promoting growth hormones [35].
Many types of ARBs available in the market that induce effective plasma drug concentration, have
short half-lives and higher bioavailability. The pharmacokinetic properties of ARBs are listed
below:
29
Table 4.3.1: Pharmacokinetic Properties of ARBs
ARBs Therapeutic Bioavailability Peak Plasma Elimination
(h)
Losartan 25-100 [36] 33 [37] 1-2 [38] 2 [39]
Valsartan 40-320 [40] 10-35 [41] 2-4 [42] 2 [43]
Candesartan 4-32 15 3-4 9 [44]
Telmisartan 20-80 42-58 0.5-1 24 [45]
Irbesartan 75-300 60-80 1.5-2 11-15 [46]
Eprosartan 300 13 1-2 5-9 [47]
Olmesartan 5-40 26 1-2 13 [48]
Azilsartan 40-80 60 1.5-3 11 [49]
Renin, after releasing from the kidneys, converts the inactive plasma protein angiotensinogen to
angiotensin I. Angiotensin I is then converted to angiotensin II (active form). Angiotensin II binds
to the AT1 receptor [50]. AT1 receptor initiates Angiotensin II to cause a series of factors such as
sodium reabsorption, contractility of cardiac muscle and vasoconstriction. As a result, blood
pressure increases. ARBs act by blocking AT1 receptors thus lowers blood pressure [51]. ARBs
can block RAAS more effectively and specifically than ACE inhibitors.
30
Figure 4.3.1: Chemical Structure of ARBs
31
4.4. Antianginal Drugs
Antianginal drugs are used mainly to treat myocardial ischemia, angina, myocardial infarction,
heart failure and stroke. These are the agents that provide prophylactic or symptomatic treatment
to the patient, thus reducing the risks of severe heart failure. Antianginal drugs are classified into
several categories:
● Organic Nitrates
● Ca2+ Channel Blockers
● β-Adrenergic Receptor Blockers
● Antiplatelet and Antithrombotic Agents
All of these drugs are used in severe cases that save lives of patients and reduce the progression of
surgical procedures.
4.5. Organic Nitrates
History:
In the 1864s, Sobrero first synthesized nitroglycerin and observed that, very small quantity of this
substance causes a severe headache when placed on the tongue. Later on in 1857, a physician
named T. Lauder experimented with amyl nitrate which was known as vasopressor and he
observed that it relieves anginal pain of the patients within 30 to 60 seconds after inhalation. A
pharmacologist William Murrell observed that, nitroglycerin mimicked the action of amyl nitrate
so it could be used to treat acute anginal attack [52]. He also established that organic nitrates are
relatively safe to use for the treatment of rapid and dramatic alleviation of angina pectoris, unstable
angina, myocardial infarction and stroke. Later on, his observations were widely accepted and
organic nitrates are still used in modern medication to treat CVDs.
Pharmacology:
Organic nitrates possess a wide pharmacologic approach in therapeutics.
● Nitrates are nitro vasodilators that relax smooth muscle, arteries and veins.
● Low concentration produces dilatation of veins and arterioles, decreases the size and
pressure of left and right ventricular chamber, and decreases cardiac output and pulmonary
vascular resistance [53].
32
● Higher concentration causes venous pooling, decreases arterial resistance, decreases blood
pressure of systole and diastole, causes weakness, dizziness, restores the possibility of
tachycardia and bradycardia by restoring vascular resistance, thus restores and increases
coronary blood flow and reduces cardiac output and blood pressure [54].
● Nitrates inhibit platelet aggregation [55].
● Organic nitrates reduce myocardial infarction [56].
Nitroglycerin reduces the hydrolytic catalysis of a hepatic enzyme “glutathione-organic nitrate

reductase” by the process of biotransformation. As a result, organic nitrate esters (lipid-soluble)
are converted to inorganic nitrates and metabolites (water soluble). The pharmacological
properties of organic nitrates are listed below:
Table 4.5.1: Pharmacokinetic Properties of Organic Nitrates

Organic Therapeutic Bioavailability Peak Plasma Elimination
Nitrates Dose (%) Concentration Half-Life
Nitroglycerin 0.3-0.6 mg 40% 4 minutes 1-3 minutes [58]
(Oral) [57]
Isosorbide 2.5-40 mg (Oral) 10-90% 6 minutes 45 minutes [60]
Dinitrate [59]
Amyl Nitrate 0.3 ml >99% (in liver) __ 2.5-5 hours [62]
(Inhalation) [61]
Isosorbide 10-120 mg 100% [64] 1 hour 5.1 hours [65]
Mononitrate (Oral) [63]
Organic nitrates activate guanylyl cyclase pathway. This pathway increases cyclic GMP synthesis
in smooth muscle and other tissues [66], leading to the formation of reactive free radicals known
as nitric oxide (NO) [67]. NO activates guanylyl cycle. Guanyl cycle stimulates cyclic GMP-
dependent protein kinase, results in phosphorylation of various proteins in smooth muscle. This
process causes dephosphorylation of myosin light chain [68]. Myosin light chain contracts and
33
regulates smooth muscle. Thus NO, the active form of organic nitrate, possesses biological signals
to various cell types [69].
Figure 4.5.1: Chemical Structure of Organic Nitrates
4.6. Ca2+ Channel Blockers

History:
In the 1962s, Hass and Hartfelder reported that verapamil, which is a calcium channel blocker,
possessed negative chronotropic and inotropic actions that were not seen in organic nitrates. After
some years, Fleckenstein suggested that the negative inotropic action caused by verapamil was the
result of the blockade or reduction of Ca2+ ions into the cardiac myocytes. A derivative of
34
verapamil, known as nifedipine, showed blocking of the Ca2+ ion movement through the slow
channel and alternation of the plateau phase of the action potential of the cardiac myocytes [70].
Pharmacology:
● Involves Na+ currents.

● Depolarizes vascular smooth muscle [71].
● Increases cytosolic Ca2+ that causes binding of Ca2+ to a protein calmodulin, thus forming
calcium-calmodulin complex. This complex activates myosin light chain kinase and causes
phosphorylation of myosin light chain. This promotes contraction of smooth muscle.
● Inhibits voltage-dependent Ca2+ channels in vascular smooth muscle.
● Relaxes arterial pressure and smooth muscle.
● Increases coronary blood flow and lowers blood pressure [72].
Table 4.6.1: Pharmacokinetic Properties of Ca2+ Channel Blockers [82.83]

Ca2+ Channel Therapeutic Bioavailability Peak Plasma Elimination
Blockers Oral Dose (mg) (%) Concentration Half-Life (h)
(h)
Amlodipine 1-10 mg [73] 60-65 6-8 40-50 [74]
Bepridil 200-400 mg 60 2-3 [75] 15-33 [76]
Diltiazem 60-120 40 2-4 3-4.5 [77]
Felodipine 5-40 mg 15 2.5-5 25 [78]
Isradipine 2.5-20 mg 15-24 1.5-2.5 1.5-2 [79]
Nicardipine 2.5-60 mg 15-45 2 8.6 [80]
Nifedipine 30-80 mg 45-68 1-2 2 [81]
Nimodipine 30-60 mg (Oral) 13 1-2 8-9 [82]
Verapamil 5-10 mg (IV >90 ____ 2-5 [83]
Injection)
35
Various contractile stimuli, many hormones & neurotransmitters, intracellular and extracellular
storage sites increase the contraction of Ca2+ ions. As the Ca2+ ions increase in concentration, they
cause contraction of cardiac and vascular smooth muscle. Voltage sensitive Ca2+ channels are
divided into three subtypes such as L, N and T subtypes and contain several subunits such as α 2,
β, γ and δ [84, 85]. Only the L-type channel is sensitive to the Ca2+ channel blockers. Large divalent
cations such as Cd2+, Mn2+ can block wide ranges of Ca2+ channels.
36
Figure 4.6.1: Chemical Structure of Ca2+ Channel Blockers
4.7. β-Adrenergic Receptor Antagonists (β-Blockers)
History:
β-adrenergic receptor antagonists, also known as β-blockers, had received numerous attention
from the very beginning of its discovery to treat cardiac patients. In the 1950s, Sir James Black
and his colleagues initiated the discovery of β-blockers. The first isolated derivative of β-blocker
was pronethalol. But pronethanol showed agonist activity and was not an effective β-blocker. So,
scientists were in search of a derivative which would not show any agonist activity and have
relative affinity for β1 and β2 receptors. Atenolol and metoprolol have greater affinity for β1
receptor than for β2 receptor. Later on, a new derivative of β-blocker was identified. Celiprolol is
37
a selective β1 antagonist and β2 agonist which was widely used as a medication against
cardiovascular disease [86].
Pharmacology:
β-blockers possess a wide variety of pharmacological approaches such as:
● Slow heart rate

● Decrease myocardial contractility [87]
● Lower peripheral vascular resistance
● Reduce sinus rate
● Regulate heart rate [88]
● Increase functional refractory time of AV node
● Initiate membrane stabilizing activity [89]
● Lower blood pressure of hypertensive patients [90]
● Mediate hormone-sensitive lipase activation in fat cells
Table 4.7.1: Pharmacokinetic Properties of β-Blockers

β-Blockers Therapeutic Bioavailability Peak Plasma Elimination
(h)
Propranolol 10-80 50 1-4 3-6 [91]
Metoprolol 25-400 50 1.5-2 3.5 [92]
Nadolol 40-160 30 2-4 14-24 [93]
Atenolol 50-100 45-55 2-4 6-7 [94]
Timolol 5-20 50 2 2.5-5 [95]
Esmolol 25-300 µg (IV 60 2-6 minutes 9 minutes [96]
injection)
Pindolol 5-20 50-95 1-2 3-4 [97]
Acebutolol 200-400 35-50 2-2.5 3-4 [98]
Labetalol 100 25 2 6 [99]
38
Figure 4.7.1: Chemical Structure of β-Blockers
39
β-blockers reduce the secretion of renin that causes decrease of angiotensin II level. As a result,
blood pressure decreases. Alternation of the sympathetic nervous system occurs at high doses of
β-blockers. This alternation also stimulates the alternation of peripheral adrenergic function that
results in change of baroreceptor activity and increase of prostacyclin biosynthesis. Thus these
agents cause blockade of β-adrenergic receptors [100].
4.8. Antiarrhythmic Drugs
Antiarrhythmics are those drugs that restore abnormal and irregular heart rhythm to normal
condition. This class of drug is a lifesaving medication for a cardiac patient. Antiarrhythmics
control heart rhythm most efficiently but cannot cure completely. So, patients have to take this
medication for his lifetime. Along with many therapeutic effects, these drugs also possess some
serious side effects and adverse effects like, a patient may suffer from bradycardia, heart block,
blurry vision, nausea, rash, hypotension, dizziness, liver toxicity and worsen arrhythmia. A patient
must be taken care of if he is already taking any OTC (over-the-counter) drugs, other herbal or
medicine supplements and should consult a physician on a regular basis.
Antiarrhythmic drugs are also known as antidysrhythmic drugs. This class of cardiovascular agents
were classified by Vaughan William in 1970 based on their electrophysiological effects and are
used to treat serious arrhythmias. Four classes of drugs fall under the class of antiarrhythmic drugs
include [101]:
Table 4.8.1: Antiarrhythmic Drugs [101]

Class I Na+ Channel Blockers
Class II β-Blockers
Class III K+ Channel Blockers
Class IV Ca2+ Channel Blockers
Each class of drug exerts a different effect on the heart to control heart rhythm. Sometimes drugs
are prescribed alone or in combination with other classes of drug based on the patient’s current
situation. The classes, mechanism of action, dosage form, elimination and side effects of
antiarrhythmics are briefly described below:
40
Table 4.8.2: Summary of Antiarrhythmic Drugs
Vaughan William Classification [102]
Class Mechanism of Drug Name Dosage Elimination Side Effects
Action Form
Ia Moderately Disopyramide Capsule: Creatinine Hypotension,
blocks fast Na+ 100-150 clearance heart block,
Channels, ↓ mg <40 ml/min anticholinergic
membrane effects
responsiveness, Procainamide Injection: Creatinine Hypotension,
↓ conduction 100, clearance rash, drug
velocity, ↑ 500mg/ml <50 ml/min induced lupus
refractory Quinidine Tablet: Liver: P- ↑ pulse rate,
period. 200, glycoprotein, bradycardia,
300,324 hypotension,
mg, vertigo, diarrhoea
Injection:
80 mg/ml
Ib Weakly blocks Lidocaine Injection: Liver half- Hypotension,
fast Na+ 5, 10, 15, life: less than dizziness,
channel, ↓ 20 mg/ml 30 min drowsiness,
membrane seizures
responsiveness, Mexiletine Capsule: Liver Acute liver injury,
↑ K+ conduction 150, 200, (No renal) leukopenia,
250 mg blurry vision,
tremor
Tocainide Tablet: Renal Agranulocytosis,
400 & 600 bone marrow
mg suppression,
pulmonary
fibrosis
41
Class Mechanism of Drug Name Dosage Eliminatio Side Effects
Action Form n
Ic Strongly Flecainide Tablet: 50, Both liver New or worsened
blocks fast 100, 150 and renal. arrhythmias,
Na+ channels, mg Creatinine heart block
↓ conduction clearance <
velocity 35 ml/min
Propafenone Tablet: 150, Liver New or worsened
225, 325, arrhythmias,
425 mg agranulocytosis
II ↓ gCa++, ↑ Esmolol Injection: Half-life: 9 Bradycardia,
gK+ 100 mg/10 min heart failure,
ml, 100 mg/ bronchospasm
5 ml
III Inhibition of Amiodarone Injection: Liver Liver toxicity,
k+ 50 mg/ml, blue discoloration
conductance Tablet: 100, of the skin, optic
200, 300, neuropathy
400 mg
Bretylium Injection: Renal
100, 200,
400 mg/
100ml
Dofetilide Capsule: Creatinine
0.125, 0.25, clearance
0.5 mh <60 ml/min
Ibutilide Injection: Renal
0.1 mg/ml
Sotalol Tablet: 80, Creatinine Bradycardia,
120, 160, clearance < hypokalemia
200 mg 60 ml/min
42
Class Mechanism Drug Name Dosage Elimination Side Effects
of Action Form
IV ↓ SA and AV Diltiazem Injection: 5, Liver Bradycardia,
nodal 10 mg/ml heart block,
conduction of sick sinus
calcium ions syndrome, ↓
through the blood
blockade of pressure
voltage gated Verapamil Injection: Liver Bradycardia,
calcium 2.5 mg/ml heart block,
channels. sick sinus
syndrome, ↓
blood
pressure
Miscellaneou ↑ Adenosine Injection: 3 Half-life <10 AV block,
s parasympath mg/ml secs flushing,
etic nervous chest
system burning,
activity, ↑ gk, respiratory
↓ gCa alkalosis,
brief period
of systole
Digoxin Injection: Renal Arrhythmias,
0.1 mg/ml, bradycardia,
0.25 mg/ml heart block,
renal failure,
hypokalemia
Dronedarone Tablet: 400 Liver Heart failure,
mg heart block,
bradycardia,
liver toxicity
43
Figure 4.8.1: Chemical structure of Class Ia Antiarrhythmics
Figure 4.8.2: Chemical Structure of Class Ib Antiarrhythmics
44
Figure 4.8.3: Chemical Structure of Class Ic Antiarrhythmics
Figure 4.8.4: Chemical Structure of Class II Antiarrhythmics
45
Figure 4.8.5: Chemical Structures of Class III Antiarrhythmics
Figure 4.8.6: Chemical Structure of Class IV Antiarrhythmics
46
Figure 4.8.7: Chemical Structure of Miscellaneous Antiarrhythmics
4.9. Diuretics
Diuretics are the pharmacological agents that increase urine excretion or cause diuresis. They
promote Na+ and water excretion through the urine thus inflating urine rate. Elimination of NaCl
depends on the potency & extracellular fluid contraction. A decrease in glomerular filtration rate
and increase in renal sodium avidity results in increase of renin and aldosterone secretion [103].
Diuretics usually decrease blood pressure by 10-15 mmHg and also act as an effective
cardiovascular agent for cardiac patients [104].
There are several classes of diuretics that have different onset of action and site of action. The site
and mechanism of diuretics are listed below:
47
Table 4.9.1: Types, Location, Mechanism of Action and Examples of Diuretics [104]
Diuretics Site of Action Mechanism of Example(s)
Action
Osmotic Diuretics Proximal tubule Increase intravascular Mannitol
volume and filling
pressures.
Carbonic Proximal tubule Decrease serum k+, Acetazolamide

Anhydrase increase serum NH4,
Inhibitor precipitates
Ca2+/Mg3(PO4)2
stones in urine, and
have teratogenic
potential.
Loop Diuretics Loop of Henle Ototoxicity in elderly Furosemide
people, treatment for Bumetanide
hypercalcemia. Torsemide
Ethacrynic acid
Thiazide Diuretics Distal tubule Decrease serum k+, Hydrochlorothiazide
increase serum Chlorothiazide
glucose, uric acid, Indapamide
Ca2+, lipids;
acetazolamide-like
action.
K+ Sparing Collecting duct Increase k +, Spironolactone
Diuretics spironolactone is an Amiloride
anti-androgenic
receptor.
The mechanism of action of each diuretic is briefly discussed below:
Osmotic Diuretics:
Osmotic diuretics are freely filterable and low relative molecular mass substances because of their
restricted reabsorption. The tiny size of osmotic diuretics produce associate diffusion force within
the fluid to retard the biological reabsorption of fluids and solutes on the uriniferous tubule thus
osmotic diuresis ends up in urinary loss of water and sodium [105].
48
Mechanism of Action of Osmotic Diuretics
Osmotic diuretics primarily inhibit water reabsorption within the proximal convoluted tubule
structure and therefore the thin descending loop of Henle, collecting duct and regions of the
excretory organ become extremely porous to water. As Na+ is reabsorbed within the proximal
tubule structure, water is reabsorbed by passive diffusion. Within the presence of associate osmotic
diuretics, reabsorption of water is reduced relative to Na+ ions. In alternative words, despite the
actions of transporters to get Na+, the concentration gradient is favorable for osmotic diuretics and
urea negates its propulsion. Osmotic diuretics additionally extract water from intracellular
compartments and increase extracellular volume. Overall, the excretion flow will increase with a
comparatively tiny loss of Na+ as a result urine osmolarity decreases [106].
Carbonic Anhydrase Inhibitor:
Carbonic anhydrase inhibitors are widespread enzymes that catalyze and inhibit carbon dioxide
association with carbonate and protons. Their inhibition is exploited clinically for many years for
various categories of diuretics and systemically acting antiglaucoma agents. This class of inhibitors
shows promise for designing pharmacological agents and understanding protein-drug interactions
at the molecular level [107]. Carbonic anhydrase inhibitors foretold for the understanding of
excretory organ physiology. Therefore the role and restricted efficiency of carbonic anhydrase
inhibitors correlates well with the large magnitude of carbonic anhydrase independent bicarbonate
absorption. [108].
Mechanism of Action of Carbonic Anhydrase Inhibitor:
Bicarbonate absorption is dependent on the activity of carbonic anhydrase that converts

bicarbonate to carbon dioxide and water. Carbon dioxide rapidly diffuses across the cell membrane
of proximal tubule cells where it is rehydrated back to H2CO3 by carbonic anhydrase. H2CO3
dissociates to HCO3- and H+ and transports the ions out of the cell. Bicarbonate absorption is
dependent on the activity of carbonic anhydrase. Inhibition of carbonic anhydrase results in
increased urinary loss of bicarbonate and it also interferes with the reabsorption of Na+ and Cl-.
Na+/K+ ATPase maintains low intracellular Na+ concentration and it is important for reabsorption
of Na+. The proximal tubule also facilitates the efflux of H+ by Na+/H+ exchanger and increased
49
delivery of Na+ to the collecting duct results in reabsorption of Na+ in exchange for increasing k+
efflux [109].
Loop Diuretics:
Loop diuretics are drugs that act at the ascending limb of the loop of Henle in the kidney. These
diuretics are used to treat hypertension, congestive heart failure, or other cardiovascular diseases.
Loop diuretics are potent diuretics. The term “loop diuretics” was introduced solely when their
invention and introduction into medical aid had been recognized in 1973. They act within the thick
ascending limb of the loop of Henle and this can be valid till a diuresis of 20%-30% of glomerular
filtration rate is achieved [110]. Cellular mechanisms are responsible for NaCl reabsorption in the
thick ascending limb of the loop of Henle of the mammalian nephron and the early distal tubule of
the kidney [111].
Mechanism of Action of Loop Diuretics:
Loop diuretics bind reversibly to the Na+-2Cl--K+ transporter and this transporter is accountable
for uptaking of Cl- into the thick ascending limb section. As a consequence, these compounds
reduce NaCl reabsorption in the tubule section and result in a decreased opening by causing
hypertonicity. Therefore, a reduction of water absorption occurs. Except for these profound effects,
loop diuretics also inhibit Ca2+ and Mg2+ absorption within the thick ascending limb. They also
increase urinary K+ excretion by the rise of NaCl in the distal tubule. Water delivery occurs by the
reduction of K+ reabsorption which works under in vivo conditions within the thick ascending limb
section. Finally, by the reduction of the transporter in the thick ascending limb, these compounds
dramatically reduce substrate and oxygen dependence of this tubule section [112].
Thiazide Diuretics:
Thiazide diuretics are an FDA-approved class of drugs that inhibit the reabsorption of 3-5 % of
luminal sodium in the distal convoluted tubule. These drugs are commonly used to promote
diuresis or water loss by increasing urine production. After oral administration, they are well
absorbed and the onset of action starts within 1-2 hours [113].
50
Mechanism of Thiazide Diuretics:
Thiazide diuretic drugs exert their diuretic effect via blockage of the sodium-chloride channel
within the proximal phase of the distal convoluted tubule. When the Na+/Cl- channel is blocked,
the sodium level decreases. Therefore, decrease of the action of the sodium-potassium pump
occurs. The method of activation for thiazide diuretics is to cause a modification in sodium
concentration into the distal convoluted tubule. Afterward, ionic channels and pumps work to
balance discontinuous sodium levels. The blockage of the Na+/Cl- channel causes a rise in sodium
and water retention within the lumen and decrease sodium within the distal convoluted tubule. At
this time, blockage of the Na+/Cl- channel will increase the flow of ions through the Na+/Ca2+
channel leading to the increase of calcium reabsorption into the interstitium in exchange for
sodium return to the distal convoluted tubule. Inhibition of Na+/ Cl- channel within the proximal
phase of the distal convoluted tubule ends up in increased delivery of sodium to the distal phase
of the distal convoluted tubule and assembling tubule. This increase of sodium level causes the
aldosterone-sensitive Na+/K+ pump to extend. Sodium reabsorption within the principal cells and
the exchange of it will increase sodium transfer and increase K+ transfer into the assembling
tubules & lumen. The loss of K+ then causes intercalated cells within the assembling tubule to
extend K+ reabsorption via K+/H+ pump that is additionally aldosterone-mediated [114].
Potassium Sparing Diuretics:
Potassium-sparing diuretics have a more modest effect on sodium chloride reabsorption than the
proximal and loop diuretics. These drugs also diminish the driving force for the distal tubule by
inhibiting sodium reabsorption in the distal tubule. These drugs represent an important part of the
modern therapeutic arsenal. Their weak diuretic properties are particularly helpful in cirrhotic
patients. Potassium-sparing diuretics haven’t solely the advantage of avoiding potassium loss.
However, these diuretics will enhance the results of drugs acting in distal tubules and loop of Henle
[115].
Mechanism of Action of Potassium Sparing Diuretics:
Sodium ions enter into the cell through the epithelial Na+ channels that are present in the luminal
membrane and extruded out of the cell into the peritubular medium by Na+/K+ exchange pump and
Na+-K+-ATPase. Epithelial Na+ channel is modulated by aldosterone that binds to an intracellular
51
corticoid receptor. This receptor increases the expression of many genes and codes the epithelial
Na+ channel and the Na+/K+ ATPase. The collecting duct is the major site of action for corticoid
receptor antagonists that decrease the expression of the epithelial Na+ channel. Direct epithelial
Na+ channel inhibitors inhibit Na+ influx through the epithelial Na+ channel in the luminal
membrane [116, 117].
Figure 4.9.1: Chemical Structure of Osmotic Diuretics
Figure 4.9.2: Chemical Structure of Carbonic Anhydrase Inhibitors
52
Figure 4.9.3: Chemical Structure of Loop Diuretics
Figure 4.9.4: Chemical Structure of K+ Sparing Diuretics
53
Figure 4.9.5: Chemical Structure of Thiazide Diuretics
4.10. Renin Inhibitor
The pharmacological intervention of the renin-angiotensin system by the inhibition of angiotensin-

converting enzymes is a great medical approach for the bulk of hypertensive patients and for the
treatment of cardiovascular disease. Renin catalyzes the primary and rate-limiting step of the renin-
angiotensin system and unlike ACE, encompasses a high specificity for its endogenous
macromolecule substrate. It is a class of therapeutic agents that inhibits some specific reactions
which may be beneficial over medicinal drugs with less specific modes of action. Renin has been
created substantial progress toward potent and low mass inhibitors, probably to become helpful
therapeutic agents [118]. Renin-inhibitors are widely used for the treatment of coronary vessel
disorders and it’s usually assumed that the effects of these drugs are beneficial because of blockade
of the generation of action of angiotensin II tissue sites. Angiotensin II is generated at tissue sites
instead of blood. Renin needed for native angiotensin production is sequestered from the blood
54
circulation [119]. Renin-inhibitors are known not only to lower blood pressure but also to prevent
organ damage and ultimately reduces cardiac mortality. They reduce myocardial infarction, stroke
in a broad range of patients who are at high risk and also reduce the rates of death [120]. Renin-
inhibitors are pseudo peptides that are quickly taken up by the liver and excreted through the bile.
These drugs are subjected to a substantial first-pass effect that limits their oral bioavailability. The
plasma elimination half-life of these drugs is short and the duration of action is limited [121].
Figure 4.10.1: Chemical Structure of Renin Inhibitors.
Renin-inhibitors are a new category of medication that act as non-peptide inhibitor of renin by
binding competitively to the renin receptor and blocking the generation of angiotensin I from
angiotensin. Direct renin inhibitors act on the juxtaglomerular cells of the kidney. They cause
arterial and venous dilation by blocking the formation of angiotensin that causes downregulation
of sympathetic adrenergic activity and promotion of Na+ ions and water excretion by the kidneys
[122].
Renin-inhibitors have been available since the mid-1980s. The primary structures were designed
on the basis of the thought that a renin inhibitor would agree with the N-terminal amino sequence
of the substrate angiotensin. However, the progress was simple-minded by a mixture of factors
including poor oral availability, the short period of action, high prices of synthesis and
comparatively low efficiency of these agents. A brand new generation of renin inhibitors has
currently been designed. Now, based on the idea of reconstruction of the structure of the renin
55
inhibitors with the assistance of crystallographic analysis and process molecular modeling, the
most advanced agent is aliskiren [123].
4.11. Vasodilators
Vasodilators are drugs that dilate blood vessels and allow blood to flow more easily through the
arteries and veins. Vasodilators act by direct relaxation of smooth muscle in precapillary resistant
vessels. This drug is used in treating a variety of medical conditions, most commonly hypertension
and other diseases including myocardial infarction, angina, heart failure, stroke, chronic kidney
disease, etc. [124].
Figure 4.11.1: Chemical Structure of Vasodilators.
56
Vasodilators dilate and prevent constriction of the blood vessels, permitting blood flow to
numerous organs within the body. Several vasodilators bind to the receptors on epithelial tissue
cells of the vessel and stimulate calcium release. Calcium activates the catalyst nitric oxide
synthase, converts L-arginine into nitric oxide, diffuses the epithelial tissue cell and enters into the
vascular smooth muscle cells. Nitric oxide activates the guanylyl cyclase pathway and converts it
into cGMP. This pathway stimulates the myosin light chain enzyme that removes one phosphate
molecule from myosin and actin filaments, causes dephosphorylation of myosin and permits actin
filaments to cause vascular smooth muscle relaxation [125].
4.12. Vasopressors and Inotropic Agent:
Vasopressors are the drugs used to create vasoconstriction and increase cardiac contractility. They
also increase vasoconstriction that leads to increased systemic vascular resistance. Inotropes
increase cardiac contractility and improves cardiac output. They have stimulatory and inhibitory
actions on the heart and vascular muscle in addition to some important metabolic and central
nervous system effects. This drug is typically administered with the assumption that short to
medium-term clinical recovery will be facilitated by an increase in cardiac output [126].
Figure 4.12.1: Chemical Structure of Vasopressors.
57
4.13. Anticholinergic Chronotropic Agents
Anticholinergic drugs are responsible for blocking or reducing acetylcholine's action on the
parasympathetic nervous system. They can be nicotinic or muscarinic. When it works on the heart,
it blocks the muscarinic receptors on the heart thus causing increase of heart rate, this is why they
are called anticholinergic chronotropic agents because chronotropic agents works on maintaining
heart rate by affecting the nerves controlling heart [127, 128].
Table 4.13.1: A Short Description of Anticholinergic Chronotropic Agents [128]
Name of the Description Effect Uses Example

Drug
Anticholinergic They are parasympathetic Causes These agents are Atropine

Chronotropic agents who block the tachycardia used to treat
Agents cardiac muscarinic bradycardia and
receptors and also work heart block
on smooth muscle
relaxation, inhibition of
secretion, dilatation of
pupils, decreased gastric
motility etc.
4.14. Antihypertensive combinations
Treatment of hypertension with monotherapy by β-blockers or diuretics is an important option

however it is observed in a research by NHANES that monotherapy can only reach the target blood
pressure in 50% of the population. Therefore a combination of different pharmacological classes
is often provided for a better and adequate outcome. It allows the patient to take lower doses of
the combined agents than a single agent which enables to minimize clinical and metabolic effects
as well as increases patient compliance [129, 130].
58
Miscellaneous Combinations to treat Cardiac Patients
Table 4.14.1: Description of Antihypertensive Combinations [130]
Class of Drug Description Effects Uses Example

(Antihypertensiv
e Combinations)
β-Blockers+ Beta blockers Reduces This combination 1. Atenlol/

Thiazides blocks beta hypertension, is used to treat Chlorthalidone
adrenergic blood volume stroke, 2. Bisoprolol/
receptors in gets decreased hypertension and Hydrochlorothia
sympathetic due to diuresis, other zide
nervous system combination of cardiovascular
whereas thiazide the drugs gives diseases.
diuretics reduce additive effect on
reabsorption of hypertension
sodium and reduction than
chloride ions by monotherapy.
inhibiting
sodium/chloride
cotransporter in
the distal
convoluted
tubule and
increase the
potassium ion
loss.
Ace inhibitors+ ACE Inhibitors ACE Inhibitors It is used to 1.

Thiazides block conversion cause reduce blood Hydrochlorothia
of angiotensin 1 vasodilation pressure. zide/ Lisinopril
to angiotensin 2 because of the
by blocking reduction of
59
angiotensin angiotensin II, 2.
converting reducing blood Hydrochlorothia
enzymes pressure and zide/ Captopril
whereas blood volume. 3.
thiazides inhibit Hydrochlorothia
reabsorption of zide/ Enalapril
sodium and
chlorine ions.
Angiotensin II Angiotensin II Angiotensin II It is used to 1.

Inhibitors+ inhibitors stop inhibitors cause reduce blood Hydrochlorothia
Thiazides the activation of vasodilation, pressure and zide/ Losartan
angiotensin ii reduces blood volume 2.
receptors aldosterone, together. Hydrochlorothia
whereas vasopressin zide/ Valsartan
thiazides, as secretion, and
mentioned thiazides causes
above, reduces diuresis.
reabsorption of
sodium and
chloride ions.
Antiadrenergic Antiadrenergic Antiadrenergic It is used to treat 1.

agents+ agents stop the agents slow down tachycardia and Hydrochlorothia
Thiazides receptors in the heart beat and hypertension. zide/ Methyldopa
(Centrally acting) CNS by reducing dilates blood 2.
release and vessels, Chlorthalidone/
effect of Thiazides causes Clonidine
catecholamines decreased blood
and Thiazides volume.
reduces
60
sodium/chloride
reabsorption.
Antiadrenergic α1-selective Causes It is used to treat 1. Polythiazide/

agents+ antagonists vasodilation, hypertension. Reserpine
Thiazides block alpha widens the
(Peripherally adrenoceptors arteries, and
acting) on the vascular reduces blood
smooth muscle volume.
and Thiazides
works as
diuretic.
Potassium Potassium Combination of It is used to treat 1.

Sparing sparing diuretics these drugs edema, Hydrochlorothia
Diuretics+ reduces loss of reduce swelling hypertension. zide/ Triamterene
Thiazides potassium from and 2.
the distal inflammation due Hydrochlorothia
convoluted to sal and water zide/
tubule whereas retention in Spironolactone
Thiazides disorders of 3.
Inhibits sodium heart, kidney, Hydrochlorothia
reabsorption at liver etc. zide/ Amiloride
the beginning of
the distal
convoluted
tubule.
ACE Inhibitors+ ACE inhibitors ACE inhibitors Combination of 1. Amlodipine/

Calcium Channel block change of cause these drugs are Benazepril
Blockers angiotensin I to vasodilation, used to treat 2. Trandapril/
angiotensin II Calcium channel angina, ischemic Verapamil
61
and Calcium blockers also heart disease,
channel blockers cause hypertension etc.
block calcium vasodilation,
from entering reduces heart
the heart and contraction,
smooth muscle slows down heart
walls of blood rate, and causes
vessels. less aldosterone
secretion.
Angiotensin II Angiotensin II Angiotensin ii It is used to treat 1. Amlodipine/

Inhibitors+ inhibitors stop Inhibitors and hypertension, Valsartan
Calcium channel activation of calcium channel angina, And 2. Amlodipine/
Blockers Angiotensin II blockers together Coronary Heart Olmesartan
whereas cause reduction Diseases.
Calcium channel in vasopressin
Blockers inhibit and aldosterone
entry of calcium causing
in heart and vasodilation.
blood vessels.
Heart disease can lead a patient to very serious illness like heart attack, heart failure and other heart
rhythm problems. All of these issues can result in death to the patient. So, treating cardiovascular
disease is very important.
To treat heart disease, physicians recommend lifestyle change, various exercise programs and put
together a treatment plan for heart disease to help patients feel better. Different dose ranges are
available in the market for patients according to the severity of heart disease. If a patient follows
a physician's treatment plan strictly, then he may be able to lead a normal healthy life.
62
Chapter 5: Pharmacological Approaches for
Cardiovascular Disease: Herbal Heart Medications
63
5.1. Herbal Medications against Cardiovascular Disease
Traditional medicines are defined as the study of the medicines practiced by various ethnic groups
and relied on various natural resources like various plants, herbs and natural products. Historically,
herbs are defined as any form of plant or plant product [131], and plant extracts practiced by many
cultures and civilizations. Plants and herbs have always been a common source of medications
from the very beginning of the history of medicine [132]. Nature is a very important source for
finding new drugs that lead to the treatment of diseases. Famous drugs from herbal and plant
sources include aspirin from the Salix alba L. tree, digoxin (cardiac glycoside) from Digitalis
purpurea, ephedrine from Ephedra sinica, lovastatin from Monascus purpureus L., taxol from
Taxus brevifolia, reserpine from Rauwolfia serpentina, antimalarial drugs, quinine from the bark
of Cinchona species and artemisinin from Artemisia annua L., are some common natural plant
products that were used as traditional and herbal medicines [133, 134, 135].
The records and uses of herbal medicines were first found in Mesopotamia from around 2600 BCE
that describe the use of approximately 1000 plant-derived compounds. The best record of using
natural extracts in therapy was discovered by the Egyptians' Ebers Papyrus from 1500 BCE that
documented more than 700 natural drugs, mainly of plant origin. The Chinese Materia Medica
record described 52 natural medicinal preparations from around 1100 BCE, and the Indian
Ayurvedic record (BCE 1000) documented more than 800 natural medicinal extracts [136].
The World Health Organization reported in 1985 that approximately 65% of the world population
depended mostly on plant-derived traditional medicines. Traditional herbal and plant-derived
extracts were the main stream for the management and prevention of serious diseases as it was
thought that herbal medicines have very minimal or less side effects and have a wide safety margin
[137].
Medicinal potentials are found in four traditional herbs including Ginseng, Ginkgo biloba,
Ganoderma lucidum, and Gynostemma pentaphyllum for the treatment of CVDs, which are getting
increasing popularity for their less cost than the available allopathic medicines and for their large
emphasis on therapeutic efficacy & safety. Molecular, cellular and metabolic properties of those
herbal plants are briefly discussed here in the context of CVDs.
64
Ginseng:
Ginseng is an anciently cultivated plant approximately 2000 years ago partly due to its ritual use.
The use of ginseng in traditional medicine started about 20 centuries ago [138], but its use in
Western medicine was started from the early 20th century by two British physicians F. Porter
Smith and G.A. Stuart who were exploring Chinese herbal remedies at the time [139]. Ginseng
herbs are found in many Asian countries including Korea, China, Japan, and Vietnam and in North
American countries including Canada and the United States. Scientific name of ginseng varies
according to their localities such as Korean red ginseng is called Panax ginseng, Chinese ginseng
is known as Panax notoginseng, American ginseng is known as Panax quinquefolium L., and
Japanese ginseng is known as Panax japonicus, are the most commonly used ginsengs.
The roots of 5 to 7-year-old ginseng plants are either air-dried under the sun to produce “white
ginseng” or steam-treated at 98–100°C for 2–3 h and then sun-dried to produce the “red ginseng”.
During the steaming process, the chemical constituents of plants undergo changes that make red
ginseng more pharmacologically effective than white ginseng [140]. Nowdays ginseng is prepared
either in a liquid form: oil extracts or tea; or in a solid form: tablets, capsules, or dried roots [141].
More than 300 bioactive compounds have been isolated from ginseng. Ginsenosides are the most
bioactive constituents isolated from ginseng extracts [142].
In the context of CVDs, ginseng has been used to manage hypertension. Ginseng has hypotensive
effects due to its effect in the improvement of arterial functions. The ginsenoside Rg3, which is a
most popular bioactive form of ginseng plant, can increase NO and cGMP levels. Increase of NO
and cGMP results in the activation of Ca2+-gated potassium channels and inhibits ACE activity
which results in blockade of Ca2+-gated channels. Thus ginseng reduces hypertension and controls
heart rhythm [143, 144, 145].
Ginkgo biloba:
Ginkgo biloba is also known as the maidenhair tree in English. The name of the maidenhair tree
is due to its resemblance to the foliage of the Maidenhair fern and is one of the oldest seed plants.
It is regarded as a “living fossil” because of its continued existence without dramatic changes for
65
270 million years [146]. Its place of origin is thought to be eastern China in Yangtze River Valley
[147, 148]. From there, it became extensively distributed in Asia, Europe, North America, and
New Zealand and is now widely cultivated in various countries of the world [149, 150].
The therapeutic effects and pharmacological actions of Ginkgo biloba are majorly due to its
flavonoid constituent known as ginkgo-flavone glycosides and terpenoid constituent known as
ginkgolides and bilobalide [151]. This plant also exerts antioxidant and anti-inflammatory effects.
The antioxidant and anti-inflammatory effects are beneficial in a plethora of diseases that include
cardiovascular, pulmonary, and central nervous system disorders [152]. Ginkgo biloba possess
vasodilatory and antihypertensive properties that exerts cardio protective benefits and ACE
inhibitory activities, activation of cholinergic pathways, endothelial health improvement,
inhibition of endothelium activation and adhesion and serum lipid-lowering activities. All these
effects are very beneficial in the treatment against CVDs [153, 154, 155, 156, 157].
Ganoderma lucidum:
Ganoderma lucidum is also known as “lingzhi '' or''reishi ``. It is basically one kind of mushroom
whose different parts such as mycelia, spores, and fruit body are used to make different forms of
commercial G. Lucidum for their medicinal benefits. Commercially, G. Lucidum is available as
powders, dietary supplements, tea and other forms. Historically, the medicinal use of G. Lucidum
has been widespread in Asian countries, mainly in China, Japan, and Korea for more than 2000
years. Later, it was introduced to Western societies for its wide therapeutic safety margin. A wide
array of bioactive compounds exist in G. Lucidum including triterpenes, polysaccharides,
nucleosides, steroids, fatty acids, alkaloids, proteins, peptides, amino acids, and inorganic elements
[158]. Hot water or ethanol are used to extract the bioactive compounds from the fruit bodies, the
mycelia, or the spores of the mushroom [159].
Ganoderma lucidum is used to treat elevated blood pressure and can be detrimental to heart
function. Three peptides present in the bioactive compounds of Ganoderma lucidum are QLVP,
QDVL, and QLDL that can inhibit ACE activity and called ACE inhibitory peptides (ACEIPs)
thus controls blood pressure. QLVP can inhibit ACE by its interaction with Gln242 and Lys472
66
of ACE. QLVP is also responsible for enhancing Angiotensin I mediated phosphorylation and
reduction of mRNA and protein expression of the vasoconstrictor peptide endothelin I [160].
Gynostemma pentaphyllum:
Gynostemma pentaphyllum, also known as Jiaogulan, is an herbaceous climbing vine. The origin
of this herb is south China and now it is widely distributed in South and East Asia [161]. It is found
in subtropical Asian countries like China, Japan, Myanmar, and India [162]. The herb rapidly
grows near the rivers and in the shade of forests that surround Yangtze River and the southern
areas of China [163]. It is found in many beverages, biscuits, face washes, and bath oils as a health
supplement [164]. Gynostemma pentaphyllum extracts contain gypenoside saponins, flavonoids,
polysaccharides, and amino acids [165, 166, 167]. This herb possesses a wide variety of biological
effects including antimicrobial [168], antioxidant [169], anticancer [170], anti-inflammatory
[171], antidiabetic [172], antilipidemic [173], neuroprotective [174], anti-obesity effects [175].
The extract of Gynostemma pentaphyllum decreases CVDs incidence by lipid accumulation. A

study reported that ombuine, which is a flavonoid extract of Gynostemma pentaphyllum, acts as a
dual agonist of PPAR-α and PPAR-δ/β receptors in lipid metabolism. This agonist enhances
lipolysis by reducing intracellular concentrations of triglyceride and cholesterol and by decreasing
lipogenic gene expression to the regulatory element binding protein-1c and stearoyl-CoA
desaturase-1 [176]. As a result, cardiovascular incidence decreases and restores to normal function.
Herbal medicines have high prevalence in many developed and developing countries. The practice
of herbal medicines is becoming very popular nowadays. The practitioner should inquire about the
clinical histories and beneficial or harmful effects of the medicines before prescribing it to a
patient. Herbal medicines have potential benefits with greater therapeutic efficacy against CVDs.
Herbal drugs should be marketed for patients with legal licenses to restrict the abuse of herbs and
drug substances. Discovery of more beneficial herbal drugs are currently proceeding by the
researchers and many drugs are in clinical trials. Days are not far when herbal drugs will get the
same priority by the physicians and consumers in a manner similar to allopathic medicines.
67
Conclusion
Current standard of care for cardiac patients consists of regular screening of heart functions, testing
of blood pressure and diabetes management followed by lifestyle modification, exercise, diet along
with modern pharmacological approaches. However, despite the known benefits of all these, many
individuals still find it harder to maintain a healthier life.
In many fields, traditional medicinal knowledge offers interesting leads for pharmacological
research. In this review, a compiled data is documented on a large number of modern medicines
and some herbal medicines that are used for cardiac patients. Many of these medicines have also
displayed activity in bioassays matching their traditional uses. Based on these observations, future
extensive investigations on those particular medicines can be targeted to identify the compounds
responsible for the observed bioactivities as well as to unravel their mechanisms of action. The
informations compiled in this literature review will contribute to the successful usage of ethno-
medicinal knowledge as well as modern medicinal knowledge of drugs in the treatment of
cardiovascular disease.
A number of herbal and modern pharmacological approaches have been introduced and some are
still under research which will have a real impact in the future. Several new agents have recently
become available or are soon to become available, thus extending the range of therapy for
cardiovascular disease. This will undoubtedly offer an enhanced opportunity to improve heart
rhythm control and hence diminish the number of complications, a cloud continues to cast its
shadow over this field.
68
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69
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A Literature Review on Modern and Herbal Pharmacological Approaches to

the Treatment of Cardiovascular Diseases

A dissertation submitted to the Department of Pharmacy, East West University, in partial

Review Paper Title “A Literature Review on Modern and Herbal Pharmacological

Shaherin Islam Tuba

A Literature Review on Modern and Herbal Pharmacological Approaches to the Treatment of

Mst. Marium Begum

Dr. Chowdhury Faiz Hossain

Keywords: Cardiovascular Diseases • Pharmacology • Pharmacokinetic Properties • Medicines •

List of Graphs and Charts

CVDs: Cardiovascular Diseases

ACE: Angiotensin Converting Enzyme

ARB: Angiotensin Receptor Blockers

NO: Nitric Oxide

cGMP: Cyclic guanosine monophosphate

PPAR: Peroxisome Proliferator-Activated Receptor

RAAS: Renin-angiotensin-aldosterone system

FDA: Food and Drug Administration

WHO: World Health Organization

NHANES: National Health and Nutrition Examination Survey

Table 1.2.1: Types of Cardiovascular Diseases (CVDs) [3]

1990 2020 % of Increase

1990 2020 % of Increase

Ukraine Russia Hungary Czech Republic

Chart A: CVD mortality in Developed Countries per 100,000 (Male) [12]

CVD Mortality in Developed Countries per 100,000 (Female)

Ukarine Russia Hungary Czech Republic

Chart B: CVD mortality in Developed Countries per 100,000 (Female) [12]

Percentage of Cardiac Patient According to the Demographic Viewpoint

Graph C: Cardiac patient according to the demographic viewpoint [14].

Ischemic Heart Disease 19.9

Myocardial Infraction 20.9

Heart Failure 28.5

Lipid Level Disorder 48.7

0 50 100 150 200 250 300 350 400 450

Percentage (%) Number of Patients

Graph D: Different medical conditions observed among patients [14].

Therapeutic Classes Prescribed to those Patients

Calcium Channel Blockers 111

ACE Inhibitors 276

Beta Blockers 444

Lipid Lowering Drugs 659

0 100 200 300 400 500 600 700 800

Number of Patients Percentage (%)

Graph E: Therapeutic classes prescribed to patients [14].

Angiotensin II Receptor Antagonist+ACE Inhibitor+ 2.7

ACE Inhibitor+Beta Blocker+Antianginal 2.7

Antianginal+ACE Inhibitor+Coronary Vasodilator 27.5

Beta Blocker+Antihyperlipidemic+ACE Inhibitor 10.8

ACE Inhibitor+Antianginal+Antihyperlipidemic 5.5

Antianginal+Coronary Vasodilator 2.7

Antihyperlipidemic+Beta Blocker 5.5

ACE Inhibitor+Diuretics 2.7

Antihyperlipidemic+Coronary Vasodilator 2.7

Antihyperlipidemic+Angiotensin II Receptor Antagonist 2.7

Beta Blocker+Antianginal 10.8

ACE Inhibitor+Antianginal 10.8

ACE Inhibitor+Antihyperlipidemic 10.8