INTRODUCTION:

Cardiovascular disease (CVD) is the broad term used to define chronic medical condition and abnormal functioning of the heart and/or its associated blood vessels in the circulatory system. It is a leading cause of deaths including mortality and morbidity in developed as well as developing countries including India and their prevention is a major public health challenge globally.

The major causes of death due to different types of cardiovascular diseases includes hypertension (HTN or HT, a major risk factor), coronary artery diseases (CAD) and myocardial infarction (MI), atherosclerosis, stroke, cardiomyopathy, cardiac arrhythmia, valvular heart disease, carditis, and aortic aneurysms. Among them, the most common challenging cardiovascular diseases are hypertension, coronary artery disease, stroke, heart failure and angina. Generally, they affect the heart valves, arteries and veins in the legs, and the heart rate and rhythm (WHO, 2011)^1-7. However, after a century, the number of cardiovascular deaths has decreased in many western countries, due to the largely used dietary soy, soy proteins, supplements and food neutraceuticals in daily diet, change in life style, preventative measures and better medical care services. However, hypertension is still the leading cause of deaths worldwide (European Cardiovascular Disease Statistics 2017; WHO, 2017). The major function of the cardiovascular system is to carry the oxygen and transport blood throughout the body. When blood pressure elevated persistently throughout the arteries in the circulatory system, it causes the high blood pressure or hypertension (HTN). The major well known symptoms of CVDs are rapid or shallow breathing, chest pain (pectoris), rapid and/or irregular heart rate, high or low blood pressure, swollen veins in the neck, swelling in the feet and ankles, enlarged heart (cardiomyopathy), extra or abnormal heart sounds, fluid in the lungs, abnormal sounds of arterial blood flow throughout the body, pulsating abdominal mass (aortic aneurysm), cool extremities, and reduced or absent pulses in the extremities^8-11.

Materials:

A literature search for articles published in peer-reviewed journal articles based on hypertension, as well as electronic database searches using PubMed, Scopus, ScienceDirect, Google Scholar.

Hypertension:

Hypertension is an abnormal condition leading to various chronic diseases such as cardiovascular diseases including heart stroke, renal artery disease, diabetes and accounts for approximately 50% of cardiovascular disease worldwide. Recently, World Health Organization (WHO) reported that approximately 1 billion people are already affected by hypertension globally and it is predicted to affect 1.5billion people by year 2025 causing more than seven million deaths annually. In a recent report by Mathers and Loncar, (2006), it is described to cause 23.3million deaths by 2030. In India, cardiovascular diseases account for nearly 2.3million deaths in the year 1990 and is predicted to be double by 2020^12-19.

As per 2002 world health report, hypertension is one of the major causes of death among five non-communicable diseases universally and in every year it has been assigned for 17^th day of May month as “World Hypertension Day” by the International Society of Hypertension (ISH) for focus on consideration and special attention. Hypertension is a chronic medical condition in which the elevated blood pressure (Systolic (≥140mmHg) and diastolic (≥90mmHg) blood pressure) of the arteries persistently increased and it is also a major risk factor for coronary artery disease, stroke, heart failure, vision loss, chronic kidney disease, and peripheral vascular disease.

Zhou et al., 2017 reported, “Worldwide trends in blood pressure from 1975 to 2015: a pooled analysis of 1479 population-based measurement studies with 19·1million participants”. Therefore, Raised blood pressure is an important risk factor for cardiovascular diseases and chronic kidney disease. So, they have been estimated worldwide trends in mean systolic and mean diastolic blood pressure, and the prevalence of, and number of people with, raised blood pressure, defined as systolic blood pressure of 140mm Hg or higher or diastolic blood pressure of 90mm Hg or higher. Global age-standardised mean systolic blood pressure in 2015 was 127·0mm Hg (95% credible interval 125·7–128·3) in men and 122·3mm Hg (121·0–123·6) in women; age-standardised mean diastolic blood pressure was 78·7 mm Hg (77·9–79·5) for men and 76·7mm Hg (75·9–77·6) for women¹⁵.

High body-mass index (BMI) is an important risk factor for cardiovascular and kidney diseases, diabetes, some cancers, and musculoskeletal disorders. Concerns about the health and economic burden of increasing BMI have led to adiposity being included among the global non-communicable disease (NCD) targets, with a target of halting, by 2025 (Berrington de Gonzalez et al., 2010; Singh et al., 2013; Zheng et al., 2011). Ezzati et al., 2016 was investigated, “Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19·2 million participants” and used a Bayesian hierarchical model to these data to estimate trends from 1975 to 2014 in mean BMI and in the prevalences of BMI categories. Global age-standardised mean BMI increased from 21·7 kg/m²(95% credible interval 21·3–22·1) in 1975 to 24·2 kg/m² (24·0–24·4) in 2014 in men, and from 22·1 kg/m²(21·7–22·5) in 1975 to 24·4 kg/m²(24·2–24·6) in 2014 in women^1-9.

The Blood pressure varies widely from one person to another person and also in one individual at different times and environmental situations. Hypertension is also a part of chronic metabolic syndrome with elevated blood pressure and its components are associated with other major metabolic disorders such as diabetes mellitus, hyperlipidemia, obesity and this co-occurrence increases the risk of cardiovascular disease. Thus, hypertension is also a major risk factor for coronary artery disease, stroke, heart failure, peripheral vascular disease, vision loss, and chronic kidney disease. Hypertension is of two types: primary (essential) and secondary hypertension. Approximately 90% cases were reported as a primary (essential) hypertension, defined as high blood pressure due to the nonspecific lifestyle activities and genetic factors. Lifestyle activities which increases the risk includes excess salt consumption, excess body weight, smoking and tobacco habit, physical inactivity and alcohol habit. A recent study has been published in Lancet based on, “Global, regional and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, between 1990 and 2015: a systematic analysis for the Global Burden of Disease Study 2015.” In this investigation, The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015^15-29.

Major risk factors for Hypertension:

Common risks factor for any disease or illness more likely prone to develop the symptoms of the disease very quickly and easily to their patients. Major risk factors for development of hypertension are age, sex, tobacco consumption, physical inactivity, excessive alcohol consumption, unhealthy diet, obesity, genetic predisposition and family history of cardiovascular disease (genetic), raised blood pressure (hypertension), raised blood sugar (diabetes mellitus), raised blood cholesterol (hyperlipidemia), and air pollution etc. CVDs symptoms may be different for men and women (WHO, 2017)^1-9.

Global prospective of cardiovascular diseases:

Presently, CVDs are the number one causes of death globally, and more people die annually from CVDS then any other cause or diseases, particularly in developed countries. The prevalence of cardiovascular disease is rising globally and according to the WHO, this increasing tendency is likely to continue in the coming years. While in 2012, cardiovascular disease caused 17.5 million deaths, representing 31% population of all global deaths, it is projected to be responsible for 22.2 million deaths in 2030. Of these deaths, an estimated approx. 7.4 million were due to coronary heart disease (CHD) and 6.7million were due to stroke problems (WHO, 2014). Over three quarters of CVD deaths take place in low- and middle-income countries. Out of the 16 million deaths under the age of 70 due to noncommunicable diseases, 82% are in low- and middle-income countries and 37% are caused by CVDs. According to Global Burden of Disease (GBD) study, reported in 1990, nearly 5.2 million death accounts from CVDs in developed countries and 9.1 million deaths from the same causes in developing countries. However, whereas about one-quarter of all CVDs deaths occurred in persons who were less than 70 years of age in the developed world, more than about half of these deaths occurred in those less than 70 years of age in the developing world. It has been predicted that by the year 2020, there will be an increase by almost 75% in the global CVDs burden. Almost all of this increase will occur in developing countries^11-19.

Global scenario of Hypertension:

According to World Health Statistics 2015, an estimated 56.4 million global deaths occurred in 2015 and out of total deaths, 39.5million or 70% were due to non-communicable diseases (NCDs). The largest proportion of NCD deaths is caused by cardiovascular diseases amounting to 17.7million deaths (45% of all NCD deaths) followed by cancers (22%), diabetes and chronic lung diseases. In terms of attributable deaths, raised blood pressure (hypertension) is one of the leading behavioral and physiological risk factors to which 13% of global deaths are attributed (Global Status Report on NCDs, 2015). The global burden of these NCDs is raising disproportionately among lower income countries and in 2015, over three quarters, 30.7 million or 48% of NCD deaths occurred in low and middle-income countries occurring before the age of 70^5-9.

The Global Burden of Diseases and Chronic Disease Risk Factors Collaborating Group has reported trends of 35 year data between1980-2005 in mean levels of body mass index (BMI), systolic BP and cholesterol in 199 high, middle and low-income countries. Mean systolic BP declined in high and middle-income countries but increased in low-income countries and is now more than in high-income countries. The India specific data are similar to the overall trends in low-income countries^11-19.

Indian scenario of Hypertension:

Hypertension was more prevalent in 20–40% among urban and 12–17% among rural adults, and was affecting an estimated population of 118 million inhabitants in India in 2000 and was projected to almost double to 214 million in 2025. According to World Health Organization (WHO, 2002), CVDs will be the number one leading cause of death including mortality and morbidity by year 2020 in India from 1.17 million in 1991 to 1.59 million in 2000 and 2.03 million in 2010. The prevalence of hypertension varied from among different studies in India including rural (2-8%) as well as urban (2-15%) region from the late nineties and early twentieth century. In India, Hypertension is directly responsible for 57% of stroke and 24% of all coronary heart disease deaths. Review of epidemiological studies suggested that, the prevalence of hypertension has increased in both urban and rural subjects and presently is 25% in urban adults and 10-15% among rural adults. Low and middle income population in urban in India have greater cardiovascular risk. People in rural India are more prone to coronary risk factors such as smoking and hypertension is more prevalent^27-38.

The current situation in India is more alarming and it has been predicted first rank among all of the mortality in India by 2015 with 9 million deaths in 1990 and alone CVDs accounts for 2.4million or 25% deaths in India. It has been predicted that by 2020, there would be a 111% increase in cardiovascular deaths in India. This increase is much more than 77% for China, 106% for other Asian countries and 15% for economically developed countries. Control of the predicted increase in CVDs will require modification of risk factors that have two characteristics. First, the risk factors must have a high attributable risk or high prevalence, or both. Second, most or all of the risks must be reversible cost effectively. Blood pressure (BP) is directly associated with risks of several types of CVDs and the associations of BP with disease risk are continuous indicating that large proportions of most populations have non-optimal BP values. Moreover, most or all BP-related risk appears to be reversible within a few years with inexpensive interventions²⁹.

The ICMR-WHO study report on Burden of Disease reviewed literature till 2003 on NCDs. The meta-analysis of eight studies reveals that data between 1995 and 2002 in urban areas gives a pooled prevalence rate of hypertension as 164 and 157 per thousand in rural areas. The combined urban and rural pooled estimate of prevalence rate of hypertension among adults (>20 yr) was 159 per thousand. Hence, all the comprehensive review on CVDs including hypertension suggests all forms of CVDs is highly prevalent in Indian population and we need to carry out effective health promotion and intervention programme for reduction in CVDs mortality in India¹⁵.

Pharmacological mechanism of antihypertensive agents:

Clinical drugs available for treatment of hypertension and their side effects:

Hypertension is a leading cause of deaths including mortality and morbidity globally and also major risk factor for other CVDs including stroke and coronary artery disease, diabetes mellitus and kidney failure. Identification and treatment of hypertension continues to be a challenge globally. Guidelines recommend that many patients will require two or more antihypertensive agents from different classes. In view of the frequent use of available clinical antihypertensive drugs, the clinicians are faced so many problems with the potential side effects as well as adverse effects of these drugs. The most common side effects of different classes of antihypertensive drugs are: diuretics cause hypokalemia, which can lead to cardiac arrhythmias and acute myocardial infarction, β-blockers can also induce bronchoconstriction, peripheral vasoconstriction, glycogenolysis, inhibition of insulin secretion and sometimes induce severe bradycardia. In case of calcium channel blockers (CCBs) particularly nifedipine (a dihydropyridine), causes several side effects including sudden drop in BP, sympathetic activation, and reflex tachycardia, especially dangerous in coronary patients, facial flushing and headache.

Table no 1. Clinically approved drug for antihypertensive treatment with their classes and mechanism of action

Class/Category	Mechanism of action	Drug
Diuretics	Produced diuresis and increased the volume of urine flow to excrete out the excess water from the body
High ceiling/loop diuretic	Inhibits the Na-K-2Cl symporter	Bumetanide, Ethacrynic acid, Torsemide, Indapamide, Furosemide and Amiloride
Thiazides	Inhibits reabsorption by Na⁺/Cl⁻ symporter	Hydrochlorothiazide, Epitizide, Chlorothiazide, Bendroflumethiazide, Methyclothiazide, Polythiazide
Potassium-sparing diuretics (sub classified into two category)	Inhibition of Na⁺/K⁺ exchanger: Spironolactone inhibits aldosterone action, Amiloride inhibits epithelial sodium channels	Aldosterone antagonists: spironolactone, eplerenone and potassium canreonate and Epithelial sodium channel blockers: amiloride and triamterene
Calcium-sparing diuretics	Reduced concentration of calcium in the urine	Thiazides and Potassium-sparing diuretics
Osmotic diuretics	Promotes osmotic diuresis	Glucose (especially in uncontrolled diabetes), Mannitol
Xanthines	Inhibits reabsorption of Na⁺, increase glomerular filtration rate	Caffeine, Theophylline, Theobromine
Carbonic anhydrase inhibitors	Inhibits H⁺ secretion, resultant promotion of Na⁺ and K⁺ excretion	Acetazolamide and Methazolamide
Vasodilator	Directly acting on smooth muscle of the arteries	Sodium nitroprusside
Calcium Channel blocker	Block the entry of calcium channel ions into muscle cells in artery walls	Amlodipine, Cilnidipine, Clevidipine, Felodipine, Isradipine, Lercanidipine, Levamlodipine, Nicardipine, Nifedipine, Nimodipine, Nisoldipine, Nitrendipine, Diltiazem, Verapamil
Adrenergic receptor antagonist
α-blocker	α₁ adrenergic receptor blocker that inhibits the binding of norepinephrine to the α₁receptors on the membrane of vascular smooth muscle cells	Doxazosin, Phentolamine, Indoramin, Phenoxybenzamine, Prazosin, Terazosin, Tolazoline
β-blocker	Block the receptor sites for the endogenous catecholamines epinephrine and norepinephrine on adrenergic beta receptors, of the sympathetic nervous system	Atenolol, Bisoprolol, Betaxolol, Carteolol, Carvedilol, Labetalol, Metoprolol, Nadolol, Nebivolol, Oxprenolol, Penbutolol, Pindolol, Propranolol, Timolol
Mixed α and β- blocker	Blockade of α and β-receptor	Bucindolol, Carvedilol, Labetalol
Angiotensin converting enzyme (ACE) inhibitor	Inhibit the activity of angiotensin-converting enzyme (ACE), an enzyme responsible for the conversion of angiotensin I into angiotensin II, a potent vasoconstrictor	Captopril, Enalapril, Fosinopril, Lisinopril, Moexipril, Perindopril, Quinapril, Ramipril, Trandolapril, Benazepril
Angiotensin II receptor antagonist	Angiotensin II receptor antagonists work by antagonizing the activation of angiotensin receptors	Azilsartan, Candesartan, Eprosartan, Irbesartan, Losartan, Olmesartan, Telmisartan, Valsartan, Fimasartan
Renin inhibitor	Inhibit the first and rate-limiting step of the renin–angiotensin–aldosterone system (RAAS), namely the conversion of angiotensinogen to angiotensin I.	Aliskiren
α-₂ adrenergic receptor agonist	Stimulating alpha-receptors in the brain	Prazosin, Doxazosin
Endothelin receptor blocker	Blocking the receptors of the hormone endothelin	Bosentan
Potassium channel opener	facilitates ion transmission for smooth muscle relaxation through potassium channels	Nicorandil, Minoxidil

Angiotensin-converting enzyme (ACE) inhibitors also causes rare side effects and the two of them are specific: cough and angioneurotic edema and associated with the action on the bradykinin system. Hence, these antihypertensive drugs reactions cannot always be predicted from the pharmacological profile and only prolonged clinical experience will reveal their adverse effects in the hypertension patients. The common classifications of antihypertensive drugs and their mechanism of action, which are clinically approved and used for the treatment of hypertension from the various classes of drugs, are listed in table no.1^28-29.

However, a point of interest to physicians and health-care professionals is the alarming and rather unfortunate reality that high blood pressure is managed in only 34% of hypertensive patients.

The major concern that often delay treatment allude to higher costs of antihypertensive drugs, their availability and accessibility, the undesired side effects of antihypertensive drugs showed from last few decades with the risk of kidney stones in older adult’s person, pregnant women, obesity, patients of type 2 diabetes mellitus. According to meta-analysis and systemic review to evaluate the tolerability of clinically approved antihypertensive drug and their major side effects, we need to search new lead molecules for least side effects, optimal choice and antihypertensive lead should be done in accordance with the guidelines, by taking into consideration for all patients’ characteristics with hypertension treatment³⁸.

DISCUSSION:

Many medicinal plants and natural products are considered by the public as a safe, natural, and cost-effective alternative to synthetic drugs without unambiguous proof by randomized controlled clinical trials^20-25. On this background, there is an increased interest in the development of products with validated efficacy and safety, similar to the recently FDA-approved botanical drugs Veregen from sinecatechins leaf extract of Camellia sinesis, Fulyzaq extract from the red latex of the Dragon’s blood tree and Grastek Timothy grass (Phleum pretense L.) pollen allergen extract^26-31. Some herbal extracts and pure compounds are currently undergoing clinical trials for cardiometabolic indications; an overview is presented here and data, information retrieved from www.clinicaltrials.gov are as follows: BeneFlax® (Flaxseed (Linumusitatissimum L.) lignans) for Phase 2 of Hypertension, Curcumin for Non-insulin dependent diabetes, Vascular aging, Ginger for Non-alcoholic fatty liver disease, Phyllanthus niruri L. and Sida cordifolia L. (Vedicine) NCT02107469 - Diabetic peripheral, polyneuropathy, Quercetin for Diabetes mellitus, obesity, Resveratrol for Diabetes mellitus type 2, inflammation, insulin resistance, cardiovascular disease (Phase 1 and 2)^27-45.

CONCLUSION:

The phytochemical investigation of different antihypertensive phytoestrogen agents, therapeutic applications, and pharmacological mechanism of natural products. These plants compounds have all been thoroughly explored in this review for their different mechanism to treat hypertension. However, more research on the phytochemistry and the mechanisms of action of isolated substances is required to completely comprehend the phytochemical profile and the intricate pharmacological effects of these plant-based phytoestrogen are involved. To further ensure this plant's safety and suitability as a source of modern medicine, clinical and laboratory investigations on the toxicity of all plant part extracts as well as other pure phytochemicals obtained from it are crucial.

CONFLICT OF INTEREST:

The author has no conflicts of interest.

ACKNOWLEDGMENTS:

The author would like to thank NCBI, PubMed and Web of Science for the free database services for their kind support during this study.

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Received on 21.12.2022 Modified on 03.04.2023

Res. J. Pharmacology and Pharmacodynamics.2024;16(1):35-41.

DOI: 10.52711/2321-5836.2024.00007