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<b>SCHOOL OF CHEMISTRY AND LIFE SCIENCES</b>

<b>Antihypertensive drug</b>

<i>Assignment table</i>

<i><b>2023-2024</b></i>

<b> </b>

<i><small>27/10/ 023</small></i>

summarize the article

<b>Nguyễn Thị Ngọc Huệ</b> Concept of

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<b>History of discovery and development of antihypertensive drugs</b>

Ha NGUYEN Thu , Hue NGUYEN Thi Ngoc , Lam VU Thi Hoai , Kien DOAN Phu , Toan DO Duc<small>bccdea</small>

<small>a, b, c, d, e</small>Department of Pharmaceutical Chemistry & Pesticides Technology, School of Chemical Engineering,Hanoi University of Science and Technology, Hanoi, Vietnam

Hypertension, also known as high blood pressure, has existed for thousands of years. In ancient times, whenpeople lived a stressful and stressful life, high blood pressure was recorded and caused many dangerouscomplications. However, at that time, there was no specific cure for the disease, relying mainly on non-pharmacological measures, including lifestyle changes, healthy eating, and exercise. The first time a drugwas used to treat hypertension was thiazide, discovered and produced in the 1950s. This antihypertensivedrug helps reduce pressure in blood vessels and lowers blood pressure. Since then, other drugs such as beta-blockers, ACE inhibitors, calcium channel blockers, and angiotensin receptor blockers have been developedand widely used in the treatment of high blood pressure. By the 20th century, as medicine developed andtechnology advanced, antihypertensive drugs are more thoroughly researched by the medical industry.Researchers have discovered that high blood pressure can cause heart, brain, and kidney problems.Therefore, antihypertension has been developed. Medications are being tried to be applied optimally toreduce their side effects. This article will summarize the history of discovery and development of drugs totreat high blood pressure. It provides specific knowledge for researchers in their finding new drugs or

<i>Key words: hypertension, antihypertensive drugs. development, high blood pressure</i>

High blood pressure is now recognized as one ofthe leading and most common causes ofcardiovascular death and cardiovascularhospitalization. Antihypertensive drugs areresearched and divided into five mainpharmacological groups: beta blockers, diuretics,angiotensin-converting enzyme inhibitors,angiotensin II receptor antagonists and calciumchannel blockers. The first studies on how to treathypertension were performed on horses in 1733.Since then, antihypertensive drugs have beendeveloped to treat hypertension in humans. Yet, the

reality in drug development in hypertension is thatthere has not been a novel antihypertensivemechanism entering the market in more than adecade [1]. The recent development of a renininhibitor2 is perhaps an exception but is a memberof a wellestablished class of drugs regulating therenin-angiotensin system. For the most part, largepharmaceutical companies (and many biotechcompanies) have abandoned antihypertensive drugdevelopment, believing that the agedarmamentarium of drugs available to treathypertensive patients is adequate.

<b>Concept of hypertension</b>

Systemic arterial hypertension (hereafter referred toas hypertension) is characterized by persistentlyhigh blood pressure (BP) in the systemic arteries.BP is commonly expressed as the ratio of thesystolic BP (that is, the pressure that the blood

exerts on the arterial walls when the heart contracts)and the diastolic BP (the pressure when the heartrelaxes) [2]

Blood pressure is now recognized as a biomarkerfor hypertension, and a distinction is made betweenthe various stages of hypertension and global

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the cardiovascular syndrome arising from complexand interrelated etiologies. Early markers of thesyndrome are often present before blood pressureelevation is sustained; therefore, hypertensioncannot be classified solely by discrete bloodpressure thresholds.

Progression is strongly associated with functionaland structural cardiac and vascular abnormalitiesthat damage the heart, kidneys, brain, vasculature,and other organs and lead to premature morbidityand death. Reduction of blood pressure when targetorgan damage is demonstrable or the functionalprecursor of target organ damage is present and stillreversible generally reduces the risk for CV events.Note that we separate elevated BP (onemanifestation of the disease) from hypertension (thedisease) [3].

<i>Causes of hypertension</i>

Several aetiologies can underlie hypertension. Themajority (90–95%) of patients have a highlyheterogeneous essential, or primary, hypertensionwith a multifactorial gene–environment aetiology. Apositive family history is a frequent occurrence inpatients with hypertension, with the heritability (ameasure of how much of the variation in a trait isdue to variation in genetic factors) estimated to bebetween 35% and 50% in the majority of studies.Genome-wide association studies (GWAS) haveidentified ~120 loci that are associated with BPregulation and together explain 3.5% of the traitvariance [3].

In pre-industrial societies, BP levels had narrowdistributions with mean values that changed littlewith age and averaged around 115/75 mmHg, avalue that probably represents the normal (or ideal)BP for humans. However, in most contemporarysocieties, systolic BP levels rise steadily andcontinuously with age in both men and women.This ubiquitous finding could be explained by thefact that age is a proxy for the probability andduration of exposure to the numerousenvironmental factors that increase BP graduallyover time, such as excessive sodium consumption,insufficient intake of dietary potassium, overweight

Other factors, such as genetic predisposition oradverse intrauterine environment (such as ingestational hypertension or pre-eclampsia), havesmall but definite associations with high BP levelsin adulthood. Even modest rises in the meanpopulation BP led to large increases in the absolutenumber of people with hypertension [2].

<i>Disease burden</i>

Globally, 3.5 billion adults have non-optimalsystolic BP levels (that is, >110–115mmHg), and874 million adults have a systolic BP of≥140mmHg. Thus, approximately one in four adultshas hypertension. Between 1990 and 2015, therewas a 43% increase in the total global number ofhealthy life years lost to nonoptimal BP, driven bypopulation increase, population ageing and a 10%increase in the age-standardized prevalence ofhypertension. The Global Burden of Disease studyhas shown that nonoptimal BP continues to be thelargest single risk factor contributing to the globalburden of disease and to global all-cause mortality,leading to 9.4 million deaths and 212 million losthealthy life years (8.5% of the global total) eachyear [2].

<b>Classification of hypertensive drugs</b>

The five main pharmacological groups ofantihypertensive drugs commonly used in thetreatment of hypertension are: beta-blockers,diuretics, angiotensin-converting enzyme inhibitors,angiotensin II receptor antagonists, and calciumchannel blockers. In addition, four additionalpharmacological groups are introduced: renininhibitors, alpha-adrenergic receptor blockers,centrally acting drugs, and direct-actingvasodilators [4].

Beta-blocker is a heterogeneous pharmacologicalgroup and its pharmacodynamic properties dependon its cardioselectivity, partial agonist activity andvasodilatory properties. All drugs in this classreduce blood pressure to the same extent, althoughthere are differences in the degree of reduction incardiac output and vasodilation, depending on theirpharmacological properties [5].

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proposed to explain the hypotensive effects of blockers: the reduction in cardiac output in responseto bradycardia is one of the most important factorsin reducing mean blood pressure. However, beta-blockers should not be used in patients withmoderate to severe asthma (since adrenergicbronchodilator requires intact beta-2 receptors),unstable heart failure due to systolic dysfunction,second- or third-degree atrioventricular block, orsick sinus syndrome. (no pacemaker). Beta blockersmay worsen glucose intolerance and mask thesymptoms of hypoglycemia.

Diuretics have long been used for the treatment ofhypertension. Thiazide diuretics are the mostcommonly prescribed diuretics for hypertension,but other classes of diuretics may be useful inalternative circumstances. Although diuretics are nolonger considered the preferred agent for treatmentof hypertension in adults and children, they remainacceptable first-line options. Diuretics effectivelydecrease blood pressure in hypertensive patients,and in adults with hypertension reduce the risk ofadverse cardiovascular outcomes. Because of variedpharmacokinetic and pharmacodynamic differences,chlorthalidone may be the preferred thiazidediuretic in the treatment of primary hypertension..Common side effects of thiazides are mostly dose-related and involve electrolyte and metabolicabnormalities [6].

Thiazide diuretics and loop diuretics increasenatriuresis and diuresis. Both can be considered asone major therapeutic class of antihypertensivedrugs, although they represent two distinctpharmacological classes. Their major mechanismsof action and side effects are described separately.Potassium-sparing diuretics represent anothertherapeutic class.

<i>Loop diuretics</i>

Furosemide and bumetanide belong to the mostfrequently used loop diuretics. Side effects of loopdiuretics are dose-dependent and includehyponatremia (Na+ depletion and dilution),hypokalemia, metabolic alkalosis, hypovolemia,

hypocalcemia, hypomagnesemia, hyperglycemia,hyperlipidemia, urinary urgency, and impotence.Loop diuretics are contra-indicated in patients withgout [4]

Hydrochlorothiazide, chlortalidone and indapamidebelong to the most frequently used thiazidediuretics. Side effects of thiazide diuretics are dose-dependent, and include hyponatremia (Na+depletion and dilution), hypokalemia, metabolicalkalosis, hypovolemia, hypotension, and to a lesserextent hyperuricemia, hypomagnesemia,hyperglycemia, hyperlipidemia and impotence.They resemble those of loop diuretic [4].

<i>Potassium-sparing diuretics</i>

This sub-class includes competitive antagonists ofaldosterone, such as spironolactone, eplerenone,and drugs which act independently of aldosterone,such as amiloride and triamterene. These drugsinhibit active Na+ reabsorption at the level of latedistal tubule and collecting duct.

Side effect: hyperkalemia is a common side effect,particularly in patients with chronic renal disease and heart failure or diabetes, receivingpotassium-sparing diuretics or potassiumsupplements [4]

<i>ACE inhibitors</i>

The first ACEI available for hypertension treatmentwas captopril in the early 1980s, rapidly followedby enalapril, perindopril, lisinopril, ramipril,quinapril, benazepril, cilazapril, trandolapril,fosinopril, moexipril, imidapril and zofenopril. Angiotensin converting enzyme inhibitors(ACEIs) target a pluripotent zinc metalloproteinasewhich catalyses the conversion of angiotensin I toangiotensin II, so called angiotensin convertingenzyme (ACE). ACE is located in the endothelialcells of large and small vessels, capillaries andvenules, and in pulmonary endothelial cells.Importantly, ACE may modulate the amount ofangiotensin II entering the systemic arterialcirculation because of its strategic position withinthe lungs and the strategic position of the lungs inthe general circulation [4].

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However, it has some side effects such as:excessivehypotension. ACE inhibitors may cause excessivehypotension, especially in patients with malignanthypertension or heart failure. This can lead tosymptoms such as dizziness, lightheadedness, orloss of balance [7].

Respiratory side effects: Some people taking ACEinhibitors may develop respiratory side effects suchas coughing, sneezing, dry cough, and rhinitis.However, these side effects are usually not seriousand can be controlled. Loss of taste: some peopletaking ACE inhibitors may experience loss of tasteor changes in taste. This can reduce appetite andcause discomfort in eating. Side effects on kidneyfunction: some people taking ACE inhibitors mayexperience problems with kidney function,including decreased kidney function. This can bemonitored through regular kidney function tests [7].

<i>Angiotensin II receptor blockers</i>

The first angiotensin II receptor blocker (ARB)available for hypertension treatment was losartan inthe late 1990s, rapidly followed by candesartan,eprosartan, irbesartan, valsartan, telmisartan, andolmesartan.

The angiotensin II receptor blockers (ARBs)represent a newer class of antihypertensive agents.Their mechanism of action differs from that of theangiotensin-converting enzyme (ACE) inhibitors,which also affect the renin-angiotensin system. TheARBs were developed to overcome several of thedeficiencies of ACE inhibitors: competitiveinhibition of ACE results in a reactive increase inrenin and angiotensin I levels, which may overcomethe blockade effect; ACE is a relatively nonspecificenzyme that has substrates in addition toangiotensin I, including bradykinin and othertachykinins, and thus, inhibition of ACE may resultin accumulation of these substrates; production ofangiotensin II can occur through non-ACEpathways as well as through the primary ACEpathway, and these alternative pathways areunaffected by ACE inhibition; specific adverseeffects are associated with ACE inhibitor effects onthe enzyme; and ARBs may offer more completeangiotensin II inhibition [4].

some side effects [8]. Here are some common sideeffects of ARBs:

● Cough: Some people taking ARBs maydevelop a cough due to stimulation ofbradykinin receptors in the lungs. However,this side effect is usually not serious andusually reduces after using the medicine fora while.

● Dizziness and fatigue: Some people mayexperience symptoms such as dizziness andfatigue while using ARBs. This can occurdue to an excessive drop in blood pressure.● Effects on the Renal System: ARBs may

cause some effects on the renal system,including increased blood levels ofcreatinine and potassium. Therefore,monitoring of renal function is oftenrecommended when using ARBs.● Effects on the digestive system: Some

people taking ARBs may experiencesymptoms such as nausea, diarrhea andabdominal pain.

● Other effects: ARBs can also cause someother side effects such as increased liverenzymes, fever, chest tightness and weightgain.

<i>Calcium-channel blockers</i>

Calcium-channel blockers (CCBs) are aheterogeneous class of drugs, which includeverapamil (a benzothiazepine), diltiazem (aphenylalkylamine), and dihydropyridines (DHPs)such as nifedipine and amlodipine. Within the possible antihypertensive drug classescurrently available for the clinical management ofhypertension, both in monotherapy and incombination therapy, drugs inhibiting the renin–angiotensin system and calcium channel blockers(CCBs) have demonstrated to be effective and safein lowering BP levels and achieving therecommended BP targets with a good tolerabilityprofile. In particular, CCBs have been one of themost widely used classes of antihypertensive agentsin the last 20 years, based on their effectiveness inreducing BP levels, good tolerability, and abundant

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consequences of hypertension [4]

Mechanism of action of Cellualer: Calciumchannel blockers (CCBs) inhibit the influx ofextracellular calcium through specific ion channelsspanning the cell wall. Although several types ofsuch channels have been identified, currentlyavailable CCBs inhibit l-type channels in humans.When calcium inflow is inhibited, vascular smoothmuscle cells dilate, leading to vasodilation andlowering of blood pressure (BP). In themyocardium, contractility is reduced, and sinusoidsare impaired

CCBs are generally well-tolerated drugs. Highdoses of DHPs often cause ankle edema, headache,flushing and tachycardia; their mechanisms havebeen described above, in the section on mechanismsof action. High doses of verapamil can causeconstipation. Gingival hypertrophy can be observedafter all CCB [4].

<i>Other pharmacological classes</i>

<i>Renin inhibitors</i>

The only direct renin inhibitor currently availablefor treating hypertensive patients is aliskiren, anon-peptide and orally active drug. Aliskiren is ahighly potent and selective inhibitor of human renin[4].

Renin-inhibitors are contra-indicated inpregnancy, in patients with previous angioneuroticedema, hyperkalemia, and in patients with bilateralrenal artery stenosis.

Potential side effects [9]

● Cough sensation: Some patients treated withrenin inhibitors or other angiotensin inhibitorsmay experience a subsequent dry coughreaction. This is a common side effect and cancause discomfort for the patient.

● Hyperkalemia: Both drugs, renin inhibitors andangiotensin inhibitors, can cause increasedpotassium (an electrolyte) in the plasma. This isespecially concerning for patients with impairedkidney function or taking other medications thatmay increase blood potassium.

● Hypotension: Renin inhibitors and angiotensininhibitors lower blood pressure by inhibiting the

can cause excessive hypotension, especially inpeople with cardiovascular problems orimpaired kidney function.

● Effects on kidney function: Both renininhibitors and angiotensin inhibitors may affectkidney function. This can cause problems suchas kidney failure and increase the risk ofhyperkalemia.

● In addition, there are other problems such ascontact dermatitis, hypertension, etc.

<i>Alpha-adrenergic receptor blockers</i>

Alpha-adrenergic receptor blockers work through aselective mechanism, helping to reduce bloodpressure by blocking this receptor. Drugs such aspmzosin, doxazosin and terazosin have a highability to interact with this receptor and are used totreat hypertension. They help reduce total periferiresistance, a fundamental hemodynamicabnormality in hypertension [10]

Some side effects of alpha-adrenergic receptorblockers include increased heart rate and rapiddevelopment of tolerance to them. However, currentselective alpha-adrenergic receptor blockers canminimize these effects by acting selectively on thereceptor, without affecting the enhancement ofnorepinephrine release.

In addition, Alpha-adrenergic receptor blockers alsohave beneficial effects on plasma lipoproteins. Theyhelp reduce triglyceride and cholesterol levels andincrease high-density lipoprotein (HDL) cholesterollevels and the HDL cholesterol/total cholesterolratio.

<i>Centrally acting agents</i>

Centrally acting agents work by acting on thecentral nervous system, specifically on the organsthat regulate blood pressure and heart rate. Themain mechanism of action of this drug is to inhibitthe activity of the sympathetic nervous system,reducing sympathetic signals from the brain toorgans and blood vessels, leading to vasodilationand reduced blood pressure [4].

Centrally acting antihypertensive agents includedrug classes such as clonidine, methyldopa, andguanfacine. They usually work by activating alpha-2 receptors on neurons in the central nervous

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addition, some centrally acting drugs can alsoinhibit the renin-angiotensin-aldosterone system, asystem important in regulating blood pressure.While centrally acting antihypertensive drugs areeffective in treating hypertension, they can alsocause some side effects. A common side effect isdrowsiness, fatigue and decreased energy. Somepeople taking the drug may have trouble sleeping,have sleep disorders, or feel tired throughout theday. Headache, dizziness, nausea and constipationare also other possible side effects. In particular,when the drug is suddenly stopped, an increase inblood pressure may occur, because the body hasadapted to the drug and can lead to a temporaryincrease in blood pressure.

In addition, centrally acting antihypertensivedrugs can also cause other side effects such aselectrolyte imbalance, loss of concentration, weightgain and effects on sexual function.

<i>Direct-acting vasodilators</i>

Direct-acting vasodilators work by dilating bloodvessels and reducing resistance in the vascularsystem. This leads to reduced pressure in the bloodvessels and dilation of smaller blood vessels,thereby reducing blood pressure. Some examples ofdirect-acting antihypertensives include hydralazineand minoxidil.

Mechanism of minoxidil is used to dilateresistant blood vessels with little or no effect onvenous blood vessels. The drug works by activatingATP-sensitive potassium channels (adenosinetriphosphate) in the smooth muscle of bloodvessels. As a result, the smooth muscle membraneis hyperpolarized and calcium influx throughvoltage-dependent calcium channels is inhibited.Calcium concentration in cells decreases. The drug is absorbed orally at a rate of 100%.The plasma half-life is 2.8 to 4.2 hours and plasmaprotein binding is negligible. Minoxidil isextensively metabolized in the liver by fourpathways: glucuronidation (67%), hydroxylation(25%), sulphation and metabolism to anunidentified polar compound. Sulfate metabolitesare known and pharmacologically active, and mayaccount for the majority of the activity of the parentdrug.

which is particularly bothersome in women.Hypertrichosis affects mainly the forehead and faceand is most apparent in dark haired individuals.‐There is no pharmacologic treatment for excess hairgrowth, and the only remedy is removal of hair ordiscontinuation of the drug. After discontinuation,excessive hair growth reverses in a few months.Other reported side effects with minoxidil includenasal stuffiness, nausea, breast tenderness, and skinreactions.[13]

<b>History of discovery and development ofdrugs</b>

<i>History of misconceptions and successes in thedevelopments of hypertension treatments</i>

High blood pressure is now recognized as one ofthe leading and most prevalent causes for cardiovascular death and cardiovascularhospitalizations [11]. It is regarded as a highlyrelevant risk factor rather than a risk mediator,because it has been shown that blood pressurereduction reduces cardiovascular outcomes likestroke, myocardial infarction, and cardiovasculardeath dependent on blood pressure levels atbaseline, accompanying cardiovascular risk andachieved blood pressure reduction. Organperfusion, as early recognized by William Harvey,has been suggested to be dependent on bloodpressure [12].

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<b>Figure 1. Survival of patients with resistant hypertension who were untreated in 1939 and treated with</b>

diuretics 1981 (a). Press note on the death of President Roosevelt 1946 according to a cerebral hemorrhageafter long standing hypertension (b). Blood pressure values over 10 years of President Roosevelt inassociation with different historical events (c) [13]

The development of blood pressure measurement,which was first performed in a horse in 1733 andlater further developed by Riva-Rocci andKorotkoff, paved the way to recognize that bloodpressure levels beyond the requirement of organperfusion are associated with cardiovascularoutcomes and death [14].

Hypertension is essential to success and certainlife styles founded or at least influenced the term“essential hypertension” still used today. However,the strong association of elevated blood pressurewith outcomes, in particular of malignant bloodpressure (diastolic blood pressure above 110mmHg), resulted in death rates of 80% after 1 year(Fig.1a) [15]. The potential use of blood pressure-

reducing drugs was scrutinized by studies after thedevelopment and implementation of diureticsshowing that, in a similar population of patients,death rate was markedly reduced (Fig. 1a) [16].President Roosevelt died finally due to a cerebralhemorrhage. The first controlled, randomized studyin hypertension investigated the effects of treatmenton mortality and morbidity in hypertensive patientswith a diastolic blood pressure averaging 115–129mmHg. This study was based on 143 malehypertensive patients (no women) showing in arandomized study against placebo thathydrochlorothiazide or reserpine plus hydralazinesignificantly reduced blood pressure and resulted ina reduction of outcome events with 27 events in theplacebo group and 2 events in the actively treatedgroup (with 4 versus 0 death). Among those events,

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complications like intracerebral bleeding, rupturedabdominal aortic aneurysm, sudden cardiac death,and stroke, as well as myocardial infarction [17].This was later extended to patients with a lowerdiastolic blood pressure of 90–114 mmHg with asimilar outcome reductio [18]. These studies pavedthe way for future outcome trials and startedextensive efforts to develop novel, effective drugtreatments drug treatments, with acceptabletolerability.

Table: LIST OF AVAILABLEANTIHYPERTENSIVE DRUGS FROM THE1930s TO THE PRESENT

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1930s Veratrum

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