Pharmacology Report: Hypertension, Antihypertensive Drug Treatments

This report delves into the complexities of hypertension, a prevalent health condition with significant global implications. It begins by outlining the disease's prevalence, mortality rates, and the World Health Organization's goals for its reduction. The report then explores the causes, including lifestyle factors and cellular changes, and the underlying mechanisms of hypertension, emphasizing the role of the thymus and the renin-angiotensin system. It provides a comprehensive overview of current pharmacological treatments, including diuretics, vasodilators (ACE inhibitors, ARBs, and calcium channel blockers), and cardioinhibitory drugs (beta-blockers). The report discusses the rationale, mechanism of action, and potential side effects of each drug class. Furthermore, it examines existing guidelines from various organizations for hypertension management. The report concludes by introducing Clotopress, a novel drug designed to inhibit clot formation, and its potential to address the challenges associated with current treatments, including its mechanism of action and preclinical testing results. The report also references the need for further research to validate the efficacy of this new drug.

Running head: PHARMACOLOGY
Pharmacology
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Introduction:
High blood pressure or hypertension is a widely prevalent health condition with high cost
implications. Hypertension affects every one in three individuals in U.S and 2 million people are
diagnosed with the disease every year. In 2014, it was a major cause of mortality for more than
410, 000 Americans (CDC, 2016). Globally, the prevalence of hypertension is alarming as it
affects an estimated 1.3 billion people in low and middle-income countries. Considering the
increase in the number of new cases reported each year, the World Health Organization has
prioritized minimizing the prevalence of hypertension by 25% by the year 2025 (WHO 2019).
Controlling hypertension has been prioritized to decrease the risk of stroke, heart disease and
peripheral vascular disease. The main goal of hypertension treatment is to maintain the BP value
below 140/90mm Hg. During the early phase of the disease, life style modifications can decrease
the rate of complications in patient. However, most patients require pharmacological intervention
to treat blood pressure. The first line of medications used to treat the disease includes diuretics,
beta-blockers, calcium channel blockers and angiotensin-converting enzyme (ACE) inhibitors.
Many patients also require more than one drug to reduce the morbidity and mortality associated
with hypertension (Jarari et al. 2016). Most recently some of the challenges found in
antihypertensive medications included risk of bleeding, carcinogenic effects and drug toxicity
due to high dose (Rao 2016). This issue has triggered range of experiments and search for a new
drug that has the property of inhibiting clot formation to lower blood pressure.
More information about the condition:
Hypertension is a systemic chronic disorder that mainly leads to structural and functional
macro vascular and micro vascular alterations. Some of the micro vascular abnormalities

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witnessed in patient includes abnormality in vasomotor tone, changes in wall to lumen ratio and
decrease in vasodilation reserve. Patients with hypertension need to be strictly monitored
because such form of changes can also increase risk of cardiovascular events in hypertensive
patients. Similarly, macro vascular alterations lead to chronic renal insufficiency, diabetes and
lipidemia too. The main purpose of pharmacological intervention is to decrease the risk
associated with blood pressure and organ damage (Oparil & Schmieder 2015). Jarari et al.
(2016) explains that antihypertensive drugs minimize the risk of stroke, myocardial infarction,
heart failure and end stage renal disease. The main cause behind high prevalence of hypertension
includes ageing and behavioral risk factors like unhealthy diet, sedentary lifestyle, stress, obesity
and excess use of alcohol.
Hypertension is a condition associated with many cellular changes. Different cell types
and the autonomic nervous system are involved in the pathophysiology of hypertension. Good
understanding of the mechanism of hypertension is important to understand how
antihypertensive therapy controls blood pressure. According to Dai et al. (2018), thymus is the
key organ involved in the pathological processes of high blood pressure. The main function of
the thymus is to promote the development and maturation of the thymus. Any changes in the
thymus affect the inflammatory process and this consequently plays a role in the
pathophysiology of hypertension too. Some of the inflammatory factors can cause endothelial
damage and active the rennin system. Hence, activation renal-angiotensin system (RAS) is the
main factor linked to the pathophysiology of hypertension. In addition, other factors like nitric
oxide, superoxide, C-reactive protein (CRP), TNF and IL-6. Research evidence has shown
elevated level of CRP is found in patients with hypertension. The main mechanism that results in
systemic hypertension due to higher level of CRP includes decrease in the production of NO in

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endothelial cells and increase in the production of endothelin 1 thus leading to vasoconstrictions
(Abo-Zaid, 2016). To conclude, the above evidences indicate that therapeutic interventions for
hypertension can use novel targets involves in thymus function to modify the course of the
disease.
Current pharmacological treatment:
The first line of drugs pharmacological treatment for hypertension involves use of
diuretics, ACE inhibitors, beta blockers and calcium channel blockers. The choice of drug to be
chosen for individual patient is decided based on the presence of other co-morbidities in patient
like stroke and renal disease. This section will give an overview of the rationale for using these
drugs and their mechanism of action:
Diuretics: Diuretics is a class of medication that is used to remove excess salt and water from
the body. It is used to treat hypertension and three types of diuretics mainly prescribed to
hypertensive patient include thiazide, loop diuretics and potassium-sparing diuretics. Diuretic
works to promote urine output by the kidney by changing the way kidney deals with sodium. The
process of dieresis is induced by diuretics by inhibiting re-absorption of sodium. Loop diuretics
work to inhibit the sodium-potassium-chloride co-transporter and inhibition of this pump lead to
a vast increase in sodium concentration. In contrast to loop diuretics, thiazide diuretics play a
role in inhibiting sodium chloride transported in the distal tubule. Some side-effects of diuretics
include dizziness, dehydration, muscle cramps and headache (Blowey 2016).
Vasodilators: Another most common class of drug used to treat high blood pressure includes
vasodilators. Drugs coming under this class include ACE inhibitors, angiotensin receptor
blockers (ARBs), nitrodilators and calcium channel blockers. The main rationale for using

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vasodilator is that it relaxes the smooth muscles in the blood vessels leading to vasodilation. This
helps to overcome vascular resistance and lead to a decrease in arterial blood pressure. The
vasodilation process also lead to a decrease in venous blood pressure too. This class of drug is
used for treatment of hypertension, heart failure and angina (Wecker 2018). The mechanism of
action for different drugs in this class will be discussed below:
 ACE inhibitors are used to dilate the blood vessels by inhibiting the formation of
angiotensin II. The main function of angiotensin II is to produce vasoconstriction and
ACE inhibitor acts to minimize the enzyme that converts angiotensin I to angiotensin II.
This action minimizes the production of angiotensin II thus leading to decreased blood
pressure and prevention smooth muscle remodeling. However, some of the problem
associated with the use of this drug is that it can lead to hypertension and hyperkalemia
too. ACE also has function in blocking aldosterone, which is involved in potassium
excretion from the body. But blocking of aldosterone can lead to accumulation of
potassium and increase in the concentration of sodium (Herman and Bashir 2019).
 Calcium channel blockers (CCBs) are also used to treat hypertension and angina. In case
of patients with hypertension, CCB lowers blood pressure by decreasing systemic
vascular resistance and causing relaxation of the vascular smooth muscles. The side
effects associated with the use of this drug includes low blood pressure, dizziness, rash
and headaches (He et al., 2017).
 ARBs are similar in effect to ACE inhibitors. However, the mechanism of action of the
drug is different from that of ACE inhibitors. As the drug is a receptor antagonist, it
blocks the Angiotensin receptors on the blood vessels. These receptors are normally
involved in stimulating vascular smooth muscle contraction. However, unlike ACE,

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ARBs do not increase the concentration of Bradykinin. For this reason, the drugs
contribute to vasodilation as well as an increase in side effects such as cough and
angioedema (He et al., 2017). Examples of medicines under this category include
valsartan and telmisartan.
Cardioinhibitory drugs: The therapeutic use of this drug is prescribed in the treatment of
arterial blood pressure, angina, heart failure and arrhythmias. In case of patients with
hypertension, the therapeutic effect of the drug is achieved by an increase in cardiac output or
systemic vascular resistance. Common drugs which are part of this class of drug include beta-
blockers, calcium channel blockers (CCBs) and centrally acting symphalotics. Beta blockers
work by blocking the effects of epinephrine and nonepinephrine. It prevents the hormones from
binding to the beta adrenoreceptors by competing for the binding site. This form of inhibition
decreases cardiac output and lead to decrease in blood pressure. CCBs bind to L type calcium
channels and blocks the entry of calcium thus resulting in a decrease in electrical conduction
within the heart and dilation of the arteries ().National Clinical Guideline Centre (UK), (2011)
reported issues related to high frequency of adverse events with the use of ARBs and CCBs such
as high rate of oedema, dizziness and headache.
Worldwide, many guidelines have been developed to reduce the morbidity and mortality
associated with hypertension. Some of the agencies or bodies involved in developing guidelines
for the development and management of hypertension includes American Society of
Hypertension, Joint National Committee on Detection, Evaluation and Treatment of High Blood
Pressure, National Institute for Health and Care Excellence (NICE) (Gabb et al. 2016). The
National Heart Foundation of Australia is the governing body involved in developing the

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guidelines for the management of hypertension in adults. The main recommendations according
to the updated guideline by the National Heart Foundation were as follows:
 There is a need to start antihypertensive therapy for all those patients who have a BP of
greater than 160/100 mm Hg.
 It was also recommended to start antihypertensive therapy for those patients who were at
moderate risk of absolute cardiovascular risk due to persistent BP value of 140/90 mmHg
 In addition, for patients with BP greater than 140/90, there is a need to initiate treatment
and interventions that controls BP level (Gabb et al. 2016).
The significance of the above updated guideline is that this has been developed following
systematic search for studies in database like CINAHL, MEDLINE, Cochrane and Embase.
Recommendations were taken from high quality studies like systematic reviews and
randomized controlled trials. There are different recommendations for patients with history
of other medical conditions such as myocardial infarction, and chronic heart failure and old
age. For those with a history of myocardial infarction, treatment with ACE inhibitor and beta
blockers are recommended. In case of elder patients, any of the first line drugs that control
blood pressure is recommended. In case of patients with chronic heart failure, there is strong
evidence for the use of ACE inhibitors and selected b-blockers. For those who cannot tolerate
ACE inhibitors, ARBs are recommended (Gabb et al., 2016).
Clotopress, a novel clot inhibition drug for treatment of hypertension:
Mechanism of action
Due to many efficacy issues associated with the use of combined drugs like CCBs and
diuretics for treatment of hypertension, this has led researcher to search for other alternative

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drugs that could have better efficacy and lesser side effects (Dabrowski 2015). This has led to
the discovery of an innovative drug called Clotopress that has the ability to inhibit clot formation
and prevent hypertension. This drug is specifically effective for those people who have
hypertension as well as a history of cardiovascular event. Although there was lack of established
studies related to effective anticoagulant drugs for hypertension, however Clotopress has solved
all the problems. It has the potential to address prothrombotic complications occurring due to
hypertension by acting as a platelet inhibitor. Clotopress has the potential to inhibit the uptake of
adenosine into platelets, endothelial cells and erythrocytes. By this form of inhibition, the drug
results in an increase in local concentration of adenosine and stimulation of platelet adenylate
cyclase. This process increases the platelet cyclic-3',5'-adenosine monophosphate (cAMP). By
this mechanism, platelet aggregation is prevented. The rennin angiotensin system (RAS) plays an
important role in the artheroscelorotic complications and RAS causes abnormalities in the
platelet function. Thus, the clinical efficacy of this drug is that it particularly works to regulate
abnormalities in platelet function. In case of untreated patients with hypertension, platelet
aggregation increases (Remková and Remko 2010). Thus, Clotopress has the potential to reduce
thrombotic complications in hypertensive patients.
Preclinical testing of Clotopress:
Many preclinical testing of the new drug has been done in animal studies. The drug was
directly administered to mice and rats. The drug was given in different doses and no evidence for
drug related carcinogenesis was found. The maximum daily oral dose for humans was also
administered and no major negative effect was found. The mutagenecity test of the drug with
bacterial and mammalian cell system was done and negative result was found for this parameter
too. At doses greater than 12 times, no evidence of impaired fertility for both male and female

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was found. Hence, these experimental studies confirmed that fatal effect is minimum if the drug
is taken in large numbers.
As Clotopress is mainly an antiplatelet and anticoagulant drug for hypertension, there is a
need for assessment of thrombotic bleeding risk or the efficacy of the antiplatelet treatment. This
form of assessment is necessary because the main issue associated with the use of antiplatelet
and anticoagulant drug is that rapid platelet aggregation induces by such drug leads to thrombus
formation and thrombus blocks the platelet function thus increasing the chances of bleeding risk.
Hence, to observe this effect of the drugs on human subject, it is proposed to carry out
experiments on human subjects to observe to what extent the drug can lead to bleeding risk with
regular use. Different population group may have different platelet reactivity levels because of
variations in platelet phenotype (Metharom et al. 2015). Hence, it is proposed to conduct reliable
functional or platelet testing that predicts the bleeding risk or the efficacy of the drugs in
inducing antiplatelet effects. Thus, cues from new experimental evidence can increase
understanding about platelet function and regulation and improve the potential of Clotopress in
using antiplatelet approach to improving clinical outcomes of patient.
Thrombosis is a multifactorial complication leading to blockage of the blood flow to the
tissues and this can increase the risk of heart attacks and mortality. Apart from other risk factors
smoking, diabetes and visceral adiposity, hypertension is one of the risk factors for this
condition. In the past many clinical trials for antiplatelet drugs has been done and this has mainly
evaluated the efficacy of the dosage of the drugs in high and low risk cohorts
(Rao 2016). It is proposed to conduct similar trials for Clotopress before it could be actively used
for treatment of hypertension. The drug will be used for direct comparison in high risk patients

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with a dose of 75 to 100 mg daily and the effectiveness of the dosage for individuals will be
evaluated. This will be done by repeated trials so that reliability of the outcome is achieved.
Conclusion
To conclude, from the review of pharmacological treatment for hypertension, it has been
found that the condition presents new risk for those with other disease like heart disease. The
thrombotic mechanism associated with the drug is a complication that increases risk for patient
and this increased the demand for a novel drug that has antiplatelet activity. The Clotopress is the
novel drug that inhibits platelet function and inhibits clot formation by platelet aggregation.
However, as evidence shows several bleeding risk associated with use of antiplatelet drugs,
designing appropriate preclinical studies for this purpose was important. Based on the proposed
clinical study outcome, it is expected that the test will be positive. This will be followed by phase
1 clinical trials after which the drug may find use in pathological laboratories and ultimately
pharmacies.

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