COURSE NOTES

THERAPEUTIC AREA:
Cardiovascular

COURSE:
Hypertension: Treatment

Publication Date: May 2021

INTRODUCTION
1. Course Information

Transcript
Welcome to the Hypertension: Treatment course.

Before beginning, please take a moment to read the course details.

Select the “Course Notes” button to download a PDF version of the course. The course notes
contain all the text associated with the course, including objectives, transcripts, and progress
checks.

Course Details
Course Length: Approximately 45 minutes. Your time may vary based on connection speed,
prerequisite knowledge, and other factors.
Date Published: May 2021

2
INTRODUCTION
2. Course Overview

Introduction
Hypertension is a major global healthcare problem that is a risk factor for heart attacks, strokes,
and other cardiovascular diseases. This course explains the therapies used to treat and prevent
hypertension and hypertension-related diseases.

Transcript
This course is divided into four sections.

 The first section, PROGNOSIS, explains the process of end-organ damage and
describes the symptoms and consequences of hypertensive conditions.

 The second section, NONPHARMACOLOGIC TREATMENT, describes the reasoning

behind nonpharmacologic antihypertensive therapy.

 The third section, PHARMACOLOGIC TREATMENT, discusses the mechanisms of

action and recommendations for use of pharmacologic therapies.

 The final section, CLINICAL TRIALS, discusses clinical trials that have documented the
effects of various therapies on hypertension.

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PROGNOSIS
3. Objectives

Introduction
In the United States, nearly half of adults have high blood pressure (hypertension), defined as
systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥80 mmHg1, meaning that about
108 million adults have hypertension in the US.2 In 2018, 95,876 deaths in the US were primarily
attributed to hypertension and 494,873 deaths listed hypertension as a primary or contributing
cause.3, 4

Transcript
These are the objectives for this section.

Onscreen Text: Objectives

After you finish this section, you should be able to:
 Describe the role of hypertension in the etiology of atherosclerosis
 Describe the consequences of hypertension, including the risk for cardiovascular
diseases
 Explain the clinical picture seen with nephropathy due to hypertension and to
diabetes
 Describe the etiology and pathogenesis of end-organ damage directly due to
hypertension and atherosclerotic plaque formation

1 AHA. Understanding blood pressure readings. https://www.heart.org/en/health-topics/high-blood-

pressure/understanding-blood-pressure-readings#.WigW8e-nFhG. Accessed May 2021.
2 Centers for Disease Control. Facts about hypertension. https://www.cdc.gov/bloodpressure/facts.htm. Accessed

May 2021.
3 American Heart Association. 2021 Heart Disease and Stroke Statistics Update Fact Sheet: At-A-Glance.

https://www.heart.org/-/media/phd-files-2/science-news/2/2021-heart-and-stroke-stat-
update/2021_heart_disease_and_stroke_statistics_update_fact_sheet_at_a_glance.pdf. Accessed May 2021.
4 Centers for Disease Control. Facts about hypertension. https://www.cdc.gov/bloodpressure/facts.htm. Accessed

May 2021.
4
PROGNOSIS
4. Consequences of Hypertension

Transcript
Hypertension has both direct and indirect consequences. Hemorrhagic stroke, brain hemorrhage,
and congestive heart failure (CHF) are direct consequences of hypertension; that is, they are
directly caused by increased vascular pressure, but efforts to adequately treat the hypertension
can help lower the risks for such events.5

High blood pressure is also one of the most significant risk factors for atherosclerosis, which is an
indirect consequence of hypertension. Increased blood pressure damages the endothelial cells in
blood vessels, prompting the formation of atherosclerotic plaques. These plaques narrow the
vessel lumen and restrict blood flow, reducing the supply of oxygen to target organs.6 Coronary
heart disease (CHD) and peripheral artery disease (PAD) are results of this atherosclerotic
vascular narrowing.7 ,8 Although atherosclerosis can develop in the absence of hypertension, high
blood pressure exacerbates the process.9

5 Victor RG. Systemic hypertension: Mechanisms and diagnosis. In: Bonow RO, Mann DL, Zipes DP, Libby P, eds.
Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 9th ed. Philadelphia, PA: Saunders Elsevier;
2012:935-954.
6 American Heart Association. Atherosclerosis. https://www.heart.org/en/health-topics/cholesterol/about-

cholesterol/atherosclerosis. Accessed May 2021.

7 National Heart, Lung, and Blood Institute. Coronary heart disease. https://www.nhlbi.nih.gov/health-

topics/coronary-heart-disease#. Accessed May 2021.

8 National Heart, Lung, and Blood Institute. Peripheral artery disease. https://www.nhlbi.nih.gov/health-

topics/peripheral-artery-disease. Accessed May 2021.

9 Alexander RW. Hypertension and the pathogenesis of atherosclerosis. Hypertension. 1995; 25:155-161.

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PROGNOSIS
5. Cardiovascular Disease

Transcript
Hypertension accelerates atherosclerotic plaque formation in the coronary arteries, resulting in
vessel narrowing and a reduced ability to deliver oxygen-rich blood to the heart.10, 11 At the same
time, hypertension forces the heart to pump against higher peripheral resistance, increasing its
workload and concomitant need for oxygen. The ensuing oxygen shortage can result in ischemia
and angina pectoris.12 If a coronary artery becomes completely occluded, death of heart muscle,
known as myocardial infarction or heart attack, occurs.13 Hypertension can also increase the risk
for stroke, atrial fibrillation (AF), aortic dissection, and peripheral arterial disease, and left
ventricular hypertrophy (LVH) can contribute to this increased risk. 14

In people with hypertension, the left ventricle must work against increased arterial pressure in
order to pump blood. As a result, the left ventricle grows thicker and more muscular, a process
known as left ventricular hypertrophy (LVH).15 The cross section on the right compares the
thickness of a hypertrophied left ventricular wall to the thickness of a normal left ventricular wall.

Initially, hypertrophy enables the left ventricle to pump more forcefully. Eventually, however, the
heart can no longer pump sufficient blood to meet the body’s oxygen demands. When this
happens, blood may back up into the pulmonary veins, leading to pulmonary edema and
congestive heart failure.16

10 Alexander RW. Hypertension and the pathogenesis of atherosclerosis. Hypertension. 1995; 25: 155-161.
11 National Heart, Lung, and Blood Institute. Coronary heart disease. https://www.nhlbi.nih.gov/health-
topics/coronary-heart-disease#. Accessed May 2021.
12 Libby P. The vascular biology of atherosclerosis. In: Bonow RO, Mann DL, Zipes DP, Libby P, eds. Braunwald’s Heart

Disease: A Textbook of Cardiovascular Medicine. 9th ed. Philadelphia, PA: Saunders Elsevier; 2012:897-.913
13 National Heart, Lung, and Blood Institute. Heart attack. https://www.nhlbi.nih.gov/health-topics/heart-attack#.

Accessed May 2021.

14 Victor RG. Systemic hypertension: Mechanisms and diagnosis. In: Bonow RO, Mann DL, Zipes DP, Libby P, eds.

Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 9th ed. Philadelphia, PA: Saunders Elsevier;
2012:935-954.
15 Cleveland Clinic. Left ventricular hypertrophy (LVH). https://my.clevelandclinic.org/health/diseases/17168-left-

ventricular-hypertrophy-enlarged-heart. Accessed May 2021.

16 National Heart, Lung, and Blood Institute. Heart failure. https://www.nhlbi.nih.gov/health-topics/heart-failure#.

Accessed May 2021.

6
PROGNOSIS
6. Peripheral Vascular Damage

Transcript
Over time, high blood pressure can damage peripheral blood vessels, resulting in peripheral
artery disease.17 As uncontrolled hypertension progresses, nearly every organ in the body is
affected. It exacerbates atherosclerosis and can lead to increased fibrous tissue and decreased
elastic tissue, making blood vessels less yielding and further exacerbating the hypertension. 18, 19
Both atherosclerosis and hypertension can also lead to end-organ damage, which commonly
occurs in peripheral vessels as well as vessels of the retina, brain, and kidneys. 20 End-organ
damage can be reduced or prevented by controlling blood pressure. 21,22, 23

17 National Heart, Lung, and Blood Institute. Peripheral artery disease. https://www.nhlbi.nih.gov/health-
topics/peripheral-artery-disease. Accessed May 2021.
18 Victor RG. Systemic hypertension: Mechanisms and diagnosis. In: Bonow RO, Mann DL, Zipes DP, Libby P, eds.

Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 9th ed. Philadelphia, PA: Saunders Elsevier;
2012:935-954.
19 Gray R. Hypertension. In: Marx JA, Hockberger RS, Walls RM, et al., eds. Rosen’s Emergency Medicine. 7th ed.

Philadelphia, PA: Mosby Elsevier; 2010:1076-1087.

20 The Department of Health and Human Services (DHHS). The Seventh Report of the Joint National Committee on

Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.

https://www.nhlbi.nih.gov/files/docs/guidelines/jnc7full.pdf. Accessed May 2021. Page 36 of PDF, col 2, table 6.
21 Alexander RW. Hypertension and the pathogenesis of atherosclerosis. Hypertension. 1995; 25:155-161.
22 The Department of Health and Human Services (DHHS). The Seventh Report of the Joint National Committee on

Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.

https://www.nhlbi.nih.gov/files/docs/guidelines/jnc7full.pdf. Accessed May 2021. Page 17 of PDF, col 2, para 1.
23 National Heart, Lung, and Blood Institute. Atherosclerosis. https://www.heart.org/en/health-

topics/cholesterol/about-cholesterol/atherosclerosis. Accessed May 2021.

7
PROGNOSIS
7. Retinopathy

Transcript
Hypertensive retinopathy and papilledema are signs of hypertensive damage to the eye. 24, 25

Hypertensive retinopathy, characterized by the narrowing of retinal arteries with subsequent

hemorrhage, can result in vision loss. 26 Funduscopic examination, or examination of the eye, can
be used to detect blood vessel damage in the eye. 27 Papilledema, swelling of the optic disk, is
another consequence of hypertension.28 Papilledema is typically a result of malignant
hypertension, which is an acute, severe elevation of blood pressure.29

24 Mehta S. Hypertensive retinopathy. https://www.merckmanuals.com/professional/eye-disorders/retinal-

disorders/hypertensive-retinopathy#. Accessed May 2021.
25 Garrity J. Papilledema. https://www.merckmanuals.com/professional/eye-disorders/optic-nerve-

disorders/papilledema#. Accessed May 2021.

26 Mehta S. Hypertensive retinopathy. https://www.merckmanuals.com/professional/eye-disorders/retinal-

disorders/hypertensive-retinopathy#. Accessed May 2021.

27 Schneiderman H. The funduscopic examination. In: Walker HK, Hall WD, Hurst JW, eds. Clinical Methods: The

History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths; 1990:573-580.
https://www.ncbi.nlm.nih.gov/books/NBK221/. Accessed May 2021.
28 Garrity J. Papilledema. https://www.merckmanuals.com/professional/eye-disorders/optic-nerve-

disorders/papilledema#. Accessed May 2021.

29 Victor RG. Systemic hypertension: mechanisms and diagnosis. In: Bonow RO, Mann DL, Zipes DP, Libby P, eds.

Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 9th ed. Philadelphia, PA Elsevier Saunders; 2012:
935-954.
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PROGNOSIS
8. Stroke

Transcript
In the US, more than 795,000 new or recurrent strokes occur every year.30 The most significant
risk factor for stroke is hypertension; an increase in diastolic pressure of only 10 millimeters of
mercury is associated with a two-fold increase in mortality.31

Uncontrolled hypertension places the blood vessels under a great deal of strain. In the presence
of uncontrolled hypertension, weakness in the arterial wall may develop, resulting in an
aneurysm, which is an outward bulging of a section of the vessel wall. When an aneurysm
ruptures, the vessel bleeds into the surrounding tissues. A ruptured aneurysm in the brain, known
as a hemorrhagic stroke, can cause neurologic damage and/or death.32

An ischemic stroke occurs when a vessel in the brain becomes blocked, usually by an embolus
originating elsewhere in the body. Emboli are often a result of blood clots and ruptured plaques
associated with atherosclerosis, which is accelerated by hypertension.33

Select the “i” icon for more information.

More Information
In hypertensive encephalopathy, fluid leaking from blood vessels into the brain causes
swelling (cerebral edema). This manifestation of malignant hypertension can result in
headache, irritability, altered consciousness, and other central nervous system
dysfunctions. 34, 35

Treatments for hemorrhagic and ischemic stroke are very different. In hemorrhagic
stroke, the goal is to stop bleeding into the brain by using medications and other
techniques. In ischemic stroke, however, the goal is to re-establish blood flow, and
powerful clot-dissolving agents may be administered to accomplish this.36

30 Centers for Disease Control. Stroke Facts. https://www.cdc.gov/stroke/facts.htm. Accessed May 2021.
31 The Department of Health and Human Services (DHHS). The Seventh Report of the Joint National Committee on
Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.
https://www.nhlbi.nih.gov/files/docs/guidelines/jnc7full.pdf. Accessed May 2021. Page 25 of PDF, col 1, para 1.
32 American Heart Association. How high blood pressure can lead to stroke. https://www.heart.org/en/health-

topics/high-blood-pressure/health-threats-from-high-blood-pressure/how-high-blood-pressure-can-lead-to-stroke.
Accessed May 2021.
33 American Heart Association. How high blood pressure can lead to stroke. https://www.heart.org/en/health-

topics/high-blood-pressure/health-threats-from-high-blood-pressure/how-high-blood-pressure-can-lead-to-stroke.
Accessed May 2021.
34 Victor RG. Systemic hypertension: mechanisms and diagnosis. In: Bonow RO, Mann DL, Zipes DP, Libby P, eds.

Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 9th ed. Philadelphia, PA Elsevier Saunders; 2012:
935-954.
35 National Library of Medicine (US). Malignant hypertension. https://medlineplus.gov/ency/article/000491.htm.

Accessed May 2021.

36 National Institute of Neurological Disorders and Stroke. Stroke information page.

https://www.ninds.nih.gov/Disorders/All-Disorders/Stroke-Information-Page. Accessed May 2021.

9
PROGNOSIS
9. Nephropathy

Transcript
Hypertension has been linked to an increased risk in chronic kidney disease and has been shown
to be predictive of progression to end-stage renal disease.37 Mortality due to cardiovascular
disease is up to 30 times higher in patients with end-stage renal disease on dialysis, as compared
to the normal population.38

High blood pressure causes arteriolar hypertrophy of the small renal vessels. This hypertrophy
diminishes blood flow to the kidneys and, therefore, the volume of filtrate.39 The macula densa
responds to this diminished blood flow by releasing renin from the juxtaglomerular cells. The
release of renin activates the renin-angiotensin-aldosterone system, which increases blood
pressure.40, 41

37 Taal MW. Risk factors and chronic kidney disease. In: Brenner BM, Levine SA, eds. Brenner & Rector’s The Kidney.
8th ed. Philadelphia, PA: Saunders Elsevier; 2007:758-791.
38 Alani H, Tamimi A, Tamimi N. Cardiovascular co-morbidity in chronic kidney disease: Current knowledge and future

research needs. World J Nephrol. 2014; 3(4): 156-168.

39 Anderson WP, Kett MM, Stevenson KM, Edgley AJ, Denton KM, Fitzgerald SM. Renovascular hypertension:

Structural changes in the renal vasculature. Hypertension. 2000; 36:648-652.

40 Sladen RN. Renal physiology. In: Miller RD, Eriksson LI, Fleisher LA, Wiener-Kronish JP, Young WL, eds. Miller’s

Anesthesia. 7th ed. Philadelphia, PA: Churchill Livingstone; 2009:441-476.

41 Renal function & micturition. In: Barrett KE, Barman SM, Boitano S, Brooks H., eds. Ganong’s Review of Medical

Physiology 23rd ed. New York, NY: The McGraw-Hill Companies, Inc.; 2010:639-663.
10
PROGNOSIS
10. Progress Check

Transcript
Use the terms to fill in the blanks. Not all terms are used.

Term Statement
ischemia When oxygen demands exceeds supply in heart muscle, the result is
______
aneurysm In the setting of hypertension, brain tissues will fill with blood after an
______ ruptures.
macula densa, renin The _______ responds to diminished blood flow by releasing ______
which activates the renin-angiotensin-aldosterone system, resulting in
increased blood pressure.
CAD [Not used]
juxtaglomerular cells [Not used]
myocardial infarction [Not used]
vessel [Not used]

Answer the following questions on what you have learned so far.

Which one of the following is a consequence of hypertension?

 Coronary artery disease
 Peripheral vascular disease
 Brain hemorrhage
 Atherosclerosis
 All of these are correct. (Correct)

An increase in diastolic pressure of 10 mmHg has been associated with a two-fold increased risk
of death due to which of the following?
 Coronary artery disease
 Peripheral vascular disease
 Retinopathy
 Stroke (Correct)
 All of these are correct.

11
NONPHARMACOLOGIC TREATMENT
11. Objectives

Introduction
A combination of nonpharmacologic and pharmacologic treatments is often the most effective
treatment for hypertension. Pharmacologic treatments are drug-dosing regimens that block the
body's mechanisms for increasing blood pressure. Nonpharmacologic approaches involve
lifestyle modifications such as diet, weight control, and increasing physical activity.42

Transcript
These are the objectives for this section.

Onscreen Text: Objectives

After you finish this section, you should be able to:

 Identify the lifestyle modifications that reduce blood pressure

 Describe lipid profiles and their effects on risk for cardiovascular disease
 Explain the importance of exercise, stress reduction, and smoking cessation in
cardiovascular health

42James PA, Oparil S, Carter BL, et al. 2014 evidence-based guidelines for the management of high blood pressure in
adults. Report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;
311(5):507-520.
12
NONPHARMACOLOGIC TREATMENT
12. Diet and Weight Modifications

Transcript
Increased body weight directly correlates with increased blood pressure, and obesity (body mass
index ≥30) increases the risk of hypertension by a factor of about four. 43 Losing as little as 10
pounds, however, can lower blood pressure significantly in many overweight people.44 Weight
loss also reduces the incidence of other cardiovascular risk factors, such as dyslipidemia
(abnormal concentrations of lipids in the blood) and diabetes, and increases the efficacy of
antihypertensive medications.45

Restricting sodium intake can also lower blood pressure. Ideally, dietary sodium should be limited
to 100 millimoles, or less than 2.4 grams, per day.46 Hypertension is rare in communities where
salt intake is low.47 A vegetarian diet may also cause significant reductions in blood pressure.
Which component of the diet is responsible for the effect, however, is unknown. 48

Select the “i” icon for information about salt sensitivity.

Salt Sensitive Populations

In certain “salt-sensitive” populations, blood pressures correspond very closely with
sodium consumption. Salt-sensitive populations include African Americans, the elderly,
and those with diabetes.49, 50, 51

43 The Department of Health and Human Services (DHHS). The Seventh Report of the Joint National Committee on
Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.
https://www.nhlbi.nih.gov/files/docs/guidelines/jnc7full.pdf. Accessed May 2021. Page 58 of PDF, table 15.
44 American Heart Association. Managing weight to control high blood pressure. https://www.heart.org/en/health-

topics/high-blood-pressure/changes-you-can-make-to-manage-high-blood-pressure/managing-weight-to-control-
high-blood-pressure#.WVQRRPkrKCh. Accessed May 2021.
45 The Department of Health and Human Services (DHHS). The Seventh Report of the Joint National Committee on

Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.

https://www.nhlbi.nih.gov/files/docs/guidelines/jnc7full.pdf. Accessed May 2021. Page 58 of PDF, col 1, para 2, col 2,
para 1, page 57 of PDF, col 2, para 2, and page 41 of PDF, col 2, para 2.
46 The Department of Health and Human Services (DHHS). The Seventh Report of the Joint National Committee on

Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.

https://www.nhlbi.nih.gov/files/docs/guidelines/jnc7full.pdf. Accessed May 2021. Page 41 of PDF, col 2, para 2.
47 Hollenburg NK, Martinez G, McCullough M, et al. Aging, acculturation, salt intake, and hypertension in the Kuna of

Panama. Hypertension. 1997;29:171-176.

48 American Heart Association. Vegetarian diets. https://www.heart.org/en/healthy-living/healthy-eating/eat-

smart/nutrition-basics/vegetarian-vegan-and-meals-without-meat#.WimDJe-nHct. Accessed May 2021.

49 The Department of Health and Human Services (DHHS). The Seventh Report of the Joint National Committee on

Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.

https://www.nhlbi.nih.gov/files/docs/guidelines/jnc7full.pdf. Accessed May 2021. Page 42 of PDF, table 9; Page 41 of
PDF, col 2, para 2.
50 American Heart Association. Know your risk factors for high blood pressure. https://www.heart.org/en/health-

topics/high-blood-pressure/why-high-blood-pressure-is-a-silent-killer/know-your-risk-factors-for-high-blood-
pressure#.WVQSNPkrKCh. Accessed May 2021.
51 American Heart Association. High blood pressure and African-Americans. https://www.heart.org/en/health-

topics/high-blood-pressure/why-high-blood-pressure-is-a-silent-killer/high-blood-pressure-and-african-
americans#.VlSTMa6rSMA. Accessed May 2021.
13
NONPHARMACOLOGIC TREATMENT
13. Controlling Lipids

Transcript
Cholesterol is a component of animal tissues and is a precursor for steroid hormones and other
substances.52 Lipoproteins are combinations of lipids and proteins that serve as a vehicle for
cholesterol transport. Because fats are lighter (less dense) than proteins, lipoproteins that contain
relatively more cholesterol are of lower density. 53

The liver, together with enzymes in the blood, converts triglycerides and dietary cholesterol into
low-density lipoproteins (LDL). LDL, known as the “bad” cholesterol, is absorbed by the
bloodstream for use in peripheral tissues. High-density lipoprotein (HDL), known as the “good”
cholesterol, is also produced by the liver. The function of HDL is not well understood, but HDL
may be responsible for transporting lipids from the peripheral tissues to the liver for conversion to
bile salts.54, 55

Studies show that total cholesterol level is directly related to mortality from coronary artery
disease. Increased serum LDL is a major risk factor for cardiovascular disease.56 Elevated levels
of HDL have been shown to be cardioprotective, and reductions in HDL levels have been
associated with an increased risk of coronary heart disease.57

52 Berg JM, Tymoczko JL, Stryer L. Section 26.4, Important derivatives of cholesterol include bile salts and steroid
hormones. Biochemistry. 5th edition. New York: W H Freeman; 2002.
https://www.ncbi.nlm.nih.gov/books/NBK22339/. Accessed May 2021.
53 Cox RA, García-Palmieri MR. Cholesterol, triglycerides, and associated lipoproteins. In: Walker HK, Hall WD, Hurst

JW, editors. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd ed. Boston: Butterworths;
1990:. Chapter 31. https://www.ncbi.nlm.nih.gov/books/NBK351/. Accessed May 2021.
54 Berg JM, Tymoczko JL, Stryer L. Section 26.4, Important derivatives of cholesterol include bile salts and steroid

hormones. Biochemistry. 5th edition. New York: W H Freeman; 2002.

https://www.ncbi.nlm.nih.gov/books/NBK22339/. Accessed May 2021.
55 Cox RA, García-Palmieri MR. Cholesterol, triglycerides, and associated Lipoproteins. In: Walker HK, Hall WD, Hurst

JW, editors. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd ed. Boston: Butterworths;
1990:. Chapter 31. https://www.ncbi.nlm.nih.gov/books/NBK351/. Accessed May 2021.
56 National Heart, Lung, and Blood Institute. Coronary Heart Disease. https://www.nhlbi.nih.gov/health-

topics/coronary-heart-disease. Accessed May 2021.

57 National Heart, Lung, and Blood Institute. Coronary Heart Disease. https://www.nhlbi.nih.gov/health-

topics/coronary-heart-disease. Accessed May 2021.

14
Shown here are treatment guidelines related to cholesterol intake, as recommended by the
National Cholesterol Education Program of the US National Institutes of Health. 58

National Cholesterol Education Program (NCEP) Treatment Guidelines Summary

LDL Cholesterol Goal LDL (mg/dl) LDL level at which to LDL-lowering drug
Initiate TLC* (mg/dl) initiation level (after TLC*)
(mg/dl)
Without coronary heart <160 ≥160 ≥190
disease (CHD) and
<two risk factors59
Without CHD and >two <130 ≥130 ≥160
risk factors60
With CHD61 <100 ≥100 ≥130
NCEP recommends that dietary and/or drug treatment not be initiated based upon a single LDL cholesterol result.
*TLC: therapeutic lifestyle changes

58 Grundy SM, Becker D, Clark LT, et al. Third Report of the National Cholesterol Education Program (NCEP) Expert
Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).
Circulation. 2002; 106:3143-3421.
59 Grundy SM, Becker D, Clark LT, et al. Third Report of the National Cholesterol Education Program (NCEP) Expert

Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).
Circulation. 2002; 106:3143-3421. Page 104 of PDF, col 1, table IV.2-3.
60 Grundy SM, Becker D, Clark LT, et al. Third Report of the National Cholesterol Education Program (NCEP) Expert

Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).
Circulation. 2002; 106:3143-3421. Page 107 of PDF, figure IV.2-3.
61 Grundy SM, Becker D, Clark LT, et al. Third Report of the National Cholesterol Education Program (NCEP) Expert

Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).
Circulation. 2002; 106:3143-3421. Page 106 of PDF, figure IV.2-1.
15
NONPHARMACOLOGIC TREATMENT
14. Other Lifestyle Changes

Transcript
Because people who regularly exercise are also likely to control their weight and eat healthy
diets, the role of exercise in controlling hypertension has been difficult to evaluate. Studies
suggest, however, that 60 to 90 minutes of moderate exercise a week can decrease the risk of
mortality due to cardiovascular disease by about 50%.62

Stress is not a confirmed risk factor for hypertension or heart disease, but because of the short-
term effects stress can have on blood pressure via adrenaline and cortisol release, the American
Heart Association does recommend that those at risk of hypertension take steps to manage their
stress.63

Smoking is a strong independent risk factor for stroke and premature cardiac death. 64 In addition
to its links to cancer and COPD, smoking has also been shown to cause transient increases in
blood pressure and atherosclerosis. For this reason, the American Heart Association
recommends that all patients at risk of hypertension avoid all forms of tobacco, as well as
secondhand smoke.65

Select the “i” icon for more information.

Statistical Data
In the Framingham Heart Study, each 10 cigarettes smoked per day increased
cardiovascular mortality by 18% for men and 31% for women. Cessation of smoking,
however, reduced cardiovascular risk by an estimated 35% to 40% in hypertensive
patients who had smoked one pack per day.66 Consequently, smoking cessation is
essential to reduce cardiovascular morbidity and mortality in hypertensive patients. 67

62 The Department of Health and Human Services (DHHS). The Seventh Report of the Joint National Committee on
Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.
https://www.nhlbi.nih.gov/files/docs/guidelines/jnc7full.pdf. Accessed May 2021. Page 42 of PDF, table 9; Page 41 of
PDF, col 2, para 2.
63 American Heart Association. Managing stress to control high blood pressure. https://www.heart.org/en/health-

topics/high-blood-pressure/changes-you-can-make-to-manage-high-blood-pressure/managing-stress-to-control-high-
blood-pressure#.WVUqEfkrKCh. Accessed May 2021.
64 Centers for Disease Control and Prevention (US); National Center for Chronic Disease Prevention and Health

Promotion (US); Office on Smoking and Health (US). Cardiovascular Diseases. How tobacco smoke causes disease: The
biology and behavioral basis for smoking-attributable disease: A report of the Surgeon General. Atlanta (GA): Centers
for Disease Control and Prevention (US); 2010. https://www.ncbi.nlm.nih.gov/books/NBK53012//. Accessed May
2021.
65 American Heart Association. Smoking, high blood pressure and your health. https://www.heart.org/en/health-

topics/high-blood-pressure/changes-you-can-make-to-manage-high-blood-pressure/smoking-high-blood-pressure-
and-your-health#.WVUrFvkrKCh. Accessed May 2021.
66 Kannel WB, Higgins M. Smoking and hypertension as predictors of cardiovascular risk in population studies. J

Hypertens Suppl. 1990;8:S3-8.

67 American Heart Association. Smoking, high blood pressure and your health. https://www.heart.org/en/health-

topics/high-blood-pressure/changes-you-can-make-to-manage-high-blood-pressure/smoking-high-blood-pressure-
and-your-health#.WVUrFvkrKCh. Accessed May 2021.
16
NONPHARMACOLOGIC TREATMENT
15. Progress Check

Transcript
ASelect the best answer for each question.

1. Which of the following lifestyles modifications may help decrease blood pressure?
 Exercising
 Maintain a healthy weight
 Restricting sodium intake
 All of these are correct. [Correct]

2. If a patient wants to lower his/her blood pressure, how often should they engage in
moderate to vigorous physical activity?
 30 to 45 minutes three days a week
 30 to 45 minutes several days a week
 45 to 60 minutes five days a week
 60 to 90 minutes a week [Correct]

Determine whether the statements are true or false.

True or False
True Quitting smoking can lower the risk for atherosclerosis.
True Controlling serum cholesterol is an adjunct to antihypertensive therapy.
True Losing as few as 10 pounds can lower blood pressure in an overweight
person.

17
PHARMACOLOGIC TREATMENT
16. Objectives

Introduction
A combination of nonpharmacologic and pharmacologic treatments is often the most effective
approach to treatment of hypertension. Pharmacologic treatments are regimens that utilize drugs
as a means for controlling blood pressure.68

Transcript
These are the objectives for this section.

Onscreen Text: Objectives

After you finish this section, you should be able to:

 Identify comorbid conditions and the effects of antihypertensive therapies on them

 Explain the mechanisms of action and pharmacological effects of antihypertensive
drugs

68James PA, Oparil S, Carter BL, et al. 2014 evidence-based guidelines for the management of high blood pressure in
adults. Report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;
311(5):507-520.
18
PHARMACOLOGIC TREATMENT
17. ACE Inhibitors

Transcript
In the renin-angiotensin-aldosterone system (RAAS), low blood pressure in the kidneys
stimulates renin release. Renin converts angiotensinogen from the liver into angiotensin I. Next,
angiotensin-converting enzyme (ACE) from the lungs converts angiotensin I into angiotensin II. 69
Angiotensin II raises blood pressure by acting on AT 1-receptors in the heart, brain, kidneys,
adrenal glands, and peripheral vessels. 70

ACE inhibitors effectively disrupt the RAAS by preventing the formation of angiotensin II. 71
Interestingly, with chronic use of ACE inhibitors, plasma angiotensin II levels return to normal but
blood pressure remains lowered. This suggests that the hypotensive effect of ACE inhibitors is
due at least in part to mechanisms outside the RAAS.72

ACE inhibitors also lower glomerular blood pressure, primarily by causing vasodilation. Finally,
they reduce the excess quantity of protein in the urine (known as proteinuria).73,

As a group, ACE inhibitors lower blood pressure by reducing total peripheral resistance (TPR)
without significantly affecting heart rate, blood volume, or cardiac output.74

69 Sladen RN. Renal physiology. In: Miller RD, Eriksson LI, Fleisher LA, Wiener-Kronish JP, Young WL, eds. Miller’s
Anesthesia. 7th ed. Philadelphia, PA: Churchill Livingstone; 2009:441-476.
70 Victor RG. Systemic hypertension: mechanisms and diagnosis. In: Bonow RO, Mann DL, Zipes DP, Libby P, eds.

Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 9th ed. Philadelphia, PA Elsevier Saunders; 2012:
935-954.
71 Regulation of extracellular fluid composition & volume. In: Barrett KE, Barman SM, Boitano S, Brooks H., eds.

Ganong’s Review of Medical Physiology 23rd ed. New York, NY: The McGraw-Hill Companies, Inc.; 2010:665-678.
72 Brown NJ, Vaughan DE. Angiotensin-converting enzyme inhibitors. Circulation. 1998; 97:1411-1420.
73 Brown NJ, Vaughan DE. Angiotensin-converting enzyme inhibitors. Circulation. 1998; 97:1411-1420.
74 Brown NJ, Vaughan DE. Angiotensin-converting enzyme inhibitors. Circulation. 1998; 97:1411-1420.

19
PHARMACOLOGIC TREATMENT
18. Angiotensin II Receptor Blockers

Transcript
Stimulation of AT1-receptors by angiotensin II results in significant cardiovascular effects. As
shown in this table, these include vasoconstriction, increased cardiac contractility, aldosterone
release, and hypertrophy of the heart and blood vessels.

Cardiovascular Consequences of AT 1-Receptor Recognition

Organ Effect When Stimulated Result
Vasculature75 Vasoconstriction, vascular remodeling Increased TPR and blood
pressure
Heart76 Ventricular hypertrophy Increased wall thickness
Adrenal glands77 Aldosterone release Increased sodium reabsorption
78
Kidneys Increased sodium and water retention Increased fluid volume
Brain79 Increased thirst and salt craving Increased blood volume
Central nervous Increased sympathetic stimulation Increased blood pressure
system80

Angiotensin receptor blockers (ARBs) block angiotensin II from binding to AT 1-receptors. By

doing so, ARBs prevent the significant cardiovascular consequences associated with angiotensin
II.81

ARBs, like ACE inhibitors, treat hypertension and lower blood pressure without inducing
tachycardia. ARBs are distinguished by their relatively low frequency of both dose-independent
and dose-dependent side effects.82 However, they cannot be used during pregnancy. 83

75 Kaschina E, Unger T. Angiotensin AT1/AT2 receptors: regulation, signaling and function. Blood Pressure. 2003;
12:70-88.
76 Kaschina E, Unger T. Angiotensin AT1/AT2 receptors: regulation, signaling and function. Blood Pressure. 2003;

12:70-88.
77 Regulation of extracellular fluid composition & volume. In: Barrett KE, Barman SM, Boitano S, Brooks H., eds.

Ganong’s Review of Medical Physiology 23rd ed. New York, NY: The McGraw-Hill Companies, Inc.; 2010:665-678.
78 Regulation of extracellular fluid composition & volume. In: Barrett KE, Barman SM, Boitano S, Brooks H., eds.

Ganong’s Review of Medical Physiology 23rd ed. New York, NY: The McGraw-Hill Companies, Inc.; 2010:665-678.
79 McKinley MJ, Albiston AL, Allen AM, et al. The brain renin-angiotensin system: location and physiological roles.

IJBCB. 2003; 35:901-918.

80 McKinley MJ, Albiston AL, Allen AM, et al. The brain renin-angiotensin system: location and physiological roles.

IJBCB. 2003; 35:901-918.

81 Alexander MR. Hypertension medication. https://emedicine.medscape.com/article/241381-medication#showall.

Accessed May 2021.

82 Agency for Healthcare Research and Quality. Comparing two kinds of blood pressure pills: ACEIs and ARBs: A guide

for adults. https://www.ncbi.nlm.nih.gov/books/NBK45601/pdf/Bookshelf_NBK45601.pdf. Accessed May 2021.

83 Alexander MR. Hypertension medication. https://emedicine.medscape.com/article/241381-medication#showall.

Accessed May 2021.

20
PHARMACOLOGIC TREATMENT
19. Diuretics

Transcript
Diuresis is the term for enhanced urine excretion.84 A diuretic is any substance that acts on the
kidneys to increase urinary output.85 Diuretics act on nephrons to increase sodium excretion and
enhance vasodilation.86, 87 The resulting decreased fluid volume in the body reduces cardiac
output and preload, thereby lowering blood pressure, which is why diuretics have been used for
more than 50 years in treating hypertension.88In fact, they are used to regulate blood pressure
and are combined with other agents to potentiate (increase) their antihypertensive effect.89

The ascending loop of Henle, the distal convoluted tubule, and the collecting ducts are the major
areas of diuretic activity.90, 91

Thiazide diuretics inhibit the reabsorption of sodium and chloride ions mostly in the distal tubule,
thereby increasing sodium and water excretion.92 By increasing renal excretion of potassium,
however, thiazides may cause hypokalemia (low blood potassium). Hypokalemia and its
associated potential disturbances in normal heart rhythm can be prevented by the ingestion of
oral potassium dietary supplements.93

Loop diuretics act on the ascending limb of the loop of Henle to reduce sodium reabsorption.94
The potency of loop diuretics stems from the fact that 30% of sodium is normally reabsorbed in
this region.95 Like thiazides, loop diuretics cause potassium loss in the urine. 96 They are typically
used for heart failure rather than for blood pressure reduction alone.97

84 ”diuresis.” Taber’s Online Cyclopedic Dictionary. www.tabers.com. Accessed May 2021.

85 Mayo Clinic. Diuretics. https://www.mayoclinic.org/diseases-conditions/high-blood-pressure/in-
depth/diuretics/art-20048129. Accessed May 2021.
86 Renal function & micturition. In: Barrett KE, Barman SM, Boitano S, Brooks H., eds. Ganong’s Review of Medical

Physiology 23rd ed. New York, NY: The McGraw-Hill Companies, Inc.; 2010:639-663.
87 Mayo Clinic. Diuretics. https://www.mayoclinic.org/diseases-conditions/high-blood-pressure/in-

depth/diuretics/art-20048129. Accessed May 2021.

88 Hamdy RC. Hypertension: A Turning Point in the History of Medicine…and Mankind.

https://www.medscape.com/viewarticle/421419. Accessed May 2021.

89 Mayo Clinic. Diuretics. https://www.mayoclinic.org/diseases-conditions/high-blood-pressure/in-

depth/diuretics/art-20048129. Accessed May 2021.

90 Renal function & micturition. In: Barrett KE, Barman SM, Boitano S, Brooks H., eds. Ganong’s Review of Medical

Physiology 23rd ed. New York, NY: The McGraw-Hill Companies, Inc.; 2010:639-663.
91 Alexander MR. Hypertension medication. https://emedicine.medscape.com/article/241381-medication#showall.

Accessed May 2021.

92 Alexander MR. Hypertension medication. https://emedicine.medscape.com/article/241381-medication#showall.

Accessed May 2021.

93 Renal function & micturition. In: Barrett KE, Barman SM, Boitano S, Brooks H., eds. Ganong’s Review of Medical

Physiology 23rd ed. New York, NY: The McGraw-Hill Companies, Inc.; 2010:639-663.
94 Alexander MR. Hypertension medication. https://emedicine.medscape.com/article/241381-medication#showall.

Accessed May 2021.

95 Renal function & micturition. In: Barrett KE, Barman SM, Boitano S, Brooks H., eds. Ganong’s Review of Medical

Physiology 23rd ed. New York, NY: The McGraw-Hill Companies, Inc.; 2010:639-663.
96 Renal function & micturition. In: Barrett KE, Barman SM, Boitano S, Brooks H., eds. Ganong’s Review of Medical

Physiology 23rd ed. New York, NY: The McGraw-Hill Companies, Inc.; 2010:639-663.
97 Alexander MR. Hypertension medication. https://emedicine.medscape.com/article/241381-medication#showall.

Accessed May 2021.

21
Potassium-sparing diuretics increase sodium excretion by blocking sodium reabsorption in the
distal convoluted tubule, but their action is weak and causes only a mild increase in urinary
volume. Potassium is spared through the link between potassium secretion and sodium
reabsorption. Despite the weak effect, these diuretics are often combined with other potassium
losing agents to maintain normal potassium levels.98, 99

Long-term blood pressure reductions associated with diuretics stem from their effects on the
vasculature, as the increased movement of sodium from vessel walls results in vasodilation and
decreased total peripheral resistance.100

98 Alexander MR. Hypertension medication. https://emedicine.medscape.com/article/241381-medication#showall.

Accessed May 2021.
99 National Library of Medicine (US). Amiloride. https://pubchem.ncbi.nlm.nih.gov/compound/Amiloride. Accessed

May 2021.
100 Duarte JD, Cooper-DeHoff RM. Mechanisms for blood pressure lowering and metabolic effects of thiazide and

thiazide-like diuretics. Expert Rev Cardiovasc Ther. 2010; 8(6):793–802.

22
PHARMACOLOGIC TREATMENT
20. Beta-Blockers

Transcript
The sympathetic nervous system and the adrenal medulla use the neurotransmitters
norepinephrine and epinephrine, respectively, to regulate body functions.101 Both
neurotransmitters stimulate beta-adrenergic receptors to cause specific events that alter cellular
function.102

Beta-blockers, as their name suggests, prevent catecholamines from binding to beta receptors
and thus inhibit stimulatory action.103

The exact mechanisms of the blood pressure-lowering effects of beta-blockers are unclear.
However, they are probably due to reduced renin release and reduced heart rate, which result in
lowered cardiac output.104 By reducing renin secretion by the kidneys, beta-blockers diminish
angiotensin II formation, decrease systemic blood pressure, and reduce the vasoactive effects of
angiotensin II on renal blood vessels.105

There are two types of beta-receptors: beta1-receptors and beta2-receptors. Beta1-receptors are
found in the heart and kidneys, while beta2-receptors are located in the lungs, liver, pancreas,
and smooth muscle. 106 By blocking beta1-receptors in the heart, beta blockers reduce resting and
exercise heart rate and decrease myocardial contractility. 107, 108

Cardioselectivity is the term for the relative selectivity of beta-blockers for beta1-receptors. At
therapeutic doses, cardioselective beta-blockers primarily block beta1-receptors. This reduces
adverse effects related to beta2-receptor stimulation, such as airway constriction in the lungs. 109,
110

101 The autonomic nervous system. In: Barrett KE, Barman SM, Boitano S, Brooks H., eds. Ganong’s Review of Medical
Physiology 23rd ed. New York, NY: The McGraw-Hill Companies, Inc.; 2010:261-272.
102 Victor RG. Systemic hypertension: mechanisms and diagnosis. In: Bonow RO, Mann DL, Zipes DP, Libby P, eds.

Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 9th ed. Philadelphia, PA Elsevier Saunders; 2012:
935-954.
103 Kaplan NM. Systemic hypertension: therapy. In: Bonow RO, Mann DL, Zipes DP, Libby P, eds. Braunwald’s Heart

Disease: A Textbook of Cardiovascular Medicine. 9th ed. Philadelphia, PA Elsevier Saunders; 2012:955-974.
104 Kaplan NM. Systemic hypertension: therapy. In: Bonow RO, Mann DL, Zipes DP, Libby P, eds. Braunwald’s Heart

Disease: A Textbook of Cardiovascular Medicine. 9th ed. Philadelphia, PA Elsevier Saunders; 2012:955-974.
105 Victor RG. Systemic hypertension: mechanisms and diagnosis. In: Bonow RO, Mann DL, Zipes DP, Libby P, eds.

Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 9th ed. Philadelphia, PA Elsevier Saunders; 2012:
935-954.
106 Silbernagl S, Despopoulos A. Color Atlas of Physiology. 6th ed. Theieme New York. 2009; 2009:78-87.
107 American Heart Association. How do beta blocker drugs affect exercise? https://www.heart.org/en/health-

topics/consumer-healthcare/medication-information/how-do-beta-blocker-drugs-affect-exercise#.WimMae-nHct.
Accessed May 2021.
108 British Hypertension Society. Beta-adrenoreceptor antagonists (beta-blockers). https://bihsoc.org/wp-

content/uploads/2017/11/Beta-adrenoceptor-Antagonists-Final-2017.pdf. Accessed May 2021.

109 Kaplan NM. Systemic hypertension: therapy. In: Bonow RO, Mann DL, Zipes DP, Libby P, eds. Braunwald’s Heart

Disease: A Textbook of Cardiovascular Medicine. 9th ed. Philadelphia, PA Elsevier Saunders; 2012:955-974.
110 British and Irish Hypertension Society. Beta-adrenoreceptor antagonists (beta-blockers). https://bihsoc.org/wp-

content/uploads/2017/11/Beta-adrenoceptor-Antagonists-Final-2017.pdf. Accessed May 2021.

23
Beta2-receptor stimulation in the lungs and vasculature causes dilation of the bronchioles and
blood vessels. Patients with asthma or chronic obstructive pulmonary disease may experience
life-threatening bronchoconstriction with the use of nonselective beta-blockers.111

111British and Irish Hypertension Society. Beta-adrenoreceptor antagonists (beta-blockers). https://bihsoc.org/wp-

content/uploads/2017/11/Beta-adrenoceptor-Antagonists-Final-2017.pdf. Accessed May 2021.
24
PHARMACOLOGIC TREATMENT
21. Calcium Channel Blockers (CCBs)

Transcript
To induce a number of cellular events, ions flow into cells through channels. These channels are
actually specialized proteins that change shape to permit ion flow across the cell membrane. By
preventing calcium channels from opening, calcium channel blockers (CCBs) reduce the
intracellular concentration of calcium ions and reduce vasoconstriction.112 This lowers TPR and,
therefore, blood pressure.113, 114

Some calcium channel blockers also influence heart rate and other cardiac parameters. This
occurs because electrical stimuli in the sinoatrial (SA) and atrioventricular (AV) nodes are
dependent upon calcium rather than sodium. As a result, some calcium channel blockers slow
both the heart rate and the electrical conduction in the heart.115, 116

Calcium channel blockers may also slow the progression of hypertension-related renal failure,
possibly by inhibiting mesangial growth due to the actions of certain growth factors; by protecting
renal tubule cells from damage by low oxygen levels (ischemia); and by increasing survival of
renal tubule cells that have been damaged by low oxygen levels. 117

Three types of calcium channel blockers are used in antihypertensive therapy. Select each type
to highlight its cardiovascular effects.

Cardiovascular Effects of the Three Types of CCBs118, 119

dihydropyridines phenylalkylamines benzothiazepines
Effects on the electrical activity of the heart
(Increased activity=stimulation; decreased activity=inhibition)
Heart rate Increased to no Increased or Decreased to no
effect decreased effect effect
Conduction at the No effect Greatly decreased Decreased effect
SA node effect
Conduction at the No effect Greatly decreased Decreased effect
AV node effect

112 British and Irish Hypertension Society. Calcium channel blockers (CCBs). https://bihsoc.org/wp-
content/uploads/2017/11/Calcium-Channel-Blockers-Final-2017.pdf. Accessed May 2021.
113 British and Irish Hypertension Society. Calcium channel blockers (CCBs). https://bihsoc.org/wp-

content/uploads/2017/11/Calcium-Channel-Blockers-Final-2017.pdf. Accessed May 2021.

114 Alexander MR. Hypertension medication. https://emedicine.medscape.com/article/241381-medication#showall.

Accessed May 2021.

115 British and Irish Hypertension Society. Calcium channel blockers (CCBs). https://bihsoc.org/wp-

content/uploads/2017/11/Calcium-Channel-Blockers-Final-2017.pdf. Accessed May 2021.

116 Alexander MR. Hypertension medication. https://emedicine.medscape.com/article/241381-medication#showall.

Accessed May 2021.

117 Kloke HJ, Branten AJ, Huysmans FT, Wetzels JF. Antihypertensive treatment of patients with proteinuric renal

diseases: Risks or benefits of calcium channel blockers? Kidney International. 1998; 53:1559-1573.
118 Kaplan NM. Systemic hypertension: therapy. In: Bonow RO, Mann DL, Zipes DP, Libby P, eds. Braunwald’s Heart

Disease: A Textbook of Cardiovascular Medicine. 9th ed. Philadelphia, PA Elsevier Saunders; 2012:955-974.
119 Klabunde RE. Calcium-channel blockers (CCBs). https://www.cvpharmacology.com/vasodilator/CCB. Accessed May

2021.
25
 Effects on myocardial contractility
Force of Decreased to no Greatly decreased Decreased effect
myocardial effect effect
contractions

26
PHARMACOLOGIC TREATMENT
22. Agents Affecting Alpha Receptors

Transcript
In addition to beta-receptors, adrenergic receptors include alpha1-receptors and alpha2-
receptors.120

Stimulation of alpha1-receptors induces vasoconstriction in the vascular smooth muscle.121

Alpha1-antagonists, therefore, lower peripheral resistance by reducing vasoconstriction. They are
generally not recommended as initial monotherapy but can be used in combination with other
therapies to treat any stage of hypertension.122

Alpha2-receptors are found primarily in the brain, where their stimulation decreases sympathetic
outflow. Alpha2-agonists decrease blood pressure by inhibiting total sympathetic nervous system
output, increasing vasodilation, and reducing peripheral vascular resistance. They may be
effective as monotherapy, but are typically given in combination with a diuretic. Side effects
generally limit their efficacy for initial therapy in hypertension. 123, 124

120 Silbernagl S, Despopoulos A. Color Atlas of Physiology. 6th ed. Theieme New York. 2009; 2009:78-87.
121 Silbernagl S, Despopoulos A. Color Atlas of Physiology. 6th ed. Theieme New York. 2009; 2009:78-87.
122 Alexander RM. Hypertension medication. https://emedicine.medscape.com/article/241381-medication#showall.

Accessed May 2021.

123 Kaplan NM. Systemic hypertension: therapy. In: Bonow RO, Mann DL, Zipes DP, Libby P, eds. Braunwald’s Heart

Disease: A Textbook of Cardiovascular Medicine. 9th ed. Philadelphia, PA Elsevier Saunders; 2012:955-974.
124 Alexander RM. Hypertension medication. https://emedicine.medscape.com/article/241381-medication#showall.

Accessed May 2021.

27
PHARMACOLOGIC TREATMENT
23. Progress Check

Transcript
Select the treatment that matches the definition.

ACE ARBs Diuretics Beta- CCBs

Inhibitors Blockers
Block calcium channels to X
cause arteriolar
vasodilation and thereby
lower the TPR
Increase sodium excretion X
and enhance vasodilation
Lower blood pressure by X
reducing TPR without
significantly affecting heart
rate, blood volume, or
cardiac output
Blocks angiotensin II from X
binding to AT1-receptors
Prevent catecholamines X
from binding to certain
receptors in the heart,
reducing heart rate and
decreasing myocardial
contractility

28
CLINICAL PERSPECTIVE
24. Objectives

Introduction
This section discusses one of the more well-known studies of cardiovascular disease, the
Framingham Heart Study.125 It also provides details on the treatment algorithm recommended by
JNC 8.126

Transcript
These are the objectives for this section.

Onscreen Text: Objectives

After you finish this section, you should be able to:

 Describe the Framingham Heart Study

 Describe the treatment algorithm recommended by the Eighth Report of the Joint
National Committee on Prevention, Detection, Evaluation, and Treatment of High
Blood Pressure (JNC 8)

125 Framingham Heart Study. History of the Framingham Heart Study. https://framinghamheartstudy.org/fhs-
about/history/. Accessed May 2021.
126 James PA, Oparil S, Carter BL et al. 2014 Evidence-Based Guideline for the Management of High Blood Pressure in

Adults. Report from the Panel Members Appointed to the Eight Joint National Committee (JNC 8). JAMA. 2014;
311(5): 507-520.
29
CLINICAL PERSPECTIVE
25. The Framingham Heart Study

Transcript
Under the direction of the National Heart, Lung, and Blood Institute (NHLBI), formerly known
simply as the National Heart Institute, a study known as the Framingham Heart Study was
initiated in 1948 to learn more of the general causes of heart disease and stroke. 127 In order to do
so, it was designed to follow a large group of individuals over a long period of time. To qualify,
participants must not have developed overt symptoms of cardiovascular disease or suffered a
heart attack or stroke before time of enrollment.128

Over 5,000 men and women between the ages of 30 and 62 were recruited, and since the first
year, participants have returned every two years for a detailed medical history, physical
examination, and laboratory tests. Beginning in 1971, another group of more than 5,000 men and
women–adult children and their spouses of the original participants–were recruited to participate
in similar exams. Since then, the study has increased in diversity, recruiting from a new location,
and has also expanded to the third generation of the original participants’ families. 129

Observations of the participants revealed some major risk factors of cardiovascular disease, such
as high blood pressure, high blood cholesterol, smoking, obesity, diabetes, and physical
inactivity.130 Some other major research milestones reached in this study include:131
 1970: High blood pressure and atrial fibrillation increase the risk of stroke.
 1976: Menopause increases the risk of heart disease.
 1996: The progression from hypertension to heart failure was described.
 1999: The lifetime risk at age 40 of developing coronary heart disease is one in two
for men and one in three for women.
 2001: Blood pressure on the higher spectrum of normal is associated with an
increased risk of cardiovascular disease.
 2009-2010: Contributions made to the discovery of hundreds of genes underlying
major heart disease risk factors, such as body mass index (BMI), blood cholesterol,
smoking, blood pressure, and glucose/diabetes

127 Framingham Heart Study. History of the Framingham Heart Study. https://framinghamheartstudy.org/fhs-
about/history/. Accessed May 2021.
128 Framingham Heart Study. History of the Framingham Heart Study. https://framinghamheartstudy.org/fhs-

about/history/. Accessed May 2021.

129 Framingham Heart Study. History of the Framingham Heart Study. https://framinghamheartstudy.org/fhs-

about/history/. Accessed May 2021.

130 Framingham Heart Study. History of the Framingham Heart Study. https://framinghamheartstudy.org/fhs-

about/history/. Accessed May 2021.

131 Framingham Heart Study. Research milestones. https://framinghamheartstudy.org/fhs-about/research-

milestones/. Accessed May 2021.

30
CLINICAL PERSPECTIVE
26. JNC 8 Treatment Algorithm

Transcript
The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood
Pressure (JNC) is an organization of US healthcare professionals who are experts in
hypertension. Periodically, the JNC publishes a report summarizing current data on hypertension
and suggested treatment options. The JNC 8, published in 2014, is an evidence-based review
designed to address a limited number of questions deemed as high priority by the committee
members. The JNC 8 guideline suggests similar treatment strategies for all hypertensive
populations unless evidence suggests otherwise (e.g., the use of specific drug classes in racial
subgroups or in those with chronic kidney disease or diabetes). 132

This figure shows the JNC 8 treatment algorithm for hypertension. Lifestyle interventions are the
first step in treatment, followed by a pharmacologic agent based on each patient's needs. 133

132 James PA, Oparil S, Carter BL, et al. 2014 evidence-based guidelines for the management of high blood pressure in
adults. Report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;
311(5):507-520.
133 James PA, Oparil S, Carter BL et al. 2014 Evidence-Based Guideline for the Management of High Blood Pressure in

Adults. Report from the Panel Members Appointed to the Eight Joint National Committee (JNC 8). JAMA. 2014;
311(5): 507-520.
31
ACEI, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CCB, calcium channel blocker;
DBP, diastolic blood pressure; SBP, systolic blood pressure.
a. ACEIs and ARBs should not be used in combination.
b. If blood pressure fails to be maintained at goal, reenter the algorithm where appropriate based on the
current individual therapeutic plan.

32
The pharmacologic effects of the different drug types recommended are summarized in the
antihypertensive matrix table shown here.

The Antihypertensive Matrix

Antihypertensive Pharmacological Effects*

Diuretics Reduce blood volume and cardiac output134

ACE inhibitors (ACE I)** Reduce the formation of angiotensin II135 (angiotensin II
raises blood pressure by acting on AT1-receptors)136
Angiotensin II receptor blockers (ARBs) Block the effects of angiotensin II137 (angiotensin II raises
blood pressure by acting on AT1-receptors)138

Beta-blockers** Block the effects of catecholamines (vasoconstrictors) in the

heart139

Calcium channel blockers (CCBs) Block the influx of Ca++ ions (Ca++ is needed for muscle cell
(dihydropyridines) contraction in blood vessels; blockage of Ca++ lowers blood
pressure) 140, 141
Calcium channel blockers (CCBs) (non- Block the influx of Ca++ ions (Ca++ is needed for muscle cell
dihydropyridines) contraction in blood vessels; blockage of Ca++ lowers blood
pressure) 142, 143

*Fixed combinations will alter the pharmacological effects noted with single drugs 144
**May be less effective in some ethnic groups, including African Americans145

134 Alexander MR. Hypertension medication. https://emedicine.medscape.com/article/241381-medication#showallh.

Accessed May 2021.
135 Alexander MR. Hypertension medication. https://emedicine.medscape.com/article/241381-medication#showallh.

Accessed May 2021.

136 Victor RG. Systemic hypertension: mechanisms and diagnosis. In: Bonow RO, Mann DL, Zipes DP, Libby P, eds.

Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 9th ed. Philadelphia, PA Elsevier Saunders; 2012:
935-954.
137 Alexander MR. Hypertension medication. https://emedicine.medscape.com/article/241381-medication#showallh.

Accessed May 2021.

138 Victor RG. Systemic hypertension: mechanisms and diagnosis. In: Bonow RO, Mann DL, Zipes DP, Libby P, eds.

Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 9th ed. Philadelphia, PA Elsevier Saunders; 2012:
935-954.
139 Kaplan NM. Systemic hypertension: therapy. In: Bonow RO, Mann DL, Zipes DP, Libby P, eds. Braunwald’s Heart

Disease: A Textbook of Cardiovascular Medicine. 9th ed. Philadelphia, PA Elsevier Saunders; 2012:955-974.
140 British and Irish Hypertension Society. Calcium channel blockers (CCBs). https://bihsoc.org/wp-

content/uploads/2017/11/Calcium-Channel-Blockers-Final-2017.pdf. Accessed May 2021.

141 Alexander MR. Hypertension medication. https://emedicine.medscape.com/article/241381-medication#showallh.

Accessed May 2021.

142 British and Irish Hypertension Society. Calcium channel blockers (CCBs). https://bihsoc.org/wp-

content/uploads/2017/11/Calcium-Channel-Blockers-Final-2017.pdf. Accessed May 2021.

143 Alexander MR. Hypertension medication. https://emedicine.medscape.com/article/241381-medication#showallh.

Accessed May 2021.

144 The Department of Health and Human Services (DHHS). The Seventh Report of the Joint National Committee on

Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.

https://www.nhlbi.nih.gov/files/docs/guidelines/jnc7full.pdf. Accessed May 2021.
145 James PA, Oparil S, Carter BL, et al. 2014 evidence-based guidelines for the management of high blood pressure in

adults. Report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;
311(5):507-520.
33
Select the “i” icon for more information.

More Information
Diuretics, either alone or in combination with other antihypertensive agents, are
recommended by the JNC 8 as first-line therapy for uncomplicated hypertension. For
hypertensive patients with diabetes or chronic kidney disease, initial therapy options vary.
Although ACE inhibitors and calcium channel blockers have not been shown to reduce
morbidity and mortality in hypertensive patients, studies show that beta blockers and
diuretics do confer these benefits. If the blood pressure goal is not reached with initial
therapy, other drugs or second agents from different classes may be used. 146

Some antihypertensive drugs have a beneficial effect on coexisting diseases. Conversely, certain
antihypertensive drugs cause some coexisting diseases to worsen.147 The table shown here lists
common conditions and the effects that antihypertensive therapies may have on them.

Drug Therapy in Comorbid Conditions

Coexisting Condition Drug Therapy
Chronic kidney disease with proteinuria ACE inhibitors, ARBs148
Heart failure ACE inhibitors, diuretics149
Myocardial infarction Beta blockers, ACE inhibitors
May Have Favorable Effects on Comorbid Condition
Angina Beta blockers, CCBs
Atrial fibrillation ACE inhibitors, beta-blockers, ARBs150
Cyclosporine-induced hypertension (caution Combination therapy (diuretics, CCBs)151
with the dose of cyclosporine)
Diabetes mellitus (types 1 and 2) with ACE inhibitors (preferred), ARBs, CCBs,
proteinuria diuretics (often combination of some of these)
Essential tremor Beta-blockers152
Heart failure Beta-blockers
Hyperthyroidism Beta-blockers or CCBs (non-DHP)153

146 James PA, Oparil S, Carter BL et al. 2014 Evidence-Based Guideline for the Management of High Blood Pressure in
Adults. Report from the Panel Members Appointed to the Eight Joint National Committee (JNC 8). JAMA. 2014;
311(5): 507-520.
147 Alexander MR. Hypertension medication. https://emedicine.medscape.com/article/241381-medication#showallh.

Accessed May 2021.

148 James PA, Oparil S, Carter BL, et al. 2014 evidence-based guidelines for the management of high blood pressure in

adults. Report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;
311(5):507-520.
149 The Department of Health and Human Services (DHHS). The Seventh Report of the Joint National Committee on

Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.

https://www.nhlbi.nih.gov/files/docs/guidelines/jnc7full.pdf. Accessed May 2021.
150 Schaer BA, Schneider C, Jick SS, Conen D, Osswald S, Meier CR. Risk for incident atrial fibrillation in patients who

receive antihypertensive drugs: a nested case-control study. Ann Intern Med. 2010; 152(2): 78-84. Abstract. Page 1 of
PDF, last para.
151 Hulisz D, Lagzdins M. Drug-induced hypertension. https://www.medscape.com/viewarticle/582385_9. Accessed

May 2021.
152 Zesiewicz TA, Elble R, Louis ED, et al. Practice parameter: Therapies for essential tremor: Report of the Quality of

Standards Subcommittee of the American Academy of Neurology. Neurology. 2005; 64:2008-2020.

153 Reid JR, Wheeler SF. Hyperthyroidism: diagnosis and treatment. Am Fam Physician. 2005; 72(4):623-630.

34
 Osteoporosis Thiazide diuretics154
Prostatism (benign prostatic hyperplasia) Alpha blockers
Renal insufficiency (caution in renovascular ACE inhibitors155
hypertension at high risk of cardiovascular
and renal events)
May Have Unfavorable Effects on Comorbid Condition
Bronchospastic disease Beta-blockers156
Hyperglycemia Beta-blockers157
Gout Thiazide diuretics158
Heart block Beta-blocker, CCBs159
Heart failure CCBs (Non-DHP)160, alpha blockers161
Pregnancy ACE inhibitors, ARBs162
Renal insufficiency ACE inhibitors,163 ARBs164

As with all drugs, each of these therapeutic agents has associated drug-drug interactions. For
more details about such interactions, refer to the prescribing information for each specific agent.

154 Dvorak MM, De Joussineau C, Carter DH et al. Thiazide Diuretics Directly Induce Osteoblast Differentiation and
Mineralized Nodule Formation by Interacting with a Sodium Chloride Co-Transporter in Bone. J Am Soc Nephrol. 18:
2509-2516.
155 Alexander RM. Hypertension medication. https://emedicine.medscape.com/article/241381-medication#showallh.

Accessed May 2021.

156 British and Irish Hypertension Society. Beta-adrenoreceptor antagonists (beta-blockers). https://bihsoc.org/wp-

content/uploads/2017/11/Beta-adrenoceptor-Antagonists-Final-2017.pdf. Accessed May 2021.

157 British and Irish Hypertension Society. Beta-adrenoreceptor antagonists (beta-blockers). https://bihsoc.org/wp-

content/uploads/2017/11/Beta-adrenoceptor-Antagonists-Final-2017.pdf. Accessed May 2021.

158 Sica D. Diruretic-related side effects: Development and treatment.

https://www.medscape.com/viewarticle/489521_7. Accessed May 2021.

159 National Heart, Lung, and Blood Institute. Conduction Disorders. https://www.nhlbi.nih.gov/health-

topics/conduction-disorders. Accessed May 2021.

160 British and Irish Hypertension Society. Calcium channel blockers (CCBs). https://bihsoc.org/wp-

content/uploads/2017/11/Calcium-Channel-Blockers-Final-2017.pdf. Accessed May 2021.

161 British and Irish Hypertension Society. Alpha-adrenoceptor antagonists (alpha-blockers). https://bihsoc.org/wp-

content/uploads/2017/11/Beta-adrenoceptor-Antagonists-Final-2017.pdf. Accessed May 2021.

162 Alexander RM. Hypertension medication. https://emedicine.medscape.com/article/241381-medication#showallh.

Accessed May 2021.

163 British and Irish Hypertension Society. Angiotensin converting enzyme (ACE) inhibitors. https://bihsoc.org/wp-

content/uploads/2017/11/Angiotensin-Converting-Enzyme-Final-2017.pdf. Accessed May 2021.

164 British and Irish Hypertension Society. Angiotensin receptor blockers (ARBs). https://bihsoc.org/wp-

content/uploads/2017/11/Angiotensin-Receptor-Blockers-Final-2017.pdf. Accessed May 2021.

35
CLINICAL PERSPECTIVE
27. Progress Check

Transcript
Use the terms to fill in the blanks.

Fill in the Blank

Atrial fibrillation In 1970, results from the Framingham Study indicated that high blood
pressure and __________ both increase the risk of stroke.
40 The lifetime risk at age ____ of developing coronary heart disease is one
in two for men and one in three for women.
Diuretics For patients not at goal blood pressure but without complications like
diabetes or chronic kidney disease, the JNC 8 treatment algorithm
recommends _____________.

36
CONCLUSION
28. Summary

Transcript
Nonpharmacologic therapies for hypertension include diet and weight modifications, regular blood
lipid monitoring, exercise, stress reduction, and smoking cessation.

Pharmacologic antihypertensive agents include ACE inhibitors, angiotensin receptor blockers,

diuretics, beta-blockers, calcium channel blockers, and agents affecting alpha receptors.

37