receptors, inhibiting the uptake of catecholamines in smooth muscle, and cause

vasodilation. Although effective in lowering BP, they have more side effects than

first-line or second-line agents. The most prominent side effect is hypotension, which

is most evident after the first dose and with postural changes (arising from a lying

position to a standing position).

Direct vasodilators (e.g., hydralazine and minoxidil) work on the arterial

vasculature. They should be reserved for patients with specific conditions (e.g.,

severe CKD) or those with very difficult to control BP. Concomitant drug therapy

with both a diuretic and an agent that lowers heart rate (a β-blocker, diltiazem, or

verapamil) is usually needed to mitigate the associated fluid retention and reflex

tachycardia that frequently occur.

Central α2

-agonists (e.g., clonidine and methyldopa) work in the vasomotor centers

of the brain where they stimulate inhibitory neurons and decrease sympathetic

outflow from the CNS. The resultant decrease in PVR and CO lowers BP. These

agents commonly cause anticholinergic side effects (e.g., sedation, dizziness, dry

mouth, and fatigue) and possibly sexual dysfunction. Although α2

-agonists lower BP,

they often cause fluid retention and should be used in combination with a diuretic.

Adrenergic antagonists (e.g., reserpine, guanadrel, and guanethidine) are not

frequently used to treat hypertension. Reserpine depletes catecholamines from

storage granules to then decrease BP. High doses are associated with more side

effects, but low-dose reserpine (0.05–0.1 mg/day), when used as an additive therapy,

is well tolerated. Because of the potential for fluid retention, reserpine requires

concurrent diuretic therapy. Guanadrel and guanethidine have numerous significant

adverse effects and should be avoided.

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CLINICAL EVALUATION

Patient Presentation

CASE 9-1

QUESTION 1: D.C. is a 44-year-old black man who presents to his primary care provider concerned about

high BP. At an employee health screening last month, he was told he had hypertension. His medical history is

significant for allergic rhinitis. His BP was 144/84 and 146/86 mm Hg last year during an employee health

screening at work. D.C.’s father had hypertension and died of an MI at age 54. His mother had diabetes and

hypertension and died of a stroke at age 68. D.C. smokes one pack per day of cigarettes and thinks his BP is

high because of job-related stress. He does not believe that he really has hypertension. D.C. does not engage in

any regular exercise and does not restrict his diet in any way, although he knows he should lose weight.

Physical examination shows he is 175 cm tall, weighs 108 kg (body mass index [BMI] 35.2 kg/m

2

), BP is

148/88 mm Hg (left arm) and 146/86 mm Hg (right arm) while sitting, and heart rate is 80 beats/minute. Six

months ago, his BP values were 152/88 mm Hg and 150/84 mm Hg when he was seen by his primary care

provider for allergic rhinitis. Funduscopic examination reveals mild arterial narrowing and arteriovenous nicking,

with no exudates or hemorrhages. The other physical examination findings are essentially normal.

D.C.’s fasting laboratory serum values are as follows:

Blood urea nitrogen (BUN), 24 mg/dL

Creatinine, 1.0 mg/dL

Glucose, 105 mg/dL

Potassium, 4.4 mEq/L

Uric acid, 6.5 mg/dL

Total cholesterol, 196 mg/dL

Low-density lipoprotein cholesterol (LDL-C), 141 mg/dL

High-density lipoprotein cholesterol (HDL-C), 32 mg/dL

Triglycerides, 170 mg/dL

An electrocardiogram (ECG) is normal except for left ventricular hypertrophy (LVH). Why does D.C. have

hypertension?

D.C. has hypertension. He has had elevated BP values, measured in clinical

environments, and meets the diagnostic criteria for hypertension because two or more

of his BP measurements are elevated on separate days.

CASE 9-1, QUESTION 2: What is the proper assessment of D.C.’s BP?

D.C. has essential hypertension; therefore the exact cause is not known. He has

several characteristics (e.g., family history of hypertension and obesity) that may

have increased his chance of developing hypertension. Race and sex also influence

the prevalence of hypertension. Across all age groups, blacks have a higher

prevalence of hypertension than do whites and Hispanics.

1 Similar to other forms of

CV disease, hypertension is more severe, more likely to include hypertensionassociated complications, and occurs at an earlier age in black patients.

Patient Evaluation and Risk Assessment

The presence or absence of hypertension-associated complications as well as other

major CV risk factors (Table 9-4) must be assessed in D.C. Also, secondary causes

of hypertension (Table 9-2), if suggested by history and clinical examination

findings, should be identified and managed accordingly. The presence of concomitant

medical conditions (e.g., diabetes) should be assessed, and lifestyle habits should be

evaluated so that they can be used to guide therapy.

HYPERTENSION-ASSOCIATED COMPLICATIONS

CASE 9-1, QUESTION 3: Which hypertension-associated complications are present in D.C.?

A complete physical examination to evaluate hypertension-associated

complications includes examination of the optic fundi; auscultation for carotid,

abdominal, and femoral bruits; palpation of the thyroid gland; heart and lung

examination; abdominal examination for enlarged kidney, masses, and abnormal

aortic pulsation; lower extremity palpation for edema and pulses; and neurologic

assessment. Routine laboratory assessment after diagnosis should include the

following: ECG; urinalysis; fasting glucose; hematocrit; serum potassium, creatinine,

and calcium; and a fasting lipid panel. Optional testing may include measurement of

urinary albumin excretion or albumin-to-creatinine ratio, or additional tests specific

for secondary causes if suspected.

D.C. does not yet have hypertension-associated complications. He is exhibiting

early signs, however, based on his physical examination that, if left untreated, will

likely develop into such complications. These early signs have likely evolved from

his longstanding, poorly controlled hypertension. D.C.’s ECG revealed LVH,

indicating early cardiac damage. Although the gold standard for confirming LVH is

echocardiography, this confirmatory procedure is not necessary unless symptoms are

present indicating that LVH has progressed to left ventricular dysfunction (e.g.,

peripheral edema and shortness of breath). His funduscopic examination reveals mild

arterial narrowing and arteriovenous nicking, which are early signs of retinopathy

and atherosclerosis. D.C.’s serum creatinine is normal, ruling out overt CKD.

Additional testing for microalbuminuria is needed, however, to confirm that he does

not have early stage kidney disease.

CASE 9-1, QUESTION 4: What other forms of hypertension-associated complications is D.C. at risk for?

Hypertension adversely affects many organ systems, including the heart, brain,

kidneys, peripheral circulation, and eyes. These are summarized in Table 9-4.

Damage to these systems resulting from hypertension is termed hypertensionassociated complications, target-organ damage, or CV disease. There are often

misconceptions about the terms CV disease and CAD. CV disease encompasses the

broad scope of all forms of hypertension-associated complications. CAD is simply a

subset of CV disease and refers specifically to disease related to the coronary

vasculature, including ischemic heart disease and MI. Hypertension-associated

complications and major risk factors for developing such complications should be

assessed by a thorough patient history, a complete physical examination, and

laboratory evaluation.

Hypertension can affect the heart either indirectly, by promoting atherosclerotic

changes, or directly, via pressure-related effects. Hypertension can promote CV

disease and increase the risk for ischemic events, such as angina and MI.

Antihypertensive therapy has been shown to reduce the risk of these coronary events.

Hypertension also promotes the development of LVH, which is a myocardial

(cellular) change, not an arterial change. These two conditions often coexist,

however. It is commonly believed that LVH is a compensatory mechanism of the

heart in response to the increased resistance caused by elevated BP. LVH is a strong

and independent risk factor for CAD, left

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ventricular dysfunction, and arrhythmia. LVH does not indicate the presence of left

ventricular dysfunction, but is a risk for progression to left ventricular dysfunction,

which is considered a hypertension-associated complication. This may be caused by

ischemia, excessive LVH, or pressure overload. Ultimately, left ventricular

dysfunction results in a decreased ability to contract (systolic dysfunction).

Hypertension is one of the most frequent causes of cerebrovascular disease.

Cerebrovascular signs can manifest as transient ischemic attacks, ischemic strokes,

multiple cerebral infarcts, and hemorrhages. Residual functional deficits caused by

stroke are among the most devastating forms of hypertension-associated

complications. Clinical trials have demonstrated that antihypertensive therapy can

significantly reduce the risk of both initial and recurrent stroke. A sudden, prolonged

increase in BP can also cause hypertensive encephalopathy, which is classified as a

hypertensive emergency.

The GFR is used to estimate kidney function, which declines with aging. This rate

of decline is greatly accelerated by hypertension. Hypertension is associated with

nephrosclerosis, which is caused by increased intraglomerular pressure. CKD,

whether mild or severe, can progress to kidney failure (stage 5 CKD) and the need

for dialysis. Studies have demonstrated that controlling hypertension is the most

important strategy to slow the rate of kidney function decline,

29 but it may not be

entirely effective in slowing the progression of renal impairment in all patients.

CKD is staged based on estimated GFR values.

30 Stage 3 CKD (moderate) is

defined as a GFR 30 to 59 mL/minute/1.73 m2

, stage 4 CKD (severe) is 15 to 29

mL/minute/1.73 m2

, and stage 5 (kidney failure) is less than 15 mL/minute/1.73 m2 or

the requirement of dialysis. In hypertension, stage 3 CKD or worse is considered a

hypertension-associated complication. An estimated GFR of less than 60

mL/minute/1.73 m2 corresponds approximately to a serum creatinine concentration of

greater than 1.5 mg/dL in an average man and greater than 1.3 mg/dL in an average

woman. The presence of persistent albuminuria (>300 mg albumin in a 24-hour urine

collection or 200 mg albumin/g creatinine on a spot urine measurement) also

indicates significant CKD. (Note: These definitions of the stages of kidney disease

and albuminuria will be used throughout the remaining cases in this chapter.)

Assessment of kidney function is discussed in Chapter 2, Interpretation of Clinical

Laboratory Tests, and Chapter 28, Chronic Kidney Disease.

Peripheral arterial disease, a noncoronary form of atherosclerotic vascular

disease, is considered a hypertension-associated complication. It is equivalent in CV

risk to CHD.

3 Risk factor reduction, BP control, and antiplatelet agent(s) are needed

to decrease progression. Complications of peripheral arterial disease can include

infection and necrosis, which in some cases require revascularization procedures or

extremity amputation.

Hypertension causes retinopathies that can progress to blindness. Retinopathy is

evaluated according to the Keith, Wagener, and Barker funduscopic classification

system. Grade 1 is characterized by narrowing of the arterial diameter, indicating

vasoconstriction. Arteriovenous nicking is the hallmark of grade 2, indicating

atherosclerosis. Longstanding, untreated hypertension can cause cotton wool exudates

and flame hemorrhages (grade 3). In severe cases (e.g., hypertensive emergency)

papilledema occurs, and this is classified as grade 4.

MAJOR RISK FACTORS

CASE 9-1, QUESTION 5: Which major CV risk factors are present in D.C.?

Hypertension is one of nine major CV risk factors (Table 9-4). These are not risk

factors for developing hypertension; rather, they increase the risk of hypertensionassociated complications. D.C. has multiple CV risk factors: smoking, dyslipidemia,

family history of premature CHD in a first-degree relative (father), hypertension,

obesity, and physical inactivity.

D.C. is a primary prevention patient because he does not yet have any

hypertension-associated complications. He has multiple major CV risk factors, so

controlling his BP is of paramount importance to reduce the risk of developing

hypertension-associated complications. The JNC-8 guidelines, considered the gold

standard for treatment, recommend a BP goal of less than 140/90 mm Hg for D.C.

because he is a primary prevention patient less than 60 years of age.

Many of D.C.’s risk factors are modifiable. He is a smoker and this significantly

increases his CV risk and may reduce the efficacy of antihypertensive therapy.

Smoking cessation may not independently lower D.C.’s BP, but it will decrease his

overall risk of CV disease (see Chapter 91, Tobacco Use and Dependence). D.C. is

obese based on his BMI. His lack of physical activity and dietary patterns have likely

contributed to his obesity. A more focused patient interview on diet and exercise

would be helpful to reinforce the assumption that he has a sedentary lifestyle. D.C.’s

dyslipidemia increases his CV risk, and lipid-lowering therapy should be considered

to further decrease the risk of CV disease (see Chapter 8, Dyslipidemias,

Atherosclerosis, and Coronary Heart Disease).

31

Advanced age is considered a major CV risk factor. Although CHD in the elderly

is not considered premature, increasing age increases the risk of hypertensionassociated complications. Premenopausal women are at low risk for CV disease.

However, CV risk in women increases significantly after menopause, similar to the

increased risk in men. Therefore, cutoff values for age as a risk factor in men and

women are separated by 10 years (>55 years for men, >65 years for women). At age

50, D.C. does not yet have this risk factor.

CASE 9-1, QUESTION 6: What is D.C.’s BP goal?

The overarching goal of treating hypertension is to lower hypertension-associated

complications. Control of BP is the most feasible clinical end point to guide therapy

and should be viewed as a surrogate for attaining this goal. D.C.’s goal BP is less

than 140/90 mm Hg according to JNC-8.

PRINCIPLES OF TREATMENT

Goals of Therapy

CASE 9-1, QUESTION 7: What are the goals of treating D.C.?

Pharmacotherapy principles to achieve these goals include selecting a treatment

regimen with antihypertensive agent(s) that reduces risk of CV events, complemented

by appropriate lifestyle modifications (Table 9-5).

Health Beliefs and Patient Education

CASE 9-1, QUESTION 8: What patient education should be provided to D.C. regarding his hypertension?

Patient education is needed to ensure that D.C. understands his disease and its

complications (Table 9-6). This should comprehensively include information on

disease, treatment, adherence, and complications. Several approaches can be

effective, but all methods should include direct communication between the clinician

and the patient. Multidisciplinary approaches to disease-state management in

hypertension can effectively use a team of different clinicians (e.g., physicians, nurse

practitioners, physician assistants, and pharmacists). Providing face-to-face

education is most common, but the key components in patient education can be

delivered via indirect interactions (e.g., telephone).

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p. 143

Table 9-6

Patient–Provider Interactions for Hypertension

Patient Education

Assess patient’s understanding and acceptance of the diagnosis of hypertension

Discuss patient’s concerns and clarify misunderstandings

When measuring BP, inform the patient of the reading both verbally and in writing

Assure patient understands his or her goal BP value

Ask patient to rate (1–10) his or her chance of staying on treatment

Inform patient about recommended treatment, including lifestyle modification. Provide specific written

information using standard brochures when available

Elicit concerns and questions and provide opportunities for patient to state specific behaviors to carry out

treatment recommendations

Emphasize

the need to continue treatment

that control does not mean cure

that elevated BP is usually not accompanied by symptoms

Individualize Treatment Regimens

Include the patient in decision making

Simplify the regimen to once-daily dosing, whenever possible

Incorporate treatment into patient’s daily lifestyle

Set realistic short-term objectives for specific components of the medication and lifestyle modification plan

Encourage discussion of diet and physical activity, adverse drug effects, and concerns

Encourage self-monitoring with validated BP devices

Minimize the cost of therapy, when possible

Discuss adherence at each clinical encounter

Encourage gradualsustained weight loss

BP, blood pressure

Education should be tailored to the patient’s specific needs. For example, some

patients are able to comprehend the importance of achieving controlled BP by

reading written materials, whereas others understand this only after implementing

self-BP monitoring. The patient education process must be continuous throughout the

duration of therapy. Not all aspects need to be discussed during each clinical

interaction. Careful selection of both written and verbal information should be

considered so that patients are not overwhelmed or intimidated. National Heart,

Lung, and Blood Institute patient education materials are available at

http://www.nhlbi.nih.gov/health/public/heart/index.htm#hbp. It is important that

clinicians review all materials provided to patients to identify the source of

information, assess ease of reading, and identify omitted information and sources of

confusion or anxiety (e.g., drug side effects).

Patients such as D.C. often incorrectly explain BP elevation as stress related.

Although certain patients (e.g., those with white-coat hypertension) may have BP that

is more highly reactive, most patients with essential hypertension will have an

elevated BP regardless of their stress level. D.C. should be informed about the cause

of his disease and the lack of correlation between stress or symptoms and high BP.

Importantly, D.C. needs to realize that elevated BP is almost always asymptomatic

and that it can cause serious long-term complications. It is essential that he

understand the chronic nature of hypertension and the need for long-term therapy.

Otherwise, he may adhere to his treatment only when he “feels his BP is high” or

during stressful events.

Some patients believe they can control their BP by stress management rather than

with antihypertensive drug therapy and lifestyle modifications. Controlled trials have

not consistently proven that stress management is beneficial in treating

hypertension.

32

It is important to determine the patient’s health beliefs and attitudes

and to provide education about the etiology and management of hypertension to

promote BP control.

Another common myth patients believe is that treating hypertension commonly

leads to fatigue, lethargy, and sexual dysfunction. This misconception can

compromise adherence and be a limiting factor in appropriate management. Clinical

trials have repeatedly reported that quality of life is better with active medication

than with placebo.

33–36 Data have indicated that as many as 27% of men with

hypertension have erectile dysfunction.

5 Although many patients believe this to be a

medication-related side effect and that incidence rates vary among antihypertensive

agents and classes, erectile dysfunction is likely caused by penile arterial changes

(probably atherosclerosis), which is related to uncontrolled or untreated

hypertension.

37

Benefits of Treatment

CASE 9-1, QUESTION 9: How can antihypertensive drug therapy reduce D.C.’s risk of hypertensionassociated complications?

Without a doubt, antihypertensive therapy reduces the risk of CV disease and CV

events in patients with hypertension. Numerous landmark placebo-controlled studies

have clearly demonstrated these benefits. The first large-scale trial, published in

1967, was the Veterans Administration (VA) study in men with DBP between 115

and 129 mm Hg.

38 This study was prematurely stopped because benefits of treatment

were so dramatic. Antihypertensive therapy significantly reduced cerebral

hemorrhage, MI, left ventricular dysfunction, retinopathy, and kidney disease. Other

landmark placebo-controlled studies have evaluated antihypertensive therapy in

patients with less severe hypertension and have shown a reduced risk of CV events

(stroke, ischemic heart disease, and left ventricular dysfunction) and even CV

death.