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Cardiology: An Integrated Approach >

Chapter 13: Systemic Arterial Hypertension

and Antihypertensive Drugs
Hussain Ibrahim; Prerana Manohar

Learning Objectives
Learning Objectives

By the end of this chapter the student will be able to:

Discuss the pathophysiology of hypertension.

Identify and evaluate primary hypertension vs secondary hypertension.

Recognize the major complications of hypertension.

Understand the basis of antihypertensive therapy.

Discuss novel treatments and trials for hypertension.

Introduction
Hypertension is the elevated blood pressure (BP) in arterial vessels. Two important determinants of blood pressure are
cardiac output and total peripheral resistance which will be discussed in detail later in the chapter. Hypertension is one of the
most common conditions, especially in the aging population. It is commonly referred to as the silent killer because it remains
asymptomatic until it manifests as one of the life-threatening complications, for example, stroke, myocardial infarction, kidney
dysfunction, and so on.

The prevalence of hypertension is approximately 30% in the general adult population according to a study by the National
Health and Nutrition Examination Survey (NHANES). This prevalence percentage has significantly increased from previous
NHANES reports and translates into 65 million people that are affected by hypertension in the United States.

According to the latest NHANES report, prevalence is higher among the older population, women, and non-Hispanic blacks.
The incidence of hypertension has been increasing in industrial countries, which can be attributed to a large extent to dietary
habits and an increase in obesity. Furthermore, hypertension is an important worldwide public health challenge—in a pooled
data review (Kearney et al., 2005), approximately 972 million people have hypertension worldwide, 333 million in developed
countries, and 639 million in developing countries. The number of adults with hypertension is expected to increase by 60% to
a total of 1.56 billion people by 2025.

Although control of hypertension has improved significantly over the last 2 decades, it is still not adequate. NHANES reports
that approximately 72% of hypertensive individuals are being treated for hypertension, and out of those treated patients only
69% have adequate blood pressure control, defined as blood pressure below 140/90.

Pathophysiology of Hypertension
Normally, the mean arterial pressure (MAP) is the product of cardiac output (CO) and total peripheral resistance (TPR).

MAP = CO × TPR

TPR is determined by the resistance that is present in the small arteries and arterioles. In order to better comprehend the
mechanism of increased blood pressure, it is imperative to have a better understanding of the individual factors that
determine hypertension.

Cardiac output is defined as the volume of blood pumped from the right or left ventricle in 1 minute; thus, it is the product of
the stroke volume and the heart rate. Factors that increase the heart rate or stroke volume result in changes in blood
pressure.

The stroke volume is dependent on cardiac contractility and blood volume, which equates with sodium homeostasis. The
autonomic nervous system affects both cardiac contractility and stroke volume.

Another factor impacting cardiac output is the heart rate that is also controlled mainly by the autonomic nervous system.

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Systolic BP correlates with stroke volume. Diastolic BP is determined by the volume of blood in the arteries while the heart is
filling in diastole, which in turn depends on the vascular tone of the peripheral resistance of the arterioles. It also depends on
the elastic recoil of the aortae.

TPR is one of the most significant factors determining diastolic BP. Poiseuille’s relationship is extremely important in
determining the total peripheral resistance of the blood vessels. For any given blood vessel, the resistance has the following
relationship.

R = resistance

η = viscosity of blood

l = length of vessel

r4 = radius of blood vessel raised to the fourth power

As the length of the vessels and the blood viscosity remain stable, the truly important relationship in this equation is between
the peripheral resistance and the radius of the vessels raised to the power 4. Thus, small changes in the vessel radius can
cause large changes in the peripheral resistance and eventually the blood pressure.

Vasodilators decrease TPR and cause a drop in the blood pressure.

Both environmental and genetic factors play an important role in blood pressure control. Obesity is the most important
environmental factor. Intracellular calcium has been associated with increased muscle tone of the vascular smooth muscle
and increased blood pressure. However, a calcium-rich diet causes the suppression of the parathyroid hormone, resulting in a
decrease in the intracellular calcium concentration, and ultimately resulting in a slight decrease in blood pressure. A calcium-
rich diet has also been associated with a reduction in the lipogenesis in the fat cells, thus providing an additional beneficial
effect on blood pressure. Overall, an individual’s cardiovascular risk profile improves with an increased dietary calcium intake.
Dietary potassium decreases the blood pressure as well. Other environmental factors include low levels of physical activity,
increased stress, increased levels of alcohol intake, dyslipidemia, personality traits (eg, a hostile attitude or time urgency,
impatience) can negatively impact the blood pressure.

Genetic factors also play a major role in the pathogenesis of hypertension. High blood pressure before the age of 55 occurs
3.8 times more frequently among individuals with a positive family history of hypertension. Several genes have been
implicated in the development of hypertension and thus it is called a polygenic disorder. An important genetic mutation
involved in the pathogenesis of hypertension is the Adducin family of genes (genes for cytoskeleton protein Adducin), which
can lead to increased sodium reabsorption from the kidneys. The Connexin 40 gene mutation (a gap junction protein gene in
the juxtaglomerular apparatus) has also been implicated in the pathogenesis of hypertension. Another important mutation is
the angiotensinogen gene, which leads to increased levels of angiotensinogen, a precursor for angiotensin. Altogether, the
interplay of both environmental and genetic factors determines the increased levels of blood pressure.

Blood pressure is regulated through autonomic and hormonal mechanisms. The baroreceptor reflex regulates blood pressure
on a minute-to-minute basis. Stretch-sensitive sensory nerve root endings are located in the carotid sinuses and the aortic
arch. As the arterial pressure rises, the rate of firing of these neurons increases, causing a decrease of sympathetic outflow,
which in turn causes a decrease in the heart rate and arterial pressure. This is the primary mechanism for the regulation of
blood pressure in an acute setting, and acts as the buffer in changes of posture and acute changes in the blood volume.
However, if the blood pressure remains elevated, a downregulation of the baroreceptor reflex occurs, and is set to a higher
pressure point. Long-term blood pressure maintenance is dependent mainly on intravascular blood volume through the renin-
angiotensin-aldosterone mechanism. As the intravascular volume increases, the stroke volume and cardiac output increases,
and this causes the blood pressure to rise. However, if blood pressure remains elevated for a long period of time, the total
peripheral resistance will decrease and the cardiac output will become normal. In such situations, the TPR becomes the major
factor in determining the degree of blood pressure elevation (Fig. 13.1).

Figure 13.1

Regulation of blood pressure by sympathetic system activation.

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Primary versus Secondary Hypertension

Primary hypertension, or hypertension without an identifiable cause (formerly called essential hypertension), accounts for
approximately 95% of all cases of hypertension. Pathogenesis of primary hypertension is poorly understood. Although it is
idiopathic in nature, there are many genetic and environmental factors that interact with one another to cause and develop
primary hypertension. Important factors that can contribute to this condition include increased sympathetic activity and
responsiveness of the adrenergic system. Increased angiotensin II activity and mineralocorticoid excess are other important
considerations.

Familial and genetic predisposition are one of the most important associations for the development of primary hypertension.
Primary hypertension is 4 times more common in African Americans and progresses more rapidly, and is associated with
more complications as compared to rates of primary hypertension in Caucasians. The incidence of primary hypertension
increases with age. The pathophysiology behind age relates the increase in blood pressure to the loss of elasticity, stiffening
of the arteries, and a decrease in the renal ability to excrete sodium.

There is a strong pathogenic association of insulin resistance with hypertension. Frequently, high blood pressure is noted
along with obesity (especially excess fat around the waist), high triglyceride levels, low HDLs (ie, high-density lipoprotein),
high fasting blood sugar levels, or insulin resistance. When 3 of these 5 manifestations are present in a patient, metabolic
syndrome is diagnosed. Metabolic syndrome increases the risk of heart disease, stroke, and diabetes mellitus. The exact
mechanism by which insulin resistance induces hypertension is still unknown; however, insulin is known to increase both
sympathetic activity and sodium and water retention. This seems to be the most plausible hypothesis for the correlation of
insulin and hypertension. Salt sensitivity, another common mechanism for primary hypertension, also increases in insulin-
resistance states.

CLINICAL CORRELATION 13.1

Insulin resistance is a condition in which the body normally secretes insulin from β-cells of the pancreas, but does not use it
effectively. Thus, the blood glucose level increases, which leads to an increase in the secretion of insulin as it attempts to
compensate for the high glucose level. Eventually, the patient develops type 2 diabetes mellitus.

Secondary Hypertension

Secondary hypertension is a hypertension with an identifiable cause. The age of onset of hypertension before 30 or after 55
years of age raises the possibility of the presence of secondary hypertension and requires further workup (ie, diagnostic
tests). Other important clues to the presence of secondary hypertension include severe or resistant hypertension (resistant
hypertension is defined as hypertension that is not being controlled by 3 antihypertensive agents, one of them being a
diuretic), and malignant or accelerated hypertension (Table 13.1).

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Table 13.1 Miscellaneous causes of secondary hypertension
Other
causes of
Clinical presentation Workup Treatment options
secondary
hypertension
Diagnosis is made with Behavior modifications including avoidance
Sleep disturbances, snoring,
polysomnography on which there of evening respiratory suppressants like
Obstructive resuscitative snorts, apnea,
is increased frequency of sleep alcohol, weight loss, appropriate sleep
sleep apnea daytime somnolence, fatigue,
apnea and daytime symptoms of position; positive airway pressure; oral
hypertension
sleep disturbance appliances; rarely surgery
Hypertension, variability in
Workup includes ECG, chest
the blood pressure in upper
Coarctation of radiography; confirmation is If significant, patient will need surgical repair;
and lower extremities,
aorta based on the findings on the another option is balloon angioplasty
headaches, epistaxis, heart
echocardiography
failure, dissection

Renovascular Hypertension

Renovascular hypertension is the most common cause of secondary hypertension and is potentially correctable. It can be
atherosclerotic or fibromuscular in origin (Table 13.2). The former is common in older patients who generally have other
manifestations of atherosclerotic disease. Generally, atherosclerotic plaque involves the proximal renal arteries at their origin
in patients with atherosclerotic disease. Fibromuscular dysplasia is more frequently associated with young Caucasian females
(8 times more common than in other population groups). Lesions are usually bilateral and involve distal portions of the
arteries.

Table 13.2 Types of renovascular hypertension: Atherosclerotic vs fibromuscular

Types Age Gender History and exam
Smoking, flash pulmonary
edema, severe or uncontrolled
hypertension, coronary artery
disease, peripheral artery
disease, flank bruits, advanced
Mostly
Atherosclerotic Older retinopathy, increase in
men
creatinine of more than 30%
after treatment with ACE
inhibitors or ARBs (usually
occurs with bilateral
renovascular disease)
Clues are mostly related to age,
Mostly
Fibromuscular Younger gender and general features of
women
secondary hypertension
Labs Diagnostic tests Treatment
Gold standard for
evaluation of
renovascular In patients with
disease is renal atherosclerotic renal
Hypokalemia arteriography; artery stenosis, vascular
and elevated however, because repair is done if medical
renin and of its invasive management fails or on
aldosterone nature, less deterioration of renal
levels might invasive function. Options for
be noticed alternatives are vascular repair are
used first including PTRA and surgical
duplex Doppler vascular repair
ultrasound, CTA,
and MRA
Generally in patients
with fibromuscular
dysplasia, vascular
repair is more favorable
as patients that are
Same as younger, generally do
Same as above
above not have any comorbid
conditions and
hypertension resolves
after the repair without
the need for lifelong
antihypertensive agents

Careful selection of patients for further evaluation of renovascular disease is important because of the potential risks involved
with testing, particularly in patients with impaired renal function who are at an increased risk for contrast-induced nephropathy
and nephrogenic systemic fibrosis, a condition associated with gadolinium exposure during magnetic resonance angiography
(MRA). The specific choice of the test depends on the condition of the patient and the available expertise.

Once a diagnosis is established, treatment options depend upon patient characteristics and the goals of treatment. Options
for medical management and vascular repair are available. Options for vascular repair include percutaneous transluminal
renal angioplasty (PTRA) and surgical vascular repair. Surgery is only performed if PTRA fails, a lesion is not amenable to
stenting/PTRA, or a patient is undergoing aortic surgery for aneurysm repair (see Table 13.2 and Fig. 13.2).

Figure 13.2

Angiograms in a 70-year old man with a history of coronary artery disease, previous coronary artery bypass graft surgery, and
hypertension. (Reproduced, with permission, from Fuster V, Walsh RA, Harrington RA, eds. Hurst’s The Heart. 13th ed. New
York, NY: McGraw-Hill; 2011.)

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Cushing Syndrome

Cortisol increases blood pressure by acting on mineralocorticoid receptors. The majority of Cushing syndrome patients have
hypertension. Causes of Cushing syndrome include iatrogenic (most commonly, the ingestion of exogenous glucocorticoids),
ectopic adrenocorticotropic hormone (ACTH) syndrome, adrenal tumors, and Cushing disease. Characteristic signs and
symptoms raise the suspicion of the presence of Cushing syndrome. These include supraclavicular fat pads, purplish skin
striae, moon face, obesity, hypertension, menstrual irregularity, and glucose intolerance.

Before starting the workup for other causes of Cushing syndrome it is necessary to rule out the use of glucocorticoids, which
can be the underlying cause.

Diagnosis of Cushing syndrome is made on the basis of biochemical tests; however, imaging is only done later to locate
hyperplasia or a tumor. Appropriate management of Cushing syndrome depends on the underlying cause, so it is imperative
to determine the exact etiology of Cushing syndrome (Figs. 13.3 and 13.4).

Figure 13.3

Workup of hypercortisolism. The initial test is 24-hour urine collection showing hypercortisolism. Check the
adrenocorticotropic hormone (ACTH) level as the next step. In ACTH-dependent hypercortisolism, a dexamethasone
suppression test is done as the next step before the imaging studies are done. In case there is ACTH-independent
hypercortisolism, computed tomography (CT) of the abdomen is done to assess the adrenal glands.

Figure 13.4

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Typical findings in Cushing syndrome. (Reproduced, with permission, from Hammer GD, McPhee SJ. Pathophysiology of
Disease: An Introduction to Clinical Medicine. 7th ed. New York, NY: McGraw-Hill; 2014.)

Primary Aldosteronism

Nonsuppressible (primary) hypersecretion of aldosterone is an important and less commonly documented cause of
hypertension. Common causes of primary aldosteronism include aldosterone-producing adenoma (the most common) and
bilateral idiopathic hyperaldosteronism.

The effects of hyperaldosteronism can be linked to the mechanism of action of aldosterone. It increases sodium reabsorption
in the renal tubules and at the same time is responsible for the secretion of potassium and hydrogen ions. The osmotic
gradient that is formed with sodium being reabsorbed causes the fluid to follow, which is the basic underlying cause of
increased blood pressure in hyperaldosteronism (Table 13.3).

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Table 13.3 Common causes of primary hyperaldosteronism
Important causes Presenting clinical features Lab workup Imaging studies Treatment options
Plasma renin
activity (PRA) and
plasma aldosterone
concentration Adrenal CT to For unilateral adenoma,
Hypertension, hypokalemia, and (PAC). PAC and distinguish between surgical adrenalectomy
metabolic alkalosis. Other PAC/PRA ratio is adenoma vs is the treatment of
electrolyte abnormalities include increased. If PRA is hyperplasia vs adrenal choice. For patients with
mild hypernatremia and increased and carcinoma. Adrenal bilateral hyperplasia,
hypomagnesaemia. Muscle PAC/PRA ratio is venous sampling done medical therapy is the
Aldosterone-
weakness can occur but decreased, suspect if CT scan is negative treatment of choice.
producing generally it is rare if the or shows bilateral Aldosterone antagonists,
secondary
adenoma (most potassium level is more than 2.5. hyperaldosteronism. abnormalities or has ie, spironolactone and
common) Patients with hyperaldosteronism unilateral abnormality eplerenone are the first-
have greater left ventricular mass Confirmation by but patient is more than line agents used in this
Bilateral idiopathic
aldosterone
hyperaldosteronism and thus it is one of the risk 40 years of age. condition. Serum
factors for the development of suppression test, Unilateral disease will potassium, creatinine,
cardiovascular disease. Also can which is either have increased PAC on and blood pressure
have increased GFR and renal performed with the side of tumor while should be monitored
perfusion pressure independent orally administered in bilateral hyperplasia; frequently during the first
of hypertension. sodium chloride or little difference between 4-6 weeks of medical
with IV sodium the two sides exists. therapy.
chloride loading and
measurement of
PAC.

The aldosterone escape phenomenon prevents fluid accumulation and edema formation. Sodium-wasting forces counteract
the sodium-retaining action of aldosterone. Factors responsible for the escape phenomenon include atrial natriuretic peptide
(ANP) and pressure natriuresis.

Hypokalemia also does not reach profound levels, as hypokalemia itself counteracts the potassium-wasting effects of
aldosteronism. Thus, a relatively lower potassium level is found in hyperaldosteronism, but severe hypokalemia does not
occur unless there is a precipitating factor, such as diuretic therapy.

Pheochromocytoma

Catecholamine-secreting tumors that arise from the chromaffin cells of the adrenal medulla and the sympathetic ganglia are
referred to as pheochromocytoma and catecholamine-secreting paragangliomas, respectively. Both have the same (or similar)
clinical features.

Approximately 50% of pheochromocytoma cases are detected by autopsy. Overall, about 10% of catecholamine-secreting
tumors are malignant. The only reliable clue to the presence of a malignant pheochromocytoma is local invasion into
surrounding tissues and organs (eg, the kidneys, liver) or distant metastasis (Table 13.4).

Table 13.4 Pheochromocytoma clinical features, lab workup, and treatment summary
Clinical features Lab workup Imaging studies Treatment
Both CT and MRI are
Initial test to identify catecholamine-
quite sensitive but not Surgical resection for
secreting tumor is to measure
very specific as there are confirmed cases of
fractionated metanephrine and
many adrenal pheochromocytoma is
Episodic headaches, catecholamine in 24-hour urine
incidentalomas. At any treatment of choice. Preop
sweating, and tachycardia. collection. Plasma fractionated rate, CT/MRI are done preparation with α blockage
metanephrine is not specific enough to
Fifty percent of patients first. for 10-14 days prior to
have paroxysmal be recommended as a first-line test.
surgery followed by β
hypertension while the rest In patients with possible MEN 2/VHL 123-I- blockage.
have primary hypertension syndrome, plasma fractionated metaiodobenzylguanidine
or normal blood pressure. (MIBG) scintigraphy is β-adrenergic blockage
metanephrines can be used as first line
test of choice if suspicion should never be initiated first
test as likelihood of having
of pheochromocytoma as it can cause fatal
pheochromocytoma is high in these
remains high but CT/MRI hypertensive crisis.
patients.
have failed to show it.

Complications of Hypertension
Major complications associated with hypertension include coronary artery disease, congestive heart failure, stroke, and
peripheral artery disease. The likelihood of developing these complications starts to increase once the blood pressure
exceeds 115/75 in all age groups. In addition, the presence of other risk factors also increases the chances of developing
these complications.

These complications will be discussed based on the primary organs that are affected by hypertension.

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1. Heart: Hypertension is the single most important risk factor for the development of premature heart disease. Heart
disease is the most common cause of death in hypertensive patients. Left ventricular hypertrophy is commonly seen in
hypertensive patients and it can in turn lead to diastolic heart failure, cardiac arrhythmia, myocardial infarction, and
sudden death.

In order to identify patients with left ventricular hypertrophy and diastolic dysfunction, an echocardiogram is the most
accurate noninvasive test. Cardiac catheterization still remains the gold standard for diagnostic purposes but is not
performed routinely because of its invasive nature and risk of complications. Diastolic heart failure is commonly
associated with hypertension and the systolic function is preserved. Optimal treatment of hypertension leads to the
normalization of the blood pressure and nonprogression or even regression of left ventricular hypertrophy. Thus,
patients with hypertension should be treated aggressively.

2. Brain: Hypertension is the most common and important risk factor for stroke, both ischemic and hemorrhagic. Optimal
blood pressure control is the best strategy to prevent strokes in a high-risk population.

Hypertension has also been found to have a strong association with impaired cognition in the elderly. The mechanism of
cognitive decline needs further research; however, currently suggested mechanisms include either a large vessel infarct
or multiple small lacunar infarcts.

Hypertensive encephalopathy is another important hypertension-related brain complication. It occurs at extremely high
blood pressure, usually more than 180/120. It is characterized by signs of cerebral edema caused by breakthrough
hyper-perfusion, which is a result of sudden and severe rises in blood pressure. Such severe rises in blood pressure
cause a failure in the autoregulation mechanism of cerebral perfusion and a disruption of the vascular endothelial
function. Signs and symptoms of hypertensive encephalopathy include nausea, vomiting, headaches, neurological signs
such as restlessness and confusion, with a possible progression to coma and death if left untreated. Magnetic
resonance imaging (MRI) should be done to rule out stroke in patients with neurological manifestations. MRIs of the
brain may show reversible posterior leukoencephalopathy syndrome (RPLS) with characteristic edema of white matter
in the parieto-occipital regions. This condition is initially treated with parenteral agents with the goal of lowering the
blood pressure by not more than 25% in 4 to 6 hours.

3. Kidneys: Hypertension is a risk factor for chronic kidney disease and end-stage renal disease. Systolic hypertension is
more strongly associated with the development of renal disease as compared to diastolic hypertension. African
Americans are also more likely to develop renal complications as compared to Caucasians, even at with same level of
blood pressure. African Americans have several times more risk of developing hypertension-related end-stage renal
disease.

Hypertension can both directly cause kidney disease (called hypertensive nephrosclerosis) as well as accelerate the
progression of other underlying renal diseases. Hypertensive nephrosclerosis is a disorder associated with chronic
hypertension. Three important risk factors include African American genetics; patients with more marked elevations in
blood pressure; and those with underlying chronic renal disease, particularly those with diabetic nephropathy.
Histologically, hypertensive nephrosclerosis is characterized by vascular, glomerular and tubulointerstitial involvement.
The histologic pattern of malignant hypertension is different and consists of fibrinoid necrosis of the afferent arterioles.
Sometimes it can involve the glomeruli that results in focal necrosis of the glomerular tuft.

4. Peripheral arteries: Blood vessels are also one of the common targets of hypertension-related complications. The
basic underlying mechanism of the development of peripheral vascular disease is atherosclerosis. Common
manifestations of stenotic lesions of the lower extremities are claudication of the legs that presents as reproducible pain
on ambulation, which is relieved on rest. The ankle-brachial index (ABI) is a useful tool for the evaluation of peripheral
artery disease, where values less than 0.90 are considered diagnostic.

CLINICAL CORRELATION 13.2

The ankle-brachial index (ABI) is measured by comparing the systolic blood pressure at the ankle and the systolic blood
pressure at the arm (the brachial artery). It assesses the peripheral circulation and the severity of peripheral arterial disease
(PAD). Continuous wave Doppler is used to measure the blood pressure. The patient should rest for 15 to 30 minutes before
the measurements of pressure. First, the blood pressure is measured in both ankles and then in both arms (the brachial
arteries). The higher of the blood pressure from the 2 ankles is then divided by the blood pressure of the 2 brachial arteries to
calculate the ABI. A normal ABI value is between 0.9 to 1.3. Values above 1.3 are generally secondary to noncompressible
arteries and are caused by calcified vessels. Additional studies are needed in these patients. A value less than 0.90 is
diagnostic for occlusive peripheral artery disease. A value less than 0.40 is indicative of multilevel involvement of the vessels.

Pharmacologic Treatment of Hypertension

Hypertension is defined by the average of 2 or more properly recorded readings at each of 2 or more visits after an initial
screen. Table 13.5 classifies the hypertension stages.

Table 13.5 Stages of hypertension

Hypertension category Systolic blood pressure Diastolic blood pressure
Normal blood pressure <120 <80
Prehypertension 120–139 80–89
Stage 1 hypertension 140–159 90–99
Stage 2 hypertension ≥160 ≥100

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These definitions and stages are based on the assumption that the patient is not currently on any antihypertensive
medications and there is no acute illness present at the time of measurement.

In children and adolescents, hypertension is defined as blood pressure above the 95th percentile for a given age, sex, and
height. If the blood pressure falls between the 90th and 95th percentile, it is defined as prehypertension.

In order to eliminate white coat hypertension, various strategies can be used, including 24-hour ambulatory blood pressure
readings, home blood pressure monitoring, and measuring nighttime blood pressure. If the average awake-time blood
pressure is more than 135/85 and the sleep-time blood pressure is more than 120/75, these levels correlate roughly with a
clinical blood pressure of 140/90.

CLINICAL CORRELATION 13.3

White coat hypertension is a situation in which the patient’s office blood pressure readings average more than 140/90;
however, reliable out-of-hospital blood pressure readings are less than 140/90. It is generally attributed to the anxiety that
patients experience in clinical/hospital settings. Blood pressure tends to decrease on the follow-up visits.

However, it should be kept in mind that relatively higher ambulatory blood pressure and white coat hypertension are related to
an increase in the progression of hypertension and also increases the risk for end-organ damage. A nighttime blood pressure
dip is a normal phenomenon, while attenuation of it can lead to an increase in cardiovascular risk.

Antihypertensive medications should generally be initiated if the systolic blood pressure remains persistently above 140
systole (in patients younger than 60 years of age) or more than 150 systole (in patients 60 years and older). For diastolic
blood pressure, the threshold for the initiation of therapy is a blood pressure that remains persistently above 90 in the office
and at home.

Goal blood pressure is below 140/90 in all hypertensive patients below the age of 60.

Measurement of Blood Pressure

The standard procedure for blood pressure measurement uses the mercury sphygmomanometer and Korotkoff sounds.
Correct patient position and cuff size are very important for an accurate measurement of blood pressure. The patient should
be sitting for at least 5 minutes prior to the blood pressure measurement. The patient should be relaxed, sitting upright with
the legs uncrossed, and the back and arms supported. The middle of the cuff should be at level with the right atrium. The cuff
length should be 80% of the arm circumference and the width should be 40% of the arm circumference. After positioning the
cuff, the radial pulse should be palpated and the cuff should be inflated to note the level at which the pulse disappears. The
cuff should be inflated to 30 mmHg above that level. Deflation should be at a rate of 2 to 3 mmHg. Systolic blood pressure is
determined at the point where the auscultatory pulsations (Korotkoff sounds) are first heard as the cuff deflates. The point at
which the auscultatory pulsations disappear represents the diastolic blood pressure.

Lifestyle Modifications
Lifestyle modifications are an important part of hypertension management. The JNC (Joint National Committee) (James et al,
2014) recommends the following changes to lifestyle for BP reduction, lowering and decreasing the cardiovascular risk:

Reduce weight (approximate reduction of 5-20 mmHg per 10 kg loss of weight)

Limit alcohol intake to 1 oz (30 mL) of ethanol per day for men and 0.5 oz (15 mL) of ethanol for women

Reduce sodium intake to less than 100 mmol/day (2.4 g sodium or 6 g sodium chloride; range of approximate BP
reduction is 2-8 mmHg)

Maintain an adequate amount of potassium intake (approximately 90 mmol/day)

Maintain an adequate amount of calcium and magnesium intake

Stop smoking and decrease the amount of dietary saturated fat and cholesterol (use of the DASH diet)

Aerobic exercise for least 30 minutes daily for most days of the week (approximate systolic blood pressure [SBP]
reduction of 4-9 mmHg)

Dietary Approaches to Stop Hypertension (DASH) is a balanced diet that has been shown to decrease blood pressure and is
recommended for all hypertensive patients. The DASH eating plan focuses on increasing the amount of vegetables, fruits,
and low-fat dairy products in food. It also includes whole grains, fish, poultry, beans, and seeds. Another important focus of
the DASH diet is to limit sodium, sweets, sugary beverages and red meat. The DASH diet is low in saturated and trans-fats. It
is also rich in electrolytes, including potassium, calcium, magnesium, fiber, and protein.

JNC 8 (Joint National Committee) Recommendations

Following are the new recommended changes in the most recent report of the JNC.

Blood pressure goals

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For patients more than 60 years of age, the goal BP is <150/90

For patients less than 60 years of age, the goal BP is <140/90

For hypertensive patients with diabetes and chronic kidney disease, the BP goal is <140/90

First-line medications

For most patients, including diabetic patients, the first line of antihypertensive agents include angiotensin-
converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), calcium channel blockers, and
thiazide diuretics

For African American patients, CCBs and thiazide diuretics should be included in the initial drug regimen

For patients with chronic kidney disease (CKD), ACE inhibitors or ARBs are used as first-line agents regardless of
race

Treatment Strategies

If blood pressure goals are not met in the first month of treatment, the doses should be increased, or a second drug from the
first-line agents should be added. If blood pressure goals are still not met, a third medication from the first line of
antihypertensive agents should be added and titrated. However, ACE inhibitors and ARBs should not be used together.

Second-line antihypertensive medications can be used in patients with uncontrolled blood pressure on 3
antihypertensive medications and those in whom there is a contraindication to the use of first-line antihypertensive
agents.

First-Line Antihypertensive Agents

Currently, there are 4 first-line antihypertensive agents. These include thiazide diuretics, ACE inhibitors, ARBs, and calcium
channel blockers.

Diuretics

There are 4 major categories of diuretics depending on where they affect the renal tubule. These include carbonic anhydrase
inhibitors, loop diuretics, thiazide diuretics, and potassium-sparing diuretics.

Thiazide Diuretics

Thiazide diuretics are the first-line treatment for hypertension, alone or in combination with other antihypertensive medications
(Table 13.6).

Table 13.6 Adverse effects of thiazide diuretics

Diuretic
Adverse effects
category
Electrolyte imbalances include hypokalemia, hyponatremia, and hypomagnesaemia, hypercalcemia
(thus their use in osteoporosis)

Thiazide Metabolic side effects of insulin resistance resulting in hyperglycemia and dyslipidemia at higher doses
diuretic
Hyperuricemia and precipitation of acute gout

Kidney stone formation, erectile dysfunction, renal cell carcinoma, and sulfa sensitivity

Mode of action: Thiazide diuretics inhibit the Na/Cl pump in the distal convoluted tubule, resulting in natriuresis. The
initial antihypertensive action is thus through increased sodium excretion, which is associated with a decrease in intra-
and extracellular volumes. Over days to weeks, the cardiac output normalizes and the extracellular fluid volume returns
to normal. Long-term antihypertensive properties of thiazide diuretics are secondary to decreased total peripheral
resistance and vasodilation.

Uses: Low-dose thiazide diuretics are most often used as first-line antihypertensive agents. These are cost effective,
efficacious, and have good additive antihypertensive action when combined with other agents, especially ACE inhibitors,
ARBs, and β-blockers. Generally, doses of 6.25 to 50 mg are used. Once a day dosing is available, which provides
antihypertensive coverage for 24 hours.

Other Diuretics

Loop diuretics act mainly on the Na-K-2Cl cotransporter in the thick ascending limb of the loop of Henle. They are most
commonly used in hypertensive patients when renal insufficiency is present as well as in those with congestive heart failure or
sodium retention.

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Potassium-sparing agents are used in combination with a thiazide diuretics. Eplerenone and spironolactone are aldosterone
antagonists. Spironolactone is effective in low-renin hypertension and primary aldosteronism as its mode of action makes it a
potent agent in these scenarios. It is effective in the prevention of fibrosis of myocardial tissue and has a mortality benefit in
heart failure patients.

Major side effects include gynecomastia, sexual side effects of impotency and menstrual irregularity as it binds to the
progesterone and androgen receptors. Triamterene and amiloride inhibit the sodium channels in the distal nephrons and
have a direct inhibitory action on the potassium secretion. These agents are weak antihypertensive agents but are effective in
preventing hypokalemia in patients using thiazide diuretics.

Calcium Channel Blockers

These are very effective antihypertensive agents and are among 1 of the 4 first-line therapies (Table 13.7). Major
classifications are dihydropyridines (DHPs) including amlodipine (long acting) and nifedipine (short acting), and non--
dihydropyridines (NDPPs) (including verapamil and diltiazem).

Table 13.7 Adverse effects of calcium channel blockers

Drug category Adverse effects
Headaches, flushing, dizziness, lightheadedness, and peripheral edema; caused by
vasodilation
Calcium channel
blockers Constipation

Edema (not relieved by the use of diuretics)

Mode of action: These agents block L-type voltage-gated calcium channels and thus decrease intracellular calcium.
The predominant site of this action depends on the drug category. Dihydropyridines (DHPs) act mainly on the peripheral
vasculature and cause vasodilation. There is no major direct action seen in the cardiac tissue with the non-
dihydropyridines. Non-dihydropyridines (have a major impact on cardiac automaticity, conduction, and contractility).

Uses: Calcium channel blockers (CCBs) generally work well in patients of all ages and races.

DHPs are used in patients with angina.

NDHPs are used in post-MI patients, patients with supraventricular tachycardia, and angina.

Calcium channel blockers can be used in the treatment of Reynaud phenomenon.

CCB use is safe in patients with COPD/asthma.

NDHPs decrease the cardiac contractility and slow down the conduction. These agents should be avoided with other nodal
blockers, such as β-blockers, patients with AV blocks, and sick sinus syndrome. They are safe to use as long-acting DHPs for
patients with heart failure; however, use of non-DHPs and short-acting DHPs should be avoided in these patients.

Angiotensin-Converting Enzyme Inhibitors

Also a first-line agent for the treatment of hypertension.

Mode of action: These block the angiotensin-converting enzyme that converts angiotensin 1 to angiotensin 2, thus
decreasing the production of angiotensin 2. As angiotensin 2 is an effective hormone that exerts its action on the AT1
receptor, its decreased production renders the renin-angiotensin-aldosterone mechanism inactive. These drugs also
increase the bradykinin levels as the ACE is needed to convert bradykinin to inactive metabolites. The increased
bradykinin levels also have vasodilatory effects. Another possible mechanism of antihypertensive action is their ability to
reduce sympathetic nervous system activity.

Uses: These agents are potent antihypertensive agents.

They are the mainstay of the combination therapies as they are well tolerated when used in combinations

Common indications are congestive heart failure (CHF) patients, post-MI patients, and patients with nephropathy

There is a significant mortality benefit when used in patients with CHF

Mortality benefits are observed when used in post-MI patients

They are the first-line treatment in patients with CKD

In diabetics, these agents decrease the progression of diabetic nephropathy

African Americans and elderly patients have lower levels of renin, therefore ACE inhibitors are not very effective in these
patient populations. These agents should not be used in renal failure, bilateral renal artery stenosis, pregnancy, and
hyperkalemia (Table 13.8).

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Table 13.8 Adverse effects of ACE inhibitors and ARBs
Drug category Adverse effects
Rash, taste alterations

Dry hacking cough occurs in almost 15% of patients

Angioedema occurs in <1% of patients

ACE inhibitors
Hyperkalemia

Renal insufficiency can occur in patients with renovascular hypertension

Contraindicated in pregnancy

Lower rates of cough and angioedema as compared to ACE inhibitors

ARBs
ARBs cause hypotension more frequently compared to ACE inhibitors

Angiotensin II Receptor Blockers

Mode of action: They act by competitively blocking the AT1 receptor of angiotensin II thus antagonizing all of its
functions, causing a drop in peripheral resistance.

Uses:

Same spectrum of indications as ACE inhibitors

Used in patients who are unable to tolerate ACE inhibitors due to cough

Angioedema incidence is also markedly reduced in patients on ARBs

These agents should not be used simultaneously with ACE inhibitors

Other Antihypertensive Medications

β-Blockers

β-blockers have been divided based on their cardioselectivity and intrinsic sympathomimetic activity. β-blocking agents differ
based on these properties; however, the antihypertensive action and control is the same (Table 13.9).

Table 13.9 Adverse effects of β-blockers

Drug
Adverse effects
category
Fatigue, somnolence, and sexual dysfunction

Bronchospasm and peripheral artery disease can worsen. Cardioselective β-blockers can be used in mild to
moderate reactive airway disease and COPD

Increase in insulin resistance and diabetes

β-Blockers Can mask the symptoms of hypoglycemia; and diabetic patients using these agents might not experience
the usual warning signs

Increased triglyceride levels and decreased HDL levels

Fetal abnormalities

Hypertensive crisis in patients with pheochromocytoma if used alone with α-adrenergic blockage

Mode of action: β-adrenergic receptor blockers decrease cardiac output by reducing both the heart rate and
contractility, thus lowering blood pressure. They are also known to decrease renin release and thus the renin-
angiotensin-aldosterone system has a decrease in activity as well. On initiation of therapy, the peripheral resistance
increases as there is unopposed α-adrenergic activity, but with time, the peripheral resistance returns to normal.

Uses:

Specific indications for the use of these agents include angina, CHF, post-MI patients, sinus tachycardia, and
ventricular tachyarrhythmia

There are mortality benefits in patients with CHF; combined α- and β-blocking agent carvedilol is the preferred
agent in this situation

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Contraindications to use include moderate to severe reactive airway disease, second- or third-degree heart blockage, and
sick sinus syndrome.

Cardioselective drugs are preferred in patients with reactive airway disease. β-blocking agent’s hypotensive potency is
enhanced by coadministration with diuretics.

Direct Vasodilators

Hydralazine is a commonly used vasodilator agent. Other agents include nitroprusside, nitroglycerine, and minoxidil (Table
13.10).

Table 13.10 Adverse effects of direct vasodilators

Drug category Adverse effects
Direct vasodilators
Hydralazine Lupus-like syndrome; dose-dependent; and reversible with the discontinuation of drug

Facial hirsutism
Minoxidil
Pericardial effusions

Hydralazine

Mode of action: It dilates the arterioles and can be used in the treatment of refractory or severe hypertension. A
decrease in total peripheral resistance is the mechanism of lowering blood pressure.

Uses: Generally, it is used in combination with diuretics and β-blockers to prevent a reflex increase in the blood
pressure secondary to increased sympathetic activity.

Minoxidil

Mode of action: Minoxidil causes the opening of potassium channels in vascular smooth muscle resulting in
vasodilation.

Uses: It has been found to be useful in patients with severe hypertension and renal failure. It is also used mostly in
combination with diuretics and β-blockers to prevent a reflex increase in sympathetic activity.

Sympatholytic Agents

Major drugs in this category include methyldopa and clonidine. They are useful in patients with autonomic neuropathy with
significant variations in blood pressure (Table 13.11).

Table 13.11 Adverse effects of sympatholytic agents

Drug category Adverse effects
Sympatholytics
Sedation, headaches, dry mouth

Methyldopa Hyperprolactinemia causing galactorrhea and impotence

Myocarditis, hemolytic anemia, and hepatitis are rare

Sedation, dry mouth, bradycardia, drowsiness, and headaches

Clonidine Rebound hypertension on discontinuation

Withdrawal symptoms include tachycardia, restlessness, and sweating

Methyldopa

Mode of action: Methyldopa stimulates the central α2-adrenergic receptors thus reducing sympathetic outflow from the
central nervous system (CNS). It results in a decrease in peripheral resistance.

Uses: Methyldopa has been used for the control of hypertension in pregnant patients.

Clonidine

Mode of action: Clonidine also stimulates the central α2-adrenergic receptors and has a similar mode of action to
methyldopa.

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α-Adrenergic Blockers

These agents are divided into selective and nonselective agents. Selective agents include prazosin, doxazosin, and terazosin.
Phenoxybenzamine is the major nonselective agent in this class of drugs (Table 13.12).

Table 13.12 Adverse effects of α-adrenergic blockers

Drug category Adverse effects
Palpitations, dizziness, headaches, drowsiness, and weakness

α-Adrenergic blockers Orthostatic hypotension and syncope especially after the first dose

Angina symptoms

Mode of action: Selective agents block the postsynaptic α-adrenergic receptors and decrease the blood pressure by
reducing the peripheral vascular resistance.

Uses: These agents are effective antihypertensive medications and can be used as single agents or in combination with
other drugs.

Preferred agents in patients with benign prostatic hypertrophy (BPH) as they treat both conditions

Preferred by physically active patients as they do not have any significant impact on cardiac output

Lack of insulin resistance and derangements of the lipid profile; there is no mortality benefit in patients with
coronary artery disease (CAD) and CHF

Nonselective α-adrenergic receptor antagonists bind to both postsynaptic and presynaptic receptors. Their major use is in the
management of pheochromocytoma.

Experimental Treatments for the Management of Resistant Hypertension

Experimental treatments are underway to treat resistant hypertension patients. Two modalities that have shown promise are
renal denervation and baroreflex activation therapy (BAT).

Renal Denervation

This therapy depends on catheter-based radiofrequency ablation of the renal sympathetic nerve. The effectiveness has not
clearly been established as different studies have shown variable results and further research is needed before it can become
a standard treatment. Because it is an invasive procedure, there are associated adverse effects involved and the benefits and
risks have to be weighed for such therapy.

Baroreflex Activation Therapy

This treatment is based on electrical activation of the carotid sinus baroreceptors. A device is surgically placed to stimulate
the carotid sinus baroreceptors. It is still experimental with ongoing studies for determining its efficacy. There are concerns for
possible side effects associated with this treatment with nerve injury being a major complication.

Key Points
Hypertension remains asymptomatic until it presents with one of the complications.

The mean arterial blood pressure is the product of cardiac output and total peripheral resistance.

The interplay between genetic and environmental factors have an important role in the pathogenesis of hypertension.

Primary hypertension is generally idiopathic and is the predominant form.

Secondary hypertension occurs in 5% of the patients with hypertension and is suspected in patients presenting before
30 years or after 55 years of age. Resistant hypertension also provides a clue to the presence of secondary
hypertension.

The heart, brain, kidneys, and peripheral arteries are the major targets damaged by uncontrolled hypertension.

Important lifestyle modifications that have been shown to improve blood pressure control include weight reduction, the
DASH diet, physical activity, limiting sodium intake, and smoking cessation.

The threshold for starting antihypertensive medications is persistently elevated systolic blood pressure of more than 140
mmHg in patients less than 60 years old and more than 150 mmHg in patients over 60 years old. For diastolic blood
pressure, the threshold is more than 90 mmHg.

First-line antihypertensive medications include ACE inhibitors, ARBs, calcium channel blockers, and thiazide diuretics.

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Second-line agents are added when there is uncontrolled hypertension on 3 first-line antihypertensive medications or
there are contraindications for the use of the first-line medications.

Particular situations warrant the use of specific antihypertensive medications. An example is the use of α-adrenergic
blockers in hypertensive patients with BPH.

Case Studies
CASE 13.1 A 41-year-old female presents to the emergency room with headaches, profuse sweating, and palpitations. Her
past medical history is positive for rheumatoid arthritis. Current medications include oral contraceptive pills and intermittent
use of nonsteroidal anti-inflammatory drugs (NSAIDs). On examination, the patient is profusely sweating and is tremulous.
Vital signs include heart rate of 115, blood pressure of 195/105, respiratory rate of 17, and oxygen saturation of 98%, with a
temperature of 37.7°C. Her body mass index (BMI) is 24.

1. Based on the history and physical examination, what is the most likely diagnosis in this patient?

a. Essential hypertension

b. Pheochromocytoma

c. Cushing disease

d. Primary hyperaldosteronism

e. Migraine headaches

The correct answer is b.

Symptoms of headaches, profuse sweating, and palpitations in association with elevated blood pressure which rises
episodically are indicative of pheochromocytoma. Other typical features and associations are discussed in the chapter.

2. What is the best initial test for diagnosing this patient?

a. 24-hour urine metanephrine and catecholamine levels

b. Plasma metanephrine level

c. CT scan to look for tumor

d. ACTH stimulation test

The correct answer is a.

3. On further investigation, a CT scan shows a pheochromocytoma in the right adrenal gland for which a surgical resection is
planned. Which of the following blood pressure medications is contraindicated in this patient as the initial therapy during the
preoperative period?

a. Labetalol

b. Propranolol

c. Phenoxybenzamine

d. Lisinopril

The correct answer is b.

Use of b-blockers without the concurrent use of a-blockers can cause unopposed stimulation of a receptors resulting in
extremely high blood pressure. Thus, b-blockers should not be used alone in the treatment of pheochromocytoma.

CASE 13.2 A 31-year-old man presents with headaches, generalized weakness, and high blood pressure of 165/90. No other
physical exam findings are significant and he has otherwise normal vitals. Lab data show a potassium level of 2.9 and sodium
level of 151. The patient does not have a family history of hypertension and has a BMI of 22. Which of the following is the
most likely cause of the patient’s hypertension?

a. Essential hypertension

b. Pheochromocytoma

c. Primary hyperaldosteronism

d. Fibromuscular dysplasia

e. Coarctation of aorta

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The correct answer is c.

Typical presentation of primary hyperaldosteronism is a patient coming in with elevated blood pressure, refractory to
treatment, and on lab workup there is a demonstration of hypokalemia. Weakness is not usually associated with this condition
unless hypokalemia becomes profound. Another feature of hyperaldosteronism can be increased blood sodium levels which
is present in this patient. These lab abnormalities are not typical features of the other conditions given in the options.

Suggested Readings
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Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation and treatment of High Blood
Pressure. Hypertension. 2003;42:1206–1252. [PubMed: 14656957]
Egan BM, Zhao Y, Axon RN. US trends in prevalence, awareness, treatment, and control of hypertension, 1988-2008.
JAMA. 2010;303:2043. [PubMed: 20501926]
[JAMA and JAMA Network Journals Full Text]
Gillespie C, Hurvitz K. CDC, MMWR 2013; 62(03);144–148.
Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics-2013 update: a report from the American Heart
Association. Circulation. 20l3;127.e6–245.
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 Eighth Joint National Committee (JNC 8). JAMA. 2014;311(5):507–520.
[PubMed: 24352797]
[JAMA and JAMA Network Journals Full Text]
Kearney PM, Whelton M, Reynolds K, et al. Global burden of hypertension: analysis of worldwide data. Lancet.
2005;365:217. [PubMed: 15652604]
Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J. Harrison’s Principles of Internal Medicine. 18th ed.
New York: McGraw-Hill; 2011.
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Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European
Society of Cardiology (ESC). J Hypertens. 2013;31(7):1281–1357. [PubMed: 23817082]
Textor SC, Lerman L. Renovascular hypertension and ischemic nephropathy. Am J Hypertens. 2010;23:1159. [PubMed:
20864945]
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