Goldman: Cecil Textbook of Medicine, 22nd ed., Copyright © 2004 W. B. Saunders Company


Ronald Victor

In populations, blood pressures fit a normal distribution, but the attendant risks of heart disease and stroke increase curvilinearly with increasing levels of blood pressure, without any obvious breakpoint ( Fig. 63-1 ). Thus, the separation of normal from high blood pressure is arbitrary, and the definition of hypertension has been a moving target. The first estimate was that systolic blood pressure should be 100 plus a person’s age and that only higher values needed to be treated. This formula was predicated on the incorrect notion that the progressive increase in blood pressure with advancing age is essential to maintain blood flow through atherosclerotic arteries, hence the term essential hypertension. Later, hypertension in adults was redefined as a blood pressure of 160/95 mm Hg or greater, regardless of age, because this is the value above which the risk of stroke or myocardial infarction roughly doubles compared with the risk associated with pressures below 120/80 mm Hg. Now, however, based on the results of randomized clinical drug trials, hypertension is defined as a blood pressure of 140/90 mm Hg or greater because this is the

Figure 63-1 Adjusted relative risk of cardiovascular mortality by systolic blood pressure (BP) levels in men screened for the Multiple Risk Factor Intervention Trial (MRFIT). (From the National High Blood Pressure Education Program Working Group. Arch Intern Med 1993;153:186–208.)


Figure 63-2 Percentage of hypertensive patients whose blood pressures are both treated and controlled to either less than 140/90 mm Hg or less than 160/95 mm Hg in different countries. (From Laragh J: Laragh’s lessons in pathophysiology and clinical pearls for treating hypertension. Am J Hypertens 2001;14:84–86. Redrawn with permission from Mancia G, Grassi G: Rationale for the use of a fixed dose combination in the treatment of hypertension. Eur Heart J 1999;1 [suppl L]:L14–L19.)
value above which the benefits of treatment appear to outweigh the risks. Prehypertension is now defined as a blood pressure of 130–139/80–89 mm Hg. Individuals with blood pressure in this range are twice as likely to progress to hypertension compared with individuals with lower blood pressures.
Affecting one fourth of the adult population (50 million in the United States and 1 billion people worldwide), arterial hypertension is the most common cause for a visit to a physician and the most widely recognized treatable risk factor for stroke ( Chapter 439 and Chapter 440 ), myocardial infarction ( Chapter 68 and Chapter 69 ), heart failure ( Chapter 55 and Chapter 56 ), peripheral vascular disease ( Chapter 78 ), aortic dissection ( Chapter 75 ), and chronic renal failure ( Chapter 117 ). Despite this knowledge and unequivocal scientific proof that treating hypertension dramatically reduces its attendant morbidity and mortality, hypertension remains untreated or poorly treated in the majority of affected individuals in all countries, including those with the most advanced health care ( Fig. 63-2 ). Inadequate treatment of hypertension is a major factor contributing to some of the adverse secular trends in the last decade, including an increased incidence of stroke, heart failure, and renal failure plus a leveling off of the decline in coronary heart disease mortality.
Patients often ask what is more important: systolic or diastolic blood pressure? The answer depends on the age of the patient. In industrialized societies, systolic pressure rises progressively with age; if individuals live long enough, almost all develop systolic hypertension. This age-dependent rise in blood pressure is not an essential part of human biology, because in less industrialized societies, where the consumption of calories and salt is low, blood pressures remain low and do not rise with age. In industrialized societies, diastolic pressure rises until age 50 and decreases thereafter, producing a dramatic rise in pulse pressure (systolic pressure minus diastolic pressure) ( Fig. 63-3 ).
Different hemodynamic faults underlie hypertension in younger and older individuals. The minority of patients who develop hypertension before the age of 50 typically have combined systolic and diastolic hypertension: systolic pressure greater than 140 mm Hg and diastolic pressure greater than 90 mm Hg. The risks of coronary heart disease and stroke increase curvilinearly with either systolic or diastolic blood pressure. The main hemodynamic fault is vasoconstriction at the level of the resistance arterioles. In contrast, the majority of patients who develop hypertension after the age of 50 have isolated systolic hypertension: systolic pressure greater than 140 mm Hg but diastolic pressure less than 90 mm Hg. In these older patients, cardiovascular risk increases curvilinearly with increasing systolic pressure but is inversely related to diastolic pressure. A blood pressure of 170/70 mm Hg carries twice the risk of coronary heart disease as a blood pressure of 170/110 mm Hg! (see Fig. 63-4 .)
In isolated systolic hypertension, the main hemodynamic fault is decreased distensibility of the large conduit arteries. This problem is

Figure 63-3 Age-dependent changes in systolic and diastolic blood pressure in the United States. (From Burt V, Whelton P, Rocella EJ, et al: Prevalence of hypertension in the U.S. adult population. Results from the Third National Health and Nutrition Examination Survey, 1988–1991. Hypertension 1995;25:305–313.)
caused by the replacement of elastin by collagen and fibrous tissue in the elastic lamina of the aorta, an age-dependent process that is accelerated by atherosclerosis and hypertension. The cardiovascular risk associated with isolated systolic hypertension is related to pulsatility, the repetitive pounding of the blood vessels with each cardiac cycle and a more rapid return of the arterial pulse wave from the periphery, both begetting more systolic hypertension. The importance of these findings for patients and physicians is that the prior clinical emphasis on diastolic blood pressure was misplaced. In the United States, the majority of uncontrolled hypertension occurs in older patients with isolated systolic hypertension, a problem perpetuated by a persistent focus on lowering diastolic blood pressure, a fear of lowering blood pressure excessively in older patients, and an inherently greater difficulty in achieving systolic blood pressure goals with available medications.
Before age 50, the prevalence of hypertension is lower in women than in men, suggesting a protective effect of estrogen. After menopause, the prevalence of hypertension increases rapidly in women and exceeds that in men.
Within the United States, the prevalence of hypertension varies widely by ethnicity, being most prevalent in African Americans. Hypertension is present in one in three African American adults compared with one in four or five white or Mexican American adults. Compared with all other ethnic groups, hypertension in African Americans is not only more prevalent but also starts at a younger age and causes much more target organ damage, leading to excessive and premature disability and death. In the Bogalusa Heart Study, higher blood pressures in black than in white children were already evident


Figure 63-4 Joint influences of systolic blood pressure (SBP) and diastolic blood pressure on coronary heart disease (CHD) risk in the Framingham cohort of people 50 to 79 years of age (A). At levels of SBP between 110 and 170 mm Hg, CHD risk was found to be inversely related to diastolic blood pressure. Joint influences of SBP and pulse pressure (B). At levels of SBP between 110 and 170 mm Hg, CHD risk increases with increasing pulse pressure (PP). (From Franklin S, Khan SA, Wong DH, Larson MG, Levy D. Is pulse pressure useful in predicting risk for coronary heart disease? Circulation 1999;100:354–360.)
by grade school. Gene-environment interactions have been postulated, as the prevalence of hypertension is low in Africans living in Africa and intermediate in African-Caribbeans.
Mechanisms of Hypertension
In 95% of hypertensive patients in general practice, a single reversible cause of the elevated blood pressure cannot be identified, hence the term primary hypertension. However, in most patients with primary hypertension, readily identifiable behaviors—habitually excessive consumption of calories, salt, or alcohol—contribute importantly to the elevated blood pressure. In the remaining 5%, a more discrete mechanism can be identified, and the condition is termed secondary hypertension. At the organ-system level, hypertension can result from a gain in function of pathways that promote vasoconstriction and renal retention of salt and water and/or a loss in function of pathways that promote vasodilatation and renal excretion of salt and water.
The most important behavioral determinants of blood pressure are related to dietary consumption of calories and salt. In all populations studied, the prevalence of hypertension increases linearly with body mass index. With the rapidly growing incidence of obesity in industrialized societies, reaching epidemic proportions in the United States, increasing attention is being paid to the metabolic syndrome that often accompanies hypertension. The metabolic syndrome refers to the frequent clustering of hypertension with abdominal (“male-pattern”) adiposity, insulin resistance, and a dyslipidemic pattern consisting typically of elevated plasma triglyceride and low high-density lipoprotein (HDL) cholesterol levels. Although the causal links remain to be elucidated, this constellation of metabolic abnormalities dramatically increases cardiovascular risk. In the Framingham Heart Study, obesity has been estimated to account for 50 to 60% of the new cases of hypertension. The underlying mechanisms by which weight gain leads to hypertension are incompletely understood, but there is mounting evidence for an expanded plasma volume plus sympathetic overactivity. The latter is thought to be a compensatory attempt to burn fat but at the expense of peripheral vasoconstriction, renal salt and water retention, and hypertension. In some obese individuals, sleep apnea ( Chapter 96 ) is an important cause of hypertension. Repeated arterial desaturation sensitizes the carotid body chemoreceptors, causing sustained sympathetic overactivity.
Dietary sodium intake is another key behavioral determinant of human hypertension. The epidemiologic, clinical, and experimental support for this association is strong. In the Intersalt Study of 52 locations around the world, the risk of developing hypertension over three decades of adult life was linearly and very tightly related to dietary sodium intake. Dietary sodium reduction and diuretics have proved to be effective treatments for primary hypertension. However, both normotensive and hypertensive persons show tremendous interindividual variability in their blood pressure responses to dietary sodium loading and sodium restriction. This variability, which has led to some questioning about the “salt hypothesis,” indicates a strong genetic underpinning.
The familial aggregation of hypertension documents an important genetic component. Concordance of blood pressures is greater within families than in unrelated individuals, greater between monozygotic than between dizygotic twins, and greater between biological than between adoptive siblings living in the same household. About 70% of the familial aggregation of blood pressure is attributed to shared genes rather than shared environment. Thus, hypertension can be viewed as a maladaptative interplay between the human genome and modern society. However, very little is known about the genetic determinants of blood pressure variation in the general population. The number of sequence variations, the specific loci, and their individual and combined effects remain conjectural.
In contrast, dazzling genetic research has elucidated the molecular mechanisms by which rare forms of human hypertension and hypotension are inherited as Mendelian traits. Mutations have been identified in eight genes that cause Mendelian forms of hypertension and in nine genes that cause Mendelian forms of hypotension. In every case, the mechanism involves the renal handling of salt and water and emphasizes the pivotal importance of the renin-angiotensin-aldosterone system in human blood pressure regulation. The Mendelian forms of hypertension altogether are responsible for a very small portion of the 50 million cases of hypertension in the United States. The Mendelian hypotensive and hypertensive traits represent the extremes of human blood pressure variation, and the key question is whether milder mutations in any of these 17 genes, alone or in combination, confer resistance against or sensitivity to the hypertensive effects of the common environmental exposures in the general population.
Clinical Manifestations
Hypertension has been termed the “silent killer,” a chronic illness with a long asymptomatic phase that, if undetected and untreated, silently damages the heart, brain, and kidneys. Although headaches are common in patients with mild-to-moderate hypertension ( Chapter 428 ), episodes of headaches do not correlate with fluctuations in ambulatory blood pressure but rather with a person’s awareness of his or her diagnosis.
Initial Evaluation for Hypertension
The initial evaluation for hypertension should focus on three goals: (1) staging of the blood pressure, (2) assessment of the patient’s overall cardiovascular risk, and (3) detection of clues indicating potential identifiable causes of hypertension that require further evaluation. The initial clinical data needed to accomplish these goals are obtained

through a thorough history and physical examination, routine blood and urine tests, and a resting 12-lead electrocardiogram. In some patients, ambulatory blood pressure monitoring and an echocardiogram provide helpful additional data about the time-integral burden of blood pressure on the cardiovascular system.
Because blood pressure normally varies dramatically throughout a 24-hour period, multiple readings on more than one occasion are required to obtain a clear picture of a person’s “usual” blood pressure. For this reason, hypertension should never be diagnosed on the basis of a single elevated reading.
To minimize variability in readings, blood pressure should be measured at least twice after 5 minutes of rest with the patient seated, the back supported, and the arm at heart level. The cuff should not be too small for the arm, and tobacco and caffeine should be avoided for at least 30 minutes. Most overweight adults require a large-adult cuff. To avoid underestimation of systolic pressure in older persons who may have an auscultatory gap, radial artery palpation should be performed to estimate systolic pressure; then the cuff should be inflated to a value 20 mm Hg higher than the level that obliterates the radial pulse and deflated at a rate of 3 to 5 mm Hg/sec. Blood pressure should be measured in both arms and after 5 minutes of standing, the latter to exclude a significant postural fall in blood pressure, particularly in older persons and in those with diabetes or other conditions (e.g., Parkinson’s disease) that predispose to autonomic insufficiency.
Blood pressure is staged as normal, prehypertension, or hypertension based on the average of two or more readings taken at two or more office visits. When a person’s systolic and diastolic pressures fall into different stages, the higher stage should apply ( Table 63-1 ).

Stage 1 Hypertension
Stage 2 Hypertension
From Chobanian A, et al: The Seventh Report of the Joint National Committee on the Prevention, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report. JAMA 2003;289:2560–2572.

Figure 63-5 Twenty-four-hour ambulatory blood pressure (BP) monitor tracings in two different patients. A, Optimal blood pressure in a healthy 37-year-old woman. Note the normal variability in blood pressure, the nocturnal dip in blood pressure during sleep, and the sharp increase in blood pressure on awakening. (Tracing courtesy of Meryem Tuncel, MD, Hypertension Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.) B, Pronounced white coat effect in an 80-year-old woman referred for evaluation of medically refractory hypertension. Documentation of the white coat effect prevented overtreatment of the patient’s isolated systolic hypertension. (Tracing provided by Wanpen Vongpatanasin, MD, Hypertension Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.)
The designation of prehypertension has been added to reflect the increased risk of progression to hypertension associated with blood pressures in the 130–139/80–89 mm Hg range. The time interval for recommended followup depends on the degree of blood pressure elevation recorded at the initial examination. Patients with prehypertension should be followed at least annually, patients with stage 1 hypertension should be examined in two months, and patients with stage 2 hypertension should be seen in one month or sooner depending on the patient’s overall clinical condition.
Due to the anxiety of going to the physician, blood pressures often are higher in the physician’s office than when measured at home. Self-monitoring of blood pressure at home actively engages a patient in his or her own health care and provides a better estimate of a person’s usual blood pressure for diagnostic and therapeutic purposes. However, the devices need to be checked for accuracy in the office. Patients should be instructed to record their pressures both when relaxed and when stressed; even then, record-keeping may not be accurate.
Ambulatory blood pressure monitoring provides the best measure of the time-integral blood pressure burden on the cardiovascular system. As such, ambulatory blood pressures correlate better than office readings with target organ damage such as left ventricular hypertrophy (LVH). Recommended standards for normal ambulatory blood pressure values currently include daytime blood pressure less than 135/85 mm Hg, nighttime blood pressure less than 120/70 mm Hg, and 24-hour blood pressure less than 130/80 mm Hg.
Up to 30% of patients with elevated office blood pressures have normal home blood pressures. If the daytime ambulatory blood pressure is completely normal despite consistently elevated office readings, the patient has “office only,” or “white coat,” hypertension, presumably owing to an excessive adrenergic response to the measurement of blood pressure in the physician’s office. In such individuals with rigorously defined white coat hypertension, the 5-year mortality rate was found in one study to be indistinguishable from that for those with normal office blood pressures. However, cross-sectional data suggest that white coat hypertension may not be so benign. For example, echocardiographic left ventricular mass is higher in patients with white coat hypertension than in patients with normal office blood pressures but not as high as in patients with persistent hypertension. For now, patients with white coat hypertension should be followed every 6 months for possible progression to persistent hypertension.
In up to 30% of treated patients with persistently elevated office blood pressures, ambulatory monitoring documents adequate or excessive control of their hypertension, eliminating overtreatment. In other patients, office blood pressures underestimate ambulatory blood pressures, presumably because of sympathetic overactivity in daily life owing to job or home stress, tobacco abuse, or other adrenergic stimulants that are discontinued before coming to the office. Such documentation prevents undertreatment of this masked hypertension.


• Evaluate suspected “white coat hypertension”*
• Exclude a “white coat” effect in a patient with medically refractory hypertension
• Prevent overtreatment of hypertension in older patients
• Evaluate suspected white coat normotension or nocturnal hypertension
• Evaluate efficacy of drug treatment over entire 24-hr period
• Aid in the diagnosis and treatment of hypotension (drug induced or due to autonomic failure)
Modified from O’Brien E, Coats A, Owens P, et al: Use and interpretation of ambulatory blood pressure monitoring: Recommendations of the British Hypertension Society. BMJ 2000;320:1128–1134.

*Currently in the U.S., Medicare reimburses for ambulatory monitoring only to confirm the diagnosis of white coat hypertension that is suspected on the basis of three normal home readings in patients with no evidence of target organ damage despite elevated office blood pressure readings.

Blood pressure normally dips during sleep at night and increases sharply when a person awakens and becomes active in the morning ( Fig. 63-5 ). Persistent nocturnal hypertension increases the aggregate blood pressure burden on the cardiovascular system and increases the risk of target organ disease. The morning surge in blood pressure is strongly associated with the peak incidence of stroke, myocardial infarction, and sudden cardiac death. Thus, in high-risk individuals, medications ideally should be finely tuned to optimize the 24-hour blood pressure profile ( Table 63-2 ).
It is important to emphasize that blood pressure is only one component of cardiovascular risk, and the approach to the hypertensive patient should be highly individualized based on a thorough assessment of the person’s overall cardiovascular risk. The additive effects of multiple risk factors on atherosclerosis have been firmly established both in autopsy studies that directly measured subclinical atherosclerotic burden in young adults and in numerous longitudinal studies that evaluated clinical cardiovascular outcomes. There are three broad components to cardiovascular risk: (1) blood pressure level, (2) comorbidity, and (3) target organ damage ( Table 63-3 and Fig. 63-6 ).
The low-risk group (mild risk) includes individuals who are free of clinical cardiovascular disease, target organ damage, or other associated risk factors. Only 2% of hypertensive patients fall into this low-risk category. Low-risk individuals with prehypertension or stage 1 hypertension may be treated with lifestyle modifications alone for up to 12 months. If blood pressure does not fall to the goal, lifestyle modifications should be supplemented, not replaced, by medications. For

Cigarette smoking
Obesity* (BMI >30 kg/m2 )
Left ventricular hypertrophy
Physical inactivity
Angina pectoris
Myocardial infarction
Diabetes mellitus*
Coronary revascularization
Heart failure
Old than 55 for men
Old than 65 for women
Family history of premature CVD
Transient ischemic attack
Men under age 55
Hypertensive nephrosclerosis
Women under age 65
GFR <60 mL/min
Any chronic kidney disease
Urine protein >150 mg/24 hr
GFR <60 mL/min
Urine protein >150 mg/24rhr
Peripheral atherosclerosis
GFR = glomerular filtration rate.
Modified from Chobanian A, et al: The Seventh Report of the Joint National Committee on the Prevention, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report. JAMA 2003;289:2560–2572.

*Components of metabolic syndrome.

Figure 63-6 Hypertensive retinopathy is traditionally divided into four grades. A, Grade 1 shows very early and minor changes in a young patient: increased tortuosity of a retinal vessel and increased reflectiveness (silver wiring) of a retinal artery are seen at 1 o’clock in this view. Otherwise, the fundus is completely normal. B, Grade 2 also shows increased tortuosity and silver wiring (arrowheads). In addition, there is “nipping” of the venules at arteriovenous crossings (arrow). C, Grade 3 shows the same changes as grade 2 plus flame-shaped retinal hemorrhages and soft “cotton wool” exudates. D, In grade 4, there is swelling of the optic disc (papilledema), retinal edema is present, and hard exudates may collect around the fovea, producing a typical “macular star.” (From Forbes CD, Jackson WF: Color Atlas and Text of Clinical Medicine, 3rd ed. London, Mosby, 2003, with permission.)
low-risk patients with stage 2 hypertension, medications should be initiated without delay.
Moderate-risk patients, who represent by far the largest number of hypertensive patients (60%), include those who have one or more of the major cardiovascular risk factors (e.g., hyperlipidemia, smoking) other than diabetes but do not yet have target organ damage or clinical cardiovascular disease. Lifestyle modifications and medications should be started concomitantly.
High-risk patients are individuals with elevated blood pressure (hypertension or prehypertension) in the presence of clinically evident cardiovascular disease or target organ damage. All patients with diabetes or renal insufficiency are also defined as high risk. More than one third of hypertensive individuals fall into this high-risk category. Medications and lifestyle modifications should be initiated immediately in high-risk patients, even individuals with high-normal blood pressures.
To reduce overall cardiovascular risk in moderate- and high-risk patients, low-dose aspirin (81 mg) ( Chapter 33 ) and lipid-lowering therapy ( Chapter 211 ) should be considered, when appropriate, along with antihypertensive therapy and lifestyle modifications. In treated hypertensive patients, low-dose aspirin has been shown to reduce the risk of myocardial infarction by 36% without increasing the risk of intracerebral hemorrhage.
A thorough search for secondary causes is not cost-effective in most patients with hypertension but becomes critically important in two circumstances: (1) when there is a compelling finding on the initial evaluation, or (2) when the hypertensive process is so severe


Renal parenchymal hypertension
Elevated serum creatinine or abnormal urinalysis
24-Hour urine creatinine and protein, renal ultrasound
Renovascular disease
New elevation in serum creatinine, marked elevation in serum creatinine with initiation of ACEI or ARB, refractory hypertension, flash pulmonary edema, abdominal bruit
Captopril renogram, duplex Doppler sonography, magnetic resonance or CT angiogram, invasive angiogram
Coarctation of the aorta
Arm pulses > leg pulses, arm BP > leg BP, chest bruits, rib notching on chest radiograph
MRI, aortogram
Primary aldosteronism
Hypokalemia, refractory hypertension
Plasma renin and aldosterone, 24-hour urine potassium, 24-hour urine aldosterone and potassium after salt loading, adrenal CT scan
Cushing’s syndrome
Truncal obesity, purple striae, muscle weakness
Plasma cortisol, urine cortisol after dexamethasone, adrenal CT scan
Spells of tachycardia, headache, diaphoresis, pallor, and anxiety
Plasma metanephrine and normetanephrine, 24-hour urine catechols, adrenal CT scan
Obstructive sleep apnea
Loud snoring, daytime somnolence, obesity
Sleep study
ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; BP = blood pressure; CT = computed tomography.
Modified from Kaplan NM: Clinical Hypertension, 8th ed. Philadelphia, Williams & Wilkins, 2002.

that it either is refractory to intensive multiple drug therapy or requires hospitalization. Table 63-4 summarizes the major causes of secondary hypertension that should be suspected on the basis of a good history, physical, and routine laboratory tests.
Chronic renal failure is the most common cause of secondary hypertension ( Chapter 117 ). Hypertension is present in more than 80% of patients with chronic renal failure and is a major factor causing their increased cardiovascular morbidity and mortality. The mechanisms causing the hypertension include an expanded plasma volume and peripheral vasoconstriction, with the latter caused by both activation of vasoconstrictor pathways (renin-angiotensin and sympathetic nervous systems) and inhibition of vasodilator pathways (nitric oxide). Renal insufficiency should be considered when there is proteinuria by dipstick or when the serum creatinine level is greater than 1.2 mg/dL in hypertensive women or greater than 1.4 mg/dL in hypertensive men. The diagnosis is confirmed either by a 24-hour urine collection showing a creatinine clearance of <60 mL/min or a total protein excretion of >150 mg or by a spot urine specimen showing microalbuminuria defined as a urine albumin-to-urine creatinine ratio between 30 and 300 mg/g. In patients with mild or moderate renal insufficiency, stringent blood pressure control is imperative to slow the progression to end-stage renal disease and reduce the excessive cardiovascular risk. Specific treatment recommendations are addressed later. In patients with far-advanced renal insufficiency, hypertension often becomes difficult to treat and may require either (1) intensive medical treatment with loop diuretics, potent vasodilators (e.g., minoxidil 2.5 to 100 mg daily), ß-adrenergic blockers, and central sympatholytics or (2) initiation of chronic hemodialysis as the only effective way to reduce plasma volume. In chronic hemodialysis patients, the challenge is to control interdialytic hypertension intensively without exacerbating dialysis-induced hypotension. The gross annual mortality rate in the hemodialysis population is 25%, with half of this excessive mortality being caused by cardiovascular events that are related, at least in part, to suboptimal control of hypertension.
Unilateral or bilateral renal artery stenosis is present in less than 2% of hypertensive patients in a general medical practice but up to 30% in patients referred to a hypertension specialist for refractory hypertension. The main causes of renal artery stenosis are atherosclerosis (90% of cases), typically in older persons with other manifestations of atherosclerosis, and fibromuscular dysplasia (10% of cases), typically in women between the ages of 15 and 50 ( Chapter 124 ). Unilateral renal artery stenosis leads to underperfusion of the juxtaglomerular cells, thereby producing renin-dependent hypertension even though the contralateral kidney is able to maintain normal blood volume. In contrast, bilateral renal artery stenosis (or unilateral stenosis with a solitary kidney) constitutes a potentially reversible cause of progressive renal failure and volume-dependent hypertension. The following clinical clues increase the suspicion of renovascular hypertension: any hospitalization for urgent or emergent hypertension, recurrent “flash” pulmonary edema, refractory hypertension, severe hypertension in a young adult or after the age of 50, precipitous and progressive worsening of renal function in response to angiotensin-converting enzyme (ACE) inhibition, unilateral small kidney by any radiographic study, extensive peripheral arteriosclerosis, or a flank bruit.
The evaluation and treatment of fibromuscular dysplasia in a young women with recent-onset hypertension are straightforward. The diagnosis usually is readily supported by noninvasive testing with captopril renography, duplex Doppler ultrasonography, or magnetic resonance (MR) or spiral computed tomography (CT) angiography, the latter imaging studies showing the classic “string-of-beads” appearance of a renal artery ( Chapter 124 ). Once the diagnosis is confirmed with invasive angiography, balloon angioplasty is the treatment of choice, with complete cure of hypertension in 40% of patients, improved blood pressure control in almost all patients, and restenosis rates of about 10%. Medical therapy with an ACE inhibitor also may be effective, but the risks of teratogenicity must be considered in women of childbearing age.
In contrast, the approach to the older patient with generalized atherosclerosis and renal artery stenosis ( Fig. 63-7 ) is not straightforward and must be highly individualized. Primary and renovascular hypertension frequently coexist in older persons, and renal artery stenosis can be present without being an important cause of the hypertension. For this reason, revascularization leads to clinical

Figure 63-7 Computed tomography angiogram with three-dimensional reconstruction, showing a severe proximal stenosis of the right renal artery and mild stenosis of the left renal artery. (Image courtesy of Bart Domatch, MD, Radiology Department, University of Texas Southwestern Medical Center, Dallas, Texas.)

improvement in hypertension in less than 30% of patients, and complete cures are rare.
With current surgical procedures, the perioperative mortality rate is 2 to 6%, late graft failure requiring a second procedure occurs in 5 to 15% of patients, and the 5-year survival rate is 65 to 81%. Randomized trials show a small but probably real benefit of balloon angioplasty. Nevertheless, in this group of patients, the first line of therapy should be intensive medical treatment of hypertension and associated cardiovascular risk factors, with concomitant lipid lowering, smoking cessation, and aspirin. Surgical revascularization or stenting should be considered for the following indications: (1) medically refractory or accelerating hypertension, (2) progressive renal failure on medical therapy, and (3) bilateral renal artery stenosis.
The most common causes of primary aldosteronism ( Chapter 240 ) are (1) a unilateral aldosterone-producing adenoma in two thirds of cases and (2) bilateral adrenal hyperplasia in one third. Because aldosterone is the principal ligand for the mineralocorticoid receptor in the distal nephron, excessive aldosterone production causes excessive renal Na+ -K+ exchange, resulting in hypokalemia. The initial clue to the diagnosis is either unprovoked hypokalemia (serum K+ <3.5 mmol/L in the absence of diuretic therapy) or a tendency to develop excessive hypokalemia during diuretic therapy (serum K+ <3.0 mmol/L) in a patient with hypertension. However, up to one third of patients do not have hypokalemia on initial presentation, and the diagnosis should be considered in any patient with severe refractory hypertension.
Mendelian Forms of Mineralocorticoid-Induced Hypertension.
Almost all of the mendelian forms of hypertension, although rare, are mineralocorticoid induced and involve excessive activation of the epithelial sodium channel (ENaC), the final common pathway for reabsorption of sodium from the distal nephron ( Fig. 63-8 ). Thus, salt-dependent hypertension can be caused both by gain-of-function mutations of ENaC or the mineralocorticoid receptor and by increased production or decreased clearance of mineralocorticoid receptor ligands, which are aldosterone, deoxycorticosterone, or cortisol.
Glucocorticoid-Remediable Aldosteronism (GRA).
Fewer than 100 cases of GRA have been reported, but many additional cases likely go undetected or misdiagnosed as bilateral adrenal hyperplasia. Inherited as

Figure 63-8 Mendelian forms of hypertension that cause mineralocorticoid-induced hypertension. Aldo S = aldosterone synthase; AME = apparent mineralocorticoid excess; GRA = glucocorticoid-remediable aldosteronism; 11ß-HSD2 = 11ß-hydroxy steroid dehydrogenase type 2; DOC = deoxycorticosterone; ENaC = epithelial sodium channel; HTN = hypertension; MR = mineralocorticoid receptor. See text for explanation. (Adapted from Lifton RP, Gharavi AG, Geller DS: Molecular mechanisms of human hypertension. Cell 2001;104:545–556.)
an autosomal dominant mutation, GRA mimics an aldosterone-producing adenoma by causing severe mineralocorticoid-induced hypertension with hypokalemia, elevated plasma aldosterone, and suppressed plasma renin activity (PRA). In the normal adrenal gland, angiotensin II (Ang II) acts on the enzyme aldosterone synthase in the zona glomerulosa to drive production of aldosterone, whereas ACTH causes transcriptional activation of the enzyme 11-ß-hydroxylase in the zona fasciculata to drive production of cortisol. GRA is caused by a gene duplication arising by unequal crossing over between the genes encoding aldosterone synthase and 11-ß-hydroxylase. The resulting chimeric gene encodes a hybrid protein that has aldosterone synthase activity, is expressed “ectopically” in the zona fasciculata, and is regulated entirely by ACTH rather than by Ang II. Thus, aldosterone production becomes inappropriately linked to cortisol production. In the attempt to maintain the appropriate production of normal cortisol, aldosterone is constantly produced, resulting in volume-dependent hypertension. Although the expanded plasma volume suppresses PRA, the reduced Ang II cannot downregulate aldosterone production. The clinical clue to the diagnosis is that the hypertension is familial and discovered before age 20. In contrast, primary aldosteronism is sporadic and usually discovered between ages 30 and 60. The diagnosis of GRA is confirmed by Southern blot analysis for the chimeric gene, a test available at no cost through the International Registry for GRA (www.bwh.partners.org/gra/clinhx.htm). By suppressing ACTH, and thus aldosterone secretion from the zona fasciculata, low-dose dexamethasone completely reverses the biochemical abnormalities in GRA and is the recommended antihypertensive therapy.
The rare but distinctive hypertensive syndromes caused by deoxycorticosterone include those due to congenital deficiency of either 11ß-hydroxylase or 17a-hydroxylase. In both cases, decreased production of cortisol decreases feedback inhibition on ACTH, which drives overproduction of deoxycorticosterone (a potent mineralocorticoid). These patients typically present to the pediatrician with hypertension plus abnormal sexual development.
Although cortisol is a glucocorticoid, surprisingly it is equipotent to aldosterone in activating the mineralocorticoid receptor. As a result, both excessive production of cortisol and defective cortisol metabolism cause hypertension plus hypokalemia. Cushing’s syndrome (excessive cortisol production) is discussed in detail in Chapter 240 .
Cortisol at the mineralocorticoid receptor normally is kept at a very low local concentration because the enzyme 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) converts cortisol to cortisone, which cannot bind the mineralocorticoid receptor. The syndrome of apparent mineralocorticoid excess is an autosomal recessive disease due to a loss in function mutation of 11ß-HSD2. Loss of protection of the mineralocorticoid receptor from an excessive local concentration of cortisol results in early-onset hypertension with hypokalemia accompanied by suppressed PRA and undetectable plasma aldosterone. Glycerrhetinic acid, a metabolite found in licorice, numerous herbal supplements, and chewing tobacco, is a potent inhibitor of 11ß-HSD2. Thus, habitual ingestion of these substances by normal individuals causes a phenocopy of apparent mineralocorticoid excess. Biochemical confirmation consists of elevations in urinary free cortisol. The congenital syndrome is treated with spironolactone, whereas the phenocopy is treated with diet.
A gain-in-function mutation in the mineralocorticoid receptor has been identified as a cause of autosomal dominant, early-onset hypertension that is markedly accelerated during pregnancy. Because of missense mutation in the ligand-binding domain of the mineralocorticoid receptor, steroids that bind but do not activate the normal receptor become potent agonists of the mutant receptor, causing mineralocorticoid receptor-induced hypertension with secondary suppression of plasma renin and aldosterone. These steroids include progesterone and spironolactone, which normally is a potent receptor antagonist. Because progesterone levels increase 100-fold during pregnancy, this mutation constitutes a rare but dramatic cause of accelerated hypertension during pregnancy. All the male carriers in one family developed hypertension before age 20. Amiloride is the suggested treatment of choice, and spironolactone is contraindicated.
Liddle’s syndrome is a rare monogenic form of salt-dependent hypertension due to gain-in-function mutations in ENaC, resulting in an excessive number of channels on the

epithelial surface of the distal renal tubule. Mutations that truncate large segments of the cytoplasmic C-terminus of the beta or gamma ENaC subunits disrupt the NEDD4 ubiquitin ligase binding site so that the channels cannot be internalized. Inherited as an autosomal dominant trait, these mutations cause severe salt-dependent hypertension beginning in young adulthood. Plasma renin activity and plasma aldosterone levels are suppressed secondarily. The diagnosis is confirmed by genetic testing for the mutant gene. Because the defect is downstream from the mineralocorticoid receptor, the hypertension is unresponsive to spironolactone but is best treated with thiazides plus amiloride or triamterene, which are potassium-sparing diuretics that block ENaC.
Several large kindreds have been reported to have severe autosomal dominant hypertension associated with brachydactyly and short stature. The gene has been mapped to the short arm of chromosome 12, but the mechanism causing the hypertension is unknown. In contrast to the other mendelian forms of hypertension, plasma renin and aldosterone levels are normal, and this syndrome does not appear to represent volume-dependent hypertension.
Pheochromocytomas are rare catecholamine-producing tumors of the adrenal (or sometimes extra-adrenal) chromaffin cells ( Chapter 241 ). The diagnosis should be suspected when hypertension is accompanied by frequent or refractory headaches or by paroxysms of headache, palpitations, pallor, or diaphoresis. In some patients, pheochromocytoma may be misdiagnosed as panic disorder. A family history of early onset hypertension may suggest pheochromocytoma as part of the multiple endocrine neoplasia syndromes ( Chapter 244 ). If the diagnosis is missed, outpouring of catecholamines from the tumor can cause unsuspected hypertensive crisis and death during unrelated surgical or radiologic procedures.
Other causes of neurogenic hypertension, which can be confused with pheochromocytoma, include sympathomimetic agents (cocaine, amphetamines; Chapter 30 ), baroreflex failure, and obstructive sleep apnea. Continuous positive airway pressure or corrective surgery can improve blood pressure control in some patients with sleep apnea ( Chapter 96 ).
Coarctation of the aorta typically occurs just distal to the origin of the left subclavian artery, so the blood pressure is lower in the legs than in the arms (the opposite of the normal situation) ( Chapter 65 ). The clue is that the pulses are weaker in the lower than upper extremities, indicating the need to measure blood pressure in the legs as well as in both arms. Intercostal collaterals can produce bruits on examination and rib notching on the chest radiograph. Coarctations can be cured with surgery or angioplasty.
Thyroid disease is another cause of secondary hypertension ( Chapter 239 ). Hyperthyroidism tends to cause systolic hypertension with a wide pulse pressure, whereas hypothyroidism tends to cause mainly diastolic hypertension.
Cyclosporine has emerged as an important cause of secondary hypertension. The mechanism by which this immunosuppressive drug causes hypertension remains an enigma, but hypertension is a general property of immunosuppressive agents (e.g., tacrolimus) that inhibit calcineurin, the Ca2+ -dependent phosphatase that is expressed not only in lymphoid tissue but also in neural, vascular, and renal tissue. In the absence of outcomes data, nondihydropyridine calcium channel blockers (CCBs) have become the drugs of first choice even though they increase cyclosporine blood levels.

Prevention and Treatment of Primary Hypertension
Because primary hypertension cannot be cured, it requires lifelong treatment. However, it can usually be controlled by a combination of lifestyle modifications and medications. The objective is to reduce the blood pressure and associated metabolic abnormalities sufficiently to reduce the risk of cardiovascular and renal target organ disease without compromising the patient’s quality of life.
Every antihypertensive regimen should include lifestyle modifications. If implemented in childhood and sustained, these nondrug strategies would likely prevent millions of cases of hypertension. Once hypertension is established, however, lifestyle modifications alone are rarely sufficient to obviate the need for medications. These modifications, however, can decrease medication requirements, affect associated cardiovascular risk factors, and emphasize the active role patients can play in controlling their blood pressure.
The most consistently effective lifestyle modification is weight loss for overweight hypertensives: losing only 10 to 12 pounds often lowers blood pressure by 10/5 mm Hg.[1] Moderate dietary sodium reduction on average lowers blood pressure by 5/2 mm Hg and should be part of every antihypertensive regimen ( Chapter 12 and Chapter 233 ) despite the variable response from one patient to the next and the fact that the full benefits are not seen for 5 weeks. In addition to independent blood pressure-lowering effects, dietary sodium reduction can dramatically improve the efficacy of ACE inhibitors, angiotensin-receptor blockers (ARBs), and ß-blockers, and it can permit a reduction in the dose of diuretic and the associated need for potassium supplementation. Most dietary sodium comes from processed foods rather than the salt shaker. Without draconian measures, daily salt consumption can be reduced from 10 to 6 g (6 g of NaCl = 2.4 g of Na+ = 100 mmol of Na+ ) by teaching patients to read food labels. The Dietary Approaches to Stop Hypertension (DASH) study showed that individuals with high normal blood pressure or stage 1 hypertension can lower their blood pressures even without decreased caloric or sodium intake if they adhere to a diet rich in fresh fruits and vegetables (for high potassium content) and use low-fat dairy products. The DASH diet (www.nhlbi.nih.gov/health/public/heart/hbp/dash/) is strongly recommended because the blood pressure-lowering effects can approach the magnitude of drug monotherapy, can be enhanced by dietary sodium reduction, and are seen in all ethnic groups, especially in African-Americans.[2] How to effect these dietary changes in free-living individuals remains a considerable challenge, but these impressive trial results document what could be achieved if dietary habits could be changed throughout the population.
Smokers should be counseled in the best methods to quit because smoking is such a potent cardiovascular risk factor, not only for coronary heart disease but also for progression of hypertensive nephrosclerosis ( Chapter 14 ). Because blood pressure increases transiently by 10 to 15 mm Hg after each cigarette, smokers of more than 20 cigarettes per day often have higher blood pressures out of the office. Blood pressure increases similarly with the first morning cup of coffee, but the pressor response to caffeine habituates throughout the day. Thus, caffeine consumption need not be eliminated.
Excessive alcohol consumption is one of the most frequently overlooked reversible factors contributing to hypertension ( Chapter 17 ). The relation between alcohol consumption and mortality is J-shaped. Cardiovascular death rates are 50% lower in moderate drinkers (one or two drinks a day) than in teetotalers. Red wine may be the most cardioprotective because of its high content of polyphenols, which decrease production of endothelin. However, individuals who drink more than two standard-sized drinks a day are at greatly increased risk of developing hypertension, possibly because large quantities of alcohol activate the sympathetic nervous system. In those who drink three or more standard portions of alcohol per day, reducing alcohol consumption can improve control of hypertension. [3]
In hypertensive individuals, regular aerobic exercise can exert modest reductions in blood pressure, averaging 5/2 mm Hg ( Chapter 13 ). Although small in magnitude, these reductions can persist for up to 16 hours after a bout of aerobic exercise.[4] Relaxation techniques (e.g., meditation, biofeedback, hypnosis) can decrease blood pressure acutely but generally produce little effect on chronic hypertension. In some individuals, however, in whom overwhelming home or job strain is a major determinant of high blood pressure, as determined by ambulatory monitoring, stress management techniques or anxiolytics may be beneficial. Because patients often associate hypertension directly with life stress, patients should be counseled that stress management alone rarely is sufficient to control their hypertension.
Historical Perspective
The current approach to the treatment of the hypertensive patient began in the 1960s, with the sequential development of effective antihypertensive medications. The memoirs of President Franklin Roosevelt’s physician chronicle the frustrations of trying to manage

severe hypertension with only bed rest and sedatives, which were the ineffective mainstays of antihypertensive therapy through the end of World War II. Shortly thereafter, Kempner demonstrated the blood pressure-lowering effects of treating overweight hypertensives with a rigorously low-sodium/low-calorie diet, the first effective lifestyle modification for hypertension. With the development of the first antihypertensive drugs in the late 1950s, the vanguard VA Cooperative Studies demonstrated that lowering blood pressure with medications prolongs life and reduces morbidity, not only in patients with very severe hypertension but also in those with moderate and even mild degrees of hypertension.
Probably no other field of clinical medicine enjoys a greater scientific base. Increasingly detailed understanding of the basic mechanisms involved in blood pressure regulation has fueled the identification of new drug targets and therapeutic agents. More than 70 antihypertensive medications are marketed. Randomized controlled trials have provided unequivocal proof that lowering blood pressure with medications dramatically reduces target organ damage and the resultant morbidity and mortality. There also is mounting but still incomplete evidence that certain classes of antihypertensive agents exert organoprotective effects above and beyond their ability to lower blood pressure. Thus, in certain circumstances, all antihypertensive medications are not equal, and the treatment of hypertension is no longer totally empiric.
The major challenges now are (1) to identify the key gene-environment interactions that cause hypertension and those that confer protection from it, thereby providing the conceptual framework for preventing or curing the disordered blood pressure regulation, and in the meantime, (2) to eliminate the patient and physician barriers that impede the control of hypertension with available measures. To improve the dissemination of the rapid advances in the field, practice guidelines are regularly updated (e.g., the Joint National Committee [JNC] 7 Report).
Target Blood Pressure Levels
Based on each patient’s overall cardiovascular risk, a target level of blood pressure needs to be set, achieved, and sustained. For most patients, the goal is to intensify the medical regimen until blood pressure is lowered to systolic and diastolic values that are consistently below 140/90 mm Hg. For those with diabetes or chronic kidney disease, the high risk associated with these comorbid conditions requires that blood pressure be lowered further to values that are below 130/80 mm Hg. Unfortunately, in the United States, one third of all hypertensive individuals are unaware of their diagnosis, one half are not receiving treatment, and two thirds do not have their pressure controlled to a value less than 140/90 mm Hg. This worldwide problem (see Fig. 63-2 ) is not limited to underserved areas. In a survey of adults in Olmsted County, Minnesota, a well-educated community in proximity to the Mayo Clinic, 39% of the hypertensive participants were unaware of their diagnosis and only 17% of the affected individuals had their hypertension treated and controlled. A study from five Veterans Administration hospitals in the northeastern United States showed that, despite patients’ having ample access to clinic care by attending physicians, antihypertensive therapy was intensified during only 7% of hypertension-related visits over a 2-year period, resulting in persistently poor rates of control; blood pressure remained greater than 160/90 mm Hg in 40% of the patients. Similarly disconcerting figures have been found in numerous practice settings.
In contrast, randomized clinical trials have demonstrated that teams of physicians and nurses who adhere to a forced titration schedule can achieve target blood pressures in up to two thirds of patients. With current regimens, diastolic pressures of less than 90 mm Hg can be achieved in more than 90% of hypertensive patients, whereas systolic pressures of less than 140 mm Hg can be achieved in more than 60%. New medications with greater efficacy for systolic blood pressure are under investigation.
To improve hypertension control rates in clinical practice, a number of principles can be borrowed from the successful conduct of multicenter trials. First, greater attention needs to be paid to titrating blood pressure medications to achieve target goals. Lowering blood pressure by the additional 10/5 mm Hg often needed to achieve, rather than almost achieve, current treatment goals has been proved repeatedly to confer a remarkable degree of added protection from adverse cardiovascular outcomes.[5] Almost is not good enough. Second, to achieve these goals, most patients require two or three antihypertensive medications. To achieve the more stringent blood pressure goals indicated for diabetics and patients with chronic renal failure, three or four medications are usually needed. Third, to achieve and sustain patient compliance with multidrug regimens, greater attention needs to be paid to the patient’s quality of life.
Compliance and Quality of Life
The importance of honest patient dialogue and patient education cannot be overemphasized. Despite decades of nationwide blood pressure education programs about the “silent killer,” many patients perceive hypertension as being episodic and symptomatic. Because hypertension requires lifelong treatment and because medications can produce side effects, quality of life becomes a major issue that affects patients’ compliance. Medication costs are considerable and beyond the means of some patients. For patients who must pay for some or all of their medications, costs can be cut drastically by prescribing generic drugs.
Men are often concerned about medication-induced sexual dysfunction. However, sexual dysfunction often precedes the initiation of antihypertensive therapy. In a double-blind, prospective, placebo-controlled trial, thiazide diuretics were the only one of the six major classes of antihypertensive drugs associated with more new cases of male sexual dysfunction over the next year than placebo. Thus, the incidence of medication-induced sexual dysfunction previously has been overstated. Much of the blame assigned to the drugs is caused by impaired endothelial function (impaired nitric oxide-mediated dilation of the corpus cavernosum) due to obesity-induced insulin resistance, cigarette smoking, hyperlipidemia, and uncontrolled hypertension. Indeed, patients generally rate their overall quality of life as significantly improved when their blood pressures are controlled with medical therapy compared with when uncontrolled on placebo. In addition to these considerations, several additional principles have been shown to facilitate patients’ compliance: (1) titrating medical therapy based on home readings, which engages the patient’s active participation; (2) using long-acting preparations with once-a-day dosing; (3) using low-dose combinations of medications from different drug classes to achieve synergistic effects on blood pressure while avoiding dose-dependent side effects; and (4) using fixed-dose combinations to reduce the overall number of pills.
Choice of Initial Drug Therapy
The choice of the initial antihypertensive medication is less important now than in the stepped-care era of the 1970s (which encouraged high-dose monotherapy) because most patients require multiple medications ( Table 63-5 ). There is increasing movement toward initiating treatment with low-dose combination therapy. Based on the recent results of The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)[6] and other recent treatment trials, it takes at least two medications of different classes to treat most cases of mild hypertension and three or four different medications to treat the more difficult cases and to reach more stringent blood pressure goals in high-risk patients.[7] The JNC 7 Report recommends starting a two-drug combination regimen for patients with stage 2 hypertension. As a rule of thumb, an additional medication will be needed for each 10 mm Hg of systolic blood pressure above goal. The great majority of these multi-drug regimens should include a low-dose diuretic.
Mechanism of Action.
With initiation of diuretic therapy, contraction of blood volume explains the initial fall in blood pressure. With continued diuretic therapy, blood volume is partially restored, and vasodilator mechanisms (e.g., opening of ATP-sensitive potassium channels) sustain the antihypertensive action. Based on their sites of action in the kidney, there are three main classes of diuretics. Loop diuretics are the most potent because they block Na+ /K+ /2Cl- transport in the thick ascending loop of Henle, where a large portion of the filtered Na+ is reabsorbed. Thiazide diuretics and the indoline derivative indapamide are less potent because they block Na+ /Cl- cotransport in the distal convoluted tubule, where a small portion of the filtered sodium is reabsorbed. The potassium-sparing diuretics are the weakest because they act most distally in the collecting duct. Spironolactone prevents aldosterone from activating the mineralocorticoid receptor, thereby inhibiting activation of ENaC, the final common pathway for reabsorption of Na+ from the distal nephron.


Thiazide Diuretics
6.25–25 (1)
6.25–25 (1)
1.25–5 (1)
2.5–5 (1)
Loop Diuretics
20–160 (2)
2.5–20 (1–2)
0.5–2 (2)
Ethacrynic acid
25–100 (2)
Potassium Sparing
5–20 (1)
25–100 (1)
12.5–200 (1–2)
200–800 (2)
25–100 (1)
5–20 (1)
2.5–20 (1)
50–200 (2)
Metoprolol XL
50–200 (1)
20–320 (1)
10–80 (1)
10–60 (2)
40–160 (2)
Propranolol LA
60–180 (1)
20–60 (2)
200–1200 (2)
6.25–50 (2)
2.5–10 (1)
2.5–20 (1–2)
Isradipine CR
2.5–20 (2)
Nicardipine SR
30–120 (2)
Nifedipine XL
30–120 (1)
10–40 (1)
Diltiazem CD
120–540 (1)
Verapamil HS
120–480 (1)
10–80 (1–2)
25–150 (2)
2.5–40 (2)
10–80 (1–2)
5–80 (1)
7.5–30 (1)
4–16 (1)
5–80 (1–2)
2.5–20 (1)
1–8 (1)
8–32 (1)
400–800 (1–2)
150–300 (1)
25–100 (2)
20–80 (1)
80–320 (1)
1–40 (2–3)
1–16 (1)
1–20 (1)
20–120 (2) for pheochromocytoma
0.2–1.2 (2–3)
Clonidine patch
0.1–0.6 (weekly)
2–32 (2)
1–3 (1)
250–1000 (2)
0.05–0.25 (1)
25–200 (2)
2.5–100 (1)
37.5/25 (½–1)
25/25 (½–1)
2.5–10/6.25 (1)
5–20/6.25–25 (1)
2.5–5/10–20 (1)
2–4/180–240 (1)
16–32/12.5–25 (1)
15–30/12.5–25 (1)
50–100/12.5–25 (1)
80–160/12.5–25 (1)
ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; CCB = calcium channel blocker; HCTZ = hydrochlorothiazide.

Triamterene and amiloride block ENaC directly. Because less Na+ is presented to the Na+ ,K+ -ATPase on the apical surface (i.e., vascular side) of the collecting duct cells, less K+ is excreted in the urine.
Side Effects and Contraindications.
Thiazides and prolonged exposure to loop diuretics cause renal potassium wasting because increased Na+ is presented to the Na+ ,K+ -ATPase. The hypokalemia is dose dependent and minimized by using lower doses the equivalent of 6.25 to 12.5 mg of hydrochlorothiazide (HCTZ). Hypokalemia predisposes to ventricular arrhythmias and negates the cardioprotective benefit of lowering blood pressure. Serum Na+ also needs to be followed because thiazide diuretics occasionally cause hyponatremia, which in older patients can be severe. Although thiazides are said to elevate plasma LDL cholesterol, the effect is negligible with lower doses. Although thiazides can increase blood glucose, the effect is small with low doses, and thiazide-based therapy has been proved to reduce cardiovascular morbidity and mortality in diabetic hypertensives. They occasionally cause erectile dysfunction. Thiazide diuretics are relatively contraindicated in patients with hyperuricemia because they can precipitate gout. Potassium-sparing diuretics are contraindicated in patients who are prone to hyperkalemia, especially patients with renal failure and diabetics with hyporeninemic hypoaldosteronism. In high doses, spironolactone antagonizes the testosterone receptor, thereby producing sexual dysfunction and painful gynecomastia in men. Except for ethacrynic acid, all diuretics contain a sulfur moiety, can cause photosensitivity, and should be avoided in patients with a history of allergic reaction to sulfa drugs. Furosemide can rarely cause interstitial nephritis.
Compelling Indications and Therapeutic Principles.
Diuretics are the oldest, least expensive, and still among the best antihypertensive medications. With the marketing of new classes of antihypertensive agents since the 1970s, the number of prescriptions written for diuretics unfortunately has fallen steadily. Hopefully, this trend will change with publication of the ALLHAT, which documented that thiazide-type diuretics are at least as effective as (and in some instances more effective than) newer agents in lowering blood pressure and preventing the attendant cardiovascular morbidity and mortality. As first line therapy, the thiazide-type diuretic (chlorthalidone) was equally effective as the ACE inhibitor (lisinopril) or the dihydropyridine CCB (amlodipine) in preventing the primary endpoint of combined fatal coronary heart disease and nonfatal myocardial infarction. The effectiveness of the diuretic-based therapy was demonstrated in all patient subgroups including older persons, women, African Americans, and those with diabetes. When combined with other classes of antihypertensive medications, diuretics exert a synergistic effect on blood

pressure. The most common cause of apparent drug-resistant hypertension is the failure to include a diuretic or dose it correctly in the therapeutic regimen. Thus, thiazides remain the first drug of choice for the majority of hypertensive patients. Thiazide diuretics exert a larger effect on systolic than diastolic blood pressure and, based on hard outcomes data, are the initial drugs of choice for isolated systolic hypertension. [8] Almost every antihypertensive regimen should include a low-dose diuretic or at least a low-sodium diet.
Because of their long half-lives, thiazide diuretics are much more effective than the short-acting loop diuretics in the long-term management of chronic hypertension. Very low doses of HCTZ (6.25 mg/day in combination or 12.5 mg/day alone) maintain much of the antihypertensive efficacy while greatly minimizing the adverse metabolic profile associated with the much larger doses (50 to 100 mg/day) used previously. Chlorthalidone, the thiazide-type diuretic used in the ALLHAT and many other landmark hypertension treatment trials, is more potent and has a much longer duration of action than HCTZ, which for decades has replaced chlorthalidone as the main thiazide-type diuretic used in clinical practice. According to some experts, 25 mg of chlorthalidone is roughly equivalent to 40 mg of HCTZ. Combinations of HCTZ with potassium-sparing diuretics reduce, but do not always eliminate, the need for potassium supplements; serum K+ levels must be followed after initiating therapy. Adherence to a moderately low-salt diet also reduces the need for potassium supplements in patients taking diuretics. Thiazide diuretics, except for metolazone, are ineffective when the glomerular filtration rate falls below 30 mL/min.
Loop diuretics are the diuretics of choice for treating hypertension in patients with chronic renal insufficiency or heart failure. Because the duration of action of furosemide is 6–8 hours, twice daily dosing is required for sustained lowering of blood pressure. Torsemide may be a better alternative because of its longer half-life. The addition of low-dose metolazone (2.5 mg/day) to a loop diuretic can sometimes restore blood pressure responsiveness in patients with resistant hypertension due to severe volume expansion in the setting of advanced chronic renal failure. However, metolazone and the potent loop diuretics are not appropriate treatment for the vast majority of patients with uncomplicated hypertension.
Spironolactone (50 to 200 mg/day) is the drug of choice for the medical treatment of primary aldosteronism. Low-dose spironolactone (12.5 to 25 mg/day) also can be effective in some patients with primary low-renin hypertension. Eplerenone, a more specific mineralocorticoid receptor antagonist that does not block the testosterone receptor, is in the final stages of clinical trials and could have broad implications for the treatment of primary hypertension. Amiloride is the drug of choice for treating primary aldosteronism in men and is the drug of choice for patients with Liddle’s syndrome.
Mechanism of Action.
Interaction of epinephrine or norepinephrine with ß1 -adrenoreceptors in the heart causes G protein-linked activation of adenylate cyclase, resulting in positive chronotropic and inotropic effects. Interaction of catecholamines with ß2 -adrenoreceptors relaxes bronchiolar and arteriolar smooth muscle. With the initiation of ß-blocker therapy, blood pressure at first is little affected because the fall in cardiac output is offset by a compensatory increase in peripheral resistance. Over several weeks, blood pressure falls progressively as the peripheral vasculature relaxes. Thus, the antihypertensive effect of ß-blockade involves decreases in cardiac output (ß1 -receptors), renin release (ß1 -receptors), and norepinephrine release (prejunctional ß2 -receptors).
All 11 ß-blockers are antihypertensive. First-generation agents (e.g., propranolol) nonselectively block both ß1 – and ß2 -receptors. Second-generation agents (e.g., metoprolol, atenolol, acebutolol, bisoprolol) are relatively cardioselective. In low doses, they exert a greater inhibitory effect on ß1 – than on ß2 -receptors, but selectivity is lost at high doses. Other agents cause vasodilatation either by stimulating ß2 -adrenoreceptors (i.e., intrinsic sympathomimetic activity) (e.g., pindolol) or by blocking a1 -adrenoreceptors (labetalol, carvedilol) on vascular smooth muscle.
Side Effects and Contraindications.
ß-Adrenergic receptor blockade can cause adverse side effects through (1) contraction of smooth muscle (bronchospasm, Raynaud’s phenomenon), (2) exaggeration of therapeutic negative chronotropic and inotropic effects (heart failure, heart block), and (3) penetration of the central nervous system (CNS) (depression, nightmares). Contraindications to ß-blockers include asthma and other forms of reactive airway disease, heart block, acutely decompensated heart failure, Prinzmetal’s angina, and depression. In brittle type I diabetes, ß-blockers can mask the adrenergic signs of hypoglycemia, but this effect often can be avoided with a cardioselective ß-blocker. Before starting ß-blockers for hypertension, it should be appreciated that chronic ß-blocker therapy has been associated with a 28% increased risk of developing type II diabetes. In patients with known or suspected coronary disease, ß-blockers must be tapered slowly to avoid rebound angina.
Compelling Indications and Therapeutic Principles.
For the treatment of hypertension, the long-acting (once-a-day) and cardioselective ß-blockers are preferred, but all ß-blockers are effective, particularly when combined with a diuretic. Although numerous clinical trials have demonstrated that treating hypertension with ß-blockers reduces cardiovascular outcomes, in most cases the ß-blocker has been combined with a thiazide diuretic. ß-Blockers, which are very effective in reducing myocardial oxygen demands, are first-line therapy for hypertensive patients with coronary disease and should be prescribed in all patients who also have sustained a myocardial infarction and who can tolerate them. ß-Blockers also can be very useful in hypertensive patients who have anxiety disorders.
Mechanism of Action.
The CCBs block the opening of voltage-gated (L-type) Ca2+ channels, thereby preventing the entry of Ca2+ into cardiac myocytes and vascular smooth muscle cells. The resultant decrease in the cytosolic Ca2+ signal decreases heart rate and ventricular contractility and relaxes vascular smooth muscle. The major classes of CCBs are the dihydropyridines (e.g., nifedipine, felodipine, amlodipine) and the nondihydropyridines (verapamil and diltiazem). Dihydropyridines are more potent antihypertensive agents, but any directly negative chronotropic or inotropic effects are offset by reflex sympathetic activation. By comparison, the nondihydropyridines are weaker antihypertensive drugs because they cause less peripheral vasodilation, but they exert more pronounced negative chronotropic and inotropic effects (especially verapamil), thereby decreasing cardiac output.
Side Effects and Contraindications.
The CCBs are generally very well tolerated. Because of their negative inotropic and negative chronotropic actions, the nondihydropyridine CCBs are contraindicated in patients with severe left ventricular dysfunction and those with impaired cardiac conduction because they can precipitate heart failure or heart block. Verapamil often causes considerable constipation by blocking contraction of smooth muscle in the gut. The most frequent annoying side effects of the dihydropyridines—headaches, flushing, and ankle edema—are all related to arterial vasodilation. In the absence of venodilation, arterial vasodilation increases capillary hydrostatic pressure, leading to dose-dependent ankle edema. Short-acting dihydropyridines should not be used to treat hypertension. By triggering an abrupt fall in blood pressure with reflex sympathetic activation, these rapidly acting vasodilators can precipitate myocardial ischemia, infarction, stroke, and death.
Compelling Indications and Therapeutic Principles.
Controversy has arisen on the indications for long-acting dihydropyridine CCBs, which cause much less (but still some) reflex sympathetic activation. A meta-analysis suggests that, for the majority of patients with hypertension, cardiovascular outcomes with dihydropyridine CCBs are on balance equivalent to those seen with other classes of antihypertensive medications, with the caveat that they possibly provide less protection against myocardial infarction and heart failure but greater protection against stroke and dementia.[9] With the publication of ALLHAT, much of the conroversy around dihydropyridine CCBs has ended. After five years of treatment with a long-acting dihydroperidine CCB, the primary outcome of fatal coronary heart disease and nonfatal myocardial infarction was identical to that seen with the ACE inhibitor or the diuretic. For patients with proteinuric renal insufficiency, there is mounting evidence that dihydropyridine CCB-based therapy is less renoprotective than ARB or ACE inhibitor-based therapy.[10] However, in the vast majority of patients with renal disease, multiple classes of medications, including dihydropyridines, are required to achieve blood pressure goals. The key point is that a dihydropyridine should not be used as first-line therapy for hypertension in patients with proteinuric renal disease but may be used as adjunctive therapy once the dose of the ACE inhibitor or ARB has been maximized in combination with an appropriate diuretic. Dihydropyridine CCB-based therapy has been proved to improve cardiovascular outcomes, especially stroke, dramatically in older hypertensives and particularly in older hypertensive patients with diabetes.


Figure 63-9 The renin-angiotensin-aldosterone pathway as an antihypertensive drug target. ACE = angiotensin-converting enzyme; AGT = angiotensinogen; Ang = angiotensin; ARB = angiotensin II receptor blocker; AT1 R = angiotensin II receptor type 1.
Mechanism of Action.
The renin-angiotensin system is one of the most important targets for antihypertensive drugs ( Fig. 63-9 ). The interaction of Ang II with G protein-coupled receptors termed AT1 receptors accelerates numerous cellular processes that contribute not only to hypertension but also to its end-organ damage, including (1) aldosterone secretion, which produces renal salt and water retention, as well as collagen deposition leading to cardiac fibrosis; (2) peripheral vasoconstriction; (3) growth of cardiac and vascular smooth muscle cells, leading to cardiac and vascular hypertrophy; (4) production of superoxide anions and other reactive oxygen species that inactivate nitric oxide, thereby inhibiting endothelium-dependent vasodilatation; and (5) augmentation of both central sympathetic outflow and prejunctional modulation of norepinephrine release from peripheral sympathetic nerve terminals, thereby leading to excessive stimulation of a adrenergic receptors. For these reasons, blockade of the renin-angiotensin-aldosterone system may exert organoprotective effects above and beyond the lowering of blood pressure. ACE inhibitors block the conversion of Ang I to Ang II, leading to a dramatic fall in plasma Ang II levels with the initiation of therapy. However, with continued treatment with an ACE inhibitor, plasma Ang II levels return to normal in part because ACE inhibitors do not block alternative pathways that generate Ang II. The sustained antihypertensive action of ACE inhibitors is explained in part by their ability to block the metabolism of bradykinin, a potent endothelial-dependent vasodilator, to inactive fragments. By comparison, ARBs lower blood pressure specifically by blocking the interaction of Ang II on the AT1 receptors. Thus, ARBs do not increase bradykinin, which has been implicated in both the therapeutic and side effects of ACE inhibitors.
Side Effects and Contraindications.
The ACE inhibitors are generally well tolerated, but the ARBs have the best side effect profile to date. The most common side effect of ACE inhibitors is a dry cough, which occurs in 3 to 39% of patients and resolves in a few days after the drug is discontinued. The incidence is higher in African Americans than whites and highest in Asians. Because the cough seems to be bradykinin mediated, this annoying side effect is avoided by switching to an ARB. The rare (1 : 2000) but most serious side effect of ACE inhibitors, angioedema ( Chapter 269 ), also has been blamed on bradykinin, and thus is even rarer with ARBs. Angioedema, which can occur at any time during the course of treatment, is more common in African Americans and can be fatal. With either ACE inhibitors or ARBs, hyperkalemia can result from reduced aldosterone secretion or impairment of renal function; however, even in the setting of significant renal disease, the risk of hyperkalemia requiring drug discontinuation is low (<2%) and is seen mainly when these drugs are administered to diabetics with hyporeninemic hypoaldosteronism or are mistakenly used in patients who are also taking potassium supplements, an error that should be avoided. ACE inhibitors and ARBs can precipitate acute renal failure in patients with bilateral renal artery stenosis or hypovolemia. After correction of hypovolemia, the ACE inhibitor or ARB usually can be restarted safely at a lower dose. These drugs are contraindicated in pregnancy because they are teratogenic.
Compelling Indications and Therapeutic Principles.
Because of their low side effect profiles and ancillary benefits, ACE inhibitors and ARBs are gaining popularity for the general treatment of hypertension. At present, however, diabetic nephropathy, nondiabetic renal insufficiency, and heart failure are considered (by many authorities) to be the compelling indications for initiating hypertension treatment with an ACE inhibitor or ARB.[11] [12] [13] Randomized trials have dispelled the fear that ACE inhibitors and ARBs are contraindicated for patients with mild or moderate degrees of renal impairment by showing that the incidence of hyperkalemia or acute renal failure is very low and that renoprotection is provided. Although serum creatinine and potassium need to be monitored in all patients receiving an ACE inhibitor or ARB, small and typically transient increases at the onset of therapy are not an indication to discontinue these drugs.
All ARBs have approximately comparable antihypertensive efficacy. Losartan, the prototype, differs from the other ARBs in two ways: a shorter duration of action, requiring twice-daily dosing if used as monotherapy, and a uricosuric effect, which may be beneficial in patients with hyperuricemia.
Mechanism of Action.
By blocking the interaction of norepinephrine on vascular a-adrenergic receptors, these drugs cause peripheral vasodilation, thereby lowering blood pressure. By increasing skeletal muscle blood flow, they increase insulin sensitivity. By dilating urethral smooth muscle, they improve symptoms of prostatism. Prazosin, doxazosin, and terazosin selectively block a1 -adrenoreceptors, whereas phenoxybenzamine blocks both a1 – and a2 -receptors.
Side Effects and Contraindications.
The most troubling side effect is orthostatic hypotension, which is less often seen with the second-generation agents with a slower onset of action.
Compelling Indications and Therapeutic Principles.
Phenoxybenzamine remains the drug of choice for preoperative management of pheochromocytoma; after a-blockade is achieved, a ß-blocker should be added to block an otherwise excessive reflex tachycardia. The selective a1 -blockers are effective general antihypertensive agents and are particularly useful in older men with prostatism. It is important to emphasize that a-blockers should not be used as monotherapy because their propensity to cause fluid retention can lead to tachyphylaxis and unmask heart failure.[14] When prescribed correctly in combination with a diuretic, there is no evidence to contraindicate their use.
Mechanism of Action.
Stimulation of a2 -adrenergic receptors and imidazoline receptors in the CNS lowers central sympathetic outflow, whereas stimulation of presynaptic a2 -receptors causes feedback inhibition of norepinephrine release from peripheral sympathetic nerve terminals. The combined effect is reduced sympathetic drive to the heart and peripheral circulation, leading to decreased heart rate, cardiac output, and peripheral vascular resistance.
Side Effects and Contraindications.
Although highly effective as antihypertensive agents, the clinical utility of these agents is limited by their side effects profile. The major CNS side effects are sedation, dry mouth, and depression. Depression is a contraindication to all available central sympatholytic agents. These side effects are lessened with more selective imidazoline receptor blockers that are available in Europe. Central sympatholytics should not be combined with a ß-blocker because excessive bradycardia can ensue. Reserpine also depletes norepinephrine stores from sympathetic nerve terminals, causing dose-dependent orthostatic hypotension. a-Methyldopa can cause autoimmune hemolytic anemia and lupus erythematosus. Although clonidine does not cause these latter side effects, rebound hypertension is a major problem if oral clonidine is discontinued abruptly. Rebound hypertension is reduced by using longer acting preparations (guanfacine or transdermal clonidine).

Therapeutic Principles.
Central sympatholytics can be effective as add-on therapy for patients with difficult-to-control hypertension. Aldomet remains the drug of choice for nonemergent hypertension in pregnancy ( Chapter 253 ).
Mechanism of Action.
Minoxidil and hydralazine are potent hyperpolarizing arterial vasodilators that work by opening vascular ATP-sensitive potassium channels.
Side Effects and Contraindications.
By causing selective arterial dilation, both drugs cause profound reflex sympathetic activation and tachycardia as well as peripheral edema. When hydralazine is administered parenterally, the magnitude of the blood pressure lowering is unpredictable and can result in extreme hypotension. Chronic treatment with high doses of oral hydralazine can cause a lupus-like syndrome. Minoxidil causes diffuse hirsutism.
Therapeutic Principles.
Hydralazine has largely been replaced by the dihydropyridine CCBs because of side effect profiles. However, hydralazine remains the treatment of choice for acute severe hypertension in pregnancy ( Chapter 253 ). Difficult-to-control hypertension in chronic renal failure ( Chapter 117 ) is the main indication for minoxidil, which must be combined with a ß-blocker, to prevent excessive reflex tachycardia, and with a loop diuretic, to prevent excessive fluid retention.
Some drug combinations are particularly effective for treating hypertension, and some should be avoided. Because higher doses of diuretics cause reflex activation of both the renin-angiotensin and sympathetic nervous systems, preventing such activation with the addition of an ACE inhibitor, an ARB, or a ß-blocker produces synergistic effects on blood pressure. With fixed-dose combinations, the dose of HCTZ should be 12.5 mg or, even better, 6.25 mg. Unfortunately, many fixed-dose combinations contain 25 mg of HCTZ, which often is too high. Combining HCTZ with a potassium-sparing diuretic may obviate unpleasant potassium supplements, but again the dose of the HCTZ component often is too high, requiring that pills be cut in half.
Because dihydropyridine CCBs also produce reflex increases in plasma renin and sympathetic activity, the addition of an ACE inhibitor or ARB produces synergistic effects on blood pressure (and potentially on end-organ protection). In addition, high doses of dihydropyridine CCBs cause ankle edema because these drugs preferentially dilate arteries rather than veins, producing elevated hydrostatic pressure in the cutaneous circulation. This elevated hydrostatic pressure and the resulting ankle edema often can be relieved by the addition of an ACE inhibitor or ARB, which dilates veins as well as arteries. In contrast, the hydrostatic edema is not relieved by addition of a diuretic.
Furthermore, combining a dihydropyridine CCB with a diuretic produces less blood pressure synergy because of excessive reflex neurohormonal activation. This combination should be avoided in patients with ischemic heart disease unless a ß-blocker also is used. ß-Blockers generally should not be combined with nondihydropyridine CCBs or with clonidine or other central sympatholytics because these combinations can lead to excessive bradycardia and depression, particularly in older persons. Labetalol, although marketed for its a-blocking action, is primarily a ß-blocker and should not be combined with other ß-blockers.
Vasopeptidase inhibitors, a new class of agent under final stages of clinical investigation, inhibit both ACE and neutral endopeptidase (NEP), the enzyme that breaks down the endogenous natriuretic peptides. As a result, the natriuretic and vasodilatory actions of these peptides are enhanced. NEP inhibition alone has very little effect on blood pressure because of compensatory activation of the renin-angiotensin-aldosterone system. In contrast, simultaneous inhibition of NEP and ACE by this single molecule produces a powerful antihypertensive effect that may be particularly useful in treating systolic hypertension. However, clinical safety trials showed a greater incidence of life-threatening angioedema with the first vasopeptidase inhibitor than with a conventional ACE inhibitor. Whether serious angioedema is an unavoidable side-effect of this class of drugs remains to be determined. Studies also are under way to determine if combining an ACE inhibitor with an ARB provides more complete blockade of the renin-angiotensin system than maximal doses of either drug alone.
Grapefruit juice (even a single glass) increases the bioavailability of dihydropyridine CCBs by inhibiting the intestinal cytochrome P-450 3A4 system, which is responsible for the first-pass metabolism of many medications. This effect is marked with felodipine, which has the least bioavailability of the dihydropyridines, and less with amlodipine and nifedipine, which have greater bioavailability. By inhibiting renal sodium excretion, nonsteroidal anti-inflammatory drugs (NSAIDs), including the cyclooxygenase (COX)-2 inhibitors, can markedly impair the antihypertensive action of diuretics as well as drugs that block the renin-angiotensin system. Because a fall in renin and Ang II levels is a compensatory mechanism that normally serves to counter volume-dependent hypertension, the blood pressure-raising effects of NSAIDs appear to be particularly problematic during ACE inhibitor-based therapy, which interrupts this mechanism. Similar problems may occur with daily doses of aspirin in excess of 325 mg but do not seem to occur with 81 mg per day.
Which Drugs for Which Patients?
Ideally, precise genetic and phenotypic markers would allow each patient to be treated with the best combination of drugs. In the absence of such ideal scientific information, one approach is renin profiling, which is the measurement of PRA to divide primary hypertension into two broad pathophysiologic subsets: (1) PRA of less than 0.65, which implies volume-dependent hypertension requiring diuretics as first-line therapy, and (2) PRA of greater than 0.65, which implies renin-dependent hypertension requiring first-line therapy with one or more drugs that block the renin-angiotensin system, such as ß-blockers, ACE inhibitors, or ARBs. In hypertensive populations, PRA shows a normal distribution, with the lowest values occurring in mineralocorticoid-induced hypertension, the highest values in renovascular hypertension, and a broad distribution of values in primary hypertension. However, because of feedback inhibition of renin release and progressive loss of nephrons, PRA can decrease secondarily with increasing severity and duration of chronic hypertension regardless of the etiology. Whether renin-guided therapy improves patient outcomes remains to be determined.
Pharmacogenetic profiling is another possible approach. A few single-nucleotide polymorphisms have been associated with greater blood pressure reductions with specific drugs. However, none of the reported effects have been large enough to make specific treatment recommendations.
For most patients, the current recommendation is to choose drugs based on comorbidities and the optimization of cardiovascular-renal protection ( Table 63-6 ).
The lower plasma renin levels common in African American hypertensives may suggest volume-dependent hypertension requiring diuretic therapy. Alternatively, lower plasma renin levels may be caused by a longer duration and greater severity of hypertension or by concomitant nephrosclerosis, with the latter being a compelling indication for ACE inhibitor-based therapy (see later). As monotherapy, an ACE inhibitor or a ß-blocker yields a smaller decrease in blood pressure in older hypertensive African American men than in white men. The key point, however, is that when higher doses of an ACE inhibitor, an ARB, or a ß-blocker are used in combination with a thiazide diuretic (or low-sodium diet), antihypertensive efficacy is amplified, and ethnic differences seem to disappear. Because combination therapy is required to reach blood pressure goals in most hypertensive patients, especially those with more severe hypertension and additional cardiovascular risk factors, the results achieved with monotherapy have less and less practical relevance to modern clinical practice.
Hypertension is the second most common cause of chronic renal failure ( Chapter 117 ), accounting for 25% of cases. Hypertensive nephrosclerosis is thought to result from severe constriction of the afferent renal arteriole, resulting in chronic glomerular ischemia. Typically, proteinuria is mild (<0.5 g/24 hr), and the diagnosis should be questioned in the presence of heavier degrees of proteinuria or in the absence of additional target organ damage (retinopathy, LVH). Mild-to-moderate non-diabetic renal insufficiency is now considered to be a compelling indication for ACE inhibitor-based antihypertensive therapy.[11] ACE inhibitors preferentially dilate the efferent renal arteriole, thereby minimizing intraglomerular hypertension. In contrast, arterial vasodilators such as dihydropyridine CCBs, when used without an ACE inhibitor or ARB, preferentially dilate the afferent arteriole, thereby promoting intraglomerular hypertension. This adverse effect on the renal microcirculation opposes the beneficial effect of lowering


Most hypertension
Gout (relative)

Isolated systolic hypertension





Erectile dysfunction

Glucose intolerance, type 2 diabetes

Interstitial nephritis (loop diuretics)
Heart block
Heart block

After MI
Asthma and COPD


Peripheral vascular disease (relative)

Type 2 diabetes

Athletes (relative)
Cold extremities

ACE inhibitors
Diabetic nephropathy

Hypertensive nephrosclerosis
Bilateral renal artery stenosis


After MI


Left ventricular dysfunction

Fetal toxicity
Diabetic (type 2) nephropathy

Bilateral renal artery stenosis
Angioedema (very rare)

ACEI cough
Fetal toxicity
Dihydropyridine CCBs
As monotherapy in chronic renal disease

Isolated systolic hypertension (especially in diabetics)


Ankle edema
Nondihydropyridine CCBs
Heart block

First-degree atrioventricular block

Constipation (often severe)

Worsening of systolic function
Prostatic hypertrophy
As monotherapy for hypertension
Orthostatic hypotension

Orthostatic hypotension
Drug tolerance (in the absence of diuretic therapy)

Ankle edema

ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; CCB = calcium channel blocker; CHF = congestive heart failure; MI = myocardial infarction.

systemic blood pressure. In addition, dihydropyridine CCB monotherapy reflexively increases the activity of the sympathetic and renin-angiotensin systems, which could promote glomerular hypertrophy. In contrast, monotherapy with an ACE inhibitor decreases sympathetic activity in patients with nondiabetic renal insufficiency. In African Americans with moderate hypertensive nephrosclerosis and baseline proteinuria, an ACE inhibitor (ramipril)-based regimen is superior to a dihydropyridine CCB (amlodipine)-based regimen in slowing the progression to renal failure. The ACE inhibitor should be withdrawn only if the rise in serum creatinine exceeds 30% of the baseline value or the serum K+ increases to greater than 5.6 mmol/L.
Compared with its 25% prevalence in the general adult population, hypertension is present in 70% of diabetic patients and is a major factor contributing to excessive risk of myocardial infarction, stroke, heart failure, microvascular complications, and diabetic nephropathy progressing to end-stage renal disease ( Chapter 242 ). To reduce these risks, three current principles should guide therapy. First, in all diabetic patients, blood pressures should be lowered to less than 130/80 mm Hg.[15] Compared with less intensive treatment, more intensive reduction of blood pressure has been proved repeatedly to reduce cardiovascular and microvascular end points dramatically in patients with diabetes. In one study, for example, lowering diastolic blood pressure to 81 versus 85 mm Hg led to a 60% decrease in coronary events, a 43% reduction in stroke, and an impressive 77% decrease in mortality. The cardiovascular benefits of tight blood pressure control in diabetic patients cannot be overemphasized because they exceed and are additive to those of tight glucose control. In addition, tight blood pressure control is the key to retarding the progression of diabetic nephropathy. In those with heavy proteinuria (>1 g/24 hr), additional renal protection may be obtained if blood pressure is lowered to less than 125/75 mm Hg.
Second, to achieve such stringent blood pressure goals typically requires three or four drugs. According to most authorities, the first drug should be an ACE inhibitor or ARB, the second drug a diuretic, and the third a dihydropyridine CCB and/or a ß-blocker. The rationale is as follows.
The third therapeutic principle is that an ACE inhibitor or ARB should be the drug of first choice for the hypertensive diabetic because of mounting evidence that these agents provide special renoprotective and perhaps cardioprotective effects.[10] [12] [13] Type I diabetes with renal insufficiency is a compelling indication for ACE inhibitor-based antihypertensive therapy. Based on consistent results of three recent multicenter trials that examined renal outcomes, type II diabetes with renal insufficiency is now considered by some authorities to be a compelling indication for ARB-based antihypertensive therapy because similar data do not yet exist for ACE inhibitor-based regimens in type II diabetics.[10] [13] However, an ACE inhibitor or ARB alone rarely achieves the stringent blood pressure goals in diabetic patients with renal insufficiency. A loop diuretic is usually needed to shrink the expanded plasma volume. A dihydropyridine CCB is usually needed for antihypertensive synergy. The dihydropyridine CCB should not be started until antihypertensive therapy has been initiated with an ACE inhibitor or ARB. A ß-blocker should be added if the patient has coronary disease, which is prevalent in diabetes or heart failure.
To lower myocardial oxygen demands in patients with coronary artery disease, the antihypertensive regimen should reduce blood pressure without causing reflex tachycardia. ß-Blockers and CCBs are both antianginal and antihypertensive, but dihydropyridine CCBs should not be used without a ß-blocker. ß-Blockers are indicated for hypertensive patients who have sustained a myocardial infarction ( Chapter 69 ) and, in low doses, for most patients with chronic heart failure. ACE inhibitors are indicated for almost all patients with left ventricular systolic dysfunction and may be considered for post-myocardial infarction patients even in the absence of ventricular dysfunction ( Chapter 69 ). In patients with very high cardiovascular risk profiles but without known left ventricular dysfunction, the ACE inhibitor ramipril (10 mg/day) reduces cardiovascular outcomes, an effect that may or may not be beyond what can be explained by blood pressure reductions alone.
In older persons with isolated systolic hypertension, lowering systolic pressure from greater than 160 to less than 150 mm Hg has been unequivocally proved

to reduce the risk of stroke by 30%, myocardial infarction by 23%, and overall cardiovascular mortality by 18%, and to slow the progression of dementia.[6] [14]
Because of slower drug metabolism, slower postural autonomic reflexes, and more prevalent coronary artery disease in older persons, it is important to start with low doses of antihypertensive medications and titrate slowly (over months). Lifestyle modifications such as weight loss and moderate salt reduction reduce medication requirements. To prevent the development of orthostatic hypotension, medications should be titrated to standing blood pressure. For nondiabetic patients, low-dose thiazide diuretics (combined with a potassium-sparing diuretic) are the first-line drugs of choice because of their proved benefit in reducing risks of myocardial infarction and stroke as well as osteoporosis. HCTZ may need to be combined with an ACE inhibitor, an ARB, or a ß-blocker. However, in older persons, ß-blockers should be restricted to those with coronary disease and should be used with caution because they are more likely to precipitate heart block, impair exercise tolerance, or cause depression. For older hypertensive patients with diabetes, dihydropyridine CCBs are considered by many authorities to be the drugs of choice (in combination with an ACE inhibitor or ARB) because of even better cardiovascular outcomes than with thiazide-based therapy.[17] Trial data do not yet exist in older persons to determine whether the treatment of isolated elevations in systolic pressure between 140 and 160 mm Hg is beneficial; however, in the absence of such data, most authorities recommend treatment to prevent progression of systolic hypertension. To avoid precipitating myocardial ischemia, antihypertensive drugs may need to be reduced if diastolic (i.e., coronary perfusion) pressure falls below 65 mm Hg while attempting to lower systolic pressure below 140 mm Hg.
Most authorities do not recommend blood pressure reduction during an acute stroke ( Chapter 440 and Chapter 441 ). In middle-aged or older patients whose clinical condition was stable at least 2 weeks after a stroke or transient ischemic attack, lowering blood pressure by 12/5 mm Hg with a combination of the thiazide diuretic indapamide plus the ACE inhibitor perindopril was shown to reduce the risk of recurrent stroke by 43% in both hypertensive and normotensive patients. In such patients, therefore, a reasonable approach is to lower blood pressure slowly over several months beginning with a thiazide diuretic, adding an ACE inhibitor or additional drugs as needed.[18]
Hypertension Associated with Oral Contraceptives.
Oral contraceptives, particularly current low-dose estrogen preparations, cause a small increase in blood pressure in most women but rarely cause a large increase into the hypertensive range. The mechanism is unknown, but women over 35 and those who smoke or are overweight appear to be at increased risk. If hypertension develops, oral contraceptive therapy should be discontinued in favor of other methods of contraception.
Hypertension in Pregnancy.
Hypertension, the most common nonobstetric complication of pregnancy, is present in about 10% of all pregnancies ( Chapter 253 ). Of these cases, one third are caused by chronic hypertension and two thirds are due to preeclampsia, which is defined as an increase in blood pressure to 140/90 mm Hg or greater after the twentieth week of gestation accompanied by proteinuria and pathologic edema, sometimes accompanied by renal and hepatic abnormalities, and a tendency toward seizures (eclampsia). Given the current trend of childbearing in women over age 35, the incidence of chronic hypertension in pregnancy is rising. a-Methyldopa remains the drug of choice for chronic hypertension in pregnancy, and hydralazine remains the drug of choice for preeclampsia. In the latter condition, magnesium sulfate is predictably effective in preventing seizures but, despite being a vasodilator, has inconsistent effects on blood pressure.
Hypertension after Menopause.
In large clinical trials, oral estrogen replacement therapy has a neutral effect on blood pressure. In normotensive women, transdermal estrogen therapy has been shown to cause a small but consistent decrease in blood pressure. It is unclear whether routes of administration that bypass hepatic first-pass metabolism may unmask an antihypertensive effect of estrogen replacement therapy.
Defined as blood pressure that is not less than 140/90 mm Hg despite treatment with adequate doses of three different classes of medications, resistant hypertension is the most common reason for referral to a hypertension specialist. In practice, the problem usually falls into one of four categories: (1) pseudo-resistance, (2) an inadequate medical regimen, (3) noncompliance or ingestion of pressor substances, or (4) secondary hypertension. Pseudo-resistant hypertension is caused by either the white coat effect or panic attacks and is best diagnosed with ambulatory monitoring. The most common cause of apparent drug resistance is the absence of appropriate diuretic therapy: either no diuretic, inappropriate use of a loop diuretic in a patient with normal renal function, infrequent dosing with a short-acting loop diuretic (e.g., once-a-day furosemide), or a thiazide diuretic in a patient with impaired renal function. It is important to remember that significant impairment in renal function can be present with serum creatinine in the 1.2 to 1.4 mg/dL range or even lower. Other common shortcomings of the medical regimen include reliance on monotherapy and inadequate dosing. Several common causes of resistant hypertension are related to the patient’s behavior: noncompliance with the medical regimen, noncompliance with lifestyle modifications (obesity, a high-salt diet, excessive alcohol intake), or habitual use of pressor substances such as sympathomimetics (tobacco, cocaine, amphetamines, phenylephrine-containing herbal remedies) or NSAIDs, with the latter causing renal sodium retention. Once these causes of resistant hypertension have been excluded, the search should begin for secondary causes of hypertension (see earlier).
Twenty-five percent of all emergency department patients present with an elevated blood pressure. Hypertensive emergencies are acute, severe elevations in blood pressure that are accompanied by progressive target organ dysfunction such as myocardial or cerebral ischemia/infarction, pulmonary edema, or renal failure. Hypertensive urgencies are acute, severe elevations in blood pressure without evidence of progressive target organ dysfunction. Thus, the key distinction and approach to the patient depend on the clinical state of the patient and not the absolute level of blood pressure. Chronically elevated blood pressure, even when severe, does not necessitate urgent treatment. The full blown clinical picture of a hypertensive emergency is a critically ill patient who presents with a blood pressure greater than 220/140 mm Hg, headaches, confusion, blurred vision, nausea and vomiting, seizures, grade III or IV hypertensive retinopathy, heart failure, and oliguria. Hypertensive emergencies require immediate intensive care unit (ICU) admission for intravenous therapy and continuous blood pressure monitoring, whereas hypertensive urgencies often can be managed with oral medications and appropriate outpatient follow-up in 24 to 72 hours. The most common hypertensive cardiac emergencies include acute aortic dissection ( Chapter 75 ), hypertension after coronary artery bypass graft surgery ( Chapter 71 ), acute myocardial infarction ( Chapter 69 ), and unstable angina ( Chapter 68 ). Other hypertensive emergencies include eclampsia ( Chapter 253 ), head trauma ( Chapter 431 ), severe body burns ( Chapter 108 ), postoperative bleeding from vascular suture lines, and epistaxis that cannot be controlled with anterior and posterior nasal packing. Neurologic emergencies—acute ischemic stroke, hemorrhagic stroke, subarachnoid hemorrhage, and hypertensive encephalopathy—can be difficult to distinguish from one another ( Chapter 439 , Chapter 440 , and Chapter 441 ). Hypertensive encephalopathy ( Chapter 441 ) is characterized by severe hypertensive retinopathy (retinal hemorrhages and exudates, with or without papilledema) and a posterior leukoencephalopathy (affecting mainly the white matter of the parieto-occipital regions) seen on cerebral MR imaging or CT scanning. A new focal neurologic deficit suggests a stroke-in-evolution, which demands a much more conservative approach to the elevated blood pressure ( Chapter 440 ).
In most other hypertensive emergencies, the goal of parenteral therapy is to achieve a controlled and gradual lowering of blood pressure. A good rule of thumb is to lower the initially elevated arterial pressure by 10% in the first hour and by an additional 15% over the next 3 to 12 hours to a target blood pressure of about 170/110 mm Hg. Blood pressure can be reduced to a more normal value over the next 48 hours. The principal exceptions to this rule are aortic dissection ( Chapter 75 ) and postoperative bleeding from vascular suture lines, two situations that demand much more rapid normalization of blood pressure. In most other cases, unnecessarily rapid correction of the elevated blood pressure to completely normal values places the patient at high risk for worsening cerebral, cardiac, and renal ischemia. In chronic hypertension, cerebral autoregulation is reset to higher-than-normal blood pressures. This compensatory adjustment prevents tissue over-perfusion (increased intracranial pressure) at very high blood pressures, but it also predisposes to tissue underperfusion (cerebral ischemia) when an elevated blood pressure is lowered too quickly


Sodium nitroprusside
0.25–10 µg/kg/min IV infusion
Thiocyanate toxicity with prolonged use
5–100 µg/min IV infusion
2–5 min
Headache, tachycardia, tolerance
5–15 mg/h IV infusion
1–5 min
Protracted hypotension after prolonged use
Fenoldopam mesylate
0.1–0.3 µg/kg/min IV infusion
1–5 min
Headache, tachycardia, increased intraocular pressure
5–10 mg as IV bolus or 10–40 mg IM repeat q4-6 h
10 min IV
Unpredictable and excessive falls in pressure; tachycardia; angina exacerbation

20 min IM

0.625–1.25 mg q6 h IV bolus
15–60 min
Unpredictable and excessive falls in pressure; acute renal failure in patients with bilateral renal artery stenosis
20–80 mg as slow IV injection q10 min, or 0.5–2 mg/min IV as infusion
5–10 min
Bronchospasm, heart block, orthostatic hypotension
5 mg IV q10 min × 3 doses
5–10 min
Bronchospasm, heart block, heart failure, exacerbation of cocaine-induced myocardial ischemia
500 µg/kg IV over 3 min then 25–100 mg/kg/min as IV infusion
1–5 min
Bronchospasm, heart block, heart failure
5–10 mg IV bolus q5-15 min
1–2 min
Tachycardia, orthostatic hypotension

( Chapter 440 ). In patients with coronary disease, overly rapid or excessive reduction in diastolic blood pressure in the ICU can precipitate myocardial ischemia or infarction.
After the blood pressure has been brought under acute control, oral labetalol and dihydropyridine CCBs are particularly useful agents in weaning patients from parenteral therapy so they can be transferred from the ICU. A few doses of intravenous furosemide are often needed to overcome drug resistance due to secondary volume expansion resulting from parenteral vasodilator therapy.
Secondary causes of hypertension should be considered in every patient admitted to the ICU with a hypertensive crisis. Normal 24-hour urinary catecholamines or a normal plasma normetanephrine and metanephrine collected when the blood pressure is the highest (first 24 hours in ICU) effectively rules out pheochromocytoma ( Chapter 241 ). Renal artery stenosis and other secondary causes should be excluded after the patient has been transferred out of the ICU but before being discharged from the hospital ( Chapter 124 ).
Parenteral Agents for Hypertensive Emergency.
Sodium nitroprusside, a nitric oxide donor that causes both venous and arterial dilation, is the most popular agent because it can be titrated rapidly to control blood pressure ( Table 63-7 and Table 63-8 ). Intravenous nitroglycerin, another nitric oxide donor, is useful for reducing moderately elevated blood pressure in the setting of myocardial ischemia or infarction, but, compared with nitroprusside, the lowering of blood pressure is less predictable. Nicardipine is a parenteral dihydropyridine CCB that is particularly useful in the postoperative cardiac patient. Fenoldopam is a selective dopamine-1 receptor agonist that causes both systemic and renal vasodilation, as well as increased glomerular filtration, natriuresis, and diuresis. Intravenous labetalol is an effective treatment of hypertensive crisis particularly in the setting of myocardial ischemia with preserved ventricular function.
Oral Medications for Hypertensive Urgencies.
Most patients who present to the emergency department with hypertensive urgencies either are noncompliant with their medical regimen or are being treated with an inadequate regimen. To expedite the necessary changes in medications, outpatient follow up should be arranged within 72 hours. To manage the patient during the short interim period, labetalol is effective in a dose of 200 to 300 mg, which can be repeated in 2 to 3 hours and then prescribed in twice-daily dosing. If a ß-blocker is contraindicated, clonidine is effective in an initial dose of 0.1 or 0.2 mg followed by additional hourly doses of 0.1 mg. Patients can be discharged on 0.1 to 0.2 mg twice daily. Captopril, a short-acting ACE inhibitor, lowers blood pressure within 15 to 30 minutes of oral dosing. A small test dose of 6.25 mg should be used to avoid an excessive fall in blood pressure in hypovolemic patients; then, the full oral dose is 25 mg, which can be repeated in 1 to 2 hours and prescribed as 25–75 mg twice daily.
One of the most important prognostic factors in hypertension is electrocardiographic or echocardiographic LVH, with the latter

Myocardial ischemia/infarction
ß-Blocker + nitroprusside (or nicardipine); titrate to eliminate ischemia
Heart failure
Furosemide + nitroprusside (or fenoldopam)
Aortic dissection
ß-Blocker + nitroprusside to lower SBP to <120 mm Hg in 20 min
Postcardiac surgery hypertension
Bleeding from suture lines
Nicardipine; titrate to stop the bleeding
Uncontrolled epistaxis
Nitroprusside + short-acting anxiolytic
Hypertensive encephalopathy
Nitroprusside or nicardipine or fenoldopam
Acute stroke in evolution
No antihypertensive therapy (controversial)
Subarachnoid hemorrhage
Hematuria or acute deterioration in renal function
Phentolamine or nitroprusside + labetolol
Cocaine or amphetamines
Phentolamine or nitroprusside + labetolol
Clonidine withdrawal
MgSO4 for seizures and methyldopa + hydralazine to lower diastolic pressure below 90 mm Hg (oral nifedipine and oral labetolol are second-line drugs before cesarean section)
Modified from Calhoun DA: Hypertensive crisis. In Oparil S and Weber MA (eds): Hypertension: A Companion to Brenner and Rector’s The Kidney. Philadelphia, WB Saunders, 2000, pp 715–718.

already present in as many as 25% of patients with newly diagnosed hypertension. In a multicenter observational study of hypertensive patients with no prior history of cardiovascular or renal disease, echocardiographic LVH at baseline was accompanied by a 3-fold increase in the cumulative 4-year incidence of cardiovascular events ( Fig. 63-10 ).
Because of the firmly established prognostic significance of LVH, numerous studies have examined the ability of antihypertensive therapy to cause regression of LVH. Meta-analyses, mostly of trials of monotherapy, estimate that left ventricular mass can be reduced by 11 to 12% with an ACE inhibitor or a CCB, by 8% with a thiazide diuretic, and by only 5% with a ß-blocker. In contrast, in patients

Figure 63-10 Cumulative incidence (left) and crude rate (right) of cardiovascular (CV) events in hypertensive patients with and without echocardiographic left ventricular hypertrophy, defined as a left ventricular (LV) mass index of greater than 125 g per body surface area (BSA). (From Verdecchia P, Carini G, Circo A, et al: J Am Coll Cardiol 2001;38:1829–1835.)

Figure 63-11 Meta-analysis of randomized controlled intervention trials. The difference in systolic blood pressure between placebo and active treatment or between less intense and more intense treatment for hypertension is plotted against the relative risk of fatal or nonfatal cardiovascular events. Within the 95% confidence intervals used in this regression analysis, the reduction in cardiovascular mortality afforded by the various antihypertensive treatment regimens in these large numbers of trials is linearly related to the magnitude of blood pressure lowering. (From Staessen JA, Wang JG, Thijs L: Cardiovascular protection and blood pressure reduction: A meta-analysis. Lancet 2001;358:1305–1315.)
undergoing valve replacement for aortic stenosis, near-complete surgical normalization of systolic load results in a rapid and dramatic 35% reduction in left ventricular mass. The comparatively disappointing effects of the antihypertensive drug trials are likely related to the incomplete normalization of systolic load with monotherapy, and there is no evidence that differentiated effects on LVH should be the dominant determinant in the choice among antihypertensive medications.
Randomized controlled trials have provided unequivocal evidence that intensive lowering of blood pressure with combination therapy greatly reduces the risks of fatal and nonfatal cardiovascular events associated with untreated or inadequately treated hypertension. Until further evidence is provided, most of the cardiovascular benefit is explained by lowering the blood pressure per se rather than by the specific types of antihypertensive medication selected[10] ( Fig. 63-11 ).
Despite the impressive body of randomized clinical trial data, it remains to be determined whether even intensive antihypertensive therapy can completely normalize the excessive risks of cardiovascular and renal disease associated with untreated hypertension. In a large hypertensive referral clinic in Gothenburg, Sweden, treating hypertension in initially middle-aged men to a goal of 160/90 to 95 mm Hg with diuretics and ß-blockers for 20 years did not completely normalize the risk of myocardial infarction. The persistently elevated risks in the treated patients were related to the existence of associated risk factors, such as cigarette smoking and elevated blood lipids, and emphasize the need for global risk reduction and more intensive reductions in blood pressure. Randomized trials have not yet established whether even lower blood pressure goals than those presently endorsed would produce further reductions in cardiovascular morbidity and mortality and in the risk of end stage renal disease. Because of their relatively short duration (typically <5 years), randomized trials probably underestimate the protection against premature disability and death afforded by long-term antihypertensive therapy in clinical practice. In the Framingham Heart Study, treating hypertension for 20 years in middle-aged adults reduced total cardiovascular mortality by 60%, which is considerably greater than the results of most randomized trials despite the less intense treatment guidelines when therapy was initiated in the 1950s–1970s.



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