Hypertension

From WiserWiki

Contents 1 Hypertension 1.1 EPIDEMIOLOGY 1.2 PATHOPHYSIOLOGY 1.3 DETECTING HYPERTENSION 1.4 PATIENT EVALUATION 1.4.1 Goals of Initial Evaluation 1.4.2 Assessing Individual Risk 1.5 CLINICAL AND LABORATORY EXAMINATION 1.5.1 History 1.5.2 Physical Examination 1.5.3 Laboratory Evaluation 1.5.4 Determining Secondary Causes 1.6 ESTIMATING BENEFITS OF TREATMENT FOR THE INDIVIDUAL 1.7 MANAGEMENT 1.7.1 Nonpharmacologic Therapy 1.7.2 Lifestyle Interventions. 1.7.3 Exercise. 1.7.4 Diet. 1.7.5 Weight Loss. 1.7.6 Reducing Alcohol Intake. 1.7.7 Salt Restriction. 1.7.8 Dietary Supplementation (Table 60-7). 1.7.9 Potassium Supplementation. 1.7.10 Fish Oil Supplementation. 1.7.11 Calcium and Magnesium Intake. 1.7.12 Relaxation and Biofeedback. 1.7.13 Smoking Cessation. 1.7.14 Pharmacologic Therapy 1.7.15 Specific Drug Treatment Choices. 1.7.16 Harms and Adverse Effects of Pharmacotherapy. 1.7.17 Specific Oral Antihypertensive Agents. 1.7.18 Diuretics 1.8 Thiazide diuretics. 1.9 Loop diuretics: ethacrynic acid, furosemide, bumetanide. 1.10 Potassium-sparing diuretics: triamterene, amiloride, spironolactone. 1.10.1 Sympatholytic Agents. 1.10.2 Central Inhibition of Sympathetic Drive 1.11 Clonidine, guanabenz, and guanfacine. 1.12 Methyldopa. 1.12.1 Peripheral Adrenergic Inhibitors. 1.12.2 α-Adrenergic Blockers. 1.13 Combination α- and β-blockers. 1.14 Vasodilating agents. 1.14.1 Angiotensin-Converting Enzyme Inhibitors. 1.14.2 Angiotensin II–Receptor Blockers. 1.14.3 Calcium Channel Blockers. 1.14.4 Combination Drugs. 1.14.5 Combined Lifestyle Modifications and Pharmacologic Treatment 1.14.6 Target Blood Pressures and Therapy Titration 1.14.7 Antithrombotic Treatment in Hypertensive Patients 1.15 SPECIAL ISSUES 1.15.1 Resistant Hypertension 1.15.2 Poor Adherence to Drug Regimen. 1.15.3 Sodium Retention. 1.15.4 Excessive Alcohol Intake. 1.15.5 Secondary Hypertension. 1.15.6 Substitute More Potent Antihypertensive Agents. 1.15.7 Noncompliance with Treatment 1.16 EVIDENCE-BASED MEDICINE 1.17 REFERENCES

[edit] Hypertension

Cynthia Mulrow

Richard M. Hoffman

Harry L. GreeneII

Curtis Kapsner

The upper limit of normal adult blood pressure has been defined as 140/90 mm Hg. The Joint National Committee (JNC-VI) on Detection, Evaluation, and Treatment of High Blood Pressure further classifies hypertension into three stages based on systolic and diastolic blood pressures (Table 60-1).

Table 60-1 Classification of Blood Pressure for Adults Age 18 and Older✢

From JNC-VI.

Category	Systolic (mm Hg)		Diastolic (mm Hg)
Optimal†	<120	and	<80
Normal	<130	and	<85
High-normal	130-139	or	85-89
Hypertension‡
Stage 1	140-159	or	90-99
Stage 2	160-179	or	100-109
Stage 3	≥180	or	≥110

✢Not taking antihypertensive drugs and not acutely ill. When systolic and diastolic blood pressures fall into different categories, the higher category should be selected to classify the individual's blood pressure status. For example, 160/92 mm Hg should be classified as stage 2 hypertension, and 174/120 mm Hg should be classified as stage 3 hypertension. Isolated systolic hypertension is defined as SBP of 140 mm Hg or greater and DBP below 90 mm Hg and staged appropriately (e.g., 170/82 mm Hg is defined as stage 2 isolated systolic hypertension). In addition to classifying stages of hypertension on the basis of average blood pressure levels, physicians should specify presence or absence of target organ disease and additional risk factors. This specificity is important for risk classification and treatment (Table 60-2).However, unusually low readings should be evaluated for clinical significance.

†Optimal blood pressure with respect to cardiovascular risk is below 120/80 mm Hg.

‡Based on the average of two or more readings taken at each of two or more visits after an initial screening.

Nearly 60 million Americans have high blood pressure or are being treated with antihypertensive medications. The annual cost for hypertension, including medications, office visits, and laboratory visits, is estimated to be more than $10 billion. Although these direct costs alone are substantial, hypertension also contributes to hundreds of thousands of premature deaths each year, and is a leading risk factor for congestive heart failure, renal failure, stroke, coronary artery disease, and retinopathy.

Recognition of the public health burden from high blood pressure led to the creation of the National High Blood Pressure Education Program in 1972. Ongoing educational efforts, including publication of consensus guidelines, have considerably improved the detection, treatment, and control of hypertension. In 1972, National Health and Nutrition Examination Survey (NHANES II) data showed that only half of hypertensive patients were aware of their condition and only one in six cases was adequately controlled. By 1991, 73% of hypertensive patients were aware of their high blood pressure and nearly 30% of all cases were adequately controlled. This trend toward increased awareness and control has not been maintained, however. NHANES III (Phase 2) data collected from 1991 to 1994 showed that only 68% of hypertensive patients were aware of their high blood pressure and only 27% were controlled to a systolic pressure below 140 mm Hg and a diastolic pressure below 90 mm Hg.

[edit] EPIDEMIOLOGY

Hypertension is more prevalent with increasing age and in African-Americans, among the less educated, and in lower socioeconomic classes. Most diastolic hypertension develops in the second and third decades, although it can occur at any age. In young adulthood and early middle age, hypertension is more prevalent in men than in women, but this reverses after age 60. Isolated systolic hypertension is seen most often in the elderly.

Between 1972 and 1994, age-adjusted mortality from coronary heart disease decreased approximately 53%, and mortality from stroke decreased by nearly 60%. These declines have been observed for men and women, and for African-Americans and whites. Part of the decline is attributable to decreases in cigarette smoking and fat intake, but improved control of high blood pressure has also been an important factor. There is convincing evidence from randomized, placebo-controlled intervention trials that antihypertensive therapy reduces the risk of cardiovascular disease. A consistent finding has been a substantial decrease in the risk of stroke, with a more modest effect on coronary artery disease. Psaty et al's 1997 meta-analysis of 18 placebo-controlled trials estimated a 36% to 51% reduction in the incidence of strokes and a 1% to 28% decrease in the incidence of coronary heart disease (CHD) events.^[1]

[edit] PATHOPHYSIOLOGY

Although the exact mechanism remains elusive, many steps in the regulation of blood pressure have been discovered and a number of pathogenic mechanisms have been suggested. Blood pressure (BP) is related to cardiac output (CO) and peripheral vascular resistance (PVR). Cardiac output, in turn, is related to stroke volume and heart rate. These formulas are shown below:

BP = CO × PVR

CO = Stroke Volume × Heart Rate

Stroke volume is largely related to the venous return of blood to the heart and to cardiac contractility. A number of other organs interact through feedback loops to maintain an adequate blood pressure. Any change in blood pressure is sensed by baroreceptors located throughout the circulatory system. The receptors send afferent signals to the central nervous system (CNS), which sends efferent output to the adrenal glands that is relayed through the autonomic nervous system to the heart and blood vessels. These feedback mechanisms can increase or decrease heart rate. Catecholamine secretion may increase or decrease, leading to either vasoconstriction or vasodilatation, respectively.

Additionally, the renin-angiotensin-aldosterone system allows the kidney to play a major role in blood pressure control. Renin, a proteolytic enzyme produced by smooth muscle cells in the juxtaglomerular apparatus of the afferent arteriole in the kidney, is released in response to decreased renal perfusion pressures, low sodium concentration, and β-adrenergic stimulation.

In the liver, an α-globulin, called renin substrate, is synthesized and released into the circulation. Renin acts on this substrate to produce a decapeptide called angiotensin I, which is converted to angiotensin II after exposure to a converting enzyme in the lungs and other organs, including the heart, and blood vessels. Angiotensin II regulates renal sodium uptake, acts as a powerful vasoconstrictor, and stimulates the adrenal cortex to produce aldosterone. These effects are mediated through the binding of angiotensin II to the angiotensin II type I receptor in the various target tissues. Aldosterone acts on the renal tubules to promote the reabsorption of sodium and water. Plasma volume is increased through this reabsorption, thus increasing cardiac output. The combination of aldosterone (increasing volume) and angiotensin II (producing vasoconstriction) increases blood pressure. This process is turned off when the juxtaglomerular apparatus in the kidney decreases renin production after fluid volume, blood pressure, and angiotensin II reach threshold levels.

A number of other factors that affect blood pressure have been identified, including factors from vascular endothelial cells, the atrial natriuretic factor, calcium-regulating hormones, the kallikrein system, and vasopressin. Vascular endothelial cells produce both endothelin, a vasoconstrictor, and nitric oxide, a relaxing factor. The interplay of these substances may control vascular pressure at the local level. Another peptide, atrial natriuretic factor, is produced by atrial tissue in response to atrial dilation. This hormone causes vasodilatation, increases the glomerular filtration rate, and enhances sodium excretion. Atrial natriuretic factor release is associated with decreased renin and aldosterone secretion.

Kininogen is a plasma substrate synthesized in the liver and acted on by kallikrein (from the kidney) to produce bradykinin. Bradykinin is converted into inactive bradykinin by angiotensin-converting enzyme (ACE), the same enzyme that converts angiotensin I to angiotensin II. The calcium-controlling hormones, calcitriol (vasoconstrictor) and parathyroid hormone (vasodilator), also have vascular effects on blood pressure. Finally, antidiuretic hormone (ADH), or vasopressin, is produced by the pituitary and released in response to major hemorrhage, severe stress, or head injury. ADH is a potent vasoconstrictor and causes increased sodium and water reabsorption.

[edit] DETECTING HYPERTENSION

Hypertension control begins by routinely detecting and confirming high blood pressure. In the office, three separate readings should be taken and averaged. Kaplan has provided useful guidelines for measuring blood pressure (Box 60-1). Hypertension should not be diagnosed or treated on the basis of initial readings unless the patient has evidence of acute target-organ damage (hypertensive crisis or urgency). Table 60-2 shows recommended intervals for following elevated blood pressures.

Table 60-2 Rechecking Blood Pressures

Systolic	Diastolic	Follow-up frequency
<130	<85	2 years
130-139	85-89	1 year
140-159	90-99	2 months
160-179	100-109	Evaluate or refer ≤1 month
≥180	≥110	Evaluate or refer immediately

Box 60-1 - Guidelines for Measuring Blood Pressure✢

Conditions for the patient. Posture Some prefer readings after the patient has been supine for 5 minutes. Sitting pressures usually adequate. Patient should sit quietly with back supported for 5 minutes and the arm supported at the level of the heart. For patients who are over age 65, diabetic, or receiving antihypertensive therapy, check for postural changes by taking readings immediately and 2 minutes after the patient stands. Circumstances No caffeine for the preceding hour. No smoking for the preceding 15 minutes. No exogenous adrenergic stimulants (e.g., phenylephrine in nasal decongestants or eyedrops for pupillary dilation). A quiet warm setting. Home readings taken under varying circumstances: 24-hour ambulatory recordings may be preferable and more accurate in predicting subsequent cardiovascular disease. Equipment Cuff size: The bladder should encircle and cover two thirds of the length of the arm. If not, place the bladder over the brachial artery. If the bladder is too small, spuriously high readings may result. Manometer: Aneroid gauges should be calibrated every 6 months against a mercury manometer. (Do not use finger monitors.) Technique Number of readings On each occasion, take at least two readings, separated by as much time as is practical. If readings vary by more than 5 mm Hg, take additional readings until two are close. For diagnosis, obtain three sets of readings at least a week apart. Initially, take pressure in both arms; if pressure differs, use arm with higher pressure. If arm pressure is elevated, take pressure in one leg, particularly in patients below age 30. Performance Inflate the bladder quickly to a pressure of 20 mm Hg above the systolic, as recognized by the disappearance of the radial pulse. Deflate the bladder 3 mm Hg every second. Record the Korotkoff's phase V (disappearance) except in children, in whom use of phase IV (muffling) is advocated. If Korotkoff's sounds are weak, have the patient raise the arm and open and close the hand five to ten times, after which the bladder should be inflated quickly. ✢Modified from Kaplan NM: Arterial hypertension. In Stein JH et al, editor: Internal medicine, ed 4, St Louis. 1994, Mosby.

Ambulatory readings may help to assess blood pressure. "White-coat" hypertension or elevated blood pressure readings occurring only in the office setting may occur in as many as 10% to 25% of subjects. Studies have shown that ambulatory blood pressures correlate better with target-organ damage, particularly left ventricular hypertrophy, and with cardiovascular complications. Regression to the mean also occurs in measuring blood pressure; high pressures tend to be lower when repeated. Readings taken during emergency room visits for trauma or painful complaints should be interpreted cautiously since they are known to be misleadingly high. Conversely, hypertensive patients hospitalized with bed rest often have misleadingly low pressures. These patients may be discharged without adequate blood pressure medication, only to remanifest their hypertension soon after leaving the hospital.

Physicians should also be aware of pseudohypertension, although exact age-specific prevalences are unknown. Some elderly patients have stiff, noncompliant atheromatous arteries that can be occluded only with very high sphygmomanometric pressures, leading to falsely elevated blood pressure readings. In these patients, an intraarterial pressure reading is the only way to truly determine the blood pressure; Osler's maneuver is inaccurate. Unfortunately, determining intraarterial pressure is impractical for most patients. Pseudohypertension should be suspected in elderly patients with chronically elevated blood pressures, widened pulse pressures, orthostatic hypotension on medication, and no evidence of target-organ damage.

[edit] PATIENT EVALUATION

[edit] Goals of Initial Evaluation

The goals of initial evaluation are assessing the patient's individual risk of cardiovascular disease, the presence of target-organ damage, and whether secondary causes of hypertension warrant consideration.

[edit] Assessing Individual Risk

Assessment of individual risk is necessary to optimize decisions about whom to treat with what therapy (Table 60-3). It also identifies important comorbid cardiovascular risk factors that warrant treatment. The risk for cardiovascular morbidity and mortality increases with higher levels of systolic and diastolic pressures, and is synergistically related to the presence of other cardiovascular risk factors and target-organ damage (Box 60-2). For example, Framingham data showed that the 8-year cardiovascular risk from diastolic hypertension for 40-year-old men increased tenfold in the presence of high cholesterol, cigarette smoking, and diabetes mellitus. Simple risk equations and tables based on level of blood pressure and the presence of other risk factors (Figs. 60-1 and 60-2) are used to estimate a patient's pretreatment risk and the likely benefit of therapy.

Table 60-3 Risk Stratification and Treatment✢

From JNC-VI.

	Risk group A	Risk group B	Risk group C
Blood pressure stages (mm Hg)	No risk factors; no TOD/CCD†	At least one risk factor, not including diabetes; no TOD/CCD†	TOD/CCD† and/or diabetes, with or without other risk factors
High-normal (130-139/85-89)	Lifestyle modification	Lifestyle modification	Drug therapy§
Stage 1 (140-159/90-99)	Lifestyle modification (up to 12 months)	Lifestyle modification‡ (up to 6 months)	Drug therapy
Stages 2 and 3 (≥160/≥100)	Drug therapy	Drug therapy	Drug therapy

✢Lifestyle modification should be adjunctive therapy for all patients recommended for pharmacologic therapy. For example, a patient with diabetes and a blood pressure of 142/94 mm Hg plus left ventricular hypertrophy should be classified as having stage 1 hypertension with target-organ disease (left ventricular hypertrophy) and with another major risk factor (diabetes). This patient would be categorized as Stage 1, Risk Group C, and recommended for immediate initiation of pharmacologic treatment.

†TOD/CCD indicates target-organ disease/clinical cardiovascular disease.

‡For patients with multiple risk factors, physicians should consider drugs as initial therapy plus lifestyle modifications.

§For those with heart failure, renal insufficiency, or diabetes.

Box 60-2 - Components of Cardiovascular Risk Stratification in Patients with Hypertension

Major Risk Factors Smoking Dyslipidemia Diabetes mellitus Age older than 60 years Sex (men and postmenopausal women) Family history of cardiovascular disease: women under age 65 or men under age 55 Target-Organ Damage/Clinical Cardiovascular Disease Heart diseases Left ventricular hypertrophy Angina/prior myocardial infarction Prior coronary revascularization Heart failure Stroke or transient ischemic attack Nephropathy Peripheral arterial disease Retinopathy

[edit] CLINICAL AND LABORATORY EXAMINATION

[edit] History

Hypertension is usually asymptomatic, and is often detected only during routine screening. Patients with elevated pressures should be questioned about symptoms of cardiovascular, cerebrovascular, and renal disease and about family history of high blood pressure, cardiovascular disease, or diabetes. If hypertension has already been diagnosed, the patient should be asked about the duration and levels of blood pressure, any complications of hypertension, and the types and results of previous treatments. The history should also identify other cardiovascular risk factors, such as smoking, hyperlipidemia, inactivity, obesity, and diabetes mellitus. Other important factors to ask about include drug use and dietary intake of salt, cholesterol, and saturated fats.

A quick review of systems may suggest possible causes of secondary hypertension. Suggestive symptom clusters of uncommon secondary causes include episodic headaches, palpitations, orthostatic hypotension, pallor, and sweating (pheochromocytoma), and weight gain, central obesity, striae, hirsutism, myopathy, and amenorrhea (Cushing's syndrome).

[edit] Physical Examination

A rational physical examination in the hypertensive patient ideally includes checking for evidence of increased cardiovascular disease risk factors and target-organ damage, and for findings that may suggest secondary causes of hypertension. The most efficient and accurate examination for these checks is unknown. Many experts recommend measuring blood pressure in both arms and using the arm with the higher reading for subsequent monitoring. In patients less than age 30 years, blood pressure differences between arms and legs may be measured if coarctation of the aorta is being considered. In older patients and those with orthostatic symptoms, postural changes in blood pressures are important. Weight and height should be checked to estimate body mass index. Waist-to-hip circumference ratios may be measured to help establish risk of cardiovascular disease: ratios greater than 0.8 in women and greater than 1.0 in men correlate with higher risks.

Some experts recommend examining the optic fundus for evidence of retinopathy, although the accuracy of this examination in undilated eyes is likely to be low. Quickly examining the neck for thyroid abnormalities, elevated jugular pressure, and carotid bruits may be useful. Cardiovascular examination should focus on detection of dysrhythmias (atrial fibrillation is common in older hypertensive patients); S3 gallops, which may indicate systolic dysfunction; and murmurs. The presence or absence of rales and edema should be noted. Abdominal bruits, especially those that lateralize or have a diastolic component, may suggest renovascular disease. In some instances, abdominal aortic aneurysms may be palpable. Diminished peripheral pulses may suggest atherosclerosis. A neurologic examination including a cognitive status screen may help establish target-organ damage.

[edit] Laboratory Evaluation

Routine laboratory testing should include urinalysis, fasting blood sugar, potassium, urea nitrogen, creatinine, total cholesterol, high-density lipoprotein (HDL), and an electrocardiogram (ECG). The ECG, urinalysis, and renal panel help to determine the extent of hypertensive target-organ damage; fasting blood sugar and lipids identify other cardiovascular risk factors, and potassium levels provide baseline values for following the biochemical effects of therapy. Some experts also recommend complete blood count, 24-hour protein, low-density lipoprotein (LDL), glycosylated hemoglobin, and uric acid levels.

[edit] Determining Secondary Causes

Essential (primary) hypertension affects more than 90% of hypertensive patients and has no identifiable cause. Secondary causes are present in less than 10% of hypertensive patients, and many secondary causes are very uncommon (Box 60-3). Demographic, historical, symptomatic, physical, and laboratory findings may increase suspicion of secondary causes, although the actual sensitivity, specificity, and utility of using particular clusters of findings to guide workup for secondary hypertension is not well studied. Fig. 60-3 shows examples of clusters of findings that may suggest particular workups.

Box 60-3 - Possible Causes of Hypertension

Most Common (>90%prevalence) Essential or primary hypertension Less Common (1-10%prevalence) Renal parenchymal disease (e.g., glomerulonephritis, chronic nephritis, diabetic nephropathy, hydronephrosis, connective tissue disease, polycystic disease) Renovascular disease Acute stress (e.g., alcohol withdrawal, surgery, acute illness) Drugs (e.g., nonsteroidal antiinflammatory drugs [NSAIDs], estrogen, appetite suppressants, corticosteroids, sympathomimetics) Primary aldosteronism Uncommon (<1%Prevalence) Renal Renin-producing tumors Renoprival Primary sodium retention (Liddle syndrome, Gordon syndrome) Endocrine Acromegaly Hypothyroidism Hyperthyroidism Hypercalcemia (hyperparathyroidism) Cushing's syndrome Congenital adrenal hyperplasia Pheochromocytoma Extra-adrenal chromaffin tumors Carcinoid Mineralocorticoids: licorice Tyramine-containing foods and monoamine oxidase inhibitors Vascular Coarctation of the aorta Neurologic disorders Brain tumor Encephalitis Respiratory acidosis Quadriplegia Acute porphyria Familial dysautonomia Lead poisoning Guillain-Barré syndrome Increased cardiac output Aortic valvular regurgitation Arteriovenous fistula, patent ductus Thyrotoxicosis Paget's disease of bone Beriberi Hyperkinetic circulation

Briefly, secondary hypertension, by definition, has an identifiable underlying cause. Secondary hypertension should be suspected in patients presenting with sudden onset or worsening of hypertension, refractory hypertension, onset before age 20 or after age 50, malignant or accelerated hypertension, or suggestive features on initial clinical examination. Although less than 5% of hypertensive patients have secondary hypertension, this accounts for nearly 3 million people in the United States. Searching for a secondary cause is important because the hypertension may be curable.

The most common cause of secondary hypertension is renal parenchymal disease, which is responsible for 2% to 3% of all hypertension. The diagnosis is based on finding elevated blood urea nitrogen (BUN) and creatinine, decreased creatinine clearance, and an abnormal urinalysis.

Renovascular disease (RVD) accounts for approximately 1% of hypertension and is suggested by severe or resistant hypertension (diastolic blood pressure greater than or equal to 125 mm Hg), other evidence of vascular disease, a suggestive abdominal bruit (up to 50% of RVD patients in contrast to 9% of those with essential hypertension), worsening renal function (especially after being placed on an ACE-inhibitor), occurrence in younger women or older men, and asymmetric renal size. Although renal vascular disease can be caused by cholesterol or clot emboli, aortic dissection, compression of the arteries, or vasculitis, the most frequent etiologies are fibromuscular dysplasia and atherosclerosis. Fibromuscular dysplasia occurs principally in young, white women, whereas the more common atherosclerosis is often seen in elderly men.

Workup for renovascular disease should only be initiated in patients who are candidates for either angioplasty or surgical revascularization. Renal arteriography may be the initial step in the evaluation of patients in whom there is a high degree of suspicion for RVD because it is the gold standard for imaging the renal arteries. Also, arteriography should be considered in patients with possible ischemic nephropathy because the nephrogram phase of the arteriogram can help estimate the amount of remaining viable kidney tissue. Patients in whom there is a moderate degree of suspicion for RVD should undergo either captopril renography or duplex sonography and then proceed to arteriography if either of those tests are positive.

A number of exogenous drugs and chemicals can lead to hypertension. Physicians should always query patients about using nasal decongestants, which contain sympathomimetics, and nonsteroidal antiinflammatory drugs (NSAIDs), which cause fluid retention and interfere with antihypertensive agents. Most women who take oral contraceptives have an increase in blood pressure, usually within the normal range. After prescribing birth control pills, the physician should recheck the blood pressure within the first 2 to 4 weeks and at 3-to 6-month intervals thereafter. Low-dose postmenopausal hormone replacement is not a cause of hypertension. Other drugs to consider include corticosteroids, thyroid supplements, diet pills, caffeine, cyclosporine, erythropoietin, antidepressants, amphetamines, and cocaine.

The various medullary and cortical adrenal hyperfunctions account for approximately 0.5% of hypertension. Pheochromocytoma is associated with sustained or intermittent episodes of tachycardia, tremor, sweating, pallor, headache, and orthostatic hypotension. A spot urine test for metanephrine is the initial screening test. Values greater than 1 mg per mg of creatinine should be followed by a 24-hour urine collection for vanillylmandelic acid, metanephrines, and catecholamines. These urine assays have a sensitivity of 84% to 96% and a specificity of 99% for detecting pheochromocytomas. If the urine assays are borderline, plasma epinephrine and norepinephrine levels can be measured following a clonidine suppression test; levels remain high in patients with a pheochromocytoma.

Nearly 80% of patients with Cushing's syndrome have elevated blood pressure because the high levels of cortisol have mineralocorticoid activity. Cushing's syndrome is suggested by moon facies, truncal obesity, proximal muscle weakness, and hirsutism. The initial diagnostic test is a morning plasma cortisol after suppression with 1 mg of dexamethasone at bedtime the night before. A cortisol level under 5 μg/dl excludes Cushing's syndrome with 98% certainty. Patients with highly suggestive features should undergo both a 24-hour urine free cortisol measurement and low-dose (0.5 mg every 6 hours for 2 days) dexamethasone suppression test. Normal urine cortisol levels exclude cortisol hypersecretion.

Primary aldosteronism induces hypertension and potassium wasting, although hypokalemia is not always present. Patients with unprovoked hypokalemia or those who become severely hypokalemic on minimal diuretic therapy may have hyperaldosteronism. The most useful screening test for primary aldosteronism is measuring the plasma aldosterone/plasma renin activity ratio. A ratio of greater than 20:1 with an absolute plasma aldosterone concentration of greater than 15 ng/dl suggests primary hyperaldosteronism. A positive screening test needs to be confirmed by demonstrating inappropriate aldosterone secretion by measuring urinary aldosterone after oral sodium chloride administration or measuring plasma aldosterone after giving intravenous sodium chloride. If hyperaldosteronism is confirmed, computed tomography (CT) scanning and adrenal venous sampling can localize pathology. Bilaterally elevated aldosterone levels suggest idiopathic hyperaldosteronism, which is treated medically. Conn's syndrome is characterized by a unilateral secretion of aldosterone and an adrenal adenoma that, if removed surgically, usually results in improvement of both the hypertension and the hypokalemia. Other endocrine causes of secondary hypertension include acromegaly, hypothyroidism, hyperthyroidism, and hypercalcemia (hyperparathyroidism). These diagnoses are suggested by characteristic clinical findings (gigantism, thyromegaly, or thyroid nodules) or abnormal laboratory studies (serum calcium, thyroid function tests).

Coarctation of the aorta is suggested by delayed or absent femoral pulses and decreased lower extremity blood pressure. A chest x-ray may show the "E" sign, formed by the abnormal contour of the aortic knob and the uppermost portion of the descending aorta. Notching of rib may be noted. An aortogram confirms the diagnosis, but coarctation may also be demonstrated on CT scan or on magnetic resonance angiogram (MRA).

Other miscellaneous causes of hypertension are shown in Box 60-3.

[edit] ESTIMATING BENEFITS OF TREATMENT FOR THE INDIVIDUAL

Benefits of treating individuals vary depending on their baseline risks for cardiovascular disease and their competing risks of dying from noncardiovascular-related causes. An example of high competing risks that may minimize or negate the benefits of treating hypertension is a patient with multiple serious conditions such as Alzheimer's disease, obstructive lung disease, frequent falls, urinary incontinence, and gout.

Estimates of benefits for individuals depend on the magnitude of relative treatment benefits and the patient's baseline risks for cardiovascular disease. The relative efficacy for preventing mortality and cardiovascular events is presented as odds ratios in Table 60-4; estimates of baseline cardiovascular risks for patients with different risk factors are given in Figs. 60-1 and 60-2. Table 60-5 can be used to calculate the number of patients who would need to be treated (NNTs) for 5 years to prevent cardiovascular events. For example, the odds ratio associated with preventing a cardiovascular event in men is 0.78 (see Table 60-4). A 60-year-old diabetic man who smokes, has a total cholesterol to HDL-cholesterol ratio of 4, and a blood pressure of 160/100 would have a greater than 20% chance of experiencing a cardiovascular event in the next 5 years (see Fig. 60-1). Crossing this patient expected event rate with the corresponding odds ratio yields an approximate NNT of 30 (see Table 60-5). Conversely, if the patient was 34 and neither a smoker nor diabetic, his 5-year risk of a cardiovascular event is less than 2.5%. Crossing this expected event rate with the same odds ratio (0.78) yields an approximate NNT of 204.

Table 60-4 Estimate of Antihypertensive Treatment Effect by Sex

Modified from Queyffier F et al: Ann Intern Med 126:761-767, 1997.

Rights were not granted to include this data in electronic media. Please refer to the printed book.

Table 60-5 Calculation of the NNT from Odds Ratios

Modified from McQuay HJ, Moore RA: Ann Intern Med 712-720, 1997.

Rights were not granted to include this data in electronic media. Please refer to the printed book.

[edit] MANAGEMENT

The aim of treating high blood pressure is to prevent premature death and disease by reducing the risk of coronary heart disease and stroke, with minimum adverse effects. Treatment options for hypertension include lifestyle modifications, dietary supplementations, and pharmacologic therapy.

[edit] Nonpharmacologic Therapy

[edit] Lifestyle Interventions.

Numerous studies have shown that lifestyle changes, such as weight reduction, salt restriction, regular aerobic exercise, and decreased alcohol consumption, can lower blood pressure (Table 60-6). Although there are no long-term studies proving that using these modalities prevents the morbidity and mortality of hypertension, the interventions are generally harmless, may reduce other risk factors for cardiovascular disease, and avoid the costs and side effects of medication. Behavioral science studies show that a physician's advice alone can affect behavior, and the chance of bringing about a true lifestyle change may be increased by combining frequent follow-up visits with client-centered counseling, contracting, and setting achievable goals.

Table 60-6 Evidence of Effectiveness of Lifestyle Interventions for Essential Hypertension

'Intervention	No. of RTCs'(patients)	Trial participants	Change in targeted factor	Decrease in BP mm Hg
Exercise	29 (1533)	80% male, age 28-72	50 mins aerobic 3/week	5/3
Low-fat, high fruit and vegetable diet	1 (459)	50% male, mean age 44		5.5/3
Weight loss	18 (2611)	55% male, mean age 50	3.9% of body weight	3/3
Salt restriction	58 (2161)	Mean age 49	118 mmol/day	4/1
	28 (1131)	Mean age 47	60 mmol/day	2/0.5
Alcohol restriction	1 (44)	100% male, mean age 50	From 452-to 64-ml ethanol per week	5/3

[edit] Exercise.

Exercising aerobically at least three times a week for 30 to 45 minutes lowers blood pressure.^[2] Exercise is also a valuable adjunct to weight control. The key is to begin gradually with a realistic program that fits the patient's lifestyle. A useful start may be a simple walking program, which is easily achievable and has minimal risk of injury.

[edit] Diet.

Saturated fat increases blood pressure, independent of obesity, and a switch to polyunsaturated and monounsaturated fats may reduce blood pressure. This dietary change may impact two cardiovascular risk factors—hypertension and cholesterol. A high potassium and magnesium diet rich in fruits, vegetables, and low-fat dairy products and reduced in saturated and total fat can substantially reduce blood pressure—5.5/3.0 mm Hg—compared with the typical American diet.^[3]

[edit] Weight Loss.

Modest weight reductions of 3% to 9% of body weight can effectively reduce blood pressure in obese, hypertensive people who are sufficiently motivated to follow a long-term weight loss regimen. The effect of weight loss is independent of sodium restriction or increased exercise.

[edit] Reducing Alcohol Intake.

Daily alcohol consumption greater than 2 oz has been associated with hypertension in multiple epidemiologic studies. The relationship is generally linear, although some studies show threshold effects at two to three drinks daily. A small randomized trial in treated hypertensive men (initial blood pressures 142/85 mm Hg) who were moderate to heavy drinkers showed that reducing alcohol consumption from 452 to 64 ml of ethanol per week lowered systolic blood pressure 5 mm Hg and diastolic 3 mm Hg.^[4] People with raised blood pressure should reduce alcohol consumption to two drinks or less daily.

[edit] Salt Restriction.

Salt restriction may lead to modest reductions in blood pressure.^[5] Effects vary depending on baseline amounts of salt consumption, amount of reduction that is achievable, and age. For motivated persons older than age 45 who consume more than 3 gm of salt daily, reduction of 1 gm or more can lead to sustained reductions of approximately 6/2 mm Hg (systolic/diastolic). Practically speaking, patients could refrain from salting food at the table and while cooking, and could avoid processed foods with a high salt content. Of note, there is no direct evidence that low-salt diets are harmful, but epidemiologic data conflict, with one observational study suggesting very low salt intakes may be associated with increased myocardial infarction in men.^[6]

[edit] Dietary Supplementation (Table 60-7).

There is no direct evidence of the effect of dietary supplementation on mortality or morbidity in people with hypertension.

Table 60-7 Effectiveness of Dietary Supplementation for Essential Hypertension

Intervention	No. of RTCs (patients)	Trial participants	Change in targeted factor	Decrease in BP mm Hg
Potassium supplementation	21 (1560)	Age 19-79	60-100 mmol/day	4/2.5
Fish oil supplementation	7 (339)	Mean age 50	3 gm or more	4.5/2.5
Calcium supplementation	42 (4560)	Not clear	800-1500 mg/day	1.5/1

[edit] Potassium Supplementation.

Several small randomized trials showed an increase in potassium intake of about 60 mmol/day (60 mEq or 2000 mg) on top of typical consumption of dietary potassium produces a reduction in blood pressure of approximately 4 mm Hg systolic and 2.5 mm Hg diastolic.^[7] Greater reductions may be seen in persons with higher urinary sodium excretion and in African- Americans compared with white persons. About 2% to 10% of persons taking potassium supplementation have gastrointestinal adverse effects such as belching, flatulence, diarrhea, and abdominal discomfort.

[edit] Fish Oil Supplementation.

Large daily intakes of fish oil (200 gm/day of fish high in v₂ polyunsaturated fatty acids or 6 to 10 capsules/day) reduced blood pressure by approximately 4.5 mm Hg systolic and 2.5 mm Hg diastolic.^[8] Such high intake may be difficult to maintain. There is no evidence of beneficial effect on blood pressure at lower intakes. Belching, bad breath, fishy taste, and/or abdominal pain may occur in approximately 30% of persons taking high doses of fish oil.

[edit] Calcium and Magnesium Intake.

Calcium supplementation has minimal effects on blood pressure in people with hypertension and normal calcium levels.^[9] There is no evidence that magnesium supplementation reduces blood pressure in people with hypertension and normal magnesium levels.

[edit] Relaxation and Biofeedback.

Evidence concerning effects of relaxation and biofeedback therapies on blood pressure is equivocal. Some trials show minimal reductions, but others with sham control groups show no effects.

[edit] Smoking Cessation.

Smoking cigarettes raises blood pressure slightly and may attenuate the cardiovascular protective effect of antihypertensive therapy. Smoking cessation is strongly encouraged because it is a major risk factor for cardiovascular disease that interacts synergistically with hypertension.

[edit] Pharmacologic Therapy

Pharmacologic therapy reduces blood pressure more than lifestyle interventions.^[10] Average blood pressure reductions are approximately 12 to 16/5 to 10 mm Hg (systolic/diastolic). Randomized controlled trials involving more than 37,000 patients show particular regimens reduce stroke in people under 65 years and reduce total mortality and fatal and nonfatal cardiovascular events in older people up to 80 years of age. Trials in middle-aged adults usually compared thiazide diuretics, β-blockers, or reserpine with placebo. Drug therapy in middle-aged adults prevented one stroke (CI 0 to 2; NNT = 833) for every 1000 patient years of treatment, and did not significantly affect coronary events or mortality. Trials in older persons greater than age 60 often compared placebo with diuretics (usually thiazides with the addition of amiloride or triamterene) and β-blockers (usually atenolol or metoprolol) in a stepped-care approach. On average, treating 1000 older adults for 1 year prevented five strokes (CI 2 to 8; NNT = 197), three coronary events (CI 1 to 4; NNT = 225), and four cardiovascular deaths (CI 1 to 8; NNT = 225) (Table 60-8). Of note, trials, especially in older adults, have included people healthier than in the general population, with lower rates of cardiovascular risk factors, cardiovascular disease, and comorbidity. Patients with higher cardiovascular risk can expect greater short-term benefits than seen in the trials, whereas patients with major competing risks such as terminal cancer or end-stage Alzheimer's disease can expect lesser benefits.

Table 60-8 Benefits of Pharmacologic Treatments for Hypertension

From Gueyffier F: J Hum Hypertens 10:1-8, 1996.

Patients	Stroke	Coronary events
Middle-aged adults	Prevents 1/1000 pt yr tx	No significant effects
	(CI 0 to 2)
	(NNT=833)
Adults older than 60 years	Prevents 5/1000 pt yr tx	Prevents 3/1000 pt yr tx
	(CI 2 to 8)	(CI 1 to 4)
	(NNT=197)	(NNT=362)

[edit] Specific Drug Treatment Choices.

Ideal antihypertensive treatment should be inexpensive, be simple to take, be in long-acting formulation, and have proven mortality and morbidity benefits and minimal side effects. Initial therapy with diuretics (thiazide or combination thiazide and potassium sparing agent) or β-blockers (atenolol or metoprolol) comes closest to meeting ideal criteria. According to one large randomized controlled trial, a long-acting dihydropyridine calcium channel blocker, nitrendipine, also meets these criteria for older persons with isolated systolic hypertension.^[11]

The relative efficacy of different agents is largely unknown. Systematic reviews have compared results of trials that used diuretics as first-line agents with results of trials that used β-blockers as first-line agents.^[12][1] The findings suggest but do not prove that diuretics are superior to β-blockers as first-line therapy, particularly for older adults, and are summarized in Fig. 60-4.

As of 1999, there was no direct placebo-controlled, randomized controlled trial evidence of the effects of ACE inhibitors, α-blockers, and angiotensin II receptor antagonists on morbidity and mortality in the treatment of hypertension and only limited evidence for calcium channel blockers. In 380 hypertensive non–insulin-dependent diabetic patients, an ACE-inhibitor, fosinopril, significantly lowered risk of major vascular events compared with a long-acting dihydropyridine calcium channel blocker, amlodipine (hazards ratio = 0.49; CI 0.26 to 0.95; NNT = 15).^[13] A second trial involving 470 hypertensive non–insulin-dependent diabetic patients found a long-acting dihydropyridine calcium channel blocker, nisoldipine, controlled blood pressure as well as an ACE inhibitor, enalapril.^[14] However, nisoldipine was associated with a higher incidence of fatal and nonfatal myocardial infarctions than enalapril (adjusted risk ratio 7; CI 2.3 to 21.4; NNT = 12). Whether the ACE inhibitors were improving outcomes, the calcium channel blockers were worsening outcomes, or both effects were occurring in these two trials was not clear.

There are comorbid conditions where particular antihypertensive drugs improve clinical outcomes. Patients and physicians may preferentially opt for these drugs. The conditions, preferred drug, and outcomes are outlined in Table 60-9.

Table 60-9 Examples of Improved Clinical Outcomes with Particular Antihypertensives

Condition	Agent	Outcome
Left ventricular systolic dysfunction	ACE inhibitors, angiotensin II receptor blockers	Improves survival, functional status; decreases morbidity
Diabetes mellitus with proteinuria (Type I)	ACE inhibitors	Retards renal deterioration
Myocardial infarction	Nonintrinsic sympathomimetic β-blockers	Improves survival
Diabetes mellitus (Type 2)	Diuretics	Reduces cardiovascular morbidity and mortality

[edit] Harms and Adverse Effects of Pharmacotherapy.

Systematic reviews of randomized trials of pharmacotherapy show no increase in noncardiovascular mortality in treated hypertensive patients.^[15] Comparable data on noncardiovascular morbidity are not available, although trials and case-control studies suggest no increase in cancer incidence with antihypertensive therapy. Case-control, cohort, and randomized studies suggest short-and intermediate-acting dihydropyridine calcium channel blockers, such as nifedipine and isradipine, may increase cardiovascular morbidity and mortality.^[16] Unfortunately, as of 1998, there was only one published large, well-designed, placebo-controlled trial of a long-acting dihydropyridine calcium channel blocker in hypertensive patients.^[11] This study showed a significant reduction in cardiovascular events with active treatment. Ongoing studies with different calcium channel blockers will help clarify which ones are appropriate for which patients.

Symptomatic adverse effects vary by drug class and by agents within classes. Examples of specific adverse effects as well as costs of therapies are given in Table 60-10. A significant proportion of patients have been reported to change or discontinue treatment because of adverse effects. More recent studies of lower dose drugs show good tolerance. Over 4 years of double-blind therapy with placebo or one of five antihypertensive agents, 59% of patients on placebo and 72% assigned to pharmacotherapy remained on their initially assigned treatment.^[10] Moreover a systematic review and several recent trials show quality of life is not adversely affected and may be improved in those who remain on treatment.^[17][18] In the three long-term double-blind comparisons of low-dose diuretics, β-blockers, ACE inhibitors, and calcium channel blockers, tolerability and overall quality of life indicators tended to be more favorable for diuretics and β-blockers than for newer drugs.^[9][19][20]

Table 60-10 Dose, Cost, and Adverse Effects of Specific Drugs

Generic name	Brand name	Initial dose (frequency)	Maintenance dose (frequency)	Monthly cost in$(based on AWP)	Adverse effects
Diuretics: thiazide type
Hydrochlorothiazide	Esidrix, HydroDiuril, others	25 mg qd	12.5-25 mg qd	0.59-1.50	Hyperuricemia, hypokalemia, hypomagnesemia, hyperglycemia, hyponatremia, hypercalcemia, hypercholesterolemia, hypertriglyceridemia, pancreatitis, rashes, weakness, sexual dysfunction
Chlorthalidone	Hygroton	25 mg qd	12.5-100 mg qd	1.65-3.12
Indapamide	Lozol	1.25 mg qd	1.25-5 mg qd	9.09-20.62
Metolazone	Zaroxolyn	2.5 mg qd	2.5-10 mg qd	14.60-19.87
	Mykrox	0.5 mg qd	0.5-1 mg qd	22.09-44.18
Diuretics: loop
Bumetanide	Bumex, others	0.5-2 mg qd	0.5-5 mg qd-bid	5.15-36.22	Dehydration, circulatory collapse, hypokalemia, hyponatremia, hypomagnesemia, hypocalcemia, hyperglycemia, metabolic alkalosis, hyper-uricemia, blood dyscrasias, rashes, lipid changes as with thiazide diuretics
Ethacrynic acid	Edecrin	12.5-50 mg qd	25-100 mg qd-bid	9.66-27.54
Furosemide	Lasix	20-40 mg qd-bid	40-320 mg qd-bid	1.26-5.68
Torsemide	Demadox	5 mg qd	5-10 mg qd-bid	15.09-16.71
Diuretics: potassium-sparing
Amiloride	Midamor, others	5 mg qd	5-10 mg qd	11.07-22.14	Hyperkalemia, gastrointestinal disturbances; amiloride: rash, headache; spironolactone: hyponatremia, mastodynia, gynecomastia, agranulocytosis, menstrual abnormalities, rash; triamterene: nephrolithiasis
Spironolactone	Aldactone, others	25-50 mg qd-bid	25-100 mg qd-bid	2.24-9.41
Triamterene	Dyrenium, others	50-200 qd-bid	100-300 mg qd-bid	14.52-43.56
Diuretics: combination
HCTZ 25, spironolactone 25	Aldactazide, others	1 tablet qd	1-4 tablets qd	2.88-11.52	Same as individual components
HCTZ 50 mg, spironolactone 50 mg	Aldactazide, others	1 tablet qd	1-2 tablets qd	14.30-28.60
HCTZ 25 mg, triamterene 37.5 mg	Dyazide	1 capsule qd	1-2 capsules qd	11.26-22.52
HCTZ 25 mg, triamterene 37.5 mg	Maxzide-25	1 tablet qd	½-2 tablets qd	3.14-12.54
HCTZ 25 mg, triamterene 50 mg	Others	1 capsule qd	1-2 capsules qd	5.10-8.87
HCTZ 50 mg, triamterene 75 mg	Maxzide, others	1 tablet qd	1 tablet qd	3.53
HCTZ 50 mg, amiloride 5 mg	Moduretic	½-1 tablet qd	½-2 tablets qd	2.19-5.44
β-Adrenergic blocking drugs
Atenolol	Tenormin	25-50 mg qd	25-100 mg qd	3.99-4.04	Fatigue, depression, bradycardia, decreased exercise tolerance, congestive heart failure, aggravation of peripheral arterial insufficiency, GI disturbances, bronchospasm, masking of symptoms of hypoglycemia, Raynaud's phenomenon, insomnia, vivid dreams or hallucinations, organic brain syndrome, rare blood dyscrasias and other allergic disorders, increased serum triglycerides, decreased HDL cholesterol, generalized pustular psoriasis, transient hearing loss, sudden withdraw can lead to exacerbation of angina and myocardial infarction
Betaxolol	Kerlone	5-10 mg qd	5-40 mg qd	12.51-75.06
Bisoprolol	Zebeta	2.5-5 mg qd	2.5-20 mg qd	15.57-62.26
Metoprolol	Lopressor	50-100 mg bid	50-300 mg bid	3.96-12.79
Metoprolol sustained release	Toprol XL	50-100 mg qd	50-300 mg qd	15.90-71.82
Nadolol	Corgard	20-40 mg qd	20-320 mg qd	25.60-101.22
Propranolol	Inderal	80 mg bid	40-240 mg bid-tid	5.36-7.80
Propranolol sustained release	Inderal LA	80 mg qd	80-160 mg qd	23.76-40.59
Timolol	Blocadren	20 mg bid	10-40 mg bid	19.08-39.06
β-Adrenergic blocking drugs with intrinsic sympathomimetic activity
Acebutolol	Sectral	200-400 mg qd-bid	200-1200 mg qd-bid	25.23-90.90	Similar to other β-adrenergic blocking drugs but with less bradycardia and lipid changes; acebutolol is cardioselective at low dosages and can be associated with a positive antinuclear antibody test and occasional drug-induced lupus
Carteolol	Cartrol	2.5 mg qd	2.5-10 mg qd	31.80-63.60
Penbutolol	Levatol	20 mg qd	10-20 mg qd	19.62-37.23
Pindolol	Visken	10 mg bid	10-60 mg bid	36.96-143.10
α-βAdrenergic blocking drugs
Carvedilol	Coreg	12.5 mg bid	50 mg bid	90.00	Similar to other β-adrenergic blocking drugs but has intrinsic sympathomimetic activity and more orthostatic hypotension, fever, and hepatotoxicity
Labetalol	Normodyne, Trandate	200 mg bid	200-1200 mg bid	31.98-120.84
α-Adrenergic blocking drugs
Doxazosin	Cardura	1 mg qhs	1-16 mg qhs	29.13-64.20	Syncope with first dose (prazosin, terazosin), dizziness and vertigo, nasal congestion, palpitations, fluid retention, headache, drowsiness, weakness, priapism, urinary incontinence
Prazosin	Minipress	2-3 mg bid	2-30 mg bid	3.98-38.70
Terazosin	Hytrin	1 mg qhs	1-20 mg qhs-bid	43.50-92.40
Peripheral adrenergic inhibitors
Guanadrel	Hylorel	10 mg qd-bid	10-75 mg qd-bid	11.24-168.53	Guanethidine: orthostatic hypotension, exercise hypotension, diarrhea, may aggravate bronchial asthma, bradycardia, sodium and water retention, retrograde ejaculation; reserpine: depression, nightmares, nasal stuffiness, drowsiness, GI disturbances, bradycardia
Guanethidine	Ismelin	10 mg qd	10-100 mg qd	18.09-118.20
Reserpine	Serpasil	0.5 mg qd×2 weeks	0.1-0.25 mg qd-bid	0.89-1.05
Central sympatholytic drugs
Clonidine	Catapres	0.1-0.2 mg bid	0.1-0.6 mg bid	2.25-2.85	Clonidine: drowsiness, sedation, dry mouth, bradycardia, heart block, rebound hypertension; guanabenz: similar to clonidine; guanfacine: similar to clonidine but milder; methyldopa: similar to clonidine, also fatigue, orthostatic hypotension. GI disturbances including colitis, hepatitis, cirrhosis, hepatic necrosis; fever; Coombs' positive hemolytic anemia, lupus-like syndrome, immune thrombocytopenia, red cell aplasia
Guanabenz	Wytensin	8 mg bid	8-64 mg bid	31.92-190.08
Guanfacine	Tenex	1 mg qhs	1-2 mg qhs	21.18-29.04
Methyldopa	Aldomet	500 mg bid	500-2000 mg bid	9.01-14.52
Angiotensin-converting enzyme (ACE) inhibitors
Benazepril	Lotensin	10 mg qd	5-40 mg qd-bid	22.76-45.51	Cough, hypotension—particularly with a diuretic or volume depletion, loss of taste with anorexia, rash, acute renal failure with bilateral renal artery stenosis or stenosis of the artery to a single kidney, cholestatic jaundice, pancreatitis, angioedema, hyperkalemia, blood dyscrasias, may increase fetal mortality and should not be used during second and third trimesters of pregnancy
Captopril	Capoten	25-75 mg bid-tid	12.5-150 mg qd-tid	2.66-11.64
Enalapril	Vasotec	2.5-5 mg qd	2.5-40 mg qd-bid	24.06-91.20
Fosinopril	Monopril	10 mg qd	10-80 mg qd-bid	24.87-49.74
Lisinopril	Prinivil, Zestril	5-10 mg qd	5-40 mg qd	25.29-40.89
Moexipril	Univasc	7.5 mg qd	7.5-30 mg qd-bid	15.81-31.62
Quinapril	Accupril	5-10 mg qd	5-80 mg qd-bid	28.50-57.00
Ramipril	Altace	1.25-2.5 mg qd	1.25-20 mg qd-bid	19.89-57.90
Trandolapril	Mavik	1-2 mg qd	1-4 mg qd-bid	18.75-37.50
Angiotensin II receptor antagonists
Candesartan	Atacand	16 mg qd	8-32 mg qd-bid	36.00-50.40	Hyperkalemia, hypotension, acute renal failure with bilateral renal artery stenosis or stenosis of the artery to a single kidney
Irbesartan	Avapro	150 mg qd	75-300 mg qd	36.15-63.26
Losartan	Cozaar	50 mg qd	25-100 mg qd	36.30-72.60
Valsartan	Diovan	80 mg qd	80-320 mg qd	35.10-70.20
Calcium channel blockers
Nondihydropyridines
Diltiazem					Dizziness, headache, edema, constipation (especially verapamil), heart block, bradycardia, heart failure, gingival hyperplasia
Capsules (sustained release)	Cardizem SR	60-120 mg bid	120-360 mg bid	51.52-81.27
	Cardizem CD	180-240 mg qd	120-360 mg qd	34.20-84.72
	Dilacor-XR	180-240 mg qd	120-480 mg qd	30.30-80.40
	Tiazac	120-240 mg qd	120-540 mg qd	26.01-86.09
Verapamil
Capsules (sustained release)	Verelan	120-180 mg qd	120-480 mg qd-bid	37.50-88.80
Tablets (sustained release)	Isoptin SR	120-180 mg qd	120-480 mg qd-bid	26.01-70.34
	Calan SR	120-180 mg qd	120-480 mg qd-bid	26.01-70.34
	Covera-HS	180 mg qhs	180-480 mg qhs	33.60-92.40
Tablets (intermediate release)	Calan, Isoptin	120-240 mg tid	120-480 mg tid	24.53-35.04
Dihydropyridines					Dizziness, headache, peripheral edema, flushing, tachycardia, rash, gingival hyperplasia
Amlodipine	Norvasc	5 mg qd	2.5-10 mg qd	38.70-65.23
Felodipine	Plendil	5 mg qd	2.5-10 mg qd	28.19-50.62
Isradipine (sustained release)	DynaCirc CR	5 mg qd	5-20 mg qd	35.79-113.78
Isradipine (intermediate release)	DynaCirc	5 mg bid	5-20 mg bid	41.43-120.72
Nicardipine (sustained release)	Cardene SR	60 mg bid	60-120 mg bid	41.92-79.68
Nicardipine (intermediate release)	Cardene	60 mg tid	60-120 mg tid	35.32-70.64
Nifedipine (sustained release)	Adalat CC	30 mg qd	30-120 mg qd	28.65-88.35
	Procardia XL	30 mg qd	30-120 mg qd	40.50-121.20
Nisoldipine (sustained release)	Sular	10-20 mg qd	10-60 mg qd	26.73-53.46
Direct vasodilators
Hydralazine	Apresoline	25 mg bid	50-200 mg qd-qid	1.13-2.57	Hydralazine: GI disturbances, tachycardia, aggravation of angina, headache, dizziness, fluid retention, nasal congestion, rashes and other allergic reactions, lupus-like syndrome, hepatitis; minoxidil: tachycardia, aggravation of angina, marked fluid retention, possible pericardial effusion, hirsutism, thrombo-cytopenia, leukopenia
Minoxidil	Loniten	5 mg qd	5-40 mg qd	5.84-17.24
HCTZ, Hydrochlorothiazide; AWP, average wholesale price from the 1998 Drug Topics Red Book. The lowest priced generic was used when available. Table courtesy of David Green, PharmD.

A large number of studies have reported adverse effects of diuretics and β-blockers on blood lipids (both drug groups), blood glucose, potassium, and uric acid (diuretics). Most of these studies either were of short duration or used high doses; when diuretics and β-blockers are used in low doses, long-term follow-up indicates only minor metabolic effects that are unlikely to be clinically significant.^[21][22][23] For example, secondary analysis of results from a large diuretics treatment trial of elderly patients with isolated systolic hypertension showed similar cardiovascular relative risk reductions in diabetic and nondiabetic patients.^[24]

[edit] Specific Oral Antihypertensive Agents.

The drug treatment of hypertension is the single greatest indication for medication use in the United States. A vast array of drugs are available: diuretics, sympatholytics, ACE inhibitors, peripheral inhibitors, calcium channel blockers, angiotensin II receptor blockers, and vasodilators. Specific drugs, their doses, costs, and adverse effects are given in Table 60-10.

[edit] Diuretics

[edit] Thiazide diuretics.

Thiazide diuretics promote the excretion of sodium and water primarily by inhibiting their reabsorption in the distal renal tubule. Thiazides cause a slight fall in serum potassium in most patients, although only a few develop symptoms of severe hypokalemia. The importance of diuretic-induced hypokalemia is controversial. For patients on digitalis (where hypokalemia may exacerbate toxicity) or patients with a history of ischemic heart disease or ventricular dysrhythmias, the serum potassium is closely monitored and the potassium is replaced if hypokalemia develops. Hypokalemia can be treated with potassium replacement or with the addition of a potassium-sparing diuretic. Longer acting diuretics, such as chlorthalidone and metolazone, may produce more severe hypokalemia. Serum uric acid increases approximately 1 mg/dl in all patients started on diuretics. Unless clinical gout develops, modest hyperuricemia need not be treated. If diuretic therapy is essential for the patient with frequent gouty attacks, a uric acid–lowering agent may be added.

[edit] Loop diuretics: ethacrynic acid, furosemide, bumetanide.

Ethacrynic acid and furosemide block sodium absorption in the loop of Henle. These short-acting agents, which need to be administered twice daily, are more potent diuretics than the thiazides but have no greater antihypertensive effect. Because loop diuretics are more expensive than thiazides and have a propensity for causing large fluid shifts, they should be used as second-line drugs. In general, they are used for patients with renal failure (serum creatinine greater than 2.5 mg/dl) or for patients with fluid retention and congestive heart failure.

[edit] Potassium-sparing diuretics: triamterene, amiloride, spironolactone.

Potassium-sparing diuretics promote sodium excretion and potassium retention by preventing sodium/potassium exchange in the distal nephron. These drugs are rarely used as the sole diuretic for treating hypertension unless the patient has thiazide sensitivity, diet-controlled glucose intolerance, or gout. They are particularly useful in combination with other diuretics for patients at risk for hypokalemia. Because these drugs can cause hyperkalemia, they are best avoided for patients with impaired renal function, diabetic patients with type IV renal tubular acidosis, or those receiving a converting enzyme inhibitor.

[edit] Sympatholytic Agents.

Sympatholytic agents include β-blockers, α-blockers, and α- andalpha;-and β-adrenergic blockers. Blood pressure is lowered through β-adrenergic blockade and, at higher dosages, through a CNS mechanism. β-Blockers are ideal for hypertensive patients with angina, myocardial infarction, migraine headaches, and essential tremor.

There are a large number of β-blockers available. From a pharmacologic standpoint, these agents can be grouped into the nonspecific β-antagonists, the selective β-antagonists, and those with and without intrinsic sympathomimetic activity (ISA). At low dosages, β-blockers, such as atenolol and metoprolol, should not induce bronchospasm in patients with reactive airway disease. Agents like acebutolol and pindolol have intrinsic sympathomimetic activity and may not lower the heart rate as much as agents without sympathomimetic activity. Agents with ISA are not recommended for postmyocardial infarction patients; cardioselective agents are preferred.

[edit] Central Inhibition of Sympathetic Drive

[edit] Clonidine, guanabenz, and guanfacine.

Clonidine, guanabenz, and guanfacine are centrally adrenergic acting α₂-adrenergic agonists that decrease sympathetic output in the CNS. Clonidine is usually added to a diuretic or another agent when single therapy proves unsatisfactory. Occasionally, clonidine is a useful single-drug treatment for patients who cannot be managed with diuretics or β-blockers, but it should be given twice daily. Rebound hypertension, often accompanied by tachycardia, may occur with sudden withdrawal of clonidine or guanabenz. Readministration of the drug is usually sufficient treatment. Patients should be advised not to run out of medicine and doses should be tapered over 2 or 3 weeks when stopping the drug. These drugs should probably be avoided in patients with a history of intermittent or poor compliance.

[edit] Methyldopa.

Methyldopa is also a central-acting adrenergic agonist. It may act by a mechanism that is similar to clonidine or by forming a false neurotransmitter. Methyldopa has been used safely for more than 20 years in the treatment of mild to moderate hypertension, usually in combination with a diuretic and/or other therapeutic agents. Some physicians believe that methyldopa's side effects, such as drowsiness, fatigue, and impotence, may limit its effectiveness. Methyldopa may be safely used in pregnancy.

[edit] Peripheral Adrenergic Inhibitors.

Reserpine decreases the availability of norepinephrine, lowering sympathetic tone and peripheral vascular resistance. Reserpine also depletes catecholamines in the brain, potentially leading to sedation and depression, and in the myocardium, potentially decreasing cardiac output and slowing the heart rate. Guanethidine and guanadrel reduce peripheral resistance by decreasing the amount of norepinephrine released by stimulated adrenergic nerves. These medications blunt the normal vasoconstrictive response to assuming an upright posture and may lead to orthostatic hypotension.

[edit] α-Adrenergic Blockers.

Prazosin, terazosin, and doxazosin block the smooth muscle postsynaptic α₁-receptors, dilating arteries without causing reflex tachycardia. In general, α-adrenergic blockers are not used as initial therapy, but rather in combination with a diuretic or another sympatholytic medication. α-Adrenergic blockers may be particularly beneficial for hypertensive patients with benign prostatic hypertrophy or peripheral arterial disease.

[edit] Combination α- and β-blockers.

Labetalol has both properties, with the α effect being roughly one third of the β effect. Labetalol causes some slowing of the heart rate; however, in contrast to pure β-blockers, it does not decrease cardiac output or increase peripheral vascular resistance. For these reasons, labetalol offers some theoretic advantages over β-blockers, but its current place in the treatment of hypertension has not been clearly defined. The drug is relatively expensive and requires dosing twice daily.

[edit] Vasodilating agents.

Direct-acting vasodilators are usually added as a third drug for patients who cannot be controlled with two drugs. The medications available in this class are hydralazine and minoxidil. Hydralazine is a direct-acting vasodilator that causes decreased arterial resistance, a reflex increase in heart rate, and a secondary increase in plasma renin. It has been used for years in the therapy of hypertension. Because hydralazine induces reflex tachycardia and fluid retention, it is most often used in combination with a diuretic and a β-blocker, clonidine, or nondihydropyridine calcium antagonist.

Minoxidil is a direct-acting vasodilator that also causes reflex tachycardia and fluid retention. It is a potent antihypertensive agent used in severe resistant hypertension and may be especially effective for patients with renal failure. Cardiovascular side effects, including congestive heart failure, hypotension, and angina, can be severe, and its associated hypertrichosis and coarsening of facial features may be unacceptable to women and adolescents, although balding men may be pleased.

[edit] Angiotensin-Converting Enzyme Inhibitors.

ACE inhibitors inhibit the enzyme that converts angiotensin I (inactive) to angiotensin II, a potent vasoconstrictor that causes aldosterone secretion from the adrenal gland. Peripheral resistance is lowered without decreasing cardiac output or decreasing the glomerular filtration rate. ACE inhibitors reduce mortality for patients who have congestive heart failure and slow the progression of renal failure in diabetic patients.

Because ACE inhibitors can cause hyperkalemia, they should not be used concomitantly with potassium-sparing agents or for patients with diabetes and potassium retention. ACE inhibitors can cause serious nephrotoxicity by dramatically decreasing renal blood flow in patients with bilateral renal artery stenosis or unilateral stenosis with a solitary kidney.

[edit] Angiotensin II–Receptor Blockers.

Angiotensin II (AII)- receptor blockers prevent the binding of angiotensin II to receptors in the kidney, brain, heart, and arterial walls, thus inhibiting the renin-angiotensin system and causing a dose-dependent fall in peripheral resistance. The AII-receptor blockers inhibit the action of angiotensin II synthesized independently of ACE and do not increase kinin levels, the presumed mediator of the ACE inhibitor–induced cough. Since bradykinin stimulates the release of the vasodilator nitric oxide from the endothelium, an effect which is believed to account in part for the vasodilator effects of the ACE inhibitors, AII-receptor blockers may prove to be less effective in the long term than ACE inhibitors. AII-receptor blockers are effective in lowering blood pressure, but whether they affect morbidity and mortality from cardiovascular disease is unknown.

[edit] Calcium Channel Blockers.

Calcium is essential for muscle contraction, and increased levels of calcium may play a role in the development, if not the maintenance, of hypertension. By excluding the influx of calcium into smooth muscle cells, blood pressure can be reduced. From a functional standpoint, calcium channel blockers act as vasodilators. They come in two chemical forms: (1) the dihydropyridines (e.g., nifedipine, amlodipine, felodipine, isradipine, and nicardipine) and (2) the nondihydropyridines (e.g., verapamil and diltiazem). Although both classes of drugs lower blood pressure, verapamil and diltiazem have a substantial negative chronotropic effect and need to be used carefully in patients using β-blockers or with conduction defects. As previously mentioned, some of the dihydropyridines have been associated with possible increased morbidity and mortality. In 1998, their use in specific patients was still unclear.

[edit] Combination Drugs.

Combinations of diuretics and potassium-sparing agents have been available for many years. Recently, other combinations have been formulated, including adrenergic blockers and diuretics, ACE inhibitors and diuretics, angiotensin II receptor antagonists and diuretics, and calcium channel blockers and diuretics. Reducing the number of pills can improve compliance. Combination drugs can be synergistic, allowing lower doses of the component drugs and reducing the risk of adverse effects.

[edit] Combined Lifestyle Modifications and Pharmacologic Treatment

There is no direct evidence of the effect of combined treatment on mortality or morbidity in people with hypertension. Compared with nonpharmacologic treatment alone, the addition of drug treatment produces greater decreases in blood pressure, especially when the nonpharmacologic treatment is weight loss. Compared with drug treatment alone, the addition of salt restriction appears to be no more effective in reducing blood pressure and may reduce quality of life.

[edit] Target Blood Pressures and Therapy Titration

Although the aim of antihypertensive therapy is to reduce risk of cardiovascular events and mortality, it is not possible to titrate therapy in individual patients using these outcomes. Most physicians monitor therapy based on blood pressure level and symptomatic adverse effects. A trial involving 18,790 patients with average age of 62 years and diastolic blood pressures between 100 to 115 mm Hg evaluated target diastolic blood pressures of ≤ 90 mm Hg, ≤ 85 mm Hg, and ≤80 mm Hg.^[25] Most patients received a long-acting dihydropyridine calcium antagonist, felodipine (78%), and an ACE inhibitor (41%). There were no differences in major cardiovascular events among the three groups. The subset of diabetic patients randomized to the ≤80 group had half the rate of major cardiovascular events than those randomized to the ≤90 group (RR,90 vs. 80, 2.1; CI 1.2 to 3.4).

Strategies for titrating and changing particular drug regimens are largely opinion-based. JNC-VI recommends considering combinations of low-dose drugs rather than maximizing doses of one agent and then adding another. Their suggested algorithm for drug management is shown in Fig. 60-5.

[edit] Antithrombotic Treatment in Hypertensive Patients

Benefits and risks of treating hypertensive patients with antithrombotic treatment are finely balanced. The HOT trial showed approximately 200 older hypertensive patients would need to be treated for about 4 years with 75-mg aspirin daily to prevent one myocardial infarction. Numbers needed to harm for major or fatal bleeds were about 160.^[25] Another large placebo-controlled trial, the thrombosis prevention trial (TPT), showed low-intensity anticoagulation with warfarin (target international normalized ratio 1.5) reduced the rate of fatal and nonfatal ischemic events by 20% (95% CI 1% to 35%) in high-risk patients who were in the top 20% to 25% of a cardiovascular risk score distribution.^[26] Statistically nonsignificant excess intracranial and extracranial bleeds occurred at a rate of approximately 0.5 per 1000 individuals treated per year.

[edit] SPECIAL ISSUES

[edit] Resistant Hypertension

Almost all patients with hypertension can achieve good blood pressure control with minimal side effects, although a few patients may persistently have unacceptably high diastolic pressures (diastolic blood pressure greater than 105 mm Hg). For these patients, consider the following:

[edit] Poor Adherence to Drug Regimen.

Nonadherence to drug therapy is probably the major cause of poor blood pressure control. An estimated 50% of patients take less than 80% of their prescribed antihypertensive pills (see below).

[edit] Sodium Retention.

Patients who take one or more nondiuretic antihypertensive agents often have reflex sodium retention. Adding a diuretic (or using a more potent one) and reemphasizing the need for a low-sodium diet may improve blood pressure control.

[edit] Excessive Alcohol Intake.

If the hypertensive patient has a substantial alcohol intake, physicians should encourage total abstention from alcohol for 4 to 6 weeks while monitoring changes in blood pressure.

[edit] Secondary Hypertension.

Refer to the previous section on secondary hypertension for screening evaluations and taking a medication history.

[edit] Substitute More Potent Antihypertensive Agents.

For example, substitute minoxidil or an ACE inhibitor for hydralazine.

Close observation is essential for patients with resistant hypertension. Physicians should evaluate these patients for causes of secondary hypertension and carefully monitor the drug regimen and diet. A few patients may require hospitalization to control their blood pressure. Most patients experience a fall of 5 to 15 mm Hg in diastolic blood pressure during hospitalization, but this does not necessarily reflect increased drug effect. Occasionally, poor adherence can be diagnosed if there is a substantial blood pressure fall to almost hypotensive levels when the patient is hospitalized and continued on the prescribed medication.

[edit] Noncompliance with Treatment

Diagnosing poor compliance can be difficult and requires a frank, nonjudgmental exploration with the patient about pill-taking habits. Physicians may preface this discussion by acknowledging that pills are expensive, symbolic of illness, sometimes accompanied by unpleasant side effects, and, for many people, including physicians, difficult to take as prescribed. Another helpful approach is to identify the time of day when the patient takes medications and to review the exact number of pills taken during the previous 24 hours. Compliance occasionally may be assessed clinically or biochemically because some antihypertensive agents cause predictable physiologic effects. For example, β-blockers consistently decrease pulse, and thiazide diuretics consistently increase uric acid and usually decrease serum potassium.

Some methods that may improve adherence include:

• Educating patients. Communicate clear target goals for blood pressure and discuss in a nonthreatening way the consequences of high blood pressure and the benefits of treatment. Emphasize that treating high blood pressure does not generally make patients feel better but, rather, is designed to prevent morbidity and mortality.
  
• Encouraging patients to report side effects. Acknowledge that unpleasant side effects can occur during drug therapy and select an acceptable treatment regimen. Ask patients specifically about side effects they may be reluctant to voluntarily discuss, such as sexual dysfunction or the expense of treatment.
  
• Simplifying drug regimens. Ask if once-a-day therapy would be easier than twice-a-day therapy. If so, use long-acting preparations that provide adequate 24-hour control.
  
• Providing simple, written instructions about dosage and side effects. Review pill-taking habits with the patient. Recommend keeping pill bottles in a convenient location and emphasize the need to take pills at set times.
  
• Improving the convenience of office visits and using other health care providers (e.g., nurses, physicians' assistants) to help with case management if feasible. Sending appointment reminders, having flexible scheduling hours, and contacting patients who have missed appointments help to improve adherence. Emphasize that high blood pressure may be a lifelong problem and that patients are responsible for returning for follow-up appointments and promptly refilling their medication. Give the patient shared responsibility for treatment and monitoring.
  

[edit] EVIDENCE-BASED MEDICINE

Primary sources for this chapter were MEDLINE, Embase, and Joint National Committee VI guidelines. Electronic searches dating back to 1995 were conducted in June 1999. They focused on identifying systematic reviews, meta-analyses, and large randomized trials with clinical endpoints. Acknowledgments: Materials for drug tables were provided by David Green, PharmD.

[edit] REFERENCES