7 - Eye

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Tierney, Lawrence M., McPhee, Stephen J., Papadakis, Maxine A.
Current Medical Diagnosis & Treatment, 45th Edition

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11

Systemic Hypertension

Stephen J. McPhee MD

Barry M. Massie MD

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Fifty million Americans have elevated blood pressure (systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg); of these, 70% are aware of their diagnosis, but only 50% are receiving treatment and only 25% are under control using a threshold criterion of 140/ 90 mm Hg. Hypertension increases with age and is more common in blacks than in whites. The mortality rates for stroke and coronary heart disease, two of the major complications of hypertension, have declined by up to 60% over the past three decades but have recently leveled off. The incidence of end-stage renal disease and the incidence of heart failure—two other conditions in which hypertension plays a major causative role—continue to rise.

Cardiovascular morbidity and mortality increase as both systolic and diastolic blood pressures rise, but in individuals over age 50 years the systolic pressure and pulse pressure are better predictors of complications than diastolic pressure. Table 11-1 provides a summary of the classification and management of blood pressure in adults from the 7th Report of the U.S. Joint National Commission on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7).

Blood pressure should be measured with a well-calibrated sphygmomanometer with a cuff of proper size (the bladder width within the cuff should encircle at least 80% of the arm circumference) after the patient has been resting comfortably, back supported in the sitting or supine position, for at least 5 minutes and at least 30 minutes after smoking or coffee ingestion. Because blood pressure readings in many individuals are highly variable—especially in the office setting—the diagnosis of hypertension should be made only after noting a mean elevation on two or more readings on two or more office visits, unless the elevations are severe or associated with compelling indications such as diabetes mellitus, chronic kidney disease, heart failure, post-myocardial infarction, stroke, and high coronary disease risk (see Table 11-1). A new category in JNC 7 is designated “prehypertension,” and indicates systolic blood pressure of 120–139 mm Hg or diastolic blood pressure of 80–89 mm Hg. Transient elevation of blood pressure caused by excitement or apprehension does not constitute hypertensive disease but may indicate a propensity toward its evolution. Ambulatory 24-hour blood pressure monitoring may be helpful in evaluating patients with borderline or variable office blood pressure, approximately 20% of whom will have no evidence of hypertension elsewhere, as well as in assessing resistant hypertension and possible treatment-related hypotensive symptoms. This technique is employed only to address specific management problems because of its high cost ($200–$300).

Nonpharmacologic approaches such as the lifestyle modifications outlined in Table 11-2 should precede pharmacologic management in patients with stage I hypertension (systolic pressure 140–159 mm Hg or diastolic pressure 90–99 mm Hg) (Figure 11-1). Treatment of individuals with prehypertension and compelling indications (such as those with diabetes mellitus or chronic renal insufficiency) is indicated, particularly when agents that favorably modify risk factors are employed.

Chaudhry SI et al: Systolic hypertension in older persons. JAMA 2004;292:1074.

Chobanian AV et al: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 Report. JAMA 2003;289:2560.

Garg J et al: Evaluation and treatment of patients with systemic hypertension. Circulation 2002;105:2458.

Hart PD et al: Hypertension control rates: time for translation of guidelines into clinical practice. Am J Med 2004;117:62.

Kaplan NM et al: Clinical Hypertension, 8th ed. Lippincott Williams & Wilkins, 2002.

Pepine C: What is the optimal blood pressure and drug therapy for patients with coronary artery disease? JAMA 2004;292:2271.

Sheridan S et al: Screening for high blood pressure: a review of the evidence for the U.S. Preventive Services Task Force. Am J Prev Med 2003;25:151.

APPROACH TO HYPERTENSION

ETIOLOGY & CLASSIFICATION

A. PRIMARY (ESSENTIAL) HYPERTENSION

Primary (essential) hypertension is the term applied to the 95% of cases in which no cause for hypertension can be identified. This occurs in 10–15% of white

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adults and 20–30% of black adults in the United States. The onset is usually between ages 25 and 55 years; it is uncommon before age 20 years. In younger and older people, secondary hypertension resulting from renal insufficiency, renal artery stenosis, or coarctation of the aorta makes up a greater—but still relatively small—proportion of cases.

Table 11-1. Classification and management of blood pressure for adults aged 18 years or older.

BP Classification Systolic BP, mm Hg1 Diastolic BP, mm Hg1 Management
Lifestyle Modification Initial Drug Therapy
Without Compelling Indication With Compelling Indications2
Normal < 120 and <80 Encourage    
Prehypertension 120–139 or 80-89 Yes No antihypertensive drug indicated Drugs for the compelling indications3
Stage 1 hypertension 140–159 or 90-99 Yes Thiazide-type diuretics for most; may consider ACE inhibitor, ARB, β-blocker, CCB, or combination Drug(s) for the compelling indications
Other antihypertensive drugs (diuretics, ACE in-hibitor, ARB, β-blocker, CCB) as needed
Stage 2 hypertension ≥ 160 or ≥100 Yes Two-drug combination for most (usually thiazide- type diuretic and ACE inhibitor or ARB or β-blocker or CCB)4 Drug(s) for the compelling indications
Other antihypertensive drugs (diuretics, ACE inhibitor, ARB, β-blocker, CCB) as needed
From Chobanian AV et al: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560.
ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; BP = blood pressure; CCB = calcium channel blocker.
1Treatment determined by highest BP category.
2See Table 11-10.
3Treat patients with chronic kidney disease or diabetes to BP goal of less than 130/80 mm Hg.
4Initial combined therapy should be used cautiously in those at risk for orthostatic hypotension.

Elevations in pressure are often intermittent early in the course. Even in established cases, the blood pressure fluctuates widely in response to emotional stress and physical activity. Blood pressures taken by the patient at home or during daily activities using a portable apparatus are often lower than those recorded in the office, clinic, or hospital and may be more reliable in estimating prognosis. Patients with daytime average pressures less than 140/90 mm Hg have a low rate of cardiovascular complications and a low prevalence of left ventricular hypertrophy, suggesting that this is an appropriate ambulatory blood pressure criterion for diagnosing hypertension.

The pathogenesis of primary (essential) hypertension is multifactorial. Genetic factors play an important role. Children with one—and more so with two—hypertensive parents have higher blood pressures. Environmental factors also are significant. Increased salt intake and obesity have long been incriminated. These factors alone are probably not sufficient to raise blood pressure to abnormal levels but are synergistic with a genetic predisposition. Other factors that may be involved in the pathogenesis of primary (essential) hypertension are the following.

1. Sympathetic nervous system hyperactivity

This is most apparent in younger hypertensives, who may exhibit tachycardia and an elevated cardiac output. However, correlations between plasma catecholamines and blood pressure are poor. Insensitivity of the baroreflexes may play a role in the genesis of adrenergic hyperactivity.

2. Renin–angiotensin system

Renin, a proteolytic enzyme, is secreted by the juxtaglomerular cells surrounding afferent arterioles in response to a number of stimuli, including reduced renal perfusion pressure, diminished intravascular volume, circulating catecholamines, increased sympathetic nervous system activity, increased arteriolar stretch, and hypokalemia. Renin acts on angiotensinogen to cleave off the ten-aminoacid peptide angiotensin I. This peptide is then acted upon by angiotensin-converting enzyme to create the eight-amino-acid peptide angiotensin II, a potent

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vasoconstrictor and a major stimulant of aldosterone release from the adrenal glands. The incidence of hypertension and its complications may be increased in individuals with the DD genotype of the allele coding for angiotensin-converting enzyme. Despite the role of this system in the regulation of blood pressure, it probably does not play a primary role in the pathogenesis of most primary (essential) hypertension. Patients with low plasma renin activity may have higher intravascular volumes. Black hypertensives and older patients tend to have lower plasma renin activity; plasma levels are classified in relation to dietary sodium intake or urinary sodium excretion. Approximately 10% of patients with primary (essential) hypertension have high levels, 60% have normal levels, and 30% have low levels.

Table 11-2. Lifestyle modifications to manage hypertension.1

Modification Recommendation Approximate Systolic BP Reduction, Range
Weight reduction Maintain normal body weight (BMI, 18.5-24.9) 5–20 mm Hg/10-kg weight loss
Adopt DASH eating plan Consume a diet rich in fruits, vegetables, and low-fat dairy products with a reduced content of saturated fat and total fat 8-14 mm Hg
Dietary sodium reduction Reduce dietary sodium intake to no more than 100 mEq/L (2.4 g sodium or 6 g sodium chloride) 2-8 mm Hg
Physical activity Engage in regular aerobic physical activity such as brisk walking (at least 30 minutes per day, most days of the week) 4-9 mm Hg
Moderation of alcohol consumption Limit consumption to no more than two drinks per day (1 oz or 30 mL ethanol [eg, 24 oz beer, 10 oz wine, or 3 oz 80-proof whiskey]) in most men and no more than one drink per day in women and lighter-weight persons 2-4 mm Hg
From Chobanian AV et al: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560.
BMI = body mass index calculated as weight in kilograms divided by the square of height in meters; BP = blood pressure; DASH = Dietary Approaches to Stop Hypertension.
1For overall cardiovascular risk reduction, stop smoking. The effects of implementing these modifications are dose and time dependent and could be higher for some individuals.

Figure 11-1. Algorithm for treatment of hypertension. BP = blood pressure; ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; CCB = calcium channel blocker. (From Chobanian AV et al: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560.)

3. Defect in natriuresis

Normal individuals increase their renal sodium excretion in response to elevations in arterial pressure and to a sodium or volume load. Hypertensive patients, particularly when their blood pressure is normal, exhibit a diminished ability to excrete a sodium load. This defect may result in increased plasma volume and hypertension. During chronic hypertension, a sodium load is usually handled normally.

4. Intracellular sodium and calcium

Intracellular Na+ is elevated in blood cells and other tissues in primary (essential) hypertension. This may result from abnormalities in Na+–K+ exchange and other Na+ transport mechanisms. An increase in intracellular Na+ may lead to increased intracellular Ca2+ concentrations as a result of facilitated exchange and might explain the increase in vascular smooth muscle tone that is characteristic of established hypertension.

5. Exacerbating factors

A number of conditions elevate blood pressure, especially in predisposed individuals. Obesity is associated with an increase in intravascular volume and an elevated cardiac output. Weight reduction lowers blood pressure modestly. The relationship between sodium intake and hypertension remains controversial, and some—not all— hypertensives respond to high salt intake with substantial increases in blood pressure. Patients with high normal or elevated blood pressures should consume no more than 100 mmol/d of salt (2.4 g of sodium, 6 g of sodium chloride daily).

Excessive use of alcohol also raises blood pressure, perhaps by increasing plasma catecholamines. Hypertension can be difficult to control in patients who consume more than 40 g of ethanol (two drinks) daily or drink in “binges.” Cigarette smoking raises blood pressure, again by increasing plasma norepinephrine. Although the long-term effect of smoking on blood pressure is less clear, the synergistic effects of smoking and high blood pressure on cardiovascular risk are well documented. The relationship of exercise to hypertension is variable. Aerobic exercise lowers blood pressure in previously sedentary individuals, but increasingly strenuous exercise in already active subjects has less effect. The relationship between stress and hypertension is not established. Polycythemia, whether primary or due to diminished plasma volume, increases blood viscosity and may raise blood pressure. Nonsteroidal anti-inflammatory agents produce increases in blood pressure averaging 5 mm Hg, and are best avoided in patients with borderline or elevated blood pressures. Low potassium intake is associated with higher blood pressure in some patients; an intake of 90 mmol/d is recommended.

There is a growing recognition that the complex of abnormalities termed the “metabolic syndrome” is associated with both the development of hypertension and an increased risk of adverse cardiovascular outcomes. The metabolic syndrome (sometimes also called syndrome X or the “deadly quartet”) consists of upper body obesity, hyperinsulinemia and insulin resistance, hypertriglyceridemia, and hypertension. Affected patients usually also have low high-density lipoprotein (HDL) cholesterol levels and have been found to have elevated catecholamines and inflammatory markers such as C-reactive protein.

B. SECONDARY HYPERTENSION

Approximately 5% of patients with hypertension have specific causes (Table 11-3). The history, examination, and routine laboratory tests may identify such patients. In particular, patients who develop hypertension at an early age without a positive family history, those who first exhibit hypertension when over age 50 years, or those previously well controlled who become refractory to treatment are more likely to have secondary hypertension. Causes include the following.

1. Renal disease

Renal parenchymal disease is the most common cause of secondary hypertension. Hypertension may result from glomerular diseases, tubular interstitial disease, and polycystic kidneys. Most cases are related to increased intravascular volume or increased activity of the renin–angiotensin–aldosterone system. Hypertension accelerates progression of renal insufficiency, and rigorous control to target

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blood pressure of 130/85 mm Hg or lower will retard this progression. Diabetic nephropathy is another cause of chronic hypertension. This process is exacerbated by intraglomerular hypertension, itself worsened by systemic hypertension. Dilation of the efferent arterioles by angiotensin-converting enzyme inhibition reduces the rate of progression.

Table 11-3. Identifiable causes of hypertension.

Sleep apnea
Drug-induced or drug-related (see Table 11-11)
Chronic kidney disease
Primary aldosteronism
Renovascular disease
Chronic steroid therapy and Cushing's syndrome
Pheochromocytoma
Coarctation of the aorta
Thyroid or parathyroid disease
From Chobanian AV et al: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560.

2. Renal vascular hypertension

Renal artery stenosis is present in 1–2% of hypertensive patients. Its cause in most younger individuals is fibromuscular hyperplasia, which is most common in women under 50 years of age. The remainder of renal vascular disease is due to atherosclerotic stenoses of the proximal renal arteries. The mechanism of hypertension is excessive renin release due to reduction in renal blood flow and perfusion pressure. Renal vascular hypertension may occur when a single branch of the renal artery is stenotic, but in as many as 25% of patients both arteries are obstructed.

Renal vascular hypertension should be suspected in the following circumstances: (1) if the documented onset is below age 20 or after age 50 years, (2) if there are epigastric or renal artery bruits, (3) if there is atherosclerotic disease of the aorta or peripheral arteries (15–25% of patients with symptomatic lower limb atherosclerotic vascular disease have renal artery stenosis), or (4) if there is abrupt deterioration in renal function after administration of angiotensin-converting enzyme (ACE) inhibitors. Additional evaluation is indicated in such patients, especially if hypertension is difficult to control.

There is no ideal screening test for renal vascular hypertension. If the suspicion of renal vascular hypertension is sufficiently high, renal arteriography, the definitive diagnostic test, is the best approach. Where suspicion is moderate to low, radioisotope renography, duplex ultrasound, and magnetic resonance (MR) or computed tomography (CT) angiography have all been used successfully, but the results vary greatly among institutions. Except when stenosis is critical (> 80–90%) and unifocal, its significance may be assessed by measuring differences in renin activity between the renal veins. If the lesion is not associated with an increase in renin activity, hypertension often persists despite correction.

Young individuals and low-risk patients of any age who have not responded to medical therapy should have the lesion corrected. Percutaneous intervention with stent placement is the preferred approach for fibromuscular hyperplasia and for discrete stenotic arteriosclerotic lesions that do not involve the renal artery ostium. In older individuals with arteriosclerosis, only a minority experience complete normalization without continued drug therapy. Thus, it is reasonable to manage these patients medically if renal function does not deteriorate. Although ACE inhibitors have improved the success rate of medical therapy of hypertension due to renal artery stenosis, they have been associated with marked hypotension and renal dysfunction in individuals with bilateral renal artery stenosis. Thus, renal function and blood pressure should be closely monitored during the first weeks of therapy in patients in whom this is a consideration.

3. Primary hyperaldosteronism

Primary hyperaldosteronism occurs because of excessive unregulated secretion of aldosterone by the adrenal cortex. It may, in fact, be the commonest potentially curable and specifically treatable cause of hypertension. In the past, the diagnosis was often suspected when hypertensive patients presented with hypokalemia prior to diuretic therapy associated with excessive urinary potassium excretion (usually > 40 mEq/L on a spot specimen) and suppressed levels of plasma renin activity. However, the development and application of new screening tests to the population of hypertensives have resulted in a marked increase in the detection rate for primary hyperaldosteronism. It now appears that up to 5–15% of patients diagnosed as having primary (essential) hypertension actually have primary hyperaldosteronism, with most having normal serum potassium levels. Currently, the best screening test for primary hyperaldosteronism involves determinations of plasma aldosterone concentration (normal: 1–16 ng/dL) and plasma renin activity (normal: 1–2.5 ng/ mL/h) and calculation of the plasma aldosterone/renin ratio (normal: < 25). Patients with aldosterone/renin ratios of ≥ 25 require further evaluation for primary hyperaldosteronism. The lesion responsible is an adrenal adenoma, though some patients have bilateral adrenal hyperplasia. The lesion can be demonstrated by CT scanning or MRI.

4. Cushing's syndrome

Less commonly, patients with Cushing's syndrome (glucocorticoid excess) may present with hypertension. Among those with spontaneous Cushing's syndrome, however, hypertension occurs in about 75–85% of patients. The exact pathogenesis of the hypertension is unclear. It may be related to salt and water retention from the mineralocorticoid effects of the excess glucocorticoid. Alternatively, it may be due to increased secretion of angiotensinogen. While plasma renin activity and concentrations are generally normal or suppressed in Cushing's syndrome, angiotensinogen levels are elevated to approximately twice normal because of a direct effect of glucocorticoids on its hepatic synthesis, and angiotensin II levels are increased by about 40%. Administration of the angiotensin II antagonist saralasin to patients with Cushing's syndrome causes a prompt 8to 10-mm Hg drop in systolic and diastolic blood pressure. In addition, glucocorticoids exert permissive effects on vascular tone by a variety of mechanisms.

Diagnosis and treatment of Cushing's syndrome are discussed in Chapter 26.

5. Pheochromocytoma

Pheochromocytomas are uncommon; they are probably found in less than 0.1% of all patients with hypertension and in approximately two individuals per million population. In about 50% of patients with pheochromocytoma, hypertension

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is sustained but the blood pressure shows marked fluctuations, with peak pressures during symptomatic paroxysms. During a hypertensive episode, the systolic blood pressure can rise to as high as 300 mm Hg. In about one-third of cases, hypertension is truly intermittent. In some, hypertension is absent. The blood pressure elevation caused by the catecholamine excess results from two mechanisms: α-receptor-mediated vasoconstriction of arterioles, leading to an increase in peripheral resistance, and β1-receptor-mediated increases in cardiac output and in renin release, leading to increased circulating levels of angiotensin II. The increased total peripheral vascular resistance is probably primarily responsible for the maintenance of high arterial pressures. Chronic vasoconstriction of the arterial and venous beds leads to a reduction in plasma volume and predisposes to postural hypotension.

Indeed, the majority of patients have orthostatic decreases in blood pressure, the converse of primary (essential) hypertension. Some develop glucose intolerance. Hypertensive crisis in pheochromocytoma may be precipitated by a variety of drugs, including tricyclic antidepressants, antidopaminergic agents, metoclopramide, and naloxone. The diagnosis and treatment of pheochromocytoma are discussed in Chapter 26.

6. Coarctation of the aorta

This uncommon cause of hypertension is discussed in Chapter 10.

7. Hypertension associated with pregnancy

Hypertension occurring de novo or worsening during pregnancy, including preeclampsia and eclampsia, is one of the commonest causes of maternal and fetal morbidity and mortality (see Chapter 18).

8. Estrogen use

A small increase in blood pressure occurs in most women taking oral contraceptives, but considerable increases are noted occasionally. This is caused by volume expansion due to increased activity of the renin–angiotensin–aldosterone system. The primary abnormality is an increase in the hepatic synthesis of renin substrate. Five percent of women taking oral contraceptives chronically exhibit a rise in blood pressure above 140/90 mm Hg, twice the expected prevalence. Contraceptive-related hypertension is more common in women over 35 years of age, in those who have taken contraceptives for more than 5 years, and in obese individuals. It is less common in those taking low-dose estrogen tablets. In most, hypertension is reversible by discontinuing the contraceptive, but it may take several weeks. Postmenopausal estrogen does not generally cause hypertension, but rather maintains endothelium-mediated vasodilation.

9. Other causes of secondary hypertension

Hypertension has also been associated with hypercalcemia due to any cause: acromegaly, hyperthyroidism, hypothyroidism, and a variety of neurologic disorders causing increased intracranial pressure. A number of other medications may cause or exacerbate hypertension—most importantly cyclosporine and nonsteroidal anti-inflammatory drugs (NSAIDs).

August P: Overview: mechanisms of hypertension: cells, hormones, and the kidney. J Am Soc Nephrol 2004;15:1971.

Bravo EL: Pheochromocytoma. Cardiol Rev 2002;10:44.

Failor RA et al: Hyperaldosteronism and pheochromocytoma: new tricks and tests. Prim Care 2003;30:801.

Freel EM et al: Mechanisms of hypertension: the expanding role of aldosterone. J Am Soc Nephrol 2004;15:1993.

Hartman RP et al: Evaluation of renal causes of hypertension. Radiol Clin North Am 2003;41:909.

Loney EL et al: Renovascular hypertension. Q J Nucl Med 2002; 46:283.

Nordmann AJ et al: Balloon angioplasty versus medical therapy for hypertensive patients with renal artery obstruction. Cochrane Database Syst Rev 2003;(3):CD002944.

Nussberger J: Investigating mineralocorticoid hypertension. J Hypertens Suppl 2003;21(Suppl 2):S25.

Onusko E: Diagnosing secondary hypertension. Am Fam Physician 2003;67:67.

Oparil S et al: Pathogenesis of hypertension. Ann Intern Med 2003;139:761.

Reaven G: Insulin resistance, hypertension, and coronary heart disease. J Clin Hypertens 2003;5:269.

Stas SN et al: Pathogenesis of hypertension in diabetes. Rev Endocr Metab Disord 2004;5:221.

Strazzullo P et al: Altered renal handling of sodium in human hypertension: short review of the evidence. Hypertension 2003;41:1000.

Textor SC: Managing renal arterial disease and hypertension. Curr Opin Cardiol 2003;18:260.

Young WF Jr: Minireview: primary aldosteronism—changing concepts in diagnosis and treatment. Endocrinology 2003; 144:2208.

Complications of Untreated Hypertension

Complications of hypertension are related either to sustained elevations of blood pressure, with consequent changes in the vasculature and heart, or to atherosclerosis that accompanies and is accelerated by long-standing hypertension. The excess morbidity and mortality related to hypertension are progressive over the whole range of systolic and diastolic blood pressures; the risk approximately doubles for each 6 mm Hg increase in diastolic blood pressure. However, target-organ damage varies markedly between individuals with similar levels of office hypertension. Ambulatory pressures are more closely related to end-organ damage.

A. HYPERTENSIVE CARDIOVASCULAR DISEASE

Cardiac complications are the major causes of morbidity and mortality in primary (essential) hypertension, and preventing them is a major goal of therapy. Electrocardiographic evidence of left ventricular hypertrophy is found in up to 15% of chronic hypertensives. It is an indication of increased risk for morbidity and

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mortality; for any level of blood pressure, its presence is associated with incremental risk. Echocardiographic left ventricular hypertrophy is a powerful predictor of prognosis. Left ventricular hypertrophy may cause or facilitate many cardiac complications of hypertension, including congestive heart failure, ventricular arrhythmias, myocardial ischemia, and sudden death.

Left ventricular diastolic dysfunction, which may present with all of the symptoms and signs of congestive heart failure, is common in patients with longstanding hypertension. The occurrence of heart failure is reduced by 50% with antihypertensive therapy. Hypertensive left ventricular hypertrophy regresses with therapy and is most closely related to the degree of systolic blood pressure reduction. Diuretics have produced equal or greater reductions of left ventricular mass when compared with other drug classes.

B. HYPERTENSIVE CEREBROVASCULAR DISEASE AND DEMENTIA

Hypertension is the major predisposing cause of stroke, especially intracerebral hemorrhage but also ischemic cerebral infarction. Cerebrovascular complications are more closely correlated with systolic than diastolic blood pressure. The incidence of these complications is markedly reduced by antihypertensive therapy. Preceding hypertension is associated with a higher incidence of subsequent dementia, both the vascular and the Alzheimer types. Effective blood pressure control may modify the risk or rate of progression of cognitive dysfunction.

C. HYPERTENSIVE RENAL DISEASE

Chronic hypertension leads to nephrosclerosis, a common cause of renal insufficiency; aggressive blood pressure control attenuates the process. In patients with hypertensive nephropathy, the blood pressure should be 130/85 mm Hg or lower when proteinuria is present. Secondary renal disease is more common in blacks, particularly when accompanying diabetes is present. Hypertension also plays an important role in accelerating the progression of other forms of renal disease, most commonly diabetic nephropathy. ACE inhibitors are particularly effective in preventing the latter complication, but these agents appear to prevent the progression of other forms of nephropathy.

D. AORTIC DISSECTION

Hypertension is a contributing factor in many patients with dissection of the aorta. Its diagnosis and treatment are discussed in Chapter 12.

E. ATHEROSCLEROTIC COMPLICATIONS

Most Americans with hypertension die of complications of atherosclerosis, but the linkage between hypertension and atherosclerotic cardiovascular disease is much less close than that with the previously discussed complications. Effective antihypertensive therapy is thus less successful in preventing complications of coronary heart disease.

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Clinical Findings

The clinical and laboratory findings are mainly referable to involvement of the target organs: heart, brain, kidneys, eyes, and peripheral arteries.

A. SYMPTOMS

Mild to moderate primary (essential) hypertension is asymptomatic for many years, so the typical patient has no reason to be aware of having hypertension. The most frequent symptom, headache, is also very nonspecific. Suboccipital pulsating headaches, characteristically occurring early in the morning and subsiding during the day, are said to be characteristic, but any type of headache may occur. Accelerated hypertension is associated with somnolence, confusion, visual disturbances, and nausea and vomiting (hypertensive encephalopathy).

Patients with pheochromocytomas that secrete predominantly norepinephrine usually have sustained hypertension but may have episodic hypertension. Attacks (lasting minutes to hours) of anxiety, palpitation, profuse perspiration, pallor, tremor, and nausea and vomiting occur; blood pressure is markedly elevated, and angina or acute pulmonary edema may occur. In primary aldosteronism, patients may have muscular weakness, polyuria, and nocturia due to hypokalemia; malignant hypertension is rare. Chronic hypertension often leads to left ventricular hypertrophy, which may be associated with diastolic or, in late stages, systolic dysfunction. Exertional and paroxysmal nocturnal dyspnea may result, and ischemic heart disease is more common (especially when concomitant coronary artery disease is present).

Cerebral involvement causes (1) stroke due to thrombosis or (2) small or large hemorrhage from microaneurysms of small penetrating intracranial arteries, and focal symptoms depend upon which vessels are involved. Hypertensive encephalopathy is probably caused by acute capillary congestion and exudation with cerebral edema. The findings are usually reversible if adequate treatment is given promptly. There is no strict correlation of diastolic blood pressure with

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hypertensive encephalopathy; it usually exceeds 130 mm Hg.

B. SIGNS

Like symptoms, physical findings depend upon the cause of hypertension, its duration and severity, and the degree of effect on target organs.

1. Blood pressure

On initial examination, pressure is taken in both arms and, if lower extremity pulses are diminished or delayed, in the legs to exclude coarctation of the aorta. An orthostatic drop is present in pheochromocytoma. Older patients may have falsely elevated readings by sphygmomanometry because of noncompressible vessels. This may be suspected in the presence of Osler's sign—a palpable brachial or radial artery when the cuff is inflated above systolic pressure. Occasionally, it may be necessary to make direct measurements of intra-arterial pressure, especially in patients with apparent severe hypertension who do not tolerate therapy.

2. Retinas

Narrowing of arterial diameter to less than 50% of venous diameter, copper or silver wire appearance, exudates, hemorrhages, or papilledema are associated with a worse prognosis.

3. Heart and arteries

Left ventricular enlargement with a left ventricular heave indicates severe or longstanding hypertrophy. Older patients frequently have systolic ejection murmurs resulting from calcific aortic sclerosis, and these may evolve to significant aortic stenosis in some individuals. Aortic insufficiency may be auscultated in up to 5% of patients, and hemodynamically insignificant aortic insufficiency can be detected by Doppler echocardiography in 10–20%. A presystolic (S4) gallop due to decreased compliance of the left ventricle is quite common in patients with sinus rhythm.

4. Pulses

The timing of upper and lower extremity pulses should be compared to exclude coarctation of the aorta. All major peripheral pulses should be evaluated to exclude aortic dissection and peripheral atherosclerosis, which may be associated with renal artery involvement.

C. LABORATORY FINDINGS

Recommended testing includes the following: hemoglobin; urinalysis and renal function studies, to detect hematuria, proteinuria, and casts, signifying primary renal disease or nephrosclerosis; determinations of serum K+, plasma aldosterone concentration, and plasma renin activity and calculation of the plasma aldosterone/renin ratio to detect mineralocorticoid excess; fasting blood sugar level, since hyperglycemia is noted in diabetes and pheochromocytoma; plasma lipids, as an indicator of atherosclerosis risk and an additional target for therapy; and serum uric acid, which, if elevated, is a relative contraindication to diuretic therapy.

D. ELECTROCARDIOGRAPHY AND CHEST X-RAY

Electrocardiographic criteria are highly specific but not very sensitive for left ventricular hypertrophy. The “strain” pattern of ST–T wave changes is a sign of more advanced disease and is associated with a poor prognosis. A chest x-ray is not necessary in the workup for uncomplicated hypertension since it usually does not yield additional information.

E. ECHOCARDIOGRAPHY

Although echocardiography has been advocated to determine the need for drug therapy in patients with borderline or mildly elevated pressures, it is unusual to find left ventricular mass readings above the upper 75% confidence limits in the absence of systolic hypertension. The primary role of echocardiography should be to evaluate patients with clinical symptoms or signs of cardiac disease.

F. DIAGNOSTIC STUDIES

Only if the clinical presentation or routine tests suggest secondary or complicated hypertension are additional diagnostic studies indicated. These may include tests such as 24-hour urine free cortisol and plasma metanephrine levels for endocrine causes of hypertension, renal ultrasound to diagnose primary renal disease (polycystic kidneys, obstructive uropathy), and testing for renal artery stenosis. Further evaluation may include abdominal imaging studies (ultrasound, CT scan, or MRI) or renal arteriography.

G. SUMMARY

Since most hypertension is “primary,” few studies are necessary beyond those listed above. If conventional therapy is unsuccessful or if symptoms suggest a secondary cause, further studies are indicated.

Nonpharmacologic Therapy

Lifestyle modification may have an impact on morbidity and mortality. A diet rich in fruits, vegetables, and low-fat dairy foods and low in saturated and total fats (DASH diet) has been shown to lower blood pressure. Additional measures can prevent or mitigate hypertension or its cardiovascular consequences as shown in Table 11-2.

All patients with high-normal or elevated blood pressures, those who have a family history of cardiovascular complications of hypertension, and those who have multiple coronary risk factors should be counseled about nonpharmacologic approaches to lowering blood pressure. Approaches of proved but modest value include weight reduction, reduced alcohol consumption, and, in some patients, reduced salt intake. Gradually increasing activity levels should be encouraged in previously sedentary patients, but strenuous exercise training programs in already active individuals may have less benefit. Calcium and potassium supplements have been advocated, but their ability to lower blood pressure is limited.

Smoking cessation will reduce overall cardiovascular risk.

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Bray GA et al: A further subgroup analysis of the effects of the DASH diet and three dietary sodium levels on blood pressure: results of the DASH-Sodium Trial. Am J Cardiol 2004;94:222.

Hooper L et al: Advice to reduce dietary salt for prevention of cardiovascular disease. Cochrane Database Syst Rev 2004: CD003656.

Krousel-Wood MA et al: Primary prevention of essential hypertension. Med Clin North Am 2004;88:223.

Stewart KJ: Exercise training and the cardiovascular consequences of type 2 diabetes and hypertension: plausible mechanisms for improving cardiovascular health. JAMA 2002;288: 1622.

Whelton SP et al: Effect of aerobic exercise on blood pressure: a meta-analysis of randomized controlled trials. Ann Intern Med 2002;136:493.

Wilburn AJ et al: The natural treatment of hypertension. J Clin Hypertens (Greenwich) 2004;6:242.

Xin X et al: Effects of alcohol reduction on blood pressure: a meta-analysis of randomized controlled trials. Hypertension 2001;38:1112.

Who Should Be Treated with Medications? (Tables 11-1 and 11-4)

Many excellent trials have shown that drug therapy of patients with stage 2 hypertension reduces the incidence of stroke by 30–50%, congestive heart failure by 40–50%, and progression to accelerated hypertension syndromes. The decreases in fatal and nonfatal coronary heart disease and cardiovascular and total mortality have been less dramatic, ranging from 10% to 15%. This lesser decrease in coronary heart disease has generated controversy. Some have attributed the decreased benefit to characteristics of the drugs (primarily diuretics and β-blockers), such as their adverse effect on lipid profiles and electrolyte balance. Others believe it is due to the more chronic and multifactorial nature of coronary artery disease, the generally low-risk populations included in trials, and the large number of crossovers from placebo to active therapy. Several studies in older persons with predominantly systolic hypertension have confirmed that antihypertensive therapy prevents fatal and nonfatal myocardial infarction and overall cardiovascular mortality. These trials have also placed the focus on control of systolic blood pressure—in contrast to the historical emphasis on diastolic blood pressures.

Goals of Treatment

The decision to initiate drug therapy should be based upon the assessment of overall cardiovascular risk rather than the level of blood pressure alone. Table 11-4 lists the major risk factors for cardiovascular morbidity and mortality and the cardiovascular manifestations that predispose to further complications. Table 11-1 sets forth the criteria used to institute therapy. Thus, patients with systolic blood pressure over 140 mm Hg or with diastolic blood pressure over 90 mm Hg after repeated measurements should be treated. Those with prehypertension and at least one additional high-risk condition with compelling indication (such as chronic kidney disease or diabetes mellitus) should also be treated to achieve a target blood pressure of < 130/80 mm Hg.

Table 11-4. Cardiovascular risk factors.

Major risk factors
  Hypertension1
  Cigarette smoking
  Obesity (BMI ≥ 30)1
  Physical inactivity
  Dyslipidemia1
  Diabetes mellitus1
  Microalbuminuria or estimated GFR <60 mL/min
  Age (> 55 years for men, > 65 years for women)
  Family history of premature cardiovascular disease (men > 55 years or women 65 years)
Target-organ damage
Heart
  Left ventricular hypertrophy
  Angina or prior myocardial infarction
  Prior coronary revascularization
  Heart failure
Brain
  Stroke or transient ischemic attack
  Chronic kidney disease
  Peripheral arterial disease
  Retinopathy
From Chobanian AV et al: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560.
BMI indicates body mass index calculated as weight in kilograms divided by the square of height in meters; GFR = glomerular filtration rate.
1Components of the metabolic syndrome.

Friday G et al: Control of hypertension and risk of stroke recurrence. Stroke 2002;33:2652.

Kaplan NM: What is goal blood pressure for the treatment of hypertension? Arch Intern Med 2001;161:1480.

Lawes CM et al: Blood pressure and stroke: an overview of published reviews. Stroke 2004;35:776.

Snow V et al: The evidence base for tight blood pressure control in the management of type 2 diabetes mellitus. Ann Intern Med 2003;138:587.

Whelton PK et al: Strategies for improvement of awareness, treatment and control of hypertension: results of a panel discussion. J Hum Hypertens 2004;18:563.

Whitworth JA: 2003 World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension. J Hypertens 2003;21:1983.

DRUG THERAPY

General Principles

There are now many classes of potentially antihypertensive drugs of which five (diuretics, β-blockers, ACE

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inhibitors, calcium channel blockers, and angiotensin II receptor blockers [ARBs]) are suitable for initial or single-drug therapy based on efficacy and tolerability. A number of considerations enter into the selection of the initial drug for a given patient. These include the weight of evidence for beneficial effects on clinical outcomes, the safety and tolerability of the drug, its cost, demographic differences in response, concomitant medical conditions, and lifestyle issues. The specific classes of antihypertensive medications are discussed below, and guidelines for the choice of initial medications are offered.

Current Antihypertensive Agents (See Tables 11-5,11-6,11-7,11-8,11-9 for dosages)

A. DIURETICS (Table 11-5)

Diuretics are the antihypertensives that have been most extensively studied and most consistently effective in clinical trials. They lower blood pressure initially by decreasing plasma volume (by suppressing tubular reabsorption of sodium, thus increasing the excretion of sodium and water) and cardiac output, but during chronic therapy their major hemodynamic effect is reduction of peripheral vascular resistance. Most of the antihypertensive effect of these agents is achieved at lower dosages than used previously (typically, 12.5 or 25 mg of hydrochlorothiazide or equivalent), but their biochemical and metabolic effects are dose related. The thiazide diuretics are the most widely used. During chronic therapy, hydrochlorothiazide may be administered every other day with undiminished efficacy. The loop diuretics (such as furosemide) may lead to electrolyte and volume depletion more readily than the thiazides and have short durations of action; therefore, they should not be used in hypertension except in the presence of renal dysfunction (serum creatinine above 2.5 mg/dL). Relative to the β-blockers and the ACE inhibitors, diuretics are more potent in blacks, older individuals, the obese, and other subgroups with increased plasma volume or low plasma renin activity. Interestingly, they are relatively more effective in smokers than in nonsmokers. Chronic diuretic administration also mitigates the loss of bone mineral content in older women at risk for osteoporosis.

Overall, diuretics administered alone control blood pressure in 50% of patients with mild to moderate hypertension and can be used effectively in combination with all other agents. They are also useful for lowering isolated or predominantly systolic hypertension. Some observations suggest that the use of thiazide diuretics as initial therapy has been associated with greater reductions in myocardial infarction than β-blockers.

The adverse effects of diuretics relate primarily to the metabolic changes listed in Table 11-5. Impotence, skin rashes, and photosensitivity are less frequent. Hypokalemia has been a concern but is uncommon at the recommended dosages (12.5–25 mg hydrochlorothiazide). The risk can be minimized by limiting salt intake or a high-potassium diet; potassium replacement is not usually required to maintain serum K+ at > 3.5 mmol/L. Higher serum levels are prudent in patients at special risk from intracellular potassium depletion, such as those taking digoxin or with a history of ventricular arrhythmias. If higher doses of diuretic are required, the drug should be used in combination with a potassiumsparing agent or with an ACE inhibitor or ARB. Diuretics reduce insulin sensitivity and cause modest increases in blood glucose. Compared with ACE inhibitors and ARBs, diuretic therapy is associated with a slightly higher incidence of new-onset diabetes. Diuretics also increase serum uric acid and may precipitate gout. Increases in blood glucose, triglycerides, low-density lipoprotein cholesterol, and plasma insulin may occur but are relatively minor during long-term lowdose therapy.

B. β-ADRENERGIC BLOCKING AGENTS (Table 11-6)

These drugs are effective in hypertension because they decrease the heart rate and cardiac output. Even after continued use of β-blockers, cardiac output remains lower and systemic vascular resistance higher with agents that do not have intrinsic sympathomimetic or α-blocking activity. The β-blockers also decrease renin release and are more efficacious in populations with elevated plasma renin activity, such as younger white patients. They neutralize the reflex tachycardia caused by vasodilators and are especially useful in patients with associated conditions that benefit from the cardioprotective effects of these agents. These include individuals with angina pectoris, previous myocardial infarction, and stable congestive heart failure as well as those with migraine headaches and somatic manifestations of anxiety. In some clinical trials, β-blockers have not been as effective as diuretics in preventing first myocardial infarctions.

Although all β-blockers appear to be similar in antihypertensive potency, controlling approximately 50% of patients, they differ in a number of pharmacologic properties (these differences are summarized in Table 11-6), including those relatively specific to the cardiac β1-receptors (cardioselectivity) and whether they also block the β2-receptors in the bronchi and vasculature; at higher dosages, however, all agents are nonselective. The β-blockers also differ in their pharmacokinetics and lipid solubility—which determines whether they cross the blood–brain barrier and affect the incidence of central nervous system side effects— and route of metabolism. Labetalol and carvedilol are combined aand β-blockers and, unlike most bblockers, decrease peripheral vascular resistance.

The side effects of all β-blockers include inducing or exacerbating bronchospasm in predisposed patients (asthmatics, some patients with chronic obstructive pulmonary disease [COPD]), sinus node dysfunction and atrioventricular (AV) conduction depression (resulting in bradycardia or AV block), precipitating or worsening clinically important left ventricular failure,

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nasal congestion, Raynaud's phenomenon, and central nervous system symptoms with nightmares, excitement, depression, and confusion. Fatigue, lethargy, and impotence may occur. All β-blockers tend to increase plasma triglycerides. The nonselective and, to a lesser extent, the cardioselective (β1-selective) β-blockers tend to depress the protective HDL fraction of plasma cholesterol. As with diuretics, the changes are blunted with time and dietary changes.

Table 11-5. Antihypertensive drugs: diuretics.

Drug Proprietary Name Initial Dosage Dosage Range Cost per Unit Cost of 30 Days Treatment1 (Average Dosage) Adverse Effects Comments
THIAZIDES AND RELATED DIURETICS
Hydrochlorothiazide Esidrix, Hydro-Diuril 12.5 or 25 mg once daily 12.5-50 mg once daily $0.08/25 mg $2.40 ↓K+, ↓Mg2+, ↑Ca2+, ↓Na+, ↑ uric acid, ↑ glucose, ↑LDL cholesterol, ↑triglycerides; rash, erectile dysfunction. Low dosages effective in many patients without associated metabolic abnormalities; metolazone more effective with concurrent renal insufficiency; indapamide does not alter serum lipid levels.
Chlorthalidone Hygroton, Thaliton 12.5 or 25 mg once daily 12.5-50 mg once daily $0.23/25 mg $6.90
Metolazone Zaroxolyn 1.25 or 2.5 mg once daily 1.25-5 mg once daily $1.48/5 mg $44.40
Mykrox 0.5 mg once daily 0.5-1 mg once daily $1.24/0.5 mg $37.20
Indapamide Lozol 2.5 mg once daily 2.5-5 mg once daily $0.83/2.5 mg $24.90
LOOP DIURETICS
Furosemide Lasix 20 mg twice daily 40-320 mg in 2 or 3 doses $0.16/40 mg $9.60 Same as thiazides, but higher risk of excessive diuresis and electrolyte imbalance. Increases calcium excretion. Furosemide: Short duration of action a disadvantage; should be reserved for patients with renal insufficiency or fluid retention. Poor anti-hypertensive.Torsemide: Effective blood pressure medication at low dosage.
Ethacrynic acid Edecrin 50 mg once daily 50-100 mg once or twice dily $0.75/50 mg $45.00
Bumetanide Bumex 0.25 mg twice daily 0.5-10 mg in 2 or 3 doses $0.45/1 mg $27.00
Torsemide Demadex 2.5 mg once daily 5-10 mg once daily $0.70/10 mg $21.00
ALDOSTERONE RECEPTOR BLOCKERS
Spironolactone Aldactone 12.5 or 25 mg once daily 12.5-100 mg once daily $0.46/25 mg $13.80 Hyperkalemia, metabolic acidosis, gynecomastia. Can be useful add-on therapy in patients with refractory hypertension.
Amiloride Midamor 5 mg once daily 5-10 mg once daily $0.47/5 mg $14.10
Eplerenone Inspra 25 mg once daily 25-100 mg once daily $3.60/25 mg $108.00
COMBINATION PRODUCTS
Hydrochlorothiazide and triamterene Dyazide (25/50 mg); Maxzide (25/37.5 mg) 1 tab once daily 1 or 2 tabs once daily $0.36 $10.80 Same as thiazides plus GI disturbances, hyper-kalemia rather than hypokalemia, headache; triamterene can cause kidney stones and renal dysfunction; spironolactone causes gynecomastia. Hyperkalemia can occur if this combination is used in patients with renal failure or those taking ACE inhibitors. Use should be limited to patients with demonstrable need for a potassium-sparing agent.
Hydrochlorothiazide and amiloride Moduretic (50/5 mg) 1/2 tab once daily 1 or 2 tabs once daily $0.42 $12.60
Hydrochlorothiazide and spironolactone Aldactazide (25/25 mg) 1 tab once daily 1 or 2 tabs once daily $0.50 $15.00
LDL = low-density lipoprotein; GI = gastrointestinal; ACE = angiotensin-converting enzyme.
1Average wholesale price (AWP, for AB-rated generic when available) for quantity listed. Source: Red Book Update, Vol. 24, No. 4, April 2005. AWP may not accurately represent the actual pharmacy cost because wide contractual variations exist among institutions.

Table 11-6. Antihypertensive drugs: β-adrenergic blocking agents.

Drug Proprietary Name Initial Dosage Dosage Range Cost per Unit Cost of 30 Days Treatment (Based on Average Dosage)1 Special Properties Comments5
β1 Selectivity2 ISA3 MSA4 Lipid Solubility Renal vs Hepatic Elimination
Acebutolol Sectral 200 mg once daily 200-1200 mg in 1 or 2 doses $1.34/400 mg $ 40.20 + + + + H > R Positive ANA; rare LE syndrome; also indicated for arrhythmias.Doses > 800 mg have β1 and β2 effects.
Atenolol Tenormin 25 mg once daily 25-200 mg once daily $0.83/50 mg $24.90 + 0 0 0 R Also indicated for angina pectoris and post- MI. Doses > 100 mg have β1 and β2 effects.
Betaxolol Kerlone 10 mg once daily 10-40 mg once daily $1.10/10 mg $33.00 + 0 0 + H > R  
Bisoprolol and hydrochlorothiazide Ziac 5 mg/6.25 mg 2.5-10 mg plus 6.25 mg $1.14/2.5/6.25 mg $34.20 + 0 0 0 R = H Low-dose combination approved for initial therapy. Bisoprolol also effective for heart failure.
Carteolol Cartrol 2.5 mg once daily 2.5-10 mg once daily $1.36/5 mg $40.80 0 + 0 + R > H  
Carvedilol Coreg 6.25 mg 12.5-100 mg in 2 doses $1.83/25 mg $109.80 (25 mg twice a day) 0 0 0 +++ H > R αβ-Blocking activity 1:9; may cause orthostatic symptoms; effective for congestive heart failure.
Labetalol Normodyne, Trandate 100 mg twice daily 200-1200 mg in 2 doses $0.71/200 mg $42.60 0 0/+ 0 ++ H αβ-Blocking activity 1:3; more orthostatic hypotension, fever, hepatotoxicity.
Metoprolol Lopressor 50 mg in 1 or 2 doses 50-200 mg in 1 or 2 doses $0.55/50 mg $33.00 + 0+ + +++ H Also indicated for angina pectoris and post- MI. Approved for heart failure. Doses > 100 mg have β1 and β2 effects.
Toprol XL (SR preparation) 50 mg once daily 50-200 mg once daily $1.28/100 mg $38.40            
Nadolol Corgard 20 mg once daily 20-160 mg once daily $1.05/40 mg $31.50 0 0 0 0 R  
Penbutolol Levatol 20 mg once daily 20-80 mg once daily $1.80/20 mg $54.00 0 + 0 ++ R > H  
Pindolol Visken 5 mg twice daily 10-60 mg in 2 doses $0.70/5 mg $42.00 0 ++ + + H > R In adults, 35% renal clearance.
Propranolol Inderal 20 mg twice daily 40-320 mg in 2 doses $0.51/40 mg $30.60 0 0 ++ +++ H Once-daily SR preparation also available. Also indicated for angina pectoris and post-MI.
Timolol Blocadren 5 mg twice daily 10-40 mg in 2 doses $0.38/10 mg $ 22.80 0 0 0 ++ H > R Also indicated for post- MI. 80% hepatic clearance.
ISA = intrinsic sympathomimetic activity; MSA = membrane-stabilizing activity; ANA = antinuclear antibody; LE = lupus erythematosus; MI = myocardial infarction; SR = sustained release; 0 = no effect; +, ++, +++ = some, moderate, most effect.
1Average wholesale price (AWP, for AB-rated generic when available) for quantity listed. Source: Red Book Update, Vol. 25, No. 4, April 2005. AWP may not accurately represent the actual pharmacy cost because wide contractual variations exist among institutions.
2Agents with β1 selectivity are less likely to precipitate bronchospasm and decreased peripheral blood flow in low doses, but selectivity is only relative.
3Agents with ISA cause less resting bradycardia and lipid changes.
4MSA generally occurs at concentrations greater than those necessary for β-adrenergic blockade. The clinical importance of MSA by β-blockers has not been defined.
5Adverse effects of all β-blockers: bronchospasm, fatigue, sleep disturbance and nightmares, bradycardia and atrioventricular block, worsening of congestive heart failure, cold extremities, gastrointestinal disturbances, impotence, triglycerides, HDL cholesterol, rare blood dyscrasias.

β-Blockers have traditionally been considered contraindicated in patients with congestive heart failure. Evolving experience suggests that they have a propitious effect on the natural history of patients with chronic stable heart failure and reduced ejection fractions (see Chapter 10). β-Blockers are used cautiously in patients with type 1 diabetes, since they can mask the symptoms of hypoglycemia and prolong these episodes by inhibiting gluconeogenesis. Although they may increase blood glucose levels in type 2 diabetics, the prognosis of these patients on balance is improved. These drugs should also be used with caution in patients with advanced peripheral vascular disease associated with rest pain or nonhealing ulcers, but they are generally well tolerated in patients with mild claudication. In treatment of pheochromocytoma, β-blockers should not be administered until α-blockade has been established. Otherwise, blockade of β2-adrenergic receptors, which promote vasodilation, will allow unopposed α-adrenergic receptor activation and produce marked vasoconstriction and worsening of hypertension.

C. ANGIOTENSIN-CONVERTING ENZYME INHIBITORS (Table 11-7)

ACE inhibitors are being increasingly used as the initial medication in mild to moderate hypertension. Their primary mode of action is inhibition of the renin–angiotensin–aldosterone system, but they also inhibit bradykinin degradation, stimulate the synthesis of vasodilating prostaglandins, and, sometimes, reduce sympathetic nervous system activity. These latter actions may explain why they exhibit some effect even in patients with low plasma renin activity. ACE inhibitors appear to be more effective in younger whites. They are relatively less effective in blacks and older persons and in predominantly systolic hypertension. Although as single therapy they achieve adequate antihypertensive control in only about 40–50% of patients, the combination of an ACE inhibitor and a diuretic or calcium channel blocker is potent.

ACE inhibitors are the agents of choice in type 1 diabetics with frank proteinuria or evidence of renal dysfunction because they delay the progression to end-stage renal disease. Many authorities have expanded this indication to include type 2 diabetics and type 1 diabetics with microalbuminuria, even when they do not meet the usual criteria for antihypertensive therapy. The Heart Outcomes Prevention Evaluation (HOPE) trial demonstrated that the ACE inhibitor ramipril reduces the number of cardiovascular deaths, nonfatal myocardial infarctions, and nonfatal strokes and also reduces the incidence of new-onset heart failure, renal dysfunction, and new-onset diabetes in a population of patients at high risk for vascular events. Although this was not specifically a hypertensive population, the benefits were associated with a modest reduction in blood pressure, and the results inferentially support the use of ACE inhibitors in similar hypertensive patients. ACE inhibitors may also delay the progression of other forms of renal disease. They are a drug of choice (usually in conjunction with a diuretic and a β-blocker) in patients with congestive heart failure and are indicated also in asymptomatic patients with reduced ejection fractions whether due to myocardial infarction or to other causes.

ACE inhibitors have effects on mortality and most cardiovascular outcomes similar to those achieved with diuretics and β-blockers. However, compared with calcium channel blockers, ACE inhibitors are associated with lower incidences of coronary events and heart failure.

An advantage of the ACE inhibitors is their relative freedom from troublesome side effects. Severe hypotension can occur in patients with bilateral renal artery stenosis; acute renal failure may ensue. Hyperkalemia may develop in patients with intrinsic renal disease and type IV renal tubular acidosis (commonly seen in diabetics) and in the elderly. A chronic dry cough is common, seen in 10% of patients or more, and may require stopping the drug. Dizziness occurs but may not be related to the degree of blood pressure lowering. Skin rashes are observed with any ACE inhibitor. Taste alterations are seen more often with captopril than with the non-sulfhydryl-containing agents (enalapril and lisinopril) but often disappear with continued therapy. Angioedema is an uncommon but potentially dangerous side effect of all agents of this class because of their inhibition of kininase.

D. ANGIOTENSIN II RECEPTOR BLOCKERS (Table 11-7)

Although losartan, the first member of this group, was less potent than high doses of ACE inhibitors in reducing blood pressure, the newer ARBs (valsartan, irbesartan, candesartan, telmisartan, and eprosartan) appear to be equipotent to ACE inhibitors. A growing body of data indicates that ARBs can improve cardiovascular outcomes in hypertensives and patients with related conditions such as heart failure and type 2 diabetes with nephropathy. ARBs have not been compared with ACE inhibitors in randomized controlled trials in patients with hypertension, but two trials comparing losartan with captopril in heart failure and post-myocardial infarction left ventricular dysfunction showed trends toward worse outcomes in the losartan group. Whether this suggestion of less efficacy is specific to losartan or may also be true for other ARBs is as yet unknown. However, the Losartan Intervention for Endpoints (LIFE) trial in nearly 9000 hypertensive patients with electrocardiographic evidence of left ventricular hypertrophy—comparing losartan with the β-blocker atenolol as initial therapy—demonstrated a significant reduction in stroke with losartan. Of note is that in diabetics, death and myocardial

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infarction were also reduced, and there was a lower occurrence of new-onset diabetes. In this trial, as in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) with an ACE inhibitor, blacks exhibited less blood pressure reduction and less benefit with regard to clinical end points.

Table 11-7. Antihypertensive drugs: ACE inhibitors and angiotensin II receptor blockers.

Drug Proprietary Name Initial Dosage Dosage Range Cost per Unit Cost of 30 Days Treatment (Average Dosage)1 Adverse Effects Comments
ACE INHIBITORS
Benazepril Lotensin 10 mg once daily 5-40 mg in 1 or 2 doses $1.05/20 mg $31.50 Cough, hypotension, dizziness, renal dysfunction, hyperkalemia, angioedema; taste alteration and rash (may be more frequent with captopril); rarely, proteinuria, blood dyscrasia. Contraindicated in pregnancy. More fosinopril is excreted by the liver in patients with renal dysfunction (dose reduction may or may not be necessary). Captopril and lisinopril are active without metabolism. Captopril, enalapril, lisinopril, and quinapril are approved for congestive heart failure.
Captopril Capoten 25 mg twice daily 50-300 mg in 2 or 3 doses $0.65/25 mg $39.00
Enalapril Vasotec 5 mg once daily 5-40 mg in 1 or 2 doses $1.52/20 mg $45.60
Fosinopril Monopril 10 mg once daily 10-80 mg in 1 or 2 doses $1.19/20 mg $35.70
Lisinopril Prinivil, Zestril 5-10 mg once daily 5-40 mg once daily $1.06/20 mg $31.80
Moexipril Univasc 7.5 mg once daily 7.5-30 mg in 1 or 2 doses $1.33/ 7.5 mg $39.90
Perindopril Aceon 4 mg once daily 4-16 mg in 1 or 2 doses $2.07/8 mg $62.10
Quinapril Accupril 10 mg once daily 10-80 mg in 1 or 2 doses $1.23/20 mg $36.90
Ramipril Altace 2.5 mg once daily 2.5-20 mg in 1 or 2 doses $1.59/5 mg $47.70
Trandolapril Mavik 1 mg once daily 1-8 mg once daily $1.15/4 mg $34.50
ANGIOTENSIN II RECEPTOR BLOCKERS
Candesartan cilexitil Atacand 16 mg once daily 8-32 mg once daily $1.63/16 mg $48.95 Hyperkalemia, renal dysfunction, rare angioedema. Combinations have additional side effects. Contraindicated in pregnancy. Losartan has a very flat dose-response curve. Valsartan and irbesartan have wider dose-response ranges and longer durations of action. Addition of low-dose diuretic (separately or as combination pills) increases the response.
Candesartan cilexitil/ HCTZ Atacand HCT 16 mg/ 12.5 mg once daily 8-32 mg of candesartan once daily $2.21/16 mg/12.5 mg $66.25
Eprosartan Teveten 600 mg once daily 400-800 mg in 1-2 doses $1.44/ 600 mg $43.20
Eprosartan/ HCTZ Teveten HCT 600 mg/ 12.5 mg once daily 600 mg/12.5 mg or 600 mg/25 mg once daily $1.44/ 600 mg/ 12.5 mg $43.20
Irbesartan Avapro 150 mg once daily 150-300 mg once daily $1.69/ 150 mg $50.76
Irbesartan and hydrochlorothiazide Avalide 150 mg/ 12.5 mg once daily 150-300 mg irbesartan daily $2.09/ 150 mg $62.58
Losartan Cozaar 50 mg once daily 25-100 mg in 1 or 2 doses $1.67/50 mg $50.10
Losartan and hydrochlorothiazide Hyzaar 50 mg/ 12.5 mg once daily One or 2 tablets once daily $1.67/50 mg/12.5 mg/tablet $50.10 Hyperkalemia, renal dysfunction, rare angioedema. Combinations have additional side effects. Contraindicated in pregnancy. Losartan has a very flat dose-response curve. Valsartan and irbesartan have wider dose-response ranges and longer durations of action. Addition of low-dose diuretic (separately or as combination pills) increases the response.
Olmesartan Benicar 20 mg once daily 20-40 mg daily $1.61/20 mg $48.24
Olmesartan and HCTZ Benicar HCT 20 mg/ 12.5 mg daily 20-40 mg olmesartan daily $1.62/20 mg/12.5 mg $48.60
Telmisartan Micardis 40 mg once daily 20-80 mg once daily $1.74/40 mg $52.33
Telmisartan and HCTZ Micardis HCT 40 mg/ 12.5 mg once daily 20-80 mg telmisartan daily $1.87/40 mg/12.5 mg $56.06
Valsartan Diovan 80 mg once daily 80-320 mg once daily $1.92/ 160 mg $57.72
Valsartan and HCTZ Diovan HCT 80 mg/ 12.5 mg once daily 80-320 mg valsartan daily $2.09/ 160 mg/ 12.5 mg $62.82
ACE = angiotensin-converting enzyme; HCTZ = hydrochlorothiazide.
1Average wholesale price (AWP, for AB-rated generic when available) for quantity listed. Source: Red Book Update, Vol. 24, No. 4, April 2005. AWP may not accurately represent the actual pharmacy cost because wide contractual variations exist among institutions

Unlike ACE inhibitors, the ARBs do not cause cough and are only infrequently associated with skin rashes, the most common side effects of the ACE inhibitors. However, they still present a risk of hypotension and renal failure in patients with bilateral renal artery stenosis and hyperkalemia, and, rarely—but much less frequently than with ACE inhibitors—angioedema.

E. CALCIUM CHANNEL BLOCKING AGENTS (Table 11-8)

These agents act by causing peripheral vasodilation, which is associated with less reflex tachycardia and fluid retention than other vasodilators. They are effective as single-drug therapy in approximately 60% of patients in all demographic groups and all grades of hypertension. As a result, they may be preferable to bblockers and ACE inhibitors in blacks and older subjects. Calcium channel blockers and diuretics are less additive when given together than when either is combined with β-blockers or ACE inhibitors. However, verapamil and diltiazem should be combined cautiously with β-blockers because of their potential for depressing AV conduction and sinus node automaticity as well as contractility.

Although concerns have previously been raised about increased risk of myocardial infarction in hypertensive patients and of higher mortality in acute coronary syndromes treated with calcium channel blockers, this was not the case with amlodipine in ALLHAT. Diabetic patients receiving calcium channel blockers may have higher rates of heart failure and myocardial infarction than those receiving ACE inhibitors, and in other studies heart failure has been more common than in patients treated with diuretics or ACE inhibitors. Whether these outcomes reflect beneficial effects of the comparators or specific risks of calcium channel blockers is uncertain. A protective effect against stroke with calcium blockers is

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well established, and in two trials (ALLHAT and the Systolic Hypertension in Europe trial) these agents appeared to be more effective than diuretic-based therapy.

Table 11-8. Antihypertensive drugs: calcium channel blocking agents.

Drug Proprietary Name Initial Dosage Dosage Range Cost of 30 Days Treatment (Average Dosage)1 Special Properties Adverse Effects Comments
Peripheral Vasodilation Cardiac Automaticity and Conduction Contractility
NONDIHYDROPYRIDINE AGENTS
Diltiazem Cardizem SR 90 mg twice daily 180-360 mg in 2 doses $67.20 (120 mg twice daily) ++ ↓↓ ↓↓ Edema, headache, bradycardia, GI disturbances, dizziness, AV block, congestive heart failure, urinary frequency. Also approved for angina.
Cardizem CD; Cartia XT 180 mg daily 180-360 mg daily $53.27 (240 mg daily)
Dilacor XR 180 or 240 mg daily 180-480 mg daily $34.50 (240 mg daily)
Tiazac SA 240 mg daily 180-540 mg daily $62.74 (240 mg daily)
Verapamil Calan SR Isoptin SR Verelan

Covera HS
180 mg daily 180-480 mg in 1 or 2 doses $46.80

$66.00 (240 mg daily)
++ ↓↓↓ ↓↓↓ Same as diltiazem but more likely to cause constipation and congestive heart failure. Also approved for angina and arrhythmias.
DIHYDROPYRIDINES
Amlodipine Norvasc 5 mg daily 5-20 mg daily $68.55 (10 mg daily) +++ ↓/0 ↓/0 Edema, dizziness, palpitations, flushing, headache, hypotension, tachycardia, GI disturbances, urinary frequency, worsening of congestive heart failure (may be less common with felodipine, amlodipine). Amlodipine, nicardipine, and nifedipine also approved for angina.
Felodipine Plendil 5 mg daily 5-20 mg daily $72.30 (10 mg daily) +++ ↓/0 ↓/0
Isradipine DynaCirc 2.5 mg twice daily 2.5-5 mg twice daily $133.50 (5 mg twice daily) +++ ↓/0
DynaCirc CR 5 mg daily 5-10 mg daily $95.40 (10 mg daily)
Nicardipine Cardene 20 mg three times daily 20-40 mg three times daily $41.20 (20 mg three times daily) +++ ↓/0
Cardene SR 30 mg twice daily 30-60 mg twice daily $57.02 (30 mg twice daily)
Nifedipine Adalat CC 30 mg daily 30-120 mg daily $82.80 (60 mg daily) +++ ↓↓
Procardia XL 30 mg daily 30-120 mg daily $68.70 (60 mg daily)
Nisoldipine Sular 20 mg/d 20-60 mg/d $51.90 (40 mg daily) +++ ↓/0
GI = gastrointestinal; AV = atrioventricular.
1Average wholesale price (AWP, for AB-rated generic when available) for quantity listed. Source: Red Book Update, Vol24, No. 4, April 2005. AWP may not accurately represent the actual pharmacy cost be cause wide contractual variations exist among institutions.

The most common side effects of calcium channel blockers are headache, peripheral edema, bradycardia, and constipation (especially with verapamil in the elderly). The dihydropyridine agents—nifedipine, nicardipine, isradipine, felodipine, nisoldipine, and amlodipine—are more likely to produce symptoms of vasodilation, such as headache, flushing, palpitations, and peripheral edema. Calcium channel blockers have negative inotropic effects and may cause or exacerbate heart failure in patients with cardiac dysfunction. Amlodipine is the only calcium channel blocker with established safety in patients with severe heart failure. Most calcium blockers are now available in preparations that can be administered once daily.

F. α-ADRENOCEPTOR ANTAGONISTS (Table 11-9)

Prazosin, terazosin, and doxazosin block postsynaptic α-receptors, relax smooth muscle, and reduce blood pressure by lowering peripheral vascular resistance. These agents are effective as single-drug therapy in some individuals, but tachyphylaxis may appear during long-term therapy and side effects are relatively common. These include marked hypotension and syncope after the first dose, which, therefore, should be small and be given at bedtime. Postdosing palpitations, headache, and nervousness may continue to occur during chronic therapy; they may be less frequent or severe with doxazosin because of its more gradual onset of action.

Unlike the β-blockers and diuretics, the α-blockers have no adverse effect on serum lipid levels—in fact, they increase high-density lipoprotein cholesterol while reducing total cholesterol. Whether this is beneficial in the long term has not been established. In ALLHAT, subjects receiving doxazosin as initial therapy had a significant increase in heart failure hospitalizations and a higher incidence of stroke relative to the subjects receiving diuretics and were removed from the study. In sum, α-blockers should generally not be used as initial agents to treat hypertension—except perhaps in men with symptomatic prostatism.

G. DRUGS WITH CENTRAL SYMPATHOLYTIC ACTION (Table 11-9)

Methyldopa, clonidine, guanabenz, and guanfacine lower blood pressure by stimulating α-adrenergic receptors in the central nervous system, thus reducing efferent peripheral sympathetic outflow. These agents are effective as single therapy in some patients, but they are usually employed as secondor third-line agents because of the high frequency of drug intolerance, including sedation, fatigue, dry mouth, postural hypotension, and impotence. An important concern is rebound hypertension following withdrawal. Methyldopa also causes hepatitis and hemolytic anemia and is avoided except in individuals who have already tolerated chronic therapy. There is considerable experience with methyldopa in pregnant women, and it is still used for this population. Clonidine is available in patches and may have particular value in patients in whom compliance is a troublesome issue.

H. ARTERIOLAR DILATORS (Table 11-9)

Hydralazine and minoxidil relax vascular smooth muscle and produce peripheral vasodilation. When given alone, they stimulate reflex tachycardia, increase myocardial contractility, and cause headache, palpitations, and fluid retention. They are usually given in combination with diuretics and β-blockers in resistant patients. Hydralazine produces frequent gastrointestinal disturbances and may induce a lupus-like syndrome. Minoxidil causes hirsutism and marked fluid retention; this agent is reserved for the most refractory of patients.

I. PERIPHERAL SYMPATHETIC INHIBITORS (Table 11-9)

These agents are now used infrequently and usually in refractory hypertension. Reserpine remains a cost-effective antihypertensive agent. Its reputation for inducing mental depression and its other side effects— sedation, nasal stuffiness, sleep disturbances, and peptic ulcers—has made it unpopular, though these problems are uncommon at low dosages. Guanethidine and guanadrel inhibit catecholamine release from peripheral neurons but frequently cause orthostatic hypotension (especially in the morning or after exercise), diarrhea, and fluid retention.

Developing an Antihypertensive Regimen

A few years ago there were only a few large trials examining the impact of antihypertensive therapy on clinical outcomes; these indicated that diuretic-based—and, to a lesser extent, β-blocker-based—“step therapy” prevented stroke, with a lesser impact on mortality and myocardial infarction. Data from a number of these trials support the overall conclusion that antihypertensive therapy with diuretics and β-blockers has a major beneficial effect on a broad spectrum of cardiovascular outcomes. Similar placebo-controlled data pertaining to the newer agents are generally lacking except for stroke reduction with the calcium channel blocker nitrendipine in the Systolic Hypertension in Europe trial, although there is substantial evidence that ACE inhibitors and to a lesser extent ARBs reduce adverse cardiovascular outcomes in other related populations (patients with diabetic nephropathy, heart failure, or post-myocardial infarction, and individuals at high risk for cardiovascular events).

Therefore, all of these agents have been recommended and utilized as first-line therapy in some populations, but until recently there were few trials that compared different antihypertensive agents with clinical

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outcome end points. Now such comparative data are abundantly available. Most large clinical trials that have compared outcomes in relatively unselected patients have failed to show a difference between newer agents— such as ACE inhibitors, calcium channel blockers, and ARBs—and the older diuretics and β-blockers with regard to survival, myocardial infarction, and stroke. ALLHAT, completed in 2002, found that treatment initiated with the thiazide-like diuretic chlorthalidone, the ACE inhibitor lisinopril, and the calcium antagonist amlodipine was associated with similar incidences of the primary outcomes of death and myocardial infarction. There were somewhat fewer strokes with amlodipine and more with lisinopril, though the latter trend was seen only in blacks, who had a decreased blood pressure response with this agent. The development or worsening of heart failure was a common outcome in this trial and was more frequent in patients randomized to amlodipine and lisinopril than to chlorthalidone. A similar difference in the incidence of heart failure in ACE inhibitor patients has not been observed in other comparative antihypertensive trials, and, as with the difference in stroke, appears to occur mainly in blacks. Of note is a 6073-patient Australian trial published in 2003 comparing ACE inhibitor-based therapy with diuretic-based therapy. It found an 11% reduction in its primary outcomes—death from any cause or all cardiovascular events—and no difference in stroke events in the ACE inhibitor group.

Table 11-9. α-Adrenoceptor blocking agents, sympatholytics, and vasodilators.

Drug Proprietary Name Initial Dosage Dosage Range Cost per Unit Cost of 30 Days Treatment (Average Dosage)1 Adverse Effects Comments
α-ADRENOCEPTOR BLOCKERS
Prazosin Minipress 1 mg hs 2-20 mg in 2 or 3 doses $0.78/5 mg $46.80 (5 mg twice daily) Syncope with first dose; postural hypotension, dizziness, palpitations, headache, weakness, drowsiness, sexual dysfunction, anticholinergic effects, urinary incontinence; first-dose effects may be less with doxazosin. May HDL and LDL cholesterol. May provide short-term relief of obstructive prostatic symptoms. Less effective in preventing cardiovascular events than diuretics.
Terazosin Hytrin 1 mg hs 1-20 mg in 1 or 2 doses $1.60/1, 2, 5, 10 mg $48.00 (5 mg daily)
Doxazosin Cardura 1 mg hs 1-16 mg daily $0.97/4 mg $29.10 (4 mg daily)
CENTRAL SYMPATHOLYTICS
Clonidine Catapres 0.1 mg twice daily 0.2-0.6 mg in 2 doses $0.22/0.1 mg $13.20 (0.1 mg twice daily) Sedation, dry mouth, sexual dysfunction, headache, bradyarrhythmias; side effects may be less with guanfacine. Contact dermatitis with clonidine patch. Methyldopa also causes hepatitis, hemolytic anemia, fever. “Rebound” hypertension may occur even after gradual withdrawal. Methyldopa should be avoided in favor of safer agents.
Catapres TTS 0.1 mg/d patch weekly 0.1-0.3 mg/d patch weekly $26.73/0.2 mg $106.92 (0.2 mg weekly)
Guanabenz Wytensin 4 mg twice daily 8-64 mg in 2 doses $0.98/4 mg $58.80 (4 mg twice daily)
Guanfacine Tenex 1 mg once daily 1-3 mg daily $0.87/1 mg $26.10 (1 mg daily)
Methyldopa Aldomet 250 mg twice daily 500-2000 mg in 2 doses $0.63/500 mg $37.80 (500 mg twice daily)
PERIPHERAL NEURONAL ANTAGONISTS
Reserpine Serpasil 0.05 mg once daily 0.05-0.25 mg daily $0.32/0.1 mg $9.60 (0.1 mg daily) Depression (less likely at low dosages, ie, > 0.25 mg), night terrors, nasal stuffiness, drowsiness, peptic disease, gastrointestinal disturbances, bradycardia.elltab
DIRECT VASODILATORS
Hydralazine Apresoline 25 mg twice daily 50–300 mg in 2-4 doses $0.05/25 mg $3.00 (25 mg twice daily) GI disturbances, tachycardia, headache, nasal congestion, rash, LE-like syndrome. May worsen or precipitate angina.
Minoxidil Loniten 5 mg once daily 5-40 mg qd $1.29/10 mg $38.70 (10 mg qd) Tachycardia, fluid retention, headache, hirsutism, pericardial effusion, thrombocytopenia. Should be used in combination with β-blocker and diuretic.
GI = gastrointestinal; LE = lupus erythematosus.
1Average wholesale price (AWP, for AB-rated generic when available) for quantity listed. Source: Red Book Update, Vol. 24, No. 4, April 2005. AWP may not accurately represent the actual pharmacy cost because wide contractual variations exist among institutions.

The lack of superiority of other antihypertensive agents has led experts to recommend diuretics as the first-line treatment of most older patients with hypertension because these agents are at least as effective and less expensive. Specific exceptions are appropriate for individuals who have specific indications for another class of agent, such as post-myocardial infarction patients (β-blockers, ACE inhibitors), patients with diabetic nephropathy (ACE inhibitors, ARBs), or other comorbid conditions. Table 11-10 provides suggestions for individualizing first-line treatment.

However, in trials that include patients with systolic hypertension, the large majority of patients require two or more medications and even then a substantial proportion of patients does not achieve the goal systolic blood pressure of < 140 mm Hg (130 mm Hg in diabetics). In diabetic patients, three or four drugs are usually required to reduce systolic blood pressure to < 140 mm Hg, and many patients cannot be maintained at the recommended goal of < 130 mm Hg with any combination. As a result, debating the appropriate first-line agent is less relevant than determining the most appropriate combinations of agents. This has led many experts and practitioners to reconsider the use of fixeddose combination antihypertensive agents as first-line therapy in patients with substantially elevated systolic pressures (> 160 mm Hg) or difficult-to-control hypertension (associated diabetes or renal dysfunction). Based both on antihypertensive efficacy and complementarity, combinations of a diuretic and an ACE inhibitor (or an ARB if ACE intolerant) or a diuretic and a β-blocker are recommended. The initial use of low-dose combinations allows faster blood pressure reduction without substantially higher intolerance rates and is likely to be better accepted by patients.

When an initial agent is selected, the patient should be informed of common side effects and the need for diligent compliance. Treatment should start at a low dose, and unless the initial blood pressure is very high (> 160/100 mm Hg), follow-up visits should usually be at 4to 6-week intervals to allow for full medication effects to be established (especially with diuretics) before further titration or adjustment. If, after titration to usual doses, the patient has shown a discernible but incomplete response and a good tolerance of the initial drug, a second medication should be added. If the initial medication was a diuretic or a calcium channel blocker, the second agent should be a bblocker, ACE inhibitor, or ARB, since these combinations are generally complementary. If the initial drug was a β-blocker, ACE inhibitor, or ARB, the second drug should be a diuretic. On the other hand, if the first agent showed no effect, another should be substituted. Again, if the first drug was a diuretic or a calcium channel blocker, the substituted drug should be a β-blocker, ACE inhibitor, or ARB; if it was a bblocker, ACE inhibitor, or ARB, the substituted agent should be a diuretic or a calcium channel blocker. If therapy was initiated with a combination of a diuretic and an ACE inhibitor, ARB, or β-blocker and the patient remains uncontrolled, addition of a calcium blocker is the recommended approach.

Most patients with hypertension can be controlled with one-drug or two-drug regimens that combine complementary agents. A minority of patients require three, four, or even more medications in combination. As discussed above, multidrug regimens are more frequently needed in patients with high systolic pressures and in diabetics. Unless absolutely contraindicated, one of these components should be a diuretic. Particularly useful multidrug regimens are (1) a diuretic plus an ACE inhibitor (or ARB if ACE intolerant) plus a calcium channel blocker (or other vasodilator), (2) a diuretic plus a β-blocker plus either a calcium channel blocker or a sympatholytic (or both), and (3) a calcium channel blocker (in patients in whom a diuretic is not tolerated) plus an ACE inhibitor plus either a sympatholytic or a β-blocker (or both). Patients who are compliant with their medications and who do not respond to these combinations should usually be evaluated for secondary hypertension before proceeding to more complex regimens.

Special Considerations in the Treatment of Diabetic Hypertensive Patients

Hypertensive patients with diabetes are at particularly high risk for cardiovascular events. More aggressive treatment of hypertension in these patients prevents progressive nephropathy, myocardial infarction, and stroke. Treatment recommendations suggest a target of

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< 130/80 mm Hg. Because of their beneficial effects in diabetic nephropathy, ACE inhibitors (and ARBs in intolerant patients) should be part of the initial treatment regimen. However, most diabetics require combinations of three to five agents to achieve these goals, usually including a diuretic and a calcium channel blocker or bblocker. In addition to rigorous blood pressure control, management of diabetics should include aggressive treatment of other risk factors and early intervention for coronary disease and left ventricular dysfunction.

Table 11-10. Clinical trial and guideline basis for compelling indications for individual drug classes.

High-Risk Conditions with Compelling Indication1 Recommended Drugs Clinical Trial Basis2
Diuretic β-Blocker ACE Inhibitor ARB CCB Aldosterone Antagonist
Heart failure   ACC/AHA Heart Failure Guideline, MERIT-HF, CIBIS, COPERNICUS, SOLVD, AIRE, TRACE, ValHEFT, RALES
Post-myocardial infarction       ACC/AHA Post-MI Guideline, BHAT, SAVE, Capricorn, EPHESUS
High coronary disease risk     ALLHAT, HOPE, ANBP2, LIFE, CONVINCE
Diabetes   NKF-ADA Guideline, UKPDS, ALLHAT
Chronic kidney disease         NKF Guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK
Recurrent stroke prevention         PROGRESS
From Chobanian AV et al: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560
AASK = African American Study of Kidney Disease and Hypertension; ACC/AHA = American College of Cardiology/American Heart Association; ACE = angiotensin converting enzyme; AIRE = Acute Infarction Ramipril Efficacy; ALLHAT = Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; ANBP2 = Second Australian National Blood Pressure Study; ARB = angiotensin receptor blocker; BHAT = β-Blocker Heart Attack Trial; CCB = calcium channel blocker; CIBIS = Cardiac Insufficiency Bisoprolol Study; CONVINCE = Controlled Onset Verapamil Investigation of Cardiovascular End Points; COPERNICUS = Carvedilol Prospective Randomized Cumulative Survival Study; EPHESUS = Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study; HOPE = Heart Outcomes Prevention Evaluation Study; IDNT = Irbesartan Diabetic Nephropathy Trial; LIFE = Losartan Intervention For Endpoint Reduction in Hypertension Study; MERIT-HF = Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure; NKF-ADA = National Kidney Foundation–American Diabetes Association; PROGRESS = Perindopril Protection Against Recurrent Stroke Study; RALES = Randomized Aldactone Evaluation Study: REIN, Ramipril Efficacy in Nephropathy Study; RENAAL, Reduction of Endpoints in Non-Insulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan Study; SAVE = Survival and Ventricular Enlargement Study; SOLVD = Studies of Left Ventricular Dysfunction; TRACE = Trandolapril Cardiac Evaluation Study; UKPDS = United Kingdom Prospective Diabetes Study; ValHEFT = Valsartan Heart Failure Trial.
1Compelling indications for antihypertensive drugs are based on benefits from outcome studies or existing clinical guidelines; the compelling indication is managed in parallel with the blood pressure.
2Conditions for which clinical trials demonstrate benefit of specific classes of antihypertensive drugs.

Hypertension Management in Blacks

Substantial evidence indicates that blacks are not only more likely to become hypertensive and more susceptible to the cardiovascular complications of hypertension—they also respond differently to many antihypertensive medications. This may reflect genetic differences in the cause of hypertension or the subsequent responses to it, differences in occurrence of comorbid conditions such as diabetes or obesity, or environmental factors such as diet, activity, stress, or access to health care services. In any case, as in all hypertensives, a multifaceted program of education and lifestyle modification is warranted. Because it appears that ACE inhibitors and ARBs—in the absence of concomitant diuretics—are less effective in blacks than in whites, initial therapy should generally be a diuretic or a diuretic combination, with the use of additional agents as discussed above. Some experts have recom

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mended a goal blood pressure of 130/80 mm Hg for blacks at high risk for cardiovascular events as well as those with diabetes.

Treatment of Additional Cardiovascular Risk Factors

Because the goal is to reduce cardiovascular morbidity and mortality, attention must be paid to the management of other risk factors. Aggressive reduction of elevated low-density lipoprotein (LDL) cholesterol levels reduces the risk of myocardial infarction and death in patients with multiple risk factors. Thus, if LDL cholesterol levels remain over 130 mg/dL following an attempt at dietary intervention, drug therapy is indicated in most hypertensives. Levels under 100 mg/dL should be achieved in patients with coronary artery disease, cerebrovascular disease, peripheral arterial disease, or diabetes. Smoking cessation, regular exercise, and weight loss when indicated are other important features of hypertension management.

Follow-Up of the Treated Hypertensive

Once blood pressure is controlled on a well-tolerated regimen, follow-up visits can be infrequent and laboratory testing limited to tests appropriate for the patient and the medications utilized. Yearly monitoring of blood lipids is recommended, and an electrocardiogram (ECG) should be repeated at 2to 4-year intervals depending on whether initial abnormalities are present, the presence of coronary risk factors, and age.

Patients who have had excellent blood pressure control for several years, especially if they have lost weight and initiated favorable lifestyle modifications, should be considered for “step-down” of therapy to determine if lower doses or discontinuation of medications are feasible.

August P: Initial treatment of hypertension. N Engl J Med 2003;348:620.

Barzilay JI et al; ALLHAT Collaborative Research Group: Cardiovascular outcomes using doxazosin vs. chlorthalidone for the treatment of hypertension in older adults with and without glucose disorders: a report from the ALLHAT study. J Clin Hypertens (Greenwich) 2004;6:116.

Brewster LM et al: Systematic review: antihypertensive drug therapy in black patients. Ann Intern Med 2004;14:614.

Chobanian AV et al: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report. JAMA 2003;289:2560.

Dahlof B et al: Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359:995.

Iino Y et al; Japanese Losartan Therapy Intended for the Global Renal Protection in Hypertensive Patients (JLIGHT) Study Investigators: Renoprotective effect of losartan in comparison to amlodipine in patients with chronic kidney disease and hypertension. Hypertens Res 2004;27:21.

Julius S et al; VALUE trial group: Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004;363:2022.

Kaplan NM: Management of hypertension in patients with type 2 diabetes mellitus: guidelines based on current evidence. Ann Intern Med 2001;135:1079.

Khan NA et al; Canadian Hypertension Education Program: The 2004 Canadian recommendations for the management of hypertension: Part II—Therapy. Can J Cardiol 2004;20: 41.

Kuschnir E et al: Effects of the combination of low-dose nifedipine GITS 20 mg and losartan 50 mg in patients with mild to moderate hypertension. J Cardiovasc Pharmacol 2004; 43:300.

Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic. The Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981.

Papademetriou V et al: Stroke prevention with the angiotensin II type 1-receptor blocker candesartan in elderly patients with isolated systolic hypertension: the Study on Cognition and Prognosis in the Elderly (SCOPE). J Am Coll Cardiol 2004;44:1175.

Psaty BM et al: Health outcomes associated with various antihypertensive therapies used as first-line agents: a network meta-analysis. JAMA 2003;289:2534.

Sehgal AR: Overlap between whites and blacks in response to antihypertensive drugs. Hypertension 2004;43:566.

Staessen JA et al; Treatment of Hypertension Based on Home or Office Blood Pressure (THOP) Trial Investigators: Antihypertensive treatment based on blood pressure measurement at home or in the physician's office: a randomized controlled trial. JAMA 2004;291:955.

Stergiou GS et al; World Health Organization-International Society of Hypertension (WHO-ISH); USA Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7); European Society of Hypertension-European Society of Cardiology (ESH-ESC): New European, American and International guidelines for hypertension management: agreement and disagreement. Expert Rev Cardiovasc Ther 2004;2:359.

Verberk WJ et al: Home versus Office blood pressure Measurements: Reduction of Unnecessary treatment Study: rationale and study design of the HOMERUS trial. Blood Press 2003;12:326.

Vijan S et al: Treatment of hypertension in type 2 diabetes mellitus: blood pressure goals, choice of agents, and setting priorities in diabetes care. Ann Intern Med 2003;138:593.

Wing LM et al: A comparison of outcomes with angiotensin-converting-enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med 2003;348:583.

RESISTANT HYPERTENSION

Resistant hypertension is defined in JNC 7 as the failure to reach blood pressure control in patients who are adherent to full doses of an appropriate three-drug regimen (including a diuretic). In this situation, the clinician should first exclude potential identifiable causes of hypertension (Table 11-3), and then carefully explore reasons why the patient might not be at

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goal blood pressure (Table 11-11). The clinician should pay particular attention to the type of diuretic being employed in relation to the patient's renal function. If goal blood pressure cannot be achieved by these measures, consultation with a hypertension specialist should be considered.

Table 11-11. Causes of resistant hypertension.

Improper blood pressure measurement
Volume overload and pseudotolerance
   Excess sodium intake
   Volume retention from kidney disease
   Inadequate diuretic therapy
Drug-induced or other causes
   Nonadherence
   Inadequate doses
   Inappropriate combinations
   Nonsteroidal anti-inflammatory drugs; cyclooxygenase-2 inhibitors
   Cocaine, amphetamines, other illicit drugs
   Sympathomimetics (decongestants, anorectics)
   Oral contraceptives
   Adrenal steroids
   Cyclosporine and tacrolimus
   Erythropoietin
   Licorice (including some chewing tobacco)
   Selected over-the-counter dietary supplements and medicines (eg, ephedra, ma haung, bitter orange)
Associated conditions
   Obesity
   Excess alcohol intake
Identifiable causes of hypertension (see Table 11-3)
From Chobanian AV et al: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560.

HYPERTENSIVE URGENCIES & EMERGENCIES

Hypertensive emergencies have become less frequent in recent years but still require prompt recognition and aggressive but careful management. A spectrum of acute presentations exists, and the appropriate therapeutic approach varies accordingly.

Hypertensive urgencies are situations in which blood pressure must be reduced within a few hours. These include patients with asymptomatic severe hypertension (systolic blood pressure > 220 mm Hg or diastolic pressure > 125 mm Hg that persists after a period of observation) and those with optic disk edema, progressive target organ complications, and severe perioperative hypertension. Elevated blood pressure levels alone—in the absence of symptoms or new or progressive target organ damage—rarely require emergency therapy. Parenteral drug therapy is not usually required, and partial reduction of blood pressure with relief of symptoms is the goal.

Hypertensive emergencies require substantial reduction of blood pressure within 1 hour to avoid the risk of serious morbidity or death. Although blood pressure is usually strikingly elevated (diastolic pressure > 130 mm Hg), the correlation between pressure and end-organ damage is often poor. It is the latter that determines the seriousness of the emergency and the approach to treatment. Emergencies include hypertensive encephalopathy (headache, irritability, confusion, and altered mental status due to cerebrovascular spasm), hypertensive nephropathy (hematuria, proteinuria, and progressive renal dysfunction due to arteriolar necrosis and intimal hyperplasia of the interlobular arteries), intracranial hemorrhage, aortic dissection, preeclampsia-eclampsia, pulmonary edema, unstable angina, or myocardial infarction. Malignant hypertension is by historical definition characterized by encephalopathy or nephropathy with accompanying papilledema. Progressive renal failure usually ensues if treatment is not provided. The therapeutic approach is identical to that employed with other antihypertensive emergencies.

Parenteral therapy is indicated in most hypertensive emergencies, especially if encephalopathy is present. The initial goal in hypertensive emergencies is to reduce the pressure by no more than 25% (within minutes to 1 or 2 hours) and then toward a level of 160/100 mm Hg within 2–6 hours. Excessive reductions in pressure may precipitate coronary, cerebral, or renal ischemia. To avoid such declines, the use of agents that have a predictable, dose-dependent, transient, and not precipitous antihypertensive effect is preferable. In that regard, the use of sublingual or oral fast-acting nifedipine preparations is best avoided.

Pharmacologic Management

A. PARENTERAL AGENTS

A growing number of agents are available for management of acute hypertensive problems. (Table 11-12 lists drugs, dosages, and adverse effects.) Sodium nitroprusside is the agent of choice for the most serious emergencies because of its rapid and easily controllable action, but continuous monitoring is essential when this agent is used. In the presence of myocardial ischemia, intravenous nitroglycerin or an intravenous bblocker, such as labetalol or esmolol, is preferable.

1. Nitroprusside sodium

This agent is given by controlled intravenous infusion gradually titrated to the desired effect. It lowers the blood pressure within seconds by direct arteriolar and venous dilation. Monitoring with an intra-arterial line avoids hypotension. Nitroprusside—in combination with a β-blocker—is especially useful in patients with aortic dissection.

2. Nitroglycerin, intravenous

This agent is a less potent antihypertensive than nitroprusside and should be reserved for patients with accompanying acute ischemic syndromes.

3. Labetalol

This combined band α-blocking agent is the most potent adrenergic blocker for rapid blood pressure reduction. Other β-blockers are far less potent. Excessive blood pressure drops are unusual. Experience

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with this agent in hypertensive syndromes associated with pregnancy has been favorable.

Table 11-12. Drugs for hypertensive emergencies and urgencies.

Agent Action Dosage Onset Duration Adverse Effects Comments
PARENTERAL AGENTS (INTRAVENOUSLY UNLESS NOTED)
Nitroprusside (Nipride) Vasodilator 0.25-10 mcg/kg/min Seconds 3-5 minutes GI, CNS; thiocyanate and cyanide toxicity, especially with renal and hepatic insufficiency; hypotension. Most effective and easily titratable treatment. Use with β-blocker in aortic dissection.
Nitroglycerin Vasodilator 0.25-5 mcg/kg/min 2-5 minutes 3-5 minutes Headache, nausea, hypotension, bradycardia. Tolerance may develop. Useful primarily with myocardial ischemia.
Labetalol (Normodyne, Trandate) β- and α-Blocker 20-40 mg every 10 minutes to 300 mg; 2 mg/min infusion 5-10 minutes 3-6 hours GI, hypotension, bronchospasm, bradycardia, heart block. Avoid in congestive heart failure, asthma. May be continued orally.
Esmolol (Brevibloc) β-Blocker Loading dose 500 mcg/kg over 1 minute; maintenance, 25-200 mcg/kg/min 1-2 minutes 10-30 minutes Bradycardia, nausea. Avoid in congestive heart failure, asthma. Weak antihypertensive.
Fenoldopam (Corlopam) Dopamine receptor agonist 0.1-1.6 mcg/kg/min 4-5 minutes < 10 minutes Reflex tachycardia, hypotension, intraocular pressure. May protect renal function.
Nicardipine (Cardene) Calcium channel blocker 5 mg/h; may increase by 1–2.5 mg/h every 15 minutes to 15 mg/h 1-5 minutes 3-6 hours Hypotension, tachycardia, headache. May precipitate myocardial ischemia.
Enalaprilat (Vasotec) ACE inhibitor 1.25 mg every 6 hours 15 minutes 6 hours or more Excessive hypotension. Additive with diuretics; may be continued orally.
Furosemide (Lasix) Diuretic 10-80 mg 15 minutes 4 hours Hypokalemia, hypotension. Adjunct to vasodilator.
Hydralazine (Apresoline) Vasodilator 5-20 mg intravenously or intramuscularly (less desirable); may repeat after 20 minutes 10-30 minutes 2-6 hours Tachycardia, headache, GI. Avoid in coronary artery disease, dissection. Rarely used except in pregnancy.
Diazoxide (Hyperstat) Vasodilator 50-150 mg repeated at intervals of 5- 15 minutes, or 15-30 mg/min by intravenous infusion to a maximum of 600 mg 1-2 minutes 4-24 hours Excessive hypotension, tachycardia, myocardial ischemia, headache, nausea, vomiting, hyperglycemia. Necrosis with extravasation. Avoid in coronary artery disease and dissection. Use with β-blocker and diuretic. Mostly obsolete.
Trimethaphan (Arfonad) Ganglionic blocker 0.5-5 mg/min 1-3 minutes 10 minutes Hypotension, ileus, urinary retention, respiratory arrest. Liberates histamine; use caution in allergic individuals. Useful in aortic dissection. Otherwise rarely used.
ORAL AGENTS
Nifedipine (Adalat, Procardia) Calcium channel blocker 10 mg initially; may be repeated after 30 minutes 15 minutes 2-6 hours Excessive hypotension, tachycardia, headache, angina, myocardial infarction, stroke. Response unpredictable.
Clonidine (Catapres) Central sympatholytic 0.1-0.2 mg initially; then 0.1 mg every hour to 0.8 mg 30-60 minutes 6-8 hours Sedation. Rebound may occur.
Captopril (Capoten) ACE inhibitor 12.5-25 mg 15-30 minutes 4-6 hours Excessive hypotension.
GI = gastrointestinal; CNS = central nervous system; ACE = angiotensin-converting enzyme.

4. Esmolol

This rapidly acting β-blocker is approved only for treatment of supraventricular tachycardia but is often used for lowering blood pressure. It is less potent than labetalol and should be reserved for patients in whom there is particular concern about serious adverse events related to β-blockers.

5. Nicardipine

Intravenous nicardipine is the most potent antihypertensive agent and the longest acting of the parenteral calcium channel blockers. As a primarily arterial vasodilator, it has the potential to precipitate reflex tachycardia, and for that reason it should not be used without a β-blocker in patients with coronary artery disease.

6. Fenoldopam

Fenoldopam is a peripheral dopamine-1 (DA1) receptor agonist that causes a dosedependent reduction in arterial pressure without evidence of tolerance, rebound, or withdrawal or deterioration of renal function. In higher dosage ranges, tachycardia may occur.

7. Enalaprilat

This is the active form of the oral ACE inhibitor enalapril. The onset of action is usually within 15 minutes, but the peak effect may be delayed for up to 6 hours. Thus, enalaprilat is used primarily as an adjunctive agent.

8. Diazoxide

Diazoxide acts promptly as a vasodilator without decreasing renal blood flow. To avoid hypotension, it should be given in small boluses or as an infusion rather than as the previously recommended large bolus. One use of diazoxide has been in preeclampsia-eclampsia. Hyperglycemia and sodium and water retention may occur. The drug should be used only for short periods and is best combined with a loop diuretic.

9. Hydralazine

Hydralazine can be given intravenously or intramuscularly, but its effect is less predictable than that of other drugs in this group. It produces reflex tachycardia and should not be given without bblockers in patients with possible coronary disease or aortic dissection. Hydralazine is now used primarily in pregnancy and in children, but even in these situations, newer agents are supplanting it.

10. Trimethaphan

The ganglionic blocking agent trimethaphan is titrated with the patient sitting; its activity depends upon this. The patient can be placed supine if the hypotensive effect is excessive. The effect occurs within a few minutes and persists for the duration of the infusion. This agent has largely been replaced by nitroprusside and newer medications.

11. Diuretics

Intravenous loop diuretics can be very helpful when the patient has signs of heart failure or fluid retention, but the onset of their hypotensive response is slow, making them an adjunct rather than a primary agent for hypertensive emergencies. Low dosages should be used initially (furosemide, 20 mg or bumetanide, 0.5 mg). They facilitate the response to vasodilators, which often stimulate fluid retention.

B. ORAL AGENTS

Patients with less severe acute hypertensive syndromes can often be treated with oral therapy. Abrupt blood pressure lowering is not usually necessary in asymptomatic individuals, and the use of agents such as rapid-acting nifedipine probably causes more adverse effects than benefits.

1. Clonidine

Clonidine, 0.2 mg orally initially, followed by 0.1 mg every hour to a total of 0.8 mg, will usually lower blood pressure over a period of several hours. Sedation is frequent, and rebound hypertension may occur if the drug is stopped.

2. Captopril

Captopril, 12.5–25 mg orally, will also lower blood pressure in 15–30 minutes. The response is variable and may be excessive.

3. Nifedipine

Fast-acting nifedipine capsules are commonly employed in the emergency room or urgent care setting because they usually provide a rapid reduction in blood pressure. However, the nifedipine effect is unpredictable and may be excessive, resulting in hypotension and reflex tachycardia. Because myocardial infarction and stroke have been reported in this setting, the use of nifedipine without concomitant β-blocker therapy is not advised.

C. SUBSEQUENT THERAPY

When the blood pressure has been brought under control, combinations of oral antihypertensive agents can be added as parenteral drugs are tapered off over a period of 2–3 days. Most subsequent regimens should include a diuretic.

Cherney D et al: Management of patients with hypertensive urgencies and emergencies. J Gen Intern Med 2002;17:947.

Devlin JW et al: Fenoldopam versus nitroprusside for the treatment of hypertensive emergency. Ann Pharmacother 2004;38:755.

Khanna A et al: Malignant hypertension presenting as hemolysis, thrombocytopenia, and renal failure. Rev Cardiovasc Med 2003;4:255.

Phillips RA et al: Hypertensive emergencies: diagnosis and management. Prog Cardiovasc Dis 2002;45:33.



Current Medical Diagnosis & Treatment 2006
Current Medical Diagnosis & Treatment, 2006 (Current Medical Diagnosis and Treatment)
ISBN: 0071454101
EAN: 2147483647
Year: 2006
Pages: 71

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