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InternalMed_Harrison. threshold for renal damage and a steeper slope between blood pressure and renal damage. The result may be a vicious cycle of renal damage and nephron loss leading to more severe hypertension, glomerular hyperfiltration, and further renal damage. Glomerular pathology progresses to glomerulosclerosis, and eventually the renal tubules may also become ischemic and gradually atrophic. The renal lesion associated with malignant hypertension consists of fibrinoid necrosis of the afferent arterioles, sometimes extending into the glomerulus, and may result in focal necrosis of the glomerular tuft. Clinically, macroalbuminuria (a random urine albumin/creatinine ratio >300 mg/g) or microalbuminuria (a random urine albumin/ creatinine ratio 30–300 mg/g) are early markers of renal injury. These are also risk factors for renal disease progression and cardiovascular disease.


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InternalMed_Harrison. In addition to contributing to the pathogenesis of hypertension, blood vessels are a target organ for atherosclerotic disease secondary to long-standing elevated blood pressure. In hypertensive patients, vascular disease is a major contributor to stroke, heart disease, and renal failure. Further, hypertensive patients with arterial disease of the lower extremities are at increased risk for future cardiovascular disease. Although patients with stenotic lesions of the lower extremities may be asymptomatic, intermittent claudication is the classic symptom of PAD. The ankle-brachial index is a useful approach for evaluating PAD and is defined as the ratio of noninvasively assessed ankle to brachial (arm) systolic blood pressure. An ankle-brachial index <0.90 is considered diagnostic of PAD and is associated with >50% stenosis in at least one major lower limb vessel. An ankle-brachial index <0.80 is associated with elevated blood pressure, particularly systolic blood pressure.


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InternalMed_Harrison. From an epidemiologic perspective, there is no obvious level of blood pressure that defines hypertension. In adults, there is a continuous, incremental risk of cardiovascular disease, stroke, and renal disease across levels of both systolic and diastolic blood pressure. The Multiple Risk Factor Intervention Trial (MRFIT), which included >350,000 male participants, demonstrated a continuous and graded influence of both systolic and diastolic blood pressure on CHD mortality, extending down to systolic blood pressures of 120 mmHg. Similarly, results of a meta-analysis involving almost 1 million participants indicate that ischemic heart disease mortality, stroke mortality, and mortality from other vascular causes are directly related to the height of the blood pressure, beginning at 115/75 mmHg, without evidence of a threshold. Cardiovascular disease risk doubles for every 20-mmHg increase in systolic and 10-mmHg increase in diastolic pressure. Among older individuals, systolic blood


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InternalMed_Harrison. mmHg, without evidence of a threshold. Cardiovascular disease risk doubles for every 20-mmHg increase in systolic and 10-mmHg increase in diastolic pressure. Among older individuals, systolic blood pressure and pulse pressure are more powerful predictors of cardiovascular disease than is diastolic blood pressure.


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InternalMed_Harrison. Clinically, hypertension may be defined as that level of blood pressure at which the institution of therapy reduces blood pressure–related morbidity and mortality. Current clinical criteria for defining hypertension generally are based on the average of two or more seated blood pressure readings during each of two or more outpatient visits. A recent classification recommends blood pressure criteria for defining normal blood pressure, prehypertension, hypertension (stages I and II), and isolated systolic hypertension, which is frequent among the elderly (Table 298-1). In children and adolescents, hypertension generally is defined as systolic and/or diastolic blood pressure consistently >95th percentile for age, sex, and height. Blood pressures between the 90th Blood Pressure Classification Systolic, mmHg Diastolic, mmHg Source: Adapted from AV Chobanian et al: JAMA 289:2560, 2003. and 95th percentiles are considered prehypertensive and are an indication for lifestyle interventions.


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InternalMed_Harrison. Home blood pressure and average 24-h ambulatory blood pressure measurements are generally lower than clinic blood pressures. Because ambulatory blood pressure recordings yield multiple readings throughout the day and night, they provide a more comprehensive assessment of the vascular burden of hypertension than do a limited number of office readings. Increasing evidence suggests that home blood pressures, including 24-h blood pressure recordings, more reliably predict target organ damage than do office blood pressures. Blood pressure tends to be higher in the early morning hours, soon after waking, than at other times of day. Myocardial infarction and stroke are more common in the early morning hours. Nighttime blood pressures are generally 10–20% lower than daytime blood pressures, and an attenuated nighttime blood pressure “dip” may be associated with increased cardiovascular disease risk. Recommended criteria for a diagnosis of hypertension, based on 24-h blood pressure monitoring,


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InternalMed_Harrison. attenuated nighttime blood pressure “dip” may be associated with increased cardiovascular disease risk. Recommended criteria for a diagnosis of hypertension, based on 24-h blood pressure monitoring, are average awake blood pressure ≥135/85 mmHg and asleep blood pressure ≥120/75 mmHg. These levels approximate a clinic blood pressure of 140/90 mmHg.


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InternalMed_Harrison. Approximately 15–20% of patients with stage 1 hypertension (as defined in Table 298-1) based on office blood pressures have average ambulatory readings <135/85 mmHg. This phenomenon, so-called white coat hypertension, also may be associated with an increased risk of target organ damage, although to a lesser extent than in individuals with elevated office and ambulatory readings. Individuals with white coat hypertension are also at increased risk for developing sustained hypertension. Depending on methods of patient ascertainment, ~80–95% of hypertensive patients are diagnosed as having primary, or “essential,” hypertension. In the remaining 5–20% of hypertensive patients, a specific underlying disorder causing the elevation of blood pressure can be identified (Tables 298-2 and 298-3). In individuals with “secondary” hypertension, a specific mechanism for the blood pressure elevation is often more apparent.


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InternalMed_Harrison. Primary hypertension tends to be familial and is likely to be the consequence of an interaction between environmental and genetic factors. The prevalence of primary hypertension increases with age, and individuals with relatively high blood pressures at younger ages are at increased risk for the subsequent development of hypertension. It is 1. 2. a. b. c. d. e. f. Renal Parenchymal diseases, renal cysts (includ ing polycystic kidney disease), renal tumors (including renin-secreting tumors), obstructive Renovascular Arteriosclerotic, fibromuscular dysplasia Adrenal Primary aldosteronism, Cushing’s syndrome, 17α-hydroxylase deficiency, 11β-hydroxylase deficiency, 11-hydroxysteroid dehydrogenase deficiency (licorice), pheochromocytoma Neurogenic Psychogenic, diencephalic syndrome, familial dysautonomia, polyneuritis (acute porphyria, lead poisoning), acute increased intracranial pressure, acute spinal cord section


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InternalMed_Harrison. Neurogenic Psychogenic, diencephalic syndrome, familial dysautonomia, polyneuritis (acute porphyria, lead poisoning), acute increased intracranial pressure, acute spinal cord section Miscellaneous endocrine Hypothyroidism, hyperthyroidism, hypercalcemia, acromegaly Medications High-dose estrogens, adrenal steroids, decon gestants, appetite suppressants, cyclosporine, tricyclic antidepressants, monoamine oxidase inhibitors, erythropoietin, nonsteroidal anti- inflammatory agents, cocaine Mendelian forms of hyper-See Table 298-4 tension likely that primary hypertension represents a spectrum of disorders with different underlying pathophysiologies. In the majority of patients with established hypertension, peripheral resistance is increased and cardiac output is normal or decreased; however, in younger patients with mild or labile hypertension, cardiac output may be increased and peripheral resistance may be normal.


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InternalMed_Harrison. When plasma renin activity (PRA) is plotted against 24-h sodium excretion, ~10–15% of hypertensive patients have high PRA and 25% have low PRA. High-renin patients may have a vasoconstrictor form of hypertension, whereas low-renin patients may have volume-dependent hypertension. Inconsistent associations between plasma aldosterone and blood pressure have been described in patients with primary hypertension. The association between aldosterone and blood pressure is more striking in African Americans, and PRA tends to be low in hypertensive African Americans. This raises the possibility that subtle increases in aldosterone may contribute to hypertension in at least some groups of patients who do not have overt primary aldosteronism. Furthermore, spironolactone, an aldosterone antagonist, may be a particularly effective antihypertensive agent for some patients with primary hypertension, including some patients with “drug-resistant” hypertension.


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InternalMed_Harrison. (See also Chap. 422) There is a well-documented association between obesity (body mass index >30 kg/m2) and hypertension. Further, cross-sectional studies indicate a direct linear correlation between body weight (or body mass index) and blood pressure. Centrally located body fat is a more important determinant of blood pressure elevation than is peripheral body fat. In longitudinal studies, a direct correlation exists between change in weight and change in blood pressure over time. Sixty percent of hypertensive adults are more than 20% overweight. It has been established that 60–70% of hypertension in adults may be directly attributable to adiposity.


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InternalMed_Harrison. Hypertension and dyslipidemia frequently occur together and in association with resistance to insulin-stimulated glucose uptake. This clustering of risk factors is often, but not invariably, associated with obesity, particularly abdominal obesity. Insulin resistance also is associated with an unfavorable imbalance in the endothelial production of mediators that regulate platelet aggregation, coagulation, fibrinolysis, and vessel tone. When these risk factors cluster, the risks for CHD, stroke, diabetes, and cardiovascular disease mortality are increased further.


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InternalMed_Harrison. Depending on the populations studied and the methodologies for 1617 defining insulin resistance, ~25–50% of nonobese, nondiabetic hypertensive persons are insulin resistant. The constellation of insulin resistance, abdominal obesity, hypertension, and dyslipidemia has been designated as the metabolic syndrome. As a group, first-degree relatives of patients with primary hypertension are also insulin resistant, and hyperinsulinemia (a surrogate marker of insulin resistance) may predict the eventual development of hypertension and cardiovascular disease. Although the metabolic syndrome may in part be heritable as a polygenic condition, the expression of the syndrome is modified by environmental factors, such as degree of physical activity and diet. Insulin sensitivity increases and blood pressure decreases in response to weight loss. The recognition that cardiovascular disease risk factors tend to cluster within individuals has important implications for the evaluation and treatment of


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InternalMed_Harrison. decreases in response to weight loss. The recognition that cardiovascular disease risk factors tend to cluster within individuals has important implications for the evaluation and treatment of hypertension. Evaluation of both hypertensive patients and individuals at risk for developing hypertension should include assessment of overall cardiovascular disease risk. Similarly, introduction of lifestyle modification strategies and drug therapies should address overall risk and not focus exclusively on hypertension.


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InternalMed_Harrison. Virtually all disorders of the kidney may cause hypertension (Table 298-3), and renal disease is the most common cause of secondary hypertension. Hypertension is present in >80% of patients with chronic renal failure. In general, hypertension is more severe in glomerular diseases than in interstitial diseases such as chronic pyelonephritis. Conversely, hypertension may cause nephrosclerosis, and in some instances it may be difficult to determine whether hypertension or renal disease was the initial disorder. Proteinuria >1000 mg/d and an active urine sediment are indicative of primary renal disease. In either instance, the goals are to control blood pressure and retard the rate of progression of renal dysfunction.


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InternalMed_Harrison. Hypertension due to an occlusive lesion of a renal artery, renovascular hypertension, is a potentially curable form of hypertension. In the initial stages, the mechanism of hypertension generally is related to activation of the renin-angiotensin system. However, renin activity and other components of the renin-angiotensin system may be elevated only transiently; over time, recruitment of other pressure mechanisms may contribute to elevated arterial pressure. Two groups of patients are at risk for this disorder: older arteriosclerotic patients who have a plaque obstructing the renal artery, frequently at its origin, and patients with fibromuscular dysplasia. Atherosclerosis accounts for the large majority of patients with renovascular hypertension. Although fibromuscular dysplasia may occur at any age, it has a strong predilection for young white women. The prevalence in females is eightfold that in males. There are several histologic variants of fibromuscular dysplasia, including


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InternalMed_Harrison. occur at any age, it has a strong predilection for young white women. The prevalence in females is eightfold that in males. There are several histologic variants of fibromuscular dysplasia, including medial fibroplasia, perimedial fibroplasia, medial hyperplasia, and intimal fibroplasia. Medial fibroplasia is the most common variant and accounts for approximately two-thirds of patients. The lesions of fibromuscular dysplasia are frequently bilateral and, in contrast to atherosclerotic renovascular disease, tend to affect more distal portions of the renal artery.


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InternalMed_Harrison. Several clues from the history and physical examination may suggest renovascular hypertension. The diagnosis should be considered in patients with other evidence of atherosclerotic vascular disease. Although response to antihypertensive therapy does not exclude the diagnosis, severe or refractory hypertension, recent loss of hypertension control or recent onset of moderately severe hypertension, and unexplained deterioration of renal function or deterioration of renal function associated with an ACE inhibitor should raise the possibility of renovascular hypertension. Approximately 50% of patients with renovascular hypertension have an abdominal or flank bruit, and the bruit is more likely to be hemodynamically significant if it lateralizes or extends throughout systole into diastole.


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InternalMed_Harrison. If blood pressure is adequately controlled with a simple antihypertensive regimen and renal function remains stable, there may be little 1618 impetus to pursue an evaluation for renal artery stenosis, particularly in an older patient with atherosclerotic disease and comorbid conditions. Patients with long-standing hypertension, advanced renal insufficiency, or diabetes mellitus are less likely to benefit from renal vascular repair. The most effective medical therapies include an ACE inhibitor or an angiotensin II receptor blocker; however, these agents decrease glomerular filtration rate in a stenotic kidney owing to efferent renal arteriolar dilation. In the presence of bilateral renal artery stenosis or renal artery stenosis to a solitary kidney, progressive renal insufficiency may result from the use of these agents. Importantly, the renal insufficiency is generally reversible after discontinuation of the offending drug. If renal artery stenosis is suspected and if the clinical


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InternalMed_Harrison. from the use of these agents. Importantly, the renal insufficiency is generally reversible after discontinuation of the offending drug. If renal artery stenosis is suspected and if the clinical condition warrants an intervention such as percutaneous transluminal renal angioplasty (PTRA), placement of a vascular endoprosthesis (stent), or surgical renal revascularization, imaging studies should be the next step in the evaluation. As a screening test, renal blood flow may be evaluated with a radionuclide [131I]-orthoiodohippurate (OIH) scan, or glomerular filtration rate may be evaluated with a [99mTc]diethylenetriamine pentaacetic acid (DTPA) scan before and after a single dose of captopril (or another ACE inhibitor). The following are consistent with a positive study: (1) decreased relative uptake by the involved kidney, which contributes <40% of total renal function, (2) delayed uptake on the affected side, and (3) delayed washout on the affected side. In patients with normal, or


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InternalMed_Harrison. uptake by the involved kidney, which contributes <40% of total renal function, (2) delayed uptake on the affected side, and (3) delayed washout on the affected side. In patients with normal, or nearly normal, renal function, a normal captopril renogram essentially excludes functionally significant renal artery stenosis; however, its usefulness is limited in patients with renal insufficiency (creatinine clearance <20 mL/min) or bilateral renal artery stenosis. Additional imaging studies are indicated if the scan is positive. Doppler ultrasound of the renal arteries produces reliable estimates of renal blood flow velocity and offers the opportunity to track a lesion over time. Positive studies usually are confirmed at angiography, whereas false-negative results occur frequently, particularly in obese patients. Gadolinium-contrast magnetic resonance angiography offers clear images of the proximal renal artery but may miss distal lesions. An advantage is the opportunity to image the renal


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InternalMed_Harrison. in obese patients. Gadolinium-contrast magnetic resonance angiography offers clear images of the proximal renal artery but may miss distal lesions. An advantage is the opportunity to image the renal arteries with an agent that is not nephrotoxic. Contrast arteriography remains the “gold standard” for evaluation and identification of renal artery lesions. Potential risks include nephrotoxicity, particularly in patients with diabetes mellitus or preexisting renal insufficiency.


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InternalMed_Harrison. Some degree of renal artery obstruction may be observed in almost 50% of patients with atherosclerotic disease, and there are several approaches for evaluating the functional significance of such a lesion to predict the effect of vascular repair on blood pressure control and renal function. Each approach has varying degrees of sensitivity and specificity, and no single test is sufficiently reliable to determine a causal relationship between a renal artery lesion and hypertension. Functionally significant lesions generally occlude more than 70% of the lumen of the affected renal artery. On angiography, the presence of collateral vessels to the ischemic kidney suggests a functionally significant lesion. A lateralizing renal vein renin ratio (ratio >1.5 of affected side/contralateral side) has a 90% predictive value for a lesion that would respond to vascular repair; however, the false-negative rate for blood pressure control is 50–60%. Measurement of the pressure gradient across a renal


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InternalMed_Harrison. a 90% predictive value for a lesion that would respond to vascular repair; however, the false-negative rate for blood pressure control is 50–60%. Measurement of the pressure gradient across a renal artery lesion does not reliably predict the response to vascular repair.


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InternalMed_Harrison. In the final analysis, a decision concerning vascular repair vs. medical therapy and the type of repair procedure should be individualized. Patients with fibromuscular disease have more favorable outcomes than do patients with atherosclerotic lesions, presumably owing to their younger age, shorter duration of hypertension, and less systemic disease. Because of its low risk-versus-benefit ratio and high success rate (improvement or cure of hypertension in 90% of patients and restenosis rate of 10%), PTRA is the initial treatment of choice for these patients. Surgical revascularization may be undertaken if PTRA is unsuccessful or if a branch lesion is present. In atherosclerotic patients, vascular repair should be considered if blood pressure cannot be controlled adequately despite optimal medical therapy or if renal function deteriorates. Surgery may be the preferred initial approach for younger atherosclerotic patients without comorbid conditions; however, for most atherosclerotic


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InternalMed_Harrison. medical therapy or if renal function deteriorates. Surgery may be the preferred initial approach for younger atherosclerotic patients without comorbid conditions; however, for most atherosclerotic patients, depending on the location of the lesion, the initial approach may be PTRA and/or stenting. Surgical revascularization may be indicated if these approaches are unsuccessful, the vascular lesion is not amenable to PTRA or stenting, or concomitant aortic surgery is required, e.g., to repair an aneurysm. A National Institutes of Health–sponsored prospective, randomized clinical trial is in progress comparing medical therapy alone with medical therapy plus renal artery stenting regarding Cardiovascular Outcomes for Renal Atherosclerotic Lesions (CORAL).


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InternalMed_Harrison. Excess aldosterone production due to primary aldosteronism is a potentially curable form of hypertension. In patients with primary aldosteronism, increased aldosterone production is independent of the renin-angiotensin system, and the consequences are sodium retention, hypertension, hypokalemia, and low PRA. The reported prevalence of this disorder varies from <2% to ~15% of hypertensive individuals. In part, this variation is related to the intensity of screening and the criteria for establishing the diagnosis.


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InternalMed_Harrison. History and physical examination provide little information about the diagnosis. The age at the time of diagnosis is generally the third through fifth decade. Hypertension is usually mild to moderate but occasionally may be severe; primary aldosteronism should be considered in all patients with refractory hypertension. Hypertension in these patients may be associated with glucose intolerance. Most patients are asymptomatic; however, infrequently, polyuria, polydipsia, paresthesias, or muscle weakness may be present as a consequence of hypokalemic alkalosis. Although aldosterone is a salt-retaining hormone, patients with primary aldosteronism rarely have edema. Renal dysfunction and cardiovascular disease are strikingly increased in patients with primary aldosteronism compared to those with primary hypertension.


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InternalMed_Harrison. In a hypertensive patient with unprovoked hypokalemia (i.e., unrelated to diuretics, vomiting, or diarrhea), the prevalence of primary aldosteronism approaches 40–50%. In patients on diuretics, serum potassium <3.1 mmol/L (<3.1 meq/L) also raises the possibility of primary aldosteronism; however, serum potassium is an insensitive and nonspecific screening test. Serum potassium is normal in ~25% of patients subsequently found to have an aldosterone-producing adenoma, and higher percentages of patients with other etiologies of primary aldosteronism are not hypokalemic. Additionally, hypokalemic hypertension may be a consequence of secondary aldosteronism, other mineralocorticoidand glucocorticoid-induced hypertensive disorders, and pheochromocytoma.


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InternalMed_Harrison. The ratio of plasma aldosterone to plasma renin activity (PA/ PRA) is a useful screening test. These measurements preferably are obtained in ambulatory patients in the morning. A ratio >30:1 in conjunction with a plasma aldosterone concentration >555 pmol/L (>20 ng/dL) reportedly has a sensitivity of 90% and a specificity of 91% for an aldosterone-producing adenoma. In a Mayo Clinic series, an aldosterone-producing adenoma subsequently was confirmed surgically in >90% of hypertensive patients with a PA/PRA ratio ≥20 and a plasma aldosterone concentration ≥415 pmol/L (≥15 ng/dL). There are, however, several caveats to interpreting the ratio. The cutoff for a “high” ratio is laboratoryand assay-dependent. Some anti-hypertensive agents may affect the ratio (e.g., aldosterone antagonists, angiotensin receptor antagonists, and ACE inhibitors may increase renin; aldosterone antagonists may increase aldosterone). Current recommendations are to withdraw aldosterone antagonists for at least


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InternalMed_Harrison. receptor antagonists, and ACE inhibitors may increase renin; aldosterone antagonists may increase aldosterone). Current recommendations are to withdraw aldosterone antagonists for at least 4–6 weeks before obtaining these measurements. Because aldosterone biosynthesis is potassium-dependent, hypokalemia should be corrected with oral potassium supplements prior to screening. With these caveats, the ratio has been reported to be useful as a screening test in measurements obtained with patients taking their usual antihypertensive medications. A high ratio in the absence of an elevated plasma aldosterone level is considerably less specific for primary aldosteronism since many patients with primary hypertension have low renin levels in this setting, particularly African Americans and elderly patients.


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InternalMed_Harrison. In patients with renal insufficiency, the ratio may also be elevated because of decreased aldosterone clearance. In patients with an elevated PA/PRA ratio, the diagnosis of primary aldosteronism can be confirmed by demonstrating failure to suppress plasma aldosterone to <277 pmol/L (<10 ng/dL) after IV infusion of 2 L of isotonic saline over 4 h; post-saline infusion plasma aldosterone values between 138 and 277 pmol/L (5–10 ng/dL) are not determinant. Alternative confirmatory tests include failure to suppress aldosterone (based on test specific criteria) in response to an oral NaCl load, fludrocortisone, or captopril.


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InternalMed_Harrison. Several sporadic and familial adrenal abnormalities may culminate in the syndrome of primary aldosteronism, and appropriate therapy depends on the specific etiology. The two most common causes of sporadic primary aldosteronism are an aldosterone-producing adenoma and bilateral adrenal hyperplasia. Together, they account for >90% of all patients with primary aldosteronism. The tumor is almost always unilateral, and most often measures <3 cm in diameter. Most of the remainder of these patients have bilateral adrenocortical hyperplasia (idiopathic hyperaldosteronism). Rarely, primary aldosteronism may be caused by an adrenal carcinoma or an ectopic malignancy, e.g., ovarian arrhenoblastoma. Most aldosterone-producing carcinomas, in contrast to adrenal adenomas and hyperplasia, produce excessive amounts of other adrenal steroids in addition to aldosterone. Functional differences in hormone secretion may assist in the diagnosis of adenoma vs. hyperplasia. Aldosterone biosynthesis is more


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InternalMed_Harrison. amounts of other adrenal steroids in addition to aldosterone. Functional differences in hormone secretion may assist in the diagnosis of adenoma vs. hyperplasia. Aldosterone biosynthesis is more responsive to ACTH in patients with adenoma and more responsive to angiotensin in patients with hyperplasia. Consequently, patients with adenoma tend to have higher plasma aldosterone in the early morning that decreases during the day, reflecting the diurnal rhythm of ACTH, whereas plasma aldosterone tends to increase with upright posture in patients with hyperplasia, reflecting the normal postural response of the renin-angiotensin-aldosterone axis. However, there is overlap in the ability of these measurements to discriminate between adenoma and hyperplasia. Rare familial forms of primary aldosteronism include glucocorticoid-remediable primary aldosteronism and familial aldosteronism types II and III. Genetic testing may assist in the diagnosis of these familial disorders.


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InternalMed_Harrison. Adrenal computed tomography (CT) should be carried out in all patients diagnosed with primary aldosteronism. High-resolution CT may identify tumors as small as 0.3 cm and is positive for an adrenal tumor 90% of the time. If the CT is not diagnostic, an adenoma may be detected by adrenal scintigraphy with 6 β-[I131] iodomethyl-19norcholesterol after dexamethasone suppression (0.5 mg every 6 h for 7 days); however, this technique has decreased sensitivity for adenomas <1.5 cm.


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InternalMed_Harrison. When carried out by an experienced radiologist, bilateral adrenal venous sampling for measurement of plasma aldosterone is the most accurate means of differentiating unilateral from bilateral forms of primary aldosteronism. The sensitivity and specificity of adrenal venous sampling (95% and 100%, respectively) for detecting unilateral aldosterone hypersecretion are superior to those of adrenal CT; success rates are 90–96%, and complication rates are <2.5%. One frequently used protocol involves sampling for aldosterone and cortisol levels in response to ACTH stimulation. An ipsilateral/contralateral aldosterone ratio >4, with symmetric ACTH-stimulated cortisol levels, is indicative of unilateral aldosterone production.


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InternalMed_Harrison. Hypertension generally is responsive to surgery in patients with adenoma but not in patients with bilateral adrenal hyperplasia. Unilateral adrenalectomy, often done via a laparoscopic approach, is curative in 40–70% of patients with an adenoma. Transient hypoaldosteronism may occur up to 3 months postoperatively, resulting in hyperkalemia. Potassium should be monitored during this time, and hyperkalemia should be treated with potassium-wasting diuretics and with fludrocortisone, if needed. Patients with bilateral hyperplasia should be treated medically. The drug regimen for these patients, as well as for patients with an adenoma who are poor surgical candidates, should include an aldosterone antagonist and, if necessary, other potassium-sparing diuretics.


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InternalMed_Harrison. Glucocorticoid-remediable hyperaldosteronism is a rare, monogenic autosomal dominant disorder characterized by moderate to severe hypertension, often occurring at an early age. These patients 1619 may have a family history of hemorrhagic stroke at a young age. Hypokalemia is usually mild or absent. Normally, angiotensin II stimulates aldosterone production by the adrenal zona glomerulosa, whereas ACTH stimulates cortisol production in the zona fasciculata. Owing to a chimeric gene on chromosome 8, ACTH also regulates aldosterone secretion by the zona fasciculata in patients with glucocorticoid-remediable hyperaldosteronism. The consequence is overproduction in the zona fasciculata of both aldosterone and hybrid steroids (18-hydroxycortisol and 18-oxocortisol) due to oxidation of cortisol. The diagnosis may be established by urine excretion rates of these hybrid steroids that are 20 to 30 times normal or by direct genetic testing. Therapeutically, suppression of ACTH with low-dose


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InternalMed_Harrison. The diagnosis may be established by urine excretion rates of these hybrid steroids that are 20 to 30 times normal or by direct genetic testing. Therapeutically, suppression of ACTH with low-dose glucocorticoids corrects the hyperaldosteronism, hypertension, and hypokalemia. Aldosterone antagonists are also therapeutic options. Patients with familial aldosteronism types II and III are treated with aldosterone antagonists or adrenalectomy.


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InternalMed_Harrison. (See also Chap. 406) Cushing’s syndrome is related to excess cortisol production due either to excess ACTH secretion (from a pituitary tumor or an ectopic tumor) or to ACTH-independent adrenal production of cortisol. Hypertension occurs in 75–80% of patients with Cushing’s syndrome. The mechanism of hypertension may be related to stimulation of mineralocorticoid receptors by cortisol and increased secretion of other adrenal steroids. If clinically suspected based on phenotypic characteristics, in patients not taking exogenous glucocorticoids, laboratory screening may be carried out with measurement of 24-h excretion rates of urine free cortisol or an overnight dexamethasone-suppression test. Late night salivary cortisol is also a sensitive and convenient screening test. Further evaluation is required to confirm the diagnosis and identify the specific etiology of Cushing’s syndrome. Appropriate therapy depends on the etiology.


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InternalMed_Harrison. (See also Chap. 407) Catecholamine-secreting tumors are located in the adrenal medulla (pheochromocytoma) or in extra-adrenal paraganglion tissue (paraganglioma) and account for hypertension in ~0.05% of patients. If unrecognized, pheochromocytoma may result in lethal cardiovascular consequences. Clinical manifestations, including hypertension, are primarily related to increased circulating catecholamines, although some of these tumors may secrete a number of other vasoactive substances. In a small percentage of patients, epinephrine is the predominant catecholamine secreted by the tumor, and these patients may present with hypotension rather than hypertension. The initial suspicion of the diagnosis is based on symptoms and/or the association of pheochromocytoma with other disorders (Table 298-4). Approximately 20% of pheochromocytomas are familial with autosomal dominant inheritance. Inherited pheochromocytomas may be associated with multiple endocrine neoplasia (MEN) type 2A and


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InternalMed_Harrison. 298-4). Approximately 20% of pheochromocytomas are familial with autosomal dominant inheritance. Inherited pheochromocytomas may be associated with multiple endocrine neoplasia (MEN) type 2A and type 2B, von Hippel-Lindau disease, and neurofibromatosis (Table 298-4). Each of these syndromes is related to specific, identifiable germ-line mutations. Additionally, mutations of succinate dehydrogenase genes are associated with paraganglioma syndromes, generally characterized by head and neck paragangliomas. Laboratory testing consists of measuring catecholamines in either urine or plasma, e.g., 24-h urine metanephrine excretion or fractionated plasma free metanephrines. The urine measurement is less sensitive but more specific. Genetic screening is available for evaluating patients and relatives suspected of harboring a pheochromocytoma associated with a familial syndrome. Surgical excision is the definitive treatment of pheochromocytoma and results in cure in ~90% of patients.


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InternalMed_Harrison. Independent of obesity, hypertension occurs in >50% of individuals with obstructive sleep apnea. The severity of hypertension correlates with the severity of sleep apnea. Approximately 70% of patients with obstructive sleep apnea are obese. Hypertension related to obstructive sleep apnea also should be considered in patients with drug-resistant hypertension and patients with a history of snoring. The diagnosis can be confirmed by polysomnography. In obese patients, weight loss may alleviate or cure sleep apnea and related hypertension. Continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP) administered during sleep is an effective therapy for obstructive sleep apnea. With CPAP or BiPAP, patients with apparently drug-resistant hypertension may be more responsive to antihypertensive agents.


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InternalMed_Harrison. Coarctation of the aorta is the most common congenital cardiovascular cause of hypertension (Chap. 282). The incidence is 1–8 per 1000 live births. It is usually sporadic but occurs in 35% of children with Turner’s syndrome. Even when the anatomic lesion is surgically corrected in infancy, up to 30% of patients develop subsequent hypertension and are at risk of accelerated coronary artery disease and cerebrovascular events. Patients with less severe lesions may not be diagnosed until young adulthood. Physical findings include diminished and delayed femoral pulses and a systolic pressure gradient between the right arm and the legs and, depending on the location of the coarctation, between the right and left arms. A blowing systolic murmur may be heard in the posterior left interscapular areas. The diagnosis may be confirmed by chest x-ray and transesophageal echocardiography. Therapeutic options include surgical repair and balloon angioplasty, with or without placement of an


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InternalMed_Harrison. areas. The diagnosis may be confirmed by chest x-ray and transesophageal echocardiography. Therapeutic options include surgical repair and balloon angioplasty, with or without placement of an intravascular stent. Subsequently, many patients do not have a normal life expectancy but may have persistent hypertension, with death due to ischemic heart disease, cerebral hemorrhage, or aortic aneurysm.


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InternalMed_Harrison. Several additional endocrine disorders, including thyroid diseases and acromegaly, cause hypertension. Mild diastolic hypertension may be a consequence of hypothyroidism, whereas hyperthyroidism may result in systolic hypertension. Hypercalcemia of any etiology, the most common being primary hyperparathyroidism, may result in hypertension. Hypertension also may be related to a number of prescribed or over-the-counter medications.


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InternalMed_Harrison. In addition to glucocorticoid-remediable primary aldosteronism, a number of rare forms of monogenic hypertension have been identified (Table 298–4). These disorders may be recognized by their characteristic phenotypes, and in many instances the diagnosis may be confirmed by genetic analysis. Several inherited defects in adrenal steroid biosynthesis and metabolism result in mineralocorticoid-induced hypertension and hypokalemia. In patients with a 17α-hydroxylase deficiency, synthesis of sex hormones and cortisol is decreased (Fig. 298-3). Consequently, these individuals do not mature sexually; males may present with pseudohermaphroditism and females with primary amenorrhea and absent secondary sexual characteristics. Because cortisol-induced negative feedback on pituitary ACTH production is diminished, ACTH-stimulated adrenal steroid synthesis proximal to the enzymatic block is increased. Hypertension and hypokalemia are consequences of increased synthesis of mineralocorticoids


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InternalMed_Harrison. is diminished, ACTH-stimulated adrenal steroid synthesis proximal to the enzymatic block is increased. Hypertension and hypokalemia are consequences of increased synthesis of mineralocorticoids proximal to the enzymatic block, particularly desoxycorticosterone. Increased steroid production and, hence, hypertension may be treated with low-dose glucocorticoids. An 11β-hydroxylase deficiency results in a salt-retaining adrenogenital syndrome that occurs in 1 in 100,000 live births. This enzymatic defect results in decreased cortisol synthesis, increased synthesis of mineralocorticoids (e.g., desoxycorticosterone), and shunting of steroid biosynthesis into the androgen pathway. In the severe form, the syndrome may present early in life, including the


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InternalMed_Harrison. FIGURE 298-3 Adrenal enzymatic defects. DHEA, dehydroepiandrosterone.


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InternalMed_Harrison. newborn period, with virilization and ambiguous genitalia in females and penile enlargement in males, or in older children as precocious puberty and short stature. Acne, hirsutism, and menstrual irregularities may be the presenting features when the disorder is first recognized in adolescence or early adulthood. Hypertension is less common in the late-onset forms. Patients with an 11β-hydroxysteroid dehydrogenase deficiency have an impaired capacity to metabolize cortisol to its inactive metabolite, cortisone, and hypertension is related to activation of mineralocorticoid receptors by cortisol. This defect may be inherited or acquired, due to licorice-containing glycyrrhizin acid. The same substance is present in the paste of several brands of chewing tobacco. The defect in Liddle’s syndrome (Chaps. 63 and 406) results from constitutive activation of amiloride-sensitive epithelial sodium channels on the distal renal tubule, resulting in excess sodium reabsorption; the syndrome is


InternalMed_Harrison

InternalMed_Harrison. (Chaps. 63 and 406) results from constitutive activation of amiloride-sensitive epithelial sodium channels on the distal renal tubule, resulting in excess sodium reabsorption; the syndrome is ameliorated by amiloride. Hypertension exacerbated in pregnancy (Chap. 8) may be due to activation of the mineralocorticoid receptor by progesterone.


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InternalMed_Harrison. APPROACH TO THE PATIENT: The initial assessment of a hypertensive patient should include a complete history and physical examination to confirm a diagnosis of hypertension, screen for other cardiovascular disease risk factors, screen for secondary causes of hypertension, identify cardiovascular consequences of hypertension and other comorbidities, assess blood pressure–related lifestyles, and determine the potential for intervention.


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InternalMed_Harrison. Most patients with hypertension have no specific symptoms referable to their blood pressure elevation. Although popularly considered a symptom of elevated arterial pressure, headache generally occurs only in patients with severe hypertension. Characteristically, a “hypertensive headache” occurs in the morning and is localized to the occipital region. Other nonspecific symptoms that may be related to elevated blood pressure include dizziness, palpitations, easy fatigability, and impotence. When symptoms are present, they are generally related to hypertensive cardiovascular disease or to manifestations of secondary hypertension. Table 298-5 lists salient features that should be addressed in obtaining a history from a hypertensive patient.


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InternalMed_Harrison. Reliable measurements of blood pressure depend on attention to the details of the technique and conditions of the measurement. Proper training of observers, positioning of the patient, and selection of cuff size are essential. Owing to recent regulations preventing the use of mercury because of concerns about its potential toxicity, most office measurements are made with aneroid sphygmomanometers or with oscillometric devices. These instruments should be calibrated periodically, and their accuracy confirmed. Before the blood pressure measurement is taken, the individual should be seated quietly in a chair (not the exam table) with feet on the floor for 5 min in a private, quiet setting with a comfortable room temperature. At least two measurements should be made. The center of the cuff should be at heart level, and the width of the bladder cuff Duration of hypertension Previous therapies: responses and side effects Family history of hypertension and cardiovascular disease


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InternalMed_Harrison. Duration of hypertension Previous therapies: responses and side effects Family history of hypertension and cardiovascular disease Other risk factors: weight change, dyslipidemia, smoking, diabetes, physical inactivity Evidence of secondary hypertension: history of renal disease; change in appearance; muscle weakness; spells of sweating, palpitations, tremor; erratic sleep, snoring, daytime somnolence; symptoms of hypo-or hyperthyroidism; use of agents that may increase blood pressure Evidence of target organ damage: history of TIA, stroke, transient blindness; angina, myocardial infarction, congestive heart failure; sexual function Abbreviation: TIA, transient ischemic attack.


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InternalMed_Harrison. Evidence of target organ damage: history of TIA, stroke, transient blindness; angina, myocardial infarction, congestive heart failure; sexual function Abbreviation: TIA, transient ischemic attack. should equal at least 40% of the arm circumference; the length of the cuff bladder should encircle at least 80% of the arm circumference. It is important to pay attention to cuff placement, stethoscope placement, and the rate of deflation of the cuff (2 mmHg/s). Systolic blood pressure is the first of at least two regular “tapping” Korotkoff sounds, and diastolic blood pressure is the point at which the last regular Korotkoff sound is heard. In current practice, a diagnosis of hypertension generally is based on seated, office measurements.


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InternalMed_Harrison. Currently available ambulatory monitors are fully automated, use the oscillometric technique, and typically are programmed to take readings every 15–30 min. Twenty-four-hour ambulatory blood pressure monitoring more reliably predicts cardiovascular disease risk than do office measurements. However, ambulatory monitoring is not used routinely in clinical practice and generally is reserved for patients in whom white coat hypertension is suspected. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) has also recommended ambulatory monitoring for treatment resistance, symptomatic hypotension, autonomic failure, and episodic hypertension.


InternalMed_Harrison

InternalMed_Harrison. Body habitus, including weight and height, should be noted. At the initial examination, blood pressure should be measured in both arms and preferably in the supine, sitting, and standing positions to evaluate for postural hypotension. Even if the femoral pulse is normal to palpation, arterial pressure should be measured at least once in the lower extremity in patients in whom hypertension is discovered before age 30. Heart rate also should be recorded. Hypertensive individuals have an increased prevalence of atrial fibrillation. The neck should be palpated for an enlarged thyroid gland, and patients should be assessed for signs of hypoand hyperthyroidism. Examination of blood vessels may provide clues about underlying vascular disease and should include funduscopic examination, auscultation for bruits over the carotid and femoral arteries, and palpation of femoral and pedal pulses. The retina is the only tissue in which arteries and arterioles can be examined directly. With increasing


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InternalMed_Harrison. for bruits over the carotid and femoral arteries, and palpation of femoral and pedal pulses. The retina is the only tissue in which arteries and arterioles can be examined directly. With increasing severity of hypertension and atherosclerotic disease, progressive funduscopic changes include increased arteriolar light reflex, arteriovenous crossing defects, hemorrhages and exudates, and, in patients with malignant hypertension, papilledema. Examination of the heart may reveal a loud second heart sound due to closure of the aortic valve and an S4 gallop attributed to atrial contraction against a noncompliant left ventricle. Left ventricular hypertrophy may be detected by an enlarged, sustained, and laterally displaced apical impulse. An abdominal bruit, particularly a bruit that lateralizes and extends throughout systole into diastole, raises the possibility of renovascular hypertension. Kidneys of patients with polycystic kidney disease may be palpable in the abdomen. The physical


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InternalMed_Harrison. and extends throughout systole into diastole, raises the possibility of renovascular hypertension. Kidneys of patients with polycystic kidney disease may be palpable in the abdomen. The physical examination also should include evaluation for signs of CHF and a neurologic examination.


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InternalMed_Harrison. Table 298-6 lists recommended laboratory tests in the initial evaluation of hypertensive patients. Repeat measurements of renal function, serum electrolytes, fasting glucose, and lipids may be obtained Abbreviations: BUN, blood urea nitrogen; HDL, high-density lipoprotein; LDL, low-density lipoprotein; TSH, thyroid-stimulating hormone. after the introduction of a new antihypertensive agent and then annually or more frequently if clinically indicated. More extensive laboratory testing is appropriate for patients with apparent drug-resistant hypertension or when the clinical evaluation suggests a secondary form of hypertension.


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InternalMed_Harrison. Implementation of lifestyles that favorably affect blood pressure has implications for both the prevention and the treatment of hypertension. Health-promoting lifestyle modifications are recommended for individuals with prehypertension and as an adjunct to drug therapy in hypertensive individuals. These interventions should address overall cardiovascular disease risk. Although the impact of lifestyle interventions on blood pressure is more pronounced in persons with hypertension, in short-term trials, weight loss and reduction of dietary NaCl have been shown to prevent the development of hypertension. In hypertensive individuals, even if these interventions do not produce a sufficient reduction in blood pressure to avoid drug therapy, the number of medications or doses required for blood pressure control may be reduced. Dietary modifications that effectively lower blood pressure are weight loss, reduced NaCl intake, increased potassium intake, moderation of alcohol consumption, and an


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InternalMed_Harrison. control may be reduced. Dietary modifications that effectively lower blood pressure are weight loss, reduced NaCl intake, increased potassium intake, moderation of alcohol consumption, and an overall healthy dietary pattern (Table 298-7).


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InternalMed_Harrison. Prevention and treatment of obesity are important for reducing blood pressure and cardiovascular disease risk. In short-term trials, even modest weight loss can lead to a reduction of blood pressure and an increase in insulin sensitivity. Average blood pressure reductions of 6.3/3.1 mmHg have been observed with a reduction in mean body weight of 9.2 kg. Regular physical activity facilitates weight loss, decreases blood pressure, and reduces the overall risk of cardiovascular disease. Blood pressure may be lowered by 30 min of moderately intense physical activity, such as brisk walking, 6–7 days a week, or by more intense, less frequent workouts.


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InternalMed_Harrison. There is individual variability in the sensitivity of blood pressure to NaCl, and this variability may have a genetic basis. Based on results of meta-analyses, lowering of blood pressure by limiting daily NaCl intake to 4.4–7.4 g (75–125 meq) results in blood pressure reductions of 3.7–4.9/0.9–2.9 mmHg in hypertensive individuals and lesser reductions in normotensive individuals. Several long-term, prospective, randomized clinical trials have reported that a reduced salt intake results in a decreased incidence of cardiovascular events. Although reduced salt intakes are generally recommended for both the prevention and treatment of hypertension, overly rigorous salt restriction may have adverse cardiovascular outcomes in diabetic patients and in patients with CHF aggressively treated with diuretics. Potassium and calcium supplementation have inconsistent, modest antihypertensive effects, and, independent of blood pressure, potassium supplementation may be associated with reduced stroke


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InternalMed_Harrison. Potassium and calcium supplementation have inconsistent, modest antihypertensive effects, and, independent of blood pressure, potassium supplementation may be associated with reduced stroke mortality. Consuming three or more alcoholic drinks per day (a standard drink contains ~14 g ethanol) is associated with higher blood pressures, and a reduction of alcohol consumption is associated with a


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InternalMed_Harrison. Abbreviations: BMI, body mass index; DASH, Dietary Approaches to Stop Hypertension (trial). reduction of blood pressure. In patients with advanced renal disease, dietary protein restriction may have a modest effect in mitigating renal damage by reducing the intrarenal transmission of systemic arterial pressure. The DASH (Dietary Approaches to Stop Hypertension) trial convincingly demonstrated that over an 8-week period a diet high in fruits, vegetables, and low-fat dairy products lowers blood pressure in individuals with high-normal blood pressures or mild hypertension. Reduction of daily NaCl intake to <6 g (100 meq) augmented the effect of this diet on blood pressure. Fruits and vegetables are enriched sources of potassium, magnesium, and fiber, and dairy products are an important source of calcium.


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InternalMed_Harrison. Drug therapy is recommended for individuals with blood pressures ≥140/90 mmHg. The degree of benefit derived from antihypertensive agents is related to the magnitude of the blood pressure reduction. Lowering systolic blood pressure by 10–12 mmHg and diastolic blood pressure by 5–6 mmHg confers relative risk reductions of 35–40% for stroke and 12–16% for CHD within 5 years of the initiation of treatment. Risk of heart failure is reduced by >50%. Hypertension control is the single most effective intervention for slowing the rate of progression of hypertension-related kidney disease.


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InternalMed_Harrison. There is considerable variation in individual responses to different classes of antihypertensive agents, and the magnitude of response to any single agent may be limited by activation of counter-regulatory mechanisms. Most available agents reduce systolic blood pressure by 7–13 mmHg and diastolic blood pressure by 4–8 mmHg when corrected for placebo effect. More often than not, combinations of agents, with complementary antihypertensive mechanisms, are required to achieve goal blood pressure reductions. Selection of antihypertensive agents and combinations of agents should be individualized, taking into account age, severity of hypertension, other cardiovascular disease risk factors, comorbid conditions, and practical considerations related to cost, side effects, and frequency of dosing (Table 298-8).


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InternalMed_Harrison. Diuretics Low-dose thiazide diuretics may be used alone or in combination with other antihypertensive drugs. Thiazides inhibit the Na+/Cl− pump in the distal convoluted tubule and hence increase sodium excretion. In the long term, they also may act as vasodilators. Thiazides are safe, efficacious, inexpensive, and reduce clinical events. They provide additive blood pressure–lowering effects when combined with beta blockers, angiotensin-converting enzyme inhibitors (ACEIs), or angiotensin receptor blockers (ARBs). In contrast, addition of a diuretic to a calcium channel blocker is less effective. Usual doses of hydrochlorothiazide range from 6.25–50 mg/d. Owing to an increased incidence of metabolic side effects (hypokalemia, insulin resistance, increased cholesterol), higher doses generally are not recommended. Chlorthalidone is a diuretic structurally similar to hydrochlorothiazide, and like hydrochlorothiazide, it blocks sodium-chloride cotransport in the early distal tubule.


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InternalMed_Harrison. are not recommended. Chlorthalidone is a diuretic structurally similar to hydrochlorothiazide, and like hydrochlorothiazide, it blocks sodium-chloride cotransport in the early distal tubule. However, chlorthalidone has a longer half-life (40–60 h vs. 9–15 h) and an antihypertensive potency ~1.5–2.0 times that of hydrochlorothiazide. Potassium loss is also greater with chlorthalidone. Two potassium-sparing diuretics, amiloride and triamterene, act by inhibiting epithelial sodium channels in the distal nephron. These agents are weak antihypertensive agents but may be used in combination with a thiazide to protect against hypokalemia. The main pharmacologic target for loop diuretics is the Na+-K+-2Cl− cotransporter in the thick ascending limb of the loop of Henle. Loop diuretics generally are reserved for hypertensive patients with reduced glomerular filtration rates (reflected in serum creatinine >220 μmol/L [>2.5 mg/ dL]), CHF, or sodium retention and edema for some other reason, such


InternalMed_Harrison

InternalMed_Harrison. reserved for hypertensive patients with reduced glomerular filtration rates (reflected in serum creatinine >220 μmol/L [>2.5 mg/ dL]), CHF, or sodium retention and edema for some other reason, such as treatment with a potent vasodilator, e.g., minoxidil.


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InternalMed_Harrison. Blockers of the Renin–Angiotensin System ACEIs decrease the production of angiotensin II, increase bradykinin levels, and reduce sympathetic nervous system activity. ARBs provide selective blockade of AT1 receptors, and the effect of angiotensin II on unblocked AT2 receptors 1623 may augment their hypotensive effect. Both classes of agents are effective antihypertensive agents that may be used as monotherapy or in combination with diuretics, calcium antagonists, and alpha blocking agents. ACEIs and ARBs improve insulin action and ameliorate the adverse effects of diuretics on glucose metabolism. Although the overall impact on the incidence of diabetes is modest, compared with amlodipine (a calcium antagonist), valsartan (an ARB) has been shown to reduce the risk of developing diabetes in high-risk hypertensive patients. ACEI/ARB combinations are less effective in lower ing blood pressure than is the case when either class of these agents is used in combination with other classes of


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InternalMed_Harrison. high-risk hypertensive patients. ACEI/ARB combinations are less effective in lower ing blood pressure than is the case when either class of these agents is used in combination with other classes of agents. In patients with vascular disease or a high risk of diabetes, combination ACEI/ARB therapy has been associated with more adverse events (e.g., cardiovascular death, myocardial infarction, stroke, and hospitalization for heart failure) without increases in benefit.


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InternalMed_Harrison. Side effects of ACEIs and ARBs include functional renal insufficiency due to efferent renal arteriolar dilation in a kidney with a stenotic lesion of the renal artery. Additional predisposing conditions to renal insufficiency induced by these agents include dehydration, CHF, and use of nonsteroidal anti-inflammatory drugs. Dry cough occurs in ~15% of patients, and angioedema occurs in <1% of patients taking ACEIs. Angioedema occurs most commonly in individuals of Asian origin and more commonly in African Americans than in whites. Hyperkalemia due to hypoaldosteronism is an occasional side effect of both ACEIs and ARBs.


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InternalMed_Harrison. An alternative approach to blocking the renin-angiotensin system has recently been introduced into clinical practice for the treatment of hypertension: direct renin inhibitors. Blockade of the renin-angiotensin system is more complete with renin inhibitors than with ACEIs or ARBs. Aliskiren is the first of a class of oral, nonpeptide competitive inhibitors of the enzymatic activity of renin. Monotherapy with aliskiren seems to be as effective as an ACEI or ARB for lowering blood pressure, but not more effective. Further blood reductions may be achieved when aliskiren is used in combination with a thiazide diuretic or a calcium antagonist. Currently, aliskiren is not considered a first-line antihypertensive agent.


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InternalMed_Harrison. Aldosterone Antagonists Spironolactone is a nonselective aldosterone antagonist that may be used alone or in combination with a thiazide diuretic. It may be a particularly effective agent in patients with low-renin primary hypertension, resistant hypertension, and primary aldosteronism. In patients with CHF, low-dose spironolactone reduces mortality and hospitalizations for heart failure when given in addition to conventional therapy with ACEIs, digoxin, and loop diuretics. Because spironolactone binds to progesterone and androgen receptors, side effects may include gynecomastia, impotence, and menstrual abnormalities. These side effects are circumvented by a newer agent, eplerenone, which is a selective aldosterone antagonist.


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InternalMed_Harrison. Beta Blockers β-Adrenergic receptor blockers lower blood pressure by decreasing cardiac output, due to a reduction of heart rate and contractility. Other proposed mechanisms by which beta blockers lower blood pressure include a central nervous system effect and inhibition of renin release. Beta blockers are particularly effective in hypertensive patients with tachycardia, and their hypotensive potency is enhanced by coadministration with a diuretic. In lower doses, some beta blockers selectively inhibit cardiac β1 receptors and have less influence on β2 receptors on bronchial and vascular smooth muscle cells; however, there seems to be no difference in the antihypertensive potencies of cardioselective and nonselective beta blockers. Some beta blockers have intrinsic sympathomimetic activity, although it is uncertain whether this constitutes an overall advantage or disadvantage in cardiac therapy. Beta blockers without intrinsic sympathomimetic activity decrease the rate of sudden


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InternalMed_Harrison. although it is uncertain whether this constitutes an overall advantage or disadvantage in cardiac therapy. Beta blockers without intrinsic sympathomimetic activity decrease the rate of sudden death, overall mortality, and recurrent myocardial infarction. In patients with CHF, beta blockers have been shown to reduce the risks of hospitalization and mortality. Overall, beta blockers


InternalMed_Harrison

InternalMed_Harrison. Diuretics Thiazides Hydrochlorothiazide 6.25–50 mg (1–2) Diabetes, dyslipidemia, hyperuricemia, gout, hypokalemia Chlorthalidone 25–50 mg (1) Loop diuretics Furosemide 40–80 mg (2–3) CHF due to systolic dysfunc-Diabetes, dyslipidemia, hypertion, renal failure uricemia, gout, hypokalemia Aldosterone antagonists Spironolactone 25–100 mg (1–2) CHF due to systolic dysfunc-Renal failure, hyperkalemia tion, primary aldosteronism Renal failure, hyperkalemia Triamterene 50–100 mg (1–2) Beta blockers Asthma, COPD, 2ndor 3rd-degree heart block, sick- Cardioselective Atenolol 25–100 mg (1) Angina, CHF due to systolic sinus syndrome dysfunction, post-MI, sinus tachycardia, ventricular tachyarrhythmias Metoprolol 25–100 mg (1–2) Nonselective Propranolol 40–160 mg (2) Propranolol LA 60–180 (1) Combined alpha/beta Labetalol 200–800 mg (2) ?Post-MI, CHF Carvedilol 12.5–50 mg (2) Alpha antagonists


InternalMed_Harrison

InternalMed_Harrison. Metoprolol 25–100 mg (1–2) Nonselective Propranolol 40–160 mg (2) Propranolol LA 60–180 (1) Combined alpha/beta Labetalol 200–800 mg (2) ?Post-MI, CHF Carvedilol 12.5–50 mg (2) Alpha antagonists Central Clonidine 0.1–0.6 mg (2) Clonidine patch 0.1–0.3 mg (1/week) Methyldopa 250–1000 mg (2) Reserpine 0.05–0.25 mg (1) Guanfacine 0.5–2 mg (1) ACE inhibitors Captopril 25–200 mg (2) Post-MI, coronary syndromes, Acute renal failure, bilateral CHF with low ejection frac-renal artery stenosis, preg- Lisinopril 10–40 mg (1) tion, nephropathy nancy, hyperkalemia Ramipril 2.5–20 mg (1–2) Angiotensin II antagonists Losartan 25–100 mg (1–2) CHF with low ejection frac-Renal failure, bilateral renal tion, nephropathy, ACE inhibi-artery stenosis, pregnancy, Dihydropyridines Nifedipine (long-acting) 30–60 mg (1) Nondihydropyridines Verapamil (long-acting) 120–360 mg (1–2) Post-MI, supraventricular 2nd-or 3rd-degree heart block tachycardias, angina


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InternalMed_Harrison. Dihydropyridines Nifedipine (long-acting) 30–60 mg (1) Nondihydropyridines Verapamil (long-acting) 120–360 mg (1–2) Post-MI, supraventricular 2nd-or 3rd-degree heart block tachycardias, angina Severe coronary artery disease Minoxidil 2.5–80 mg (1–2) aAt the initiation of therapy, lower doses may be preferable for elderly patients and for select combinations of antihypertensive agents. Abbreviations: ACE, angiotensin-converting enzyme; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; MI, myocardial infarction.


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InternalMed_Harrison. may be less protective against cardiovascular and cerebrovascular α-Adrenergic Blockers Postsynaptic, selective α-adrenoreceptor endpoints, and some beta blockers may have less effect on cen-antagonists lower blood pressure by decreasing peripheral vascular tral aortic pressure than other classes of antihypertensive agents. resistance. They are effective antihypertensive agents used either However, beta blockers remain appropriate therapy for hypertensive as monotherapy or in combination with other agents. However, patients with concomitant heart disease and related comorbidi-in clinical trials of hypertensive patients, alpha blockade has not ties. Carvedilol and labetalol block both β receptors and peripheral been shown to reduce cardiovascular morbidity and mortality α-adrenergic receptors. The potential advantages of combined or to provide as much protection against CHF as other classes of βand α-adrenergic blockade in treating hypertension remain to antihypertensive agents. These


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InternalMed_Harrison. The potential advantages of combined or to provide as much protection against CHF as other classes of βand α-adrenergic blockade in treating hypertension remain to antihypertensive agents. These agents are also effective in treating be determined. Nebivolol represents another class of cardioselec-lower urinary tract symptoms in men with prostatic hypertrophy. tive beta blockers that has additional vasodilator actions related to Nonselective α-adrenoreceptor antagonists bind to postsynaptic enhancement of nitric oxide activity. Whether this confers greater and presynaptic receptors and are used primarily for the manage-clinical effectiveness remains to be determined. ment of patients with pheochromocytoma.


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InternalMed_Harrison. Sympatholytic Agents Centrally acting α2 sympathetic agonists decrease peripheral resistance by inhibiting sympathetic outflow. They may be particularly useful in patients with autonomic neuropathy who have wide variations in blood pressure due to baroreceptor denervation. Drawbacks include somnolence, dry mouth, and rebound hypertension on withdrawal. Peripheral sympatholytics decrease peripheral resistance and venous constriction by depleting nerve terminal norepinephrine. Although they are potentially effective antihypertensive agents, their usefulness is limited by orthostatic hypotension, sexual dysfunction, and numerous drug-drug interactions. Rebound hypertension is another concern with abrupt cessation of drugs with a short half-life.


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InternalMed_Harrison. Calcium Channel Blockers Calcium antagonists reduce vascular resistance through L-channel blockade, which reduces intracellular calcium and blunts vasoconstriction. This is a heterogeneous group of agents that includes drugs in the following three classes: phenylalkylamines (verapamil), benzothiazepines (diltiazem), and 1,4-dihydropyridines (nifedipine-like). Used alone and in combination with other agents (ACEIs, beta blockers, α1-adrenergic blockers), calcium antagonists effectively lower blood pressure; however, it is unclear if adding a diuretic to a calcium blocker results in a further lowering of blood pressure. Side effects of flushing, headache, and edema with dihydropyridine use are related to their potencies as arteriolar dilators; edema is due to an increase in transcapillary pressure gradients, not to net salt and water retention.


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InternalMed_Harrison. Direct Vasodilators Direct vasodilators decrease peripheral resistance and concomitantly activate mechanisms that defend arterial pressure, notably the sympathetic nervous system, the renin-angiotensin-aldosterone system, and sodium retention. Usually, they are not considered first-line agents but are most effective when added to a combination that includes a diuretic and a beta blocker. Hydralazine is a potent direct vasodilator that has antioxidant and nitric oxide– enhancing actions, and minoxidil is a particularly potent agent and is used most frequently in patients with renal insufficiency who are refractory to all other drugs. Hydralazine may induce a lupus-like syndrome, and side effects of minoxidil include hypertrichosis and pericardial effusion. Intravenous nitroprusside can be used to treat malignant hypertension and life-threatening left ventricular heart failure associated with elevated arterial pressure.


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InternalMed_Harrison. Based on pooling results from clinical trials, meta-analyses of the efficacy of different classes of antihypertensive agents suggest essentially equivalent blood pressure–lowering effects of the following six major classes of antihypertensive agents when used as monotherapy: thiazide diuretics, beta blockers, ACEIs, ARBs, calcium antagonists, and α1 blockers. On average, standard doses of most antihypertensive agents reduce blood pressure by 8–10/4–7 mmHg; however, there may be subgroup differences in responsiveness. Younger patients may be more responsive to beta blockers and ACEIs, whereas patients over age 50 may be more responsive to diuretics and calcium antagonists. There is a limited relationship between plasma renin and blood pressure response. Patients with high-renin hypertension may be more responsive to ACEIs and ARBs than to other classes of agents, whereas patients with low-renin hypertension are more responsive to diuretics and calcium antagonists. Hypertensive African


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InternalMed_Harrison. may be more responsive to ACEIs and ARBs than to other classes of agents, whereas patients with low-renin hypertension are more responsive to diuretics and calcium antagonists. Hypertensive African Americans tend to have low renin and may require higher doses of ACEIs and ARBs than whites for optimal blood pressure control, although this difference is abolished when these agents are combined with a diuretic. Beta blockers also appear to be less effective than thiazide diuretics in African Americans than in non-African Americans. Early pharmacogenetic studies, utilizing either a candidate gene approach or genome-wide scans, have shown associations of gene polymorphisms with blood pressure responsiveness to specific antihypertensive drugs. However, the reported effects have generally been too small to affect clinical decisions, and associated polymorphisms remain to be confirmed.


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InternalMed_Harrison. Currently, in practical terms, the presence of comorbidities often 1625 influences the selection of antihypertensive agents. A meta-analysis of more than 30 randomized trials of blood pressure–lowering therapy indicates that for a given reduction in blood pressure, the major drug classes seem to produce similar overall net effects on total cardiovascular events. In both non-diabetic and diabetic hypertensive patients, most trials have failed to show significant differences in cardiovascular outcomes with different drug regimens as long as equivalent decreases in blood pressure were achieved. For example, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) demonstrated that the occurrence of CHD and nonfatal myocardial infarction, as well as overall mortality, was virtually identical in hypertensive patients treated with either an ACEI (lisinopril), a diuretic (chlorthalidone), or a calcium antagonist (amlodipine).


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InternalMed_Harrison. However, in specific patient groups, ACEIs may have particular advantages, beyond that of blood pressure control, in reducing cardiovascular and renal outcomes. ACEIs and ARBs decrease intraglomerular pressure and proteinuria and may retard the rate of progression of renal insufficiency, not totally accounted for by their hypotensive effects, in both diabetic and nondiabetic renal diseases. In patients with type 2 diabetes, treatment with an ACEI, an ARB, or aliskiren decreases proteinuria and delays the progression of renal disease. In experimental models of hypertension and diabetes, renal protection with aliskiren is comparable to that with ACEIs and ARBs. However, in patients with type 2 diabetes, addition of aliskiren to an ACEI provides no additional protection against cardiovascular or renal disease and may be associated with more adverse outcomes. Among African Americans with hypertension-related renal disease, ACEIs appear to be more effective than beta blockers or


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InternalMed_Harrison. or renal disease and may be associated with more adverse outcomes. Among African Americans with hypertension-related renal disease, ACEIs appear to be more effective than beta blockers or dihydropyridine calcium channel blockers in slowing, although not preventing, the decline of glomerular filtration rate. The renoprotective effect of these renin-angiotensin blockers, compared with other antihypertensive drugs, is less obvious at lower blood pressures. In most patients with hypertension and heart failure due to systolic and/or diastolic dysfunction, the use of diuretics, ACEIs or ARBs, and beta blockers is recommended to improve survival. Independent of blood pressure, in both hypertensive and normotensive individuals, ACEIs attenuate the development of left ventricular hypertrophy, improve symptomatology and risk of death from CHF, and reduce morbidity and mortality rates in post-myocardial infarction patients. Similar benefits in cardiovascular morbidity and mortality rates in


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InternalMed_Harrison. improve symptomatology and risk of death from CHF, and reduce morbidity and mortality rates in post-myocardial infarction patients. Similar benefits in cardiovascular morbidity and mortality rates in patients with CHF have been observed with the use of ARBs. ACEIs provide better coronary protection than do calcium channel blockers, whereas calcium channel blockers provide more stroke protection than do either ACEIs or beta blockers. Results of a large, double-blind, prospective clinical trial (Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension [ACCOMPLISH Trial]) indicated that combination treatment with an ACEI (benazepril) plus a calcium antagonist (amlodipine) was superior to treatment with the ACEI plus a diuretic (hydrochlorothiazide) in reducing the risk of cardiovascular events and death among high-risk patients with hypertension. However, the combination of an ACEI and a diuretic has recently been shown to produce major


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InternalMed_Harrison. in reducing the risk of cardiovascular events and death among high-risk patients with hypertension. However, the combination of an ACEI and a diuretic has recently been shown to produce major reductions in morbidity and mortality in the very elderly.


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InternalMed_Harrison. After a stroke, combination therapy with an ACEI and a diuretic, but not with an ARB, has been reported to reduce the rate of recurrent stroke. Some of these apparent differences may reflect differences in trial design and/or patient groups.


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InternalMed_Harrison. There is a recent resurgence of interest in two nonpharmacologic, antihypertensive therapies that interrupt sympathetic outflow: (1) device-based carotid baroreflex activation by electrical stimulation of the carotid sinus; and (2) endovascular radiofrequency ablation of the renal sympathetic nerves. Whereas renal denervation is a minimally invasive procedure, carotid baroreceptor stimulation is a surgical procedure, usually performed under general anesthesia, that currently involves implanting electrodes on both the right and left carotid arteries. Both interventions inhibit sympathetic drive and 1626 decrease blood pressure by increasing the capacity of the kidney to excrete sodium and by decreasing renin release. Sustained activation of the baroreflex most likely lowers blood pressure by other mechanisms as well. Clinical experience with these interventions is limited. In the short term, blood pressure is lowered in 75–80% of patients, and the magnitude of the blood pressure


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InternalMed_Harrison. by other mechanisms as well. Clinical experience with these interventions is limited. In the short term, blood pressure is lowered in 75–80% of patients, and the magnitude of the blood pressure reduction is similar for both procedures. To date, the most impressive results have been observed in patients with “resistant” hypertension and patients with obesity-related hypertension. Awaiting the results of long-term, multicenter clinical trials to evaluate their efficacy and safety, it remains to be seen whether these interventions will be adopted into clinical practice.


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InternalMed_Harrison. Based on clinical trial data, the maximum protection against combined cardiovascular endpoints is achieved with pressures <135– 140 mmHg for systolic blood pressure and <80–85 mmHg for diastolic blood pressure; however, treatment has not reduced cardiovascular disease risk to the level in nonhypertensive individuals. In diabetic patients, effective blood pressure control reduces the risk of cardiovascular events and death as well as the risk for microvascular disease (nephropathy, retinopathy). Although guidelines for hypertension control have recommended more aggressive blood pressure targets (e.g., office or clinic blood pressure <130/80 mmHg) for patients with diabetes, CHD, chronic kidney disease, or additional cardiovascular disease risk factors, recent evidence suggests that overly aggressive targets for blood pressure control may not be advantageous, particularly in high-risk patients. For example, among hypertensive patients with diabetes and coronary heart disease, “tight


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InternalMed_Harrison. aggressive targets for blood pressure control may not be advantageous, particularly in high-risk patients. For example, among hypertensive patients with diabetes and coronary heart disease, “tight control” of systolic blood pressure (<130 mmHg) is not associated with improved cardiovascular outcomes. The concept of a “J-curve” suggests that the risk of cardiovascular events increases at blood pressures that are either too high or too low. Theoretically blood pressures that are too low may exceed the autoregulatory capacity of cerebral, coronary, and renal blood flows. There is some suggestive evidence from recent randomized clinical trials for a J-shaped relationship between blood pressure and cardiovascular outcomes (including all-cause mortality) in high-risk patients. Consequently, caution should be exercised in lowering blood pressure <130/80 mmHg in patients with diabetes, CHD, and other high-risk patients. In patients with chronic renal insufficiency, a small, nonprogressive


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InternalMed_Harrison. caution should be exercised in lowering blood pressure <130/80 mmHg in patients with diabetes, CHD, and other high-risk patients. In patients with chronic renal insufficiency, a small, nonprogressive increase in the serum creatinine concentration may occur. This generally reflects a hemodynamic response, not structural renal injury, indicating that intraglomerular pressure has been reduced. Blood pressure control should not be allowed to deteriorate in order to prevent the modest creatinine rise. Among older patients with isolated systolic hypertension, further lowering of diastolic blood pressure does not result in harm. However, relatively little information is available concerning the risk-versusbenefit ratio of antihypertensive therapy in individuals >80 years of age, and in this population, gradual blood pressure reduction to a less aggressive target level of control may be appropriate.


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InternalMed_Harrison. To achieve recommended blood pressure goals, the majority of individuals with hypertension will require treatment with more than one drug. Three or more drugs frequently are needed in patients with diabetes and renal insufficiency. For most agents, reduction of blood pressure at half-standard doses is only ~20% less than at standard doses. Appropriate combinations of agents at these lower doses may have additive or almost additive effects on blood pressure with a lower incidence of side effects.


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InternalMed_Harrison. The term resistant hypertension refers to patients with blood pressures persistently >140/90 mmHg despite taking three or more antihypertensive agents, including a diuretic. Resistant or difficultto-control hypertension is more common in patients >60 years than in younger patients. Resistant hypertension may be related to “pseudoresistance” (high office blood pressures and lower home blood pressures), nonadherence to therapy, identifiable causes of hypertension (including obesity and excessive alcohol intake), and the use of any of a number of nonprescription and prescription drugs (Table 298-3). Rarely, in older patients, pseudohypertension may be related to the inability to measure blood pressure accurately in severely sclerotic arteries. This condition is suggested if the radial pulse remains palpable despite occlusion of the brachial artery by the cuff (Osler maneuver). The actual blood pressure can be determined by direct intra-arterial measurement. Evaluation of patients with


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InternalMed_Harrison. remains palpable despite occlusion of the brachial artery by the cuff (Osler maneuver). The actual blood pressure can be determined by direct intra-arterial measurement. Evaluation of patients with resistant hypertension might include home blood pressure monitoring to determine if office blood pressures are representative of the usual blood pressure. A more extensive evaluation for a secondary form of hypertension should be undertaken if no other explanation for hypertension resistance becomes apparent.


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InternalMed_Harrison. Probably due to the widespread availability of antihypertensive therapy, in the United States there has been a decline in the numbers of patients presenting with “crisis levels” of blood pressure. Most patients who present with severe hypertension are chronically hypertensive, and in the absence of acute end organ damage, precipitous lowering of blood pressure may result in significant morbidity and should be avoided. The key to successful management of severe hypertension is to differentiate hypertensive crises from hypertensive urgencies. The degree of target organ damage, rather than the level of blood pressure alone, determines the rapidity with which blood pressure should be lowered. Tables 298-9 and 298-10 list a number of hypertension-related emergencies and recommended therapies.


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InternalMed_Harrison. Malignant hypertension is a syndrome associated with an abrupt increase of blood pressure in a patient with underlying hypertension or related to the sudden onset of hypertension in a previously normotensive individual. The absolute level of blood pressure is not as important as its rate of rise. Pathologically, the syndrome is associated with diffuse necrotizing vasculitis, arteriolar thrombi, and fibrin deposition in arteriolar walls. Fibrinoid necrosis has been observed in arterioles of kidney, brain, retina, and other organs. Clinically, the syndrome is recognized by progressive retinopathy (arteriolar spasm, hemorrhages, exudates, and papilledema), deteriorating renal function with proteinuria, microangiopathic hemolytic anemia, and encephalopathy. Historic inquiry should include questions about the use of monoamine oxidase inhibitors and recreational drugs (e.g., cocaine, amphetamines).


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InternalMed_Harrison. Although blood pressure should be lowered rapidly in patients with hypertensive encephalopathy, there are inherent risks of overly aggressive therapy. In hypertensive individuals, the upper and lower limits of autoregulation of cerebral blood flow are shifted to higher levels of arterial pressure, and rapid lowering of blood pressure to below the lower limit of autoregulation may precipitate cerebral ischemia or infarction as a consequence of decreased cerebral blood flow. Renal and coronary blood flows also may decrease with overly aggressive acute therapy. The initial goal of therapy is to reduce Hypertensive encephalopathy Nitroprusside, nicardipine, labetalol


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InternalMed_Harrison. Hypertensive encephalopathy Nitroprusside, nicardipine, labetalol Malignant hypertension (when IV Labetalol, nicardipine, nitroprusside, therapy is indicated) enalaprilat Stroke Nicardipine, labetalol, nitroprusside Myocardial infarction/unstable Nitroglycerin, nicardipine, labetalol, angina esmolol Acute left ventricular failure Nitroglycerin, enalaprilat, loop diuretics Aortic dissection Nitroprusside, esmolol, labetalol Adrenergic crisis Phentolamine, nitroprusside Postoperative hypertension Nitroglycerin, nitroprusside, labetalol, nicardipine Preeclampsia/eclampsia of Hydralazine, labetalol, nicardipine pregnancy Source: Adapted from DG Vidt, in S Oparil, MA Weber (eds): Hypertension, 2nd ed. Philadelphia, Elsevier Saunders, 2005. Nitroprusside Initial 0.3 (μg/kg)/min; usual 2–4 (μg/kg)/min; maximum 10 (μg/kg)/min for 10 min Nicardipine Initial 5 mg/h; titrate by 2.5 mg/h at 5–15 min intervals; max 15 mg/h


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InternalMed_Harrison. Nitroprusside Initial 0.3 (μg/kg)/min; usual 2–4 (μg/kg)/min; maximum 10 (μg/kg)/min for 10 min Nicardipine Initial 5 mg/h; titrate by 2.5 mg/h at 5–15 min intervals; max 15 mg/h Labetalol 2 mg/min up to 300 mg or 20 mg over 2 min, then 40–80 mg at 10-min intervals up to 300 Enalaprilat Usual 0.625–1.25 mg over 5 min every 6–8 h; maximum 5 mg/dose Esmolol Initial 80–500 μg/kg over 1 min, then 50–300 (μg/kg)/min Nitroglycerin Initial 5 μg/min, then titrate by 5 μg/min at 3–5-min intervals; if no response is seen at 20 μg/min, incremental increases of aConstant blood pressure monitoring is required. Start with the lowest dose. Subsequent doses and intervals of administration should be adjusted according to the blood pressure response and duration of action of the specific agent.


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InternalMed_Harrison. mean arterial blood pressure by no more than 25% within minutes to 2 h or to a blood pressure in the range of 160/100–110 mmHg. This may be accomplished with IV nitroprusside, a short-acting vasodilator with a rapid onset of action that allows for minute-to-minute control of blood pressure. Parenteral labetalol and nicardipine are also effective agents for the treatment of hypertensive encephalopathy. In patients with malignant hypertension without encephalopathy or another catastrophic event, it is preferable to reduce blood pressure over hours or longer rather than minutes. This goal may effectively be achieved initially with frequent dosing of short-acting oral agents such as captopril, clonidine, and labetalol.


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InternalMed_Harrison. Acute, transient blood pressure elevations that last days to weeks frequently occur after thrombotic and hemorrhagic strokes. Autoregulation of cerebral blood flow is impaired in ischemic cerebral tissue, and higher arterial pressures may be required to maintain cerebral blood flow. Although specific blood pressure targets have not been defined for patients with acute cerebrovascular events, aggressive reductions of blood pressure are to be avoided. With the increasing availability of improved methods for measuring cerebral blood flow (using CT technology), studies are in progress to evaluate the effects of different classes of antihypertensive agents on both blood pressure and cerebral blood flow after an acute stroke. Currently, in the absence of other indications for acute therapy, for patients with cerebral infarction who are not candidates for thrombolytic therapy, one recommended guideline is to institute antihypertensive therapy only for patients with a systolic blood pressure


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InternalMed_Harrison. patients with cerebral infarction who are not candidates for thrombolytic therapy, one recommended guideline is to institute antihypertensive therapy only for patients with a systolic blood pressure >220 mmHg or a diastolic blood pressure >130 mmHg. If thrombolytic therapy is to be used, the recommended goal blood pressure is <185 mmHg systolic pressure and <110 mmHg diastolic pressure. In patients with hemorrhagic stroke, suggested guidelines for initiating antihypertensive therapy are systolic >180 mmHg or diastolic pressure >130 mmHg. The management of hypertension after subarachnoid hemorrhage is controversial. Cautious reduction of blood pressure is indicated if mean arterial pressure is >130 mmHg.


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InternalMed_Harrison. In addition to pheochromocytoma, an adrenergic crisis due to catecholamine excess may be related to cocaine or amphetamine overdose, clonidine withdrawal, acute spinal cord injuries, and an interaction of tyramine-containing compounds with monoamine oxidase inhibitors. These patients may be treated with phentolamine or nitroprusside. Treatment of hypertension in patients with acute aortic dissection is discussed in Chap. 301, and treatment of hypertension in pregnancy is discussed in Chap. 8. Stephen C. Textor


InternalMed_Harrison

InternalMed_Harrison. Treatment of hypertension in patients with acute aortic dissection is discussed in Chap. 301, and treatment of hypertension in pregnancy is discussed in Chap. 8. Stephen C. Textor The renal vasculature is unusually complex with rich arteriolar flow to the cortex in excess of metabolic requirements, consistent with its primary function as a filtering organ. After delivering blood to cortical glomeruli, the postglomerular circulation supplies deeper medullary segments that support energy-dependent solute transport at multiple levels of the renal tubule. These postglomerular vessels carry less blood, and high oxygen consumption leaves the deeper medullary regions at the margin of hypoxemia. Vascular disorders that commonly threaten the blood supply of the kidney include large-vessel atherosclerosis, fibromuscular diseases, and embolic disorders. Microvascular injury, including inflammatory and primary hematologic disorders, is described in Chap. 341.


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InternalMed_Harrison. The glomerular capillary endothelium shares susceptibility to oxidative stress, pressure injury, and inflammation with other vascular territories. Rates of urinary albumin excretion (UAE) are predictive of systemic atherosclerotic disease events. Increased UAE may develop years before cardiovascular events. UAE and the risk of cardiovascular events are both reduced with pharmacologic therapy such as statins. Experimental studies demonstrate functional changes and rarefaction of renal microvessels under conditions of accelerated atherosclerosis and/or compromise of proximal perfusion pressures with large-vessel disease (Fig. 299-1).


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InternalMed_Harrison. Large-vessel renal artery occlusive disease can result from extrinsic compression of the vessel, fibromuscular dysplasia, or, most commonly, atherosclerotic disease. Any disorder that reduces perfusion pressure to the kidney can activate mechanisms that tend to restore renal pressures at the expense of developing systemic hypertension. Because restoration of perfusion pressures can reverse these pathways, renal artery stenosis is considered a specifically treatable “secondary” cause of hypertension.


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InternalMed_Harrison. Renal artery stenosis is common and often has only minor hemodynamic effects. Fibromuscular dysplasia (FMD) is reported in 3–5% of normal subjects presenting as potential kidney donors without hypertension. It may present clinically with hypertension in younger individuals (between age 15 and 50), most often women. FMD does not often threaten kidney function, but sometimes produces total occlusion and can be associated with renal artery aneurysms. Atherosclerotic renal artery stenosis (ARAS) is common in the general population (6.8% of a community-based sample above age 65), and the prevalence increases with age and for patients with other vascular conditions such as coronary artery disease (18–23%) and/or peripheral aortic or lower extremity disease (>30%). If untreated, ARAS progresses in nearly 50% of cases over a 5-year period, sometimes to total occlusion. Intensive treatment of arterial blood pressure and statin therapy appear to slow these rates and improve clinical outcomes.


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InternalMed_Harrison. Critical levels of stenosis lead to a reduction in perfusion pressure that activates the renin-angiotensin system, reduces sodium excretion, and activates sympathetic adrenergic pathways. These events lead to systemic hypertension characterized by angiotensin dependence in the early stages, widely varying pressures, loss of circadian blood pressure (BP) rhythms, and accelerated target organ injury, including left ventricular hypertrophy and renal fibrosis. Renovascular hypertension can be treated with agents that block the renin-angiotensin system and other drugs that modify these pressor pathways. It can also be treated with restoration of renal blood flow by either endovascular or surgical revascularization. Most patients require continued antihypertensive drug therapy because revascularization alone rarely lowers BP to normal.


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InternalMed_Harrison. ARAS and systemic hypertension tend to affect both the poststenotic and contralateral kidneys, reducing overall glomerular filtration rate (GFR) in ARAS. When kidney function is threatened by


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InternalMed_Harrison. FIGURE 299-1 Examples of micro-CT images from vessels defined by radiopaque casts injected into the renal vasculature. These illustrate the complex, dense cortical capillary network supplying the kidney cortex that can either proliferate or succumb to rarefaction under the influence of atherosclerosis and/or occlusive disease. Changes in blood supply are followed by tubulointerstitial fibrosis and loss of kidney function. MV, microvascular. (From LO Lerman, AR Chade: Curr Opin Nephrol Hyper 18:160, 2009, with permission.) large-vessel disease primarily, it has been labeled ischemic nephropathy. Moderately reduced blood flow that develops gradually is associated with reduced GFR and limited oxygen consumption with preserved tissue oxygenation. Hence, kidney function can remain stable during medical therapy, sometimes for years. With more advanced disease, reductions in cortical perfusion and frank tissue hypoxia develop. Unlike FMD, ARAS develops in patients with other risk factors for


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InternalMed_Harrison. medical therapy, sometimes for years. With more advanced disease, reductions in cortical perfusion and frank tissue hypoxia develop. Unlike FMD, ARAS develops in patients with other risk factors for atherosclerosis and is commonly superimposed upon preexisting small-vessel disease in the kidney resulting from hypertension, aging, and diabetes. Nearly 85% of patients considered for renal revascularization have stage 3–5 chronic kidney disease (CKD) with GFR below 60 mL/min per 1.73 m2. The presence of ARAS is a strong predictor of morbidityand mortality-related cardiovascular events, independent of whether renal revascularization is undertaken.


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InternalMed_Harrison. Diagnostic approaches to renal artery stenosis depend partly on the specific issues to be addressed. Noninvasive characterization of the renal vasculature may be achieved by several techniques, summarized in Table 299-1. Although activation of the renin-angiotensin system is a key step in developing renovascular hypertension, it is transient. Levels of renin activity are therefore subject to timing, the effects of drugs, and sodium intake, and do not reliably predict the response to vascular therapy. Renal artery velocities by Doppler ultrasound above 200 cm/s generally predict hemodynamically important lesions (above 60% vessel lumen occlusion), although treatment trials require velocity above 300 cm/s to avoid false positives. The renal resistive index has predictive value regarding the viability of the kidney. It remains operatorand institution-dependent, however. Captopril-enhanced renography has a strong negative predictive value when entirely normal. Magnetic resonance


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InternalMed_Harrison. the viability of the kidney. It remains operatorand institution-dependent, however. Captopril-enhanced renography has a strong negative predictive value when entirely normal. Magnetic resonance angiography (MRA) is now less often used, as gadolinium contrast has been associated with nephrogenic systemic fibrosis. Contrast-enhanced computed tomography (CT) with vascular reconstruction provides excellent vascular images and functional assessment, but carries a small risk of contrast toxicity.