APPROACH TO THE PATIENT: Hypertension HISTORY
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.
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 43-5 lists salient features that should be addressed in obtaining a history from a hypertensive patient. MEASUREMENT OF BLOOD PRESSURE
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 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.
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. PHYSICAL EXAMINATION
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 hypo- and 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 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 examination also should include evaluation for signs of CHF and a neurologic examination. LABORATORY TESTING
Table 43-6 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 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.
TREATMENT Hypertension LIFESTYLE INTERVENTIONS
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 overall healthy dietary pattern (Table 43-7).
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.
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 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 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. PHARMACOLOGIC THERAPY
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.
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 43-8). 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. 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 as treatment with a potent vasodilator, e.g., minoxidil.
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 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 lowering 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.
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.
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. 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. 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 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 may be less protective against cardiovascular and cerebrovascular endpoints, and some beta blockers may have less effect on central aortic pressure than other classes of antihypertensive agents. However, beta blockers remain appropriate therapy for hypertensive patients with concomitant heart disease and related comorbidities. Carvedilol and labetalol block both β receptors and peripheral α-adrenergic receptors. The potential advantages of combined β- and α-adrenergic blockade in treating hypertension remain to be determined. Nebivolol represents another class of cardioselective beta blockers that has additional vasodilator actions related to enhancement of nitric oxide activity. Whether this confers greater clinical effectiveness remains to be determined. α-Adrenergic Blockers
Postsynaptic, selective α-adrenoreceptor antagonists lower blood pressure by decreasing peripheral vascular resistance. They are effective antihypertensive agents used either as monotherapy or in combination with other agents. However, in clinical trials of hypertensive patients, alpha blockade has not been shown to reduce cardiovascular morbidity and mortality or to provide as much protection against CHF as other classes of antihypertensive agents. These agents are also effective in treating lower urinary tract symptoms in men with prostatic hypertrophy. Nonselective α-adrenoreceptor antagonists bind to postsynaptic and presynaptic receptors and are used primarily for the management of patients with pheochromocytoma. 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. 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. 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. COMPARISONS OF ANTIHYPERTENSIVES
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 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. Currently, in practical terms, the presence of comorbidities often 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 nondiabetic 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).
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 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 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 reductions in morbidity and mortality in the very elderly.
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.
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 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 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. BLOOD PRESSURE GOALS OF ANTIHYPERTENSIVE THERAPY
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 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 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-versus-benefit 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.
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.
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 difficult-to-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 43-3). 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 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. HYPERTENSIVE EMERGENCIES
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 43-9 and 43-10 list a number of hypertension-related emergencies and recommended therapies.
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).
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 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.
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 >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.
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. 46.