Chapter 2. Systemic Hypertension

• Prehypertension: systolic pressure of 120–139 mm Hg or diastolic pressure of 80–89 mm Hg.
• Stage 1 hypertension: systolic pressure of 140–159 mm Hg or diastolic pressure of 90–99 mm Hg.
• Stage 2 hypertension: systolic pressure of at least 160 mm Hg or diastolic pressure of at least 100 mm Hg.

Hypertension is a major public health problem in the United States and many countries worldwide. Prevalence of hypertension in the United States remains unchanged in the past decade at 30%, while prevalence of resistant hypertension (failure to achieve blood pressure [BP] control despite three or more medications) has almost doubled in recent years from 16% to 28%. When the risk is calculated over lifetime, the burden of hypertension in middle-aged men and women is enormous. Eight to nine out of 10 normotensive women or men over the age of 55 are expected to develop hypertension in the next 20 years. Thus, complete understanding of basic pathophysiologic mechanisms and treatment strategies is one crucial step in improving hypertension control.

Pathophysiology of primary hypertension is complex and heterogeneous. At least one or more of the mechanisms involved in BP regulation, such as vascular, neural, renal, and hormonal mechanisms, contribute to development of primary hypertension. Accordingly, therapy often requires more than one antihypertensive agent or approach to tackle hypertension in the majority of patients.

Systemic vascular resistance and cardiac output are two major determinants of BP. Thus, augmented peripheral vasoconstriction at the level of resistance vessels may lead to hypertension in the presence of normal cardiac output. More recently, large arterial stiffness has been shown to contribute to elevated systolic BP. In many epidemiologic studies, systolic BP increases with age both in men and women. However, after the fifth decade of life, systolic BP continues to increase while diastolic BP starts to fall, causing the pulse pressure to widen. Normally, elasticity of aorta helps absorb pressure during systole, and the elastic recoil of the aorta helps maintain BP during diastole. The loss of aortic elasticity causes BP to rise excessively during systole and decrease markedly during diastole. Furthermore, the aortic pulse wave travels at much faster speed in the stiff artery, and the reflected wave from the peripheral sites further amplifies the systolic BP in the central aorta. Although diastolic BP is traditionally thought to be the most important predictor of cardiovascular risk, it is an important risk factor only for the younger population. For hypertensive patients above the age of 60, systolic BP and pulse pressures are much more important in predicting long-term cardiovascular outcomes.

Neural control of BP also plays an important role in development of hypertension. Overactivity of the sympathetic nervous system has been identified in patients with uncomplicated essential hypertension, and many conditions predispose to hypertension such as obesity, renal failure, and obstructive sleep apnea. Sympathetic overactivity contributes to hypertension by stimulating increase in cardiac output while producing peripheral vasoconstriction. Activation of β1-adrenergic receptor by norepinephrine released from the sympathetic nerve terminals further increases BP by increasing renin release, causing renal sodium retention. The major hormones that contribute to hypertension include the renin-angiotensin-aldosterone system (RAAS), which will be discussed later in the section on secondary causes of hypertension. Although RAAS triggers hypertension by promoting renal sodium absorption, a large body of evidence from animal experiments suggests that its direct action on the vascular system and the central nervous system further augments hypertension.

BP Measurement

Proper BP measurement is essential in the diagnosis and treatment of hypertension. BP monitoring should be done both at home and in the clinic.

Clinic BP

In the clinical setting, BP measurement should be performed after patients are sitting quietly for at least 5 minutes with the arm supported at the heart level. The bladder of the cuff should encircle > 80% of the arm, and the width should be about 40% of the arm length. Medical personnel who perform the measurement should avoid talking to the patients during BP measurement because mental stimulation may inadvertently increase BP up to 10–15 mm Hg. Cuff should be inflated 20 mm Hg above systolic BP before deflation, and a minimum of two readings should be obtained at an interval of at least 1 minute. If BP differs by more than 5 mm Hg between the two readings, an additional one or two readings should be taken. During the initial visit, BP should be taken from both arms to exclude subtle stenosis in the subclavian or brachial artery, which could lead to underestimation of actual BP and undertreatment of hypertension. In patients with early onset of hypertension prior to the age of 40, BP should also be obtained from at least one leg to screen for aortic coarctation. In elderly patients and patients with diabetes mellitus or other conditions that predispose to autonomic failure such as Parkinson disease, BP should also be taken after 3 minutes of standing to exclude presence of orthostatic hypotension.

Home and Ambulatory BP Monitoring

Home BP measurement should be encouraged in all hypertensive patients to guide treatment because 20–40% of hypertensive subjects have elevated clinic BP with normal BP outside the doctor's office. This phenomenon, known as the white-coat effect (WCE), is more common in older patients, particularly in women with isolated systolic hypertension or diabetes. Accordingly, when home and clinic BP readings provide contradictory results, ambulatory BP monitoring should be considered to verify adequacy of BP control.

It is important to recognize that WCE is not the same as white-coat hypertension (WCH), because the latter is only limited to elevated office BP with normal awake ambulatory BP without any antihypertensive treatment. WCH is not associated with increased cardiovascular risks when compared to the population with normal BP both at home and in the clinic. In contrast, hypertensive patients with WCE during drug treatment experience increased cardiovascular events compared to untreated normotensive controls, but at the same risk observed in patients who achieve BP control both in the clinic and out of office with treatment (ie, treated normalized hypertension).

More recently, another subset of hypertensive patients with clinic BP under 140/90 mm Hg but who have elevated out-of-office BP has been recognized. This condition, termed masked hypertension, has been identified in 20–45% of patients with hypertension. Interestingly, patients with masked hypertension experience increased cardiovascular complications similar to patients with sustained hypertension. Whether treatment of masked hypertension will improve cardiovascular outcomes remains unknown.

Symptoms & Signs

Hypertension is well known as a silent killer because the majority of patients remain asymptomatic until development of target organ damage. However, some patients may have symptoms that could be related to a secondary cause of hypertension. Snoring and daytime somnolence may signify presence of obstructive sleep apnea, whereas episodes of palpitation and paroxysmal hypertension may suggest pheochromocytoma. Presence of muscle weakness, polyuria, and polydipsia might be related to hypokalemia from primary aldosteronism or hypercortisolism. Other symptoms of target organ damage and other coronary risk factors should be assessed because they help to define BP threshold for treatment of hypertension. History taking should also include the onset of hypertension and prior antihypertensive treatment as well as history of side effects from previous medications. The concomitant use of other prescription or nonprescription drugs, such as herbal products, nonsteroidal anti-inflammatory drugs, or decongestant use, which can directly increase BP or interfere with efficacy of antihypertensive medications, should be obtained. In young premenopausal women, method of contraception should be documented because certain antihypertensive medications, such as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, are teratogenic or fetotoxic. Furthermore, oral contraceptives could cause hypertension in a small number of patients, although the absolute risk is lower than 0.1% with low-dose estrogen preparation. Detailed family history with specific attention to both hypertension and stroke should be obtained because early stroke could be a presenting feature in certain genetic forms of hypertension.

High sodium intake is also a major contributor for uncontrolled hypertension, and detailed dietary assessment should be obtained in patients who fail to achieve BP goals despite multiple medications. Nonadherence to medications is the major cause of apparently resistant hypertension and should be considered in patients on a complex multidrug regimen. Questions related to adherence should not be asked in the manner that sounds judgmental or critical to the patients; otherwise, accurate assessment may not be obtained. Instead of asking, “Do you take medications regularly as the doctors prescribe?”, asking patients if they feel that taking multiple medications is difficult or if they have forgotten to take medications in the past 7 days is more likely to uncover a history of nonadherence.

Physical Examination

Physical examination should focus on signs of target organ damage such as presence of volume overload, laterally displaced apical impulses, S3 and/or S4 gallops, and hypertensive retinopathy. Particular attention should be paid to physical signs that may indicate underlying secondary hypertension. Abdominal bruit may indicate presence of renal artery stenosis. Truncal obesity, dorsocervical fat pads, hirsutism, and abdominal striae may represent cortisol excess. BP gradient between arms and legs and femoral-radial pulse delay may signify coarctation of aorta.

Diagnostic Studies

For patients with mild uncomplicated hypertension, serum electrolytes, urinalysis, and complete blood cell count should be obtained during the initial visit to assess renal function and exclude subtle target organ damage. Electrocardiogram should be obtained to screen for left ventricular hypertrophy and presence of conduction system disturbances, which may prohibit the use of β-blockers or nondihydropyridine calcium channel blockers. Echocardiography should be limited to patients with symptoms and signs of congestive heart failure or patients with syncope to exclude presence of dynamic left ventricular outflow tract obstruction, which has been identified in a subset of hypertensive patients with concentric left ventricular hypertrophy. Fasting lipid panel and plasma glucose should also be obtained to assess overall cardiovascular risks. Microalbuminuria should be tested in diabetic patients and patients with severe hypertension.

In the majority of patients with hypertension, specific etiology cannot be identified, and patients are often labeled as having essential or primary hypertension. However, in approximately 5% of unselected patients with hypertension and 10–20% of all resistant hypertensive cases, causes of hypertension are identifiable and/or potentially reversible. Screening for secondary causes of hypertension is not indicated in every patient with hypertension. Indications for additional workup are as follows:

• Abrupt onset after the age of 55 or before the age of 30
• Accelerated or malignant hypertension with grade 3–4 retinopathy
• Previously, but not presently, controlled
• Poorly controlled hypertension on three or more drugs
• Recurrent flash pulmonary edema
• Hypertension with unexplained renal insufficiency
• Suspected clinical features of secondary causes such as hypokalemia, renal bruits, and truncal obesity

Common secondary causes of resistant hypertension include obstructive sleep apnea, primary aldosteronism, renal parenchymal diseases, and renal artery stenosis. Pheochromocytoma and other endocrine disorders are much less common causes of resistant hypertension.

Obstructive Sleep Apnea

Obstructive sleep apnea (OSA) is a well-established independent risk factor for development of hypertension. Because the majority of the population in the United States is overweight or obese, OSA is now a common condition, affecting 10–20% of the population in the United States. Prevalence of OSA in drug-resistant hypertension is much greater, as high as 83% in some studies. Activation of the sympathetic nervous system via activation of chemoreceptor via repetitive hypoxia and hypercapnia is thought to play an important role in the pathogenesis of hypertension. Patients with a history of loud snoring, insomnia, and/or daytime fatigue should undergo polysomnography. Treatment with continuous positive airway pressure (CPAP) has been shown to reduce BP in hypertensive patients with OSA. However, long-term compliance is very poor; less than 50% of patients still continue to use CPAP after 6 months. Therefore, target BP is rarely achieved with CPAP alone, and further adjustment of antihypertensive medications is often needed to reach target goals.

Primary Aldosteronism

Aldosterone excess, either from idiopathic bilateral adrenal hyperplasia or aldosterone-producing adenoma, is a common cause of resistant hypertension. Primary aldosteronism (PA) has been identified in 5–10% of unselected patients with hypertension in the primary care setting and up to 20% of patients with resistant hypertension referred to a hypertension clinic or a tertiary care center. Aldosterone induces hypertension not only by increasing renal sodium retention, but also by activation of the sympathetic nervous system. Patients with hyperaldosteronism experienced higher cardiovascular event rates than those with essential hypertension, which is out of proportion to the degree of BP elevation. This is likely to be related to direct cardiovascular toxicity of aldosterone. To screen for PA, plasma renin activity (PRA) or levels and serum aldosterone levels should be obtained. However, the screening test should be performed after discontinuation of thiazide diuretics, direct renin inhibitors, angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs) for 2–3 weeks and discontinuation of aldosterone antagonists for at least 6 weeks. During the workup period, patients need to be on other antihypertensive agents such as α-blockers or calcium channel blockers. If needed, addition of β-blockers or central sympatholytic drugs may be added, but this may potentially reduce PRA. Patients who are found to have suppressed renin levels or activity in the presence of elevated serum aldosterone levels of 15 ng/dL or greater should undergo a salt loading test or be referred to hypertension specialists. Patients who have insuppressible aldosterone levels after salt loading should undergo adrenal vein sampling because imaging of adrenal glands is not reliable in separating patients with idiopathic hyperplasia from those with aldosterone-producing adenoma. Treatment includes surgical resection of tumor for patients with aldosterone-producing adenoma, which can cure hypertension in 20–60% of patients, depending on duration of hypertension and presence of target organ complications. Mineralocorticoid receptor antagonists (spironolactone or eplerenone) should be used in patients with bilateral hyperplasia or patients with unilateral adenoma in whom surgical risks are prohibitive.

Renal Parenchymal Disease

Renal parenchymal disease could be a cause or a consequence of hypertension. Hypertension is very common in chronic kidney disease (CKD) but is much more difficult to control. Despite requirement for larger numbers of antihypertensive medications, the hypertension control rate in the United States in CKD patients is less than 30% compared with 50% in non-CKD patients. Hypertension related to renal parenchymal disease has traditionally been viewed as being largely volume dependent, due to the failing kidney's inability to excrete salt and water. However, increased systemic vascular resistance from overactivation of the sympathetic nervous system has also been identified in the majority of patients.

Renovascular Hypertension

Renovascular hypertension is another common cause of secondary hypertension, accounting for 5–7% of hypertension in patients over the age of 60. Atherosclerosis is the major form of renal artery pathology in the elderly, as fibromuscular dysplasia is seen predominantly in young adults. Screening for renovascular hypertension should be considered in patients with (1) onset of hypertension at < 30 years of age or abrupt onset of hypertension after 55 years of age; (2) accelerated or malignant hypertension; (3) unexplained atrophic kidney or size discrepancy of more than 1.5 cm between each kidney; (4) sudden, unexplained pulmonary edema; (5) unexplained renal dysfunction, including individuals starting renal replacement therapy; and (6) development of new azotemia or worsening renal function after administration of an ACEI or ARB. Imaging of renal arteries with computed tomography (CT) angiography or magnetic resonance angiography should also be obtained in patients with suspected renal artery stenosis. Unfortunately, no currently available invasive or noninvasive studies are sufficiently sensitive or specific in assessing functional significance of a given stenotic lesion or in predicting BP pressure control after revascularization. Renal artery revascularization leads to significant and sustained reduction in BP in patients with fibromuscular dysplasia, but effects on BP control in patients with atherosclerotic renal artery stenosis are much less consistent. Therefore, revascularization should be considered in most patients with fibromuscular dysplasia and selected patients with atherosclerotic renal artery stenosis plus one or more of the following features: (1) bilateral disease or stenosis of the unilateral functioning kidney; (2) rapid decline in renal function; (3) resistant hypertension despite three or more antihypertensive medications; or (4) recurrent pulmonary edema.

Pheochromocytoma

Although a screening test for pheochromocytoma is often done in patients with labile hypertension or resistant hypertension, it accounts for < 1% of patients with unselected hypertension. Patients may present with paroxysmal hypertension, palpitation from sinus tachycardia or supraventricular arrhythmia, and panic/anxiety sensation from catecholamine excess. Myocardial infarction, congestive heart failure, and Takotsubo-like cardiomyopathy may be the presenting symptoms, along with hypertension in some patients. Diagnosis requires demonstration of elevated plasma/urinary metanephrines (metanephrine and/or normetanephrine) above 3–4 times the upper limit of normal without other identifiable causes. Patients with paraganglioma or extra-adrenal tumor may have isolated elevation in plasma dopamine, and thus, a plasma catecholamines panel (epinephrine, norepinephrine, and dopamine) should be obtained in patients with suspected pheochromocytoma in the absence of adrenal mass. Borderline elevation in plasma metanephrines or catecholamines is common in hypertensive patients with underlying conditions that cause sympathetic overactivity such as OSA, congestive heart failure, or CKD. These levels may return to normal after correction of the underlying problems. A clonidine suppression test should be obtained in patients with persistent but borderline (less than twofold) elevation in plasma metanephrines or catecholamines to confirm diagnosis. CT or magnetic resonance imaging (MRI) of the abdomen should be used to localize tumor after biochemical confirmation. Metaiodobenzylguanidine scan should be used when CT or MRI fails to reveal tumor.

Lifestyle Modification

Lifestyle modifications include sodium restriction to less than 1.5–2 g/day. The major source of sodium consumed in the United States comes from processed food including bread and rolls, pasta, cured meat, and snacks. Table salt contributes to only 20% of total sodium consumed. Avoiding table salt alone will not be an effective strategy in limiting sodium intake, and educating patients to read nutritional label is a key to success. A diet rich in fruits and vegetables also reduces BP independent of sodium content.

Pharmacologic Intervention

Antihypertensive treatment should be initiated in patients with stage 1 uncomplicated hypertension who fail a trial of lifestyle modification alone. Pharmacologic intervention should be offered promptly without any delay for patients with stage 2 hypertension or those with stage 1 hypertension in the presence of target organ complication, diabetes mellitus, renal failure, or high cardiovascular risks in conjunction with lifestyle modification. The list of antihypertensive drugs available in the United States is shown in Table 2–1.

Diuretics

Thiazide diuretics are considered to be the first-line drug therapy for hypertension according to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure guidelines due to their efficacy in reducing BP and low cost. Thiazide diuretics promote natriuresis by inhibiting sodium chloride cotransport at the distal convoluted tubule. Among thiazide diuretics, chlorthalidone has the longest half-life of between 40 and 60 hours compared to 8–15 hours for hydrochlorothiazide. Head-to-head comparison studies showed that chlorthalidone is at least two times more potent than hydrochlorothiazide in reducing BP. Thiazide diuretics are known to cause a number of metabolic side effects such as hypokalemia, elevated uric acid, increased fasting triglyceride, and, most importantly, increased risk of diabetes mellitus. Thiazide-induced dysglycemia or insulin resistance is mediated both by hypokalemia and potassium-independent mechanisms, which can be minimized by concomitant administration of the mineralocorticoid receptor antagonist spironolactone and, to a lesser extent, by ACEIs or ARBs.

Loop diuretics promote diuresis by inhibiting Na+/K+/Cl– cotransport at the thick ascending limb of Henle's loop. Although loop diuretics are more potent as diuretic agents than thiazide diuretics, the short half-life limits their efficacy in reducing BP. Furosemide has a half-life of only 1.5–2.5 hours and should be given every 6 hours to have sustained effects on BP; hence the name “Lasix.” Thus, it is not recommended for treatment of hypertensive patients with normal renal function. However, it is useful for patients with fluid retention from congestive heart failure, renal failure, or nephrotic syndrome. Among loop diuretics, furosemide has the least predictable absorption, whereas torsemide has the longest half-life.

Mineralocorticoid receptor (MR) antagonists, such as spironolactone and eplerenone, are known to reduce BP by inhibiting MR-dependent activation of the epithelial sodium channel in the cortical collecting duct. Furthermore, inhibition of the sympathetic nervous system and improvement in vascular endothelial function are thought to contribute to the BP-lowering effects of this class of drugs. MR antagonists are effective in lowering BP when either used alone or as add-on therapy for resistant hypertension despite use of three or more drugs. On a milligram-to-milligram basis, eplerenone is less potent than spironolactone in reducing BP in both patients with primary hypertension and PA, and thus, at least a twofold higher dose is often required to achieve BP control. However, spironolactone carries antiandrogenic side effects, including gynecomastia and testicular atrophy, and long-term use at the dose of more than 25 mg/day should be avoided in men. In these patients, the use of eplerenone, which has more than 100-fold lower affinity to androgen receptors than MRs, is preferable. Hyperkalemia is the main side effect of both agents, and serum potassium should be closely monitored in patients with CKD, diabetic patients with hyporeninemic hypoaldosteronism, or those on concomitant treatment with ACEIs, ARBs, or nonsteroidal anti-inflammatory agents. MR antagonists have been shown to reduce mortality in patients with systolic heart failure even with mild symptoms, and they should be considered in treatment of hypertension in patients with impaired ventricular function.

In addition to MR antagonists, direct inhibitors of the epithelial sodium channels (ENaCs), such as amiloride and triamterene, are also effective in lowering BP in patients with low renin essential hypertension. They are particularly useful in patients with gain-in-function mutation in the ENaC, causing excessive renal sodium absorption and renal K wasting, known as Liddle syndrome. Amiloride is also useful in patients with primary aldosteronism who cannot tolerate MR antagonists. Both amiloride and triamterene are often used in a combination pill formulation with hydrochlorothiazide (see Table 2–1).

ACEIs

ACEIs reduce BP by inhibiting conversion of angiotensin (Ang) I to potent vasoconstrictor Ang II. ACEIs also prevent degradation of the vasodilator bradykinin, which further contributes to BP reduction. ACEIs are particularly effective in reducing BP in younger patients and Caucasians and tend to be less effective in the setting of the low renin form of hypertension frequently observed in the elderly and black populations. However, the combination of ACEIs with diuretics eliminates racial and age differences in BP response to ACEIs. In addition to BP reduction, ACEIs reduce mortality in patients with congestive heart failure and improve cardiovascular outcomes in high-risk hypertensive patients without heart failure. ACEIs also slow the decline in renal function in patients with diabetic and nondiabetic kidney disease. Thus, they should be used in hypertensive patients with these comorbid conditions. The main side effects of this class of drugs are cough and angioedema from presumably excessive bradykinin accumulation. Hyperkalemia is another side effect, which may limit its use in some patients with severe CKD or bilateral renal artery stenosis.

ARBs

ARBs reduce BP by blocking the vasoconstrictor effects of Ang II on angiotensin receptor subtype 1 (AT1R) in the vascular smooth muscle. This class of drugs has remarkably minimal side effects and is generally well tolerated. It avoids side effects of cough and angioedema associated with ACEIs. In placebo-controlled clinical trials, ARBs reduced mortality in patients with systolic heart failure who were intolerant to ACEIs and offered renal protection in patients with diabetic nephropathy. Thus, they should be considered as part of regimen in hypertensive patients with these clinical features. The combination of ARBs with maximal doses of ACEIs usually yields minimal additional BP reduction and is generally not helpful in improving cardiovascular mortality. Although combination therapy offers synergistic or additive effect in reducing proteinuria, dual renin-angiotensin system blockade is associated with more renal dysfunction than either class of drugs alone. Therefore, it is not recommended as a strategy to control BP in hypertensive patients and should be reserved only for patients with proteinuria from primary renal disease such as immunoglobulin A nephropathy.

Calcium Channel Blockers (CCBs)

CCBs are divided into two major classes: the dihydropyridine (DHP) and nondihydropyridine (non-DHP) CCBs. DHP CCBs include amlodipine, felodipine, nisoldipine, and nicardipine and cause peripheral vasodilation with minimal effects on the heart rate or myocardial contractility. In contrast, non-DHP CCBs (diltiazem and verapamil) exert negative inotropic and chronotropic effects. Non-DHP CCBs are contraindicated in patients with systolic heart failure because of increased cardiovascular mortality and should be avoided in patients with symptomatic bradyarrhythmias or advanced heart block. DHP CCBs have neutral effect on survival in congestive heart failure and may be considered if BP remains elevated despite ACEIs or ARBs in systolic heart failure. All CCBs increase myocardial blood flow and are antianginal. Meta-analysis of clinical trials showed that CCBs are more effective than ACEIs in preventing stroke beyond BP reduction, but less effective than ACEIs and ARBs in preventing coronary heart disease or heart failure. DHP CCBs preferentially dilate afferent arterioles, causing increase in intraglomerular hypertension and are not as effective as ACEIs or ARBs in preventing decline in renal function in diabetic or nondiabetic kidney diseases. Therefore, they should not be used without RAAS blockade in hypertensive patients with CKD.

β-Adrenergic Receptor Blockers (BBs)

BBs reduce BP by decreasing heart rate and myocardial contractility, leading to decreased cardiac output at least initially via inhibition of β1-adrenergic receptor (AR). Inhibition of renin release from the juxtaglomerular cells via β1-AR and reduction of norepinephrine release from sympathetic nerve terminals via inhibition of presynaptic β2-AR also contribute to BP reduction. BBs are divided into two major classes: selective (β1-specific) and nonselective (β1- and β2-AR blockers), as shown in Table 2–2. Activation of β2-AR leads to peripheral vasodilation and bronchodilation. Thus, nonselective BBs should not be used in patients with asthma or in the setting of sympathetic overactivity, such as clonidine withdrawal or cocaine intoxication because of unopposed α-AR–mediated vasoconstriction. However, selectivity to β1 versus β2 is dose-dependent and not an all-or-none phenomenon. At higher doses, even selective BBs such as metoprolol, bisoprolol, atenolol, or esmolol may cause bronchospasm and should be used with caution. Certain BBs exert direct vasodilating effects, which enhance antihypertensive efficacy independent of β-AR blockade. For example, labetalol and carvedilol exert α-AR–blocking properties, whereas nebivolol promotes nitric oxide release and possesses antioxidant properties. Although BBs reduce mortality in patients with systolic heart failure and myocardial infarction, older generation BBs, particularly atenolol, are not as effective as other classes of drugs in preventing stroke or all-cause mortality in hypertensive patients with cardiovascular diseases. Thus, atenolol should not be used as initial therapy in patients with uncomplicated essential hypertension, particularly in patients with low renin hypertension, elderly patients, or African Americans.

α-AR Blockers

α-AR blockers exert antihypertensive effect by inhibiting postsynaptic α1-ARs in the vascular smooth muscle. α-AR blockers that selectively inhibit α1-AR antagonists include prazosin, terazosin, and doxazosin, whereas the nonselective blockers, which inhibit both α1- and α2-ARs, include phentolamine and phenoxybenzamine. Side effects of α-blockers are orthostatic hypotension, nasal congestion, and volume expansion. Nonselective α-blockers tend to cause more tachycardia because of inhibition of presynaptic α2-ARs, which normally exert inhibitory influence on norepinephrine release from sympathetic nerve terminals. α-Blockers should not be used as first-line therapy for hypertension because of increased risk of congestive heart failure. However, they are useful as an adjunctive treatment as the fourth- or fifth-line agent when BP fails to reach target goal. They should be considered as the first line of treatment in the setting of pheochromocytoma and are also useful in patients with hypertension related to cocaine intoxication or conditions associated with sympathetic overactivity such as drug or alcohol withdrawal.

Central Sympatholytic Drugs

Central sympatholytic drugs reduce BP mainly by stimulating presynaptic α2-ARs in the brainstem centers and sympathetic nerve terminals, thereby inhibiting sympathetic nerve discharge and neuronal release of norepinephrine to the heart and peripheral circulation. Drugs in this class include methyldopa, clonidine, guanfacine, and guanabenz. Moxonidine and rilmenidine are also centrally acting drugs used in England and other European countries but are not available in the United States. α-Methyldopa is converted to α-methylnorepinephrine to activate central α2-ARs in the brainstem, whereas clonidine, guanfacine, and guanabenz are direct α2-AR agonists. In contrast, moxonidine and rilmenidine predominantly reduce sympathetic nerve activity and BP by stimulating the imidazoline-1 (I1) receptor, rather than α2-AR. Because of several major side effects, including fatigue, sedation, and dry mouth, as well as lack of clear-cut cardiovascular benefit, these drugs should be used as fourth-line drug therapy for hypertension. Central sympatholytic drug use should be avoided in patients who are nonadherent to treatment because of precipitation of withdrawal symptoms upon abrupt drug discontinuation. Their use on an as-needed basis for treatment of episodes of asymptomatic BP surge in patients who are not on regular dosing of central α2-AR agonists should also be discouraged due to rebound hypertension.

Direct Renin Inhibitors (DRIs)

DRIs block catalytic action of circulating renin, thereby preventing formation of Ang I from angiotensinogen. DRIs also inhibit activity of the proenzyme prorenin, which can also cleave angiotensinogen into Ang I upon binding to the prorenin receptors. Inhibitory action of DRIs on renin and prorenin activity results in decreased production of Ang II and BP. Aliskiren is the only drug approved for clinical use in this class so far. Addition of aliskiren to ARBs reduces proteinuria in hypertensive patients with type 2 diabetes mellitus when compared to placebo. However, addition of aliskiren to ARBs or ACEIs is not more effective in reducing left ventricular (LV) mass in hypertensive patients or improving LV remodeling in patients after myocardial infarction than monotherapy with ARBs or ACEIs alone. Furthermore, a recent clinical trial showed that addition of aliskiren to ACEIs or ARBs in patients with diabetes mellitus and established cardiovascular disease failed to improve cardiovascular outcomes and even increased the risk of nonfatal stroke. Thus, the future role of DRIs in the treatment of hypertension is likely to be limited.

Direct Vasodilators

Hydralazine and minoxidil are the two main drugs in this class, which reduce BP by dilating resistant arterioles with minimal or no effect on the venous circulation. Hydralazine has short plasma half-life of 90 minutes, but its antihypertensive action lasts much longer than its plasma level. Thus, for the ease of administration, hydralazine should be given twice daily in hypertensive patients rather than three times a day, which is the schedule typically used in patients with heart failure. Side effects of hydralazine include lupus-like syndrome, particularly at the higher doses, reflex tachycardia, nausea, vomiting, and diarrhea. Minoxidil promotes vasodilation by activating adenosine triphosphate–sensitive potassium channels in the vascular smooth muscle. Similar to hydralazine, minoxidil-induced BP reduction is usually accompanied by reflex tachycardia and palpitation, and the addition of BBs is often needed to mitigate these side effects. Peripheral edema and volume expansion frequently occur, requiring concomitant diuretic treatment. Less common side effects include hirsutism and pericardial effusion.

Oral nitrates are nitric oxide donors, which produce venodilating effects at low doses and arterial vasodilating effects at higher doses. Although the benefits of nitrates as antianginal drugs are well validated, very few studies have addressed their efficacy as antihypertensive agents. In one small study, isosorbide mononitrate reduced systolic BP in elderly patients with resistant systolic hypertension without affecting diastolic BP. It is unknown whether these data can be extrapolated to other age groups with combined systolic-diastolic hypertension. Headache is the main side effect, and nitrate tolerance is the main limiting factor for long-term use.

Management of Uncomplicated Hypertension

In most patients, the goal BP should be < 140/90 mm Hg. Tight control of systolic BP below 120 mm Hg does not reduce cardiovascular death, but reduces the risk of stroke by 40% in patients with diabetes mellitus. Higher systolic BPs (< 150 mm Hg) may be more appropriate for patients > 80 years of age and patients with class 4 or greater CKD. In patients with mild uncomplicated hypertension, thiazide-type diuretics should be considered in patients who have a tendency to be salt sensitive, such as older patients and black patients. For younger patients, ACEIs, ARBs, and CCBs may be more suitable. The use of BBs, particularly older generation BBs such as atenolol, should be avoided in young patients with active lifestyle due to fatiguing side effects and modest efficacy in improving cardiovascular outcomes. BBs are more suitable for patients with compelling indication such as coronary artery disease or congestive heart failure. Treatment of hypertension is also beneficial in elderly patients even > 80 years old in terms of reducing stroke and cardiovascular mortality. In these patients, chlorthalidone or DHP CCB such as amlodipine should be part of the regimen given the proven benefit in reducing stroke and adverse cardiovascular events, particularly in patients with isolated systolic hypertension.

For patients with BP at least 20/10 mm Hg above the goal, the use of combination therapy is preferred over monotherapy to avoid side effects related to the use of a single agent at the high dose that is often needed to control BP. In patients with high cardiovascular risks, the combination of an ACEI and DHP CCB is superior for reducing adverse cardiovascular outcomes than the combination of an ACEI with thiazide-type diuretics. Thus, the addition of DHP CCBs should be considered in such patients whose BP reduction is not adequate with ACEIs alone.

Management of Hypertensive Crisis

Hypertensive crisis is a common condition encountered in the emergency department that can be classified as hypertensive emergency or hypertensive urgency. Hypertensive emergency is defined severe elevation in BP (often > 180/120 mm Hg) in the presence of acute target organ damage involving heart, brain, kidneys, or vascular system. Hypertensive urgency is defined as severe hypertension associated with symptoms, such as headache or chest pain, in the absence of any objective evidence of acute target organ damage. Thus, distinction between hypertensive emergency versus urgency is dependent of clinical presentation rather than severity of hypertension alone.

Once patients are identified to have hypertensive crisis, choice of therapy and rapidity of BP reduction are dependent on clinical presentation. In normotensive subjects, cerebral blood flow is maintained at a constant level despite variation in mean arterial BP between 60 and 120 mm Hg by a process known as cerebral autoregulation. At the lower end of this range, cerebral vessels dilate to maintain normal perfusion. Only when the mean BP is lower than 50–60 mm Hg, cerebral perfusion becomes pressure-dependent. Similarly, when BP rises to a higher level, myogenic vasoconstriction of the resistant arterioles prevents excessive increase in blood flow and cerebral edema. Patients with well-controlled hypertension have autoregulatory adjustment at the normal BP range similar to normotensives. However, in patients with severe hypertension, this BP range is shifted to the right between 110 and 180 mm Hg (Figure 2–1). Thus, BP lowering in patients with hypertensive encephalopathy should done cautiously by aiming for reduction by 20–25% in the first few hours but not below 140/90 mm Hg (mean BP around 107 mm Hg) in the first 24 hours. Patients with hypertensive urgency could be treated with oral antihypertensive medications in the emergency department and discharged home with close follow-up for titration of BP medications within a few days. Rapid normalization of BP with oral agents in the doctor's office or emergency department in patients with asymptomatic severe hypertension without any target organ damage may provoke hypoperfusion of the vital organs, such as brain and kidneys, and should be avoided.

In contrast to hypertensive encephalopathy, BP should be reduced to < 120/80 mm Hg as soon as possible in patients with hypertensive emergency in the setting of aortic dissection because delay in BP reduction may cause the dissection plane and false lumen to expand, which may jeopardize blood flow to the vital organs. Patients with acute pulmonary edema and acute coronary syndrome should also have more rapid BP reduction to less than 140/90 mm Hg as soon as possible to decrease LV wall stress, a major determinant of myocardial oxygen demand. Thrombolytic therapy should not be given in patients with ST elevation myocardial infarction until BP is reduced below 180/110 mm Hg to avoid the risk of intracranial hemorrhage. Patients who present with primary intracranial hemorrhage pose a challenge in management because cerebral perfusion pressure is determined both by systemic BP and intracranial pressure. Similarly, for patients with ischemic stroke, rigorous reduction in BP could further compromise the flow to the infarct area and, more importantly, the border zone. More conservative reduction in BP with the goal for BP reduction of approximately 15% within the first hour is generally recommended in these two neurologic emergencies. Treatment of hypertensive emergency in specific clinical settings is summarized in Table 2–3.

Selection of antihypertensive agents in hypertensive emergency also depends on the clinical presentation (Table 2–4). Patients with hypertensive encephalopathy or ischemic stroke should be treated with labetalol, nitroprusside, or nicardipine. Nitroprusside and nitroglycerin should be avoided in patients with intracranial hemorrhage because they may increase intracranial pressure. Phentolamine should be considered in patients with pheochromocytoma or adrenergic crisis such as cocaine intoxication. However, this drug may not be available in many countries, including the United States, on a regular basis. Nicardipine is an alternative therapy for pheochromocytoma. Labetalol, although effective in reversing cocaine-induced increase in BP, should be used with caution in pheochromocytoma because it is still a predominant BB (β-AR to α-AR blockade ratio of 4:1) and may precipitate an unopposed α-AR–mediated vasoconstriction. Nitroprusside is a potent vasodilator but should be used with caution in patients with renal failure given its propensity to cause cyanide toxicity. Nitroglycerin is suitable for use in patients with acute pulmonary edema and acute coronary syndrome because of its antianginal property and ability to relieve pulmonary congestion. Nitrate tolerance may develop quickly with continuous infusion and limit its antihypertensive efficacy. Fenoldopam is a dopamine D1-like receptor agonist, which reduces BP by promoting peripheral vasodilation. Clevidipine is a newer CCB available in intravenous form with shorter half-life (1 minute) than nicardipine (30–40 minutes). The relatively high cost of these newer agents limits routine use in clinical practice.

Management of Resistant Hypertension

Resistant hypertension is defined as failure to achieve BP target goal despite three or more drugs, one of which should be a diuretic. The first simple step in managing resistant hypertension, after excluding WCE, nonadherence to medications, and secondary hypertension, is to determine whether patients are on an appropriate class of diuretics based on renal function. Patients with estimated glomerular filtration rate (eGFR) > 50 mL/min/1.73 m2 should be treated with thiazide diuretics, particularly chlorthalidone, rather than loop diuretics because of longer half-life and proven efficacy in lowering BP. Patients with an eGFR of 30–40 mL/min/1.73 m2 or less should be on loop diuretics because the ability of thiazide diuretics to promote diuresis diminishes with impaired renal function. The use of an appropriate drug combination that provides synergistic effect on BP could minimize the number of medications needed to control hypertension. Assessment of hemodynamic variables is also helpful in deciding appropriate drug combination. For example, the use of BBs and a central sympatholytic drug generally yields minimal incremental benefit and is prohibited in patients with bradycardia or heart block. These patients should be treated with vasodilators such as DHP CCBs, ACEIs, ARBs, or hydralazine (Figure 2–2). Patients with elevated resting heart rate are more likely to derive large BP reduction with BBs, diltiazem, or verapamil because elevated heart rate is usually a good indicator for hyperkinetic circulation in hypertensive patients.

Addition of spironolactone should also be considered in patients with resistant hypertension despite adjustment of medications, as mentioned earlier. An increasing body of evidence suggests that low-dose spironolactone between 12.5 and 25 mg/day, which is not likely to produce a major diuretic effect, causes a dramatic fall in BP on average of 25/12 mm Hg, when used as add-on therapy in patients with uncontrolled hypertension. Antihypertensive effect of spironolactone is observed even in patients with essential hypertension without an elevated aldosterone-to-renin ratio. Combination of DHP and non-DHP CCBs appears to have additive effects on peripheral vasodilation and BP, possibly due to binding to different sites of the receptors, and should also be considered in these patients. In contrast, addition of an ARB to ACEI has modest effects on BP, on average of only 5/3 mm Hg. The addition of long-acting nitrates may be considered in patients with isolated systolic hypertension who are refractory to treatment because it has been shown to be beneficial in one small study.

Hypertension is a major risk factor for cardiovascular mortality, accounting for 50% of deaths from stroke and 45% from coronary heart disease worldwide. In addition, hypertension is a major risk factor for congestive heart failure, CKD, peripheral arterial disease, and the age-related decline in cognitive function. Presence of either persistent or new-onset LV hypertrophy or renal dysfunction during treatment contributes to poor prognosis. Patients with resistant hypertension experience a 20–25% higher risk of stroke and a 40–50% increase in risk of hospitalization from heart failure than hypertensive patients who achieve BP control with treatment. Thus, prompt evaluation for the underlying causes and intensification of pharmacologic and nonpharmacologic treatment is necessary to prevent target organ complications. Selection of appropriate antihypertensive medications that suit the patient characteristics and risk profile is the key to achieve BP goal. In addition to BP reduction, management of other cardiovascular risk factors is also essential in optimizing overall cardiovascular outcomes in hypertensive patients.