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TABLE 12.7 Oral Antihypertensive Agents

Dose Range, Total mg/day

Drug Diuretics

Thiazide Diuretics

Hydrochlorothiazide (HCTZ) 6.25-50 (1) Chlorthalidone 12.5-25 (1) Indapamide 1.25-5 (1) Metolazone 2.5-5 (1)

Loop Diuretics

Furosemide 20-160 (2) Torsemide 2.5-20 (1-2) Bumetanide 0.5-2 (2) Ethacrynic acid 25-100 (2)

Potassium-Sparing

Amiloride 5-20 (1) Triamterene 25-100 (1) Spironolactone 12.5-400 (1-2) Eplerenone 25-100 (1-2)

β-Blockers

Acebutolol 200-800 (2) Atenolol 25-100 (1) Betaxolol 5-20 (1) Bisoprolol 2.5-20 (1) Carteolol 2.5-10 (1) Metoprolol 50-450 (2) Metoprolol XL 50-200 (1-2) Nadolol 20-320 (1) Nebivolol 5-40 (1) Penbutolol 10-80 (1) Pindolol 10-60 (2) Propranolol 40-180 (2) Propranolol LA 60-180 (1-2) Timolol 20-60 (2)

β/α-Blockers

Labetalol 200-2400 (2) Carvedilol 6.25-50 (2)

Calcium-Channel Blockers

Dihydropyridines

Amlodipine 2.5-10 (1) Felodipine 2.5-20 (1-2) Isradipine CR 2.5-20 (2) Nicardipine SR 30-120 (2) Nifedipine XL 30-120 (1) Nisoldipine 10-40 (12)

Nondihydropyridines

Diltiazem CD 120-540 (1) Verapamil HS 120-480 (1)

Angiotensin-Converting Enzyme Inhibitors

Benazepril 10-80 (12) Captopril 25-150 (2) Enalapril 2.5-40 (2) Fosinopril 10-80 (1-2) Lisinopril 5-80 (1-2) Moexipril 7.5-30 (1) Perindopril 4-16 (1) Quinapril 5-80 (1-2)

(Doses Per Day)

CHAPTER 12 Vascular Diseases and Hypertension

Dose Range, Total mg/day

Drug

Ramipril 2.5-20 (1)

Trandolapril 1-8 (1)

Angiotensin-Receptor Blockers

Azilsartan 40-80 mg (1)

Candesartan 8-32 (1)

Eprosartan 400-800 (1-2)

Irbesartan 150-300 (1)

Losartan 25-100 (2)

Olmesartan 5-40 (1)

Telmisartan 20-80 (1)

Valsartan 80-320 (1-2)

Direct Renin Inhibitor

Aliskiren 75-300 (1)

α-Blockers

Doxazosin 1-16 (1)

Prazosin 1-40 (2-3)

Terazosin 1-20 (1)

Phenoxybenzamine 20-120 (2) for pheochromocytoma

Central Sympatholytics

Clonidine 0.2-1.2 (2-3)

Clonidine patch 0.1-0.6 (weekly)

Guanabenz 2-32 (2)

Guanfacine 1-3 (1) (q hs)

Methyldopa 250-1000 (2)

Reserpine 0.05-0.25 (1)

Direct Vasodilators

Hydralazine 10-200 (2)

Minoxidil 2.5-100 (1)

Fixed-Dose Combinations

Aliskiren/HCTZ 75-300/12.5-25 (1)

Amiloride/HCTZ 5/50 (1)

Amlodipine/benazepril 2.5-5/10-20 (1)

Amlodipine/valsartan 5-10/160-320 (1)

Amlodipine/olmesartan 5-10/20-40 (1)

Atenolol/chlorthalidone 50-100/25 (1)

Azilsartan/chlorthalidone 40-80/12.5-25 (1)

Benazepril/HCTZ 5-20/6.25-25 (1)

Bisoprolol/HCTZ 2.5-10/6.25 (1)

Candesartan/HCTZ 16-32/12.5-25 (1)

Enalapril/HCTZ 5-10/25 (1-2)

Eprosartan/HCTZ 600/12.5-25 (1)

Fosinopril/HCTZ 10-20/12.5 (1)

Irbesartan/HCTZ 15-30/12.5-25 (1)

Losartan/HCTZ 50-100/12.5-25 (1)

Olmesartan/amlodipine 20-40/5-10 (1)

Olmesartan/HCTZ 20-40/12.5-25 (1)

Olmesartan/amlodipine/HCTZ 20-40/5-10/12.5-25 (1)

Spironolactone/HCTZ 25/25 (1/2-1)

Telmisartan/HCTZ 40-80/12.5-25 (1)

Trandolapril/verapamil 2-4/180-240 (1)

Triamterene/HCTZ 37.5/25 (1/2-1)

Valsartan/HCTZ 80-160/12.5-25 (1)

Valsartan/amlodipine/HCTZ 80-160/5-10/12.5-25 (1)

(Doses Per Day)

153

154 SECTION II Cardiovascular Disease

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Pheochromocytoma is a great masquerader and the large differential diagnosis includes causes of neurogenic hypertension such as sympathomimetic agents (cocaine, methamphetamine), baroreﬂex failure, and obstructive sleep apnea. A history of surgery and radiation therapy for head-and-neck tumors suggests the possibility of baroreceptor damage. Loud snoring, obesity, and somnolence suggest obstructive sleep apnea. Weight loss, continuous positive airway pressure, and corrective surgery improve BP control in some patients with sleep apnea.

Other causes of secondary hypertension include nonsteroidal anti-inﬂammatory drugs (NSAIDs), hypothyroidism, hyperthyroidism coarctation of the aorta, and immunosuppressive drugs, especially cyclosporine and tacrolimus.

TREATMENT OF HYPERTENSION

Prescription medication is the cornerstone of treating hypertension. Lifestyle modiﬁcation should be used as an adjunct but not as an alternative to life-saving BP medication. Most dietary sodium (Na+) comes from processed foods, and daily salt consumption should be reduced to less than 4 grams, which is equivalent to 1500 mg or 65 mmol of Na+. The Dietary Approach to Stop Hypertension (DASH diet), which is rich in fresh fruits and vegetables (for high potassium content) and low-fat dairy products, has been shown to lower BP in feeding trials. Other lifestyle modiﬁcations that can lower BP include weight loss in overweight patients with hypertension, regular aerobic exercise, smoking cessation, and moderation in alcohol intake.

The list of antihypertensive drugs marketed for the treatment of hypertension in the United States is shown in Table 12.7. Major contraindications and side effects of these drugs are summarized in Table

12.8.

Patients With Uncomplicated Hypertension

The three ﬁrst-line drug classes for uncomplicated hypertension are: (1) CCB, (2) ACEI or ARB, and (3) thiazide diuretic. The 2017 ACC/ AHA high blood pressure guideline, recommended any one of these three drug classes as initial therapy for most patients with hypertension. It also recommended initiating therapy with two ﬁrst-line drugs of different classes, either as separate agents or in a ﬁxed-dose combination for individuals with BP more than 20/10 mm Hg above their target goal. β-Blockers are not recommended as ﬁrst-line therapy unless patients have other compelling indications (such as heart failure or ischemic heart disease) because it is inferior to three ﬁrst-line drug classes in preventing target organ damage and cardiovascular events. In contrast, the European Society of Hypertension endorses β-blocker as the ﬁrst-line agent, arguing that the most effective drugs are those that the patient will tolerate and take. Long-term patient adherence is best with an ARB, intermediate with an ACEI or CCB, and worst with a thiazide. Initiation of single pill combination therapy is encouraged as it allows BP control to reach target goal faster and improves longterm adherence. The European Society of Hypertension advocates a treatment strategy that is based on the patient’s age and ethnicity. It recommends upfront combination therapy of RAS blocker (either an ACE inhibitor or an ARB) with a CCB or diuretic except in frail older adults with mild hypertension, in whom a monotherapy is recommended.

A growing body of evidence from clinical trials emphasizes the overriding importance of lowering BP with combinations of drugs rather than belaboring the choice of a single, best agent to begin therapy. Primary hypertension is multifactorial, and typically several medications (at least two or more) with different mechanisms of action (see Table 12.7) are required simultaneously to reach BP goal. In most

patients with hypertension, low-dose combination drug therapy is the only way to control BP adequately and to minimize side effects. With many classes of antihypertensive medication, the dose-response relationship for BP is rather ﬂat. Most of the BP lowering occurs at the lower end of the dose range. However, many of the side effects are steeply dose-dependent, becoming problematic mainly at the high end of the clinical dose range. Thus, low-dose combinations achieve therapeutic synergy and minimize side effects. Fixed-dose combinations reduce pill burden and cost.

One highly effective well-tolerated combination is a CCB plus an ACEI or ARB. A large beneﬁt of combination therapy with an ACEI plus a dihydropyridine CCB over the combination of an ACEI plus a thiazide diuretic is reducing cardiovascular events in high-risk patients. In contrast, the combination of ARB plus an ACEI or direct renin inhibitor (“dual renin-angiotensin system blockade”) should be avoided because it results in deterioration of renal function and increases risk of hypotension without added cardiovascular beneﬁt.

Kaiser-Permanente of Northern California, a large managed care organization, has increased the control of hypertension among its membership over the past decade from 44% to an astounding 80% by: increasing access with walk-in BP checks by medical assistants, registry rounds to identify and contact patients with elevated ofﬁce BP, and institution of a system-wide simple medication treatment protocol that features once-daily combination therapy.

Along with antihypertensive medication, statin therapy should be strongly considered as an integral part of most antihypertensive regimens in patients with 10-year ASCVD risk of at least 7.5%.

Hypertension in African Americans

Hypertension disproportionately affects African Americans. The explanation is unknown, but the dominant importance of environmental factors is indicated by geographic variation in hypertension prevalence among African-origin and European-origin populations. Hypertension is rare among Africans living in Africa and is more prevalent in several European countries than it is in the United States. As monotherapy for hypertension, an ACEI (or ARB) generally yields a smaller decrease in BP in black African patients than it does in non-black patients and thus affords less protection against stroke. However, when an ACEI or ARB is used in combination with a CCB or a diuretic, antihypertensive efﬁcacy is ampliﬁed and ethnic differences disappear. In addition, combination of CCB with an ACEI (or ARB) or a diuretic is superior to combination of ACEI and diuretics in lowering BP in this population. Nevertheless, an ACEIbased treatment should be considered in African American patients with hypertensive nephrosclerosis as it slows the deterioration in renal function.

Hypertensive Nephrosclerosis

Hypertension is the second most common cause of chronic kidney disease, accounting for over 25% of cases. Hypertensive nephrosclerosis is the result of persistently uncontrolled hypertension, causing chronic glomerular ischemia. Typically, proteinuria is mild (<0.5 g/24 hr). Nondiabetic chronic kidney disease is a compelling indication for ACEI-based or ARB-based antihypertensive therapy. ACEIs cause greater dilation of the efferent renal arterioles, thereby minimizing intraglomerular hypertension. In contrast, arterial vasodilators such as dihydropyridine CCBs, when used without an ACEI or ARB, preferentially dilate the afferent arteriole and impair renal autoregulation. Glomerular hypertension can result if systemic BP is not sufﬁciently lowered. The ACEI should be withdrawn only if the rise in serum creatinine exceeds 30% of the baseline value or the serum K increases to greater than 5.6 mmol/L.

CHAPTER 12 Vascular Diseases and Hypertension

TABLE 12.8 Major Contraindications and Side Effects of Antihypertensive Drugs

Drug Class Major Contraindications Side Effects Diuretics

Thiazides Gout Insulin resistance, new onset type 2 diabetes (espe-

cially in combination with β-blockers) Hypokalemia, hyponatremia Hypertriglyceridemia Hyperuricemia, precipitation of gout Erectile dysfunction (more than other drug classes) Potentiate nondepolarizing muscle relaxants Photosensitive dermatitis

Loop diuretics Hepatic coma Interstitial nephritis

Hypokalemia Potentiate succinylcholine Potentiate aminoglycoside ototoxicity

Potassium-sparing diuretics Serum K >5.5 mEq/L Fatal hyperkalemia if used with salt substitutes, ACE

GFR <30 mg/mL/1.73 m

β-Blockers Heart block Insulin resistance, new onset type 2 diabetes (espe-

Asthma Depression Heart block, acute decompensated CHF Cocaine and/or methamphetamine abuse Bronchospasm

ACEIs Pregnancy Cough

Bilateral renal artery stenosis Hyperkalemia Hyperkalemia Angioedema

ARBs Pregnancy Hyperkalemia

Bilateral renal artery stenosis Angioedema (very rare) Hyperkalemia Fetal toxicity

Direct Renin Inhibitors Pregnancy Hyperkalemia

Bilateral renal artery stenosis Diarrhea Hyperkalemia Fetal toxicity

Dihydropyridine CCBs As monotherapy in chronic kidney disease with

proteinuria

Nondihydropyridine CCBs Heart block Bradycardia, AV block (especially with verapamil)

Systolic heart failure Constipation (often severe with verapamil)

α-Blockers Monotherapy for hypertension Orthostatic hypotension

Orthostatic hypotension Drug tolerance (in the absence of diuretic therapy) Systolic heart failure Ankle edema Left ventricular dysfunction CHF

Central sympatholytics Orthostatic hypotension Depression, dry mouth, lethargy

inhibitors, ARBs, high-potassium foods, NSAIDs

cially in combination with thiazides)

Depression, nightmares, fatigue Cold extremities, claudication (β2 effect) Stevens-Johnson syndrome Agranulocytosis

Leukopenia Fetal toxicity Cholestatic jaundice (rare fulminant hepatic necrosis if

the drug is not discontinued)

Headaches Flushing Ankle edema CHF Gingival hyperplasia Esophageal reﬂux

Worsening of systolic function, CHF Gingival edema and/or hypertrophy Increase cyclosporine blood levels Esophageal reﬂux

First-dose effect (acute hypotension) Potentiate hypotension with PDE5 inhibitors (e.g.,

sildenaﬁl)

Erectile dysfunction (dose dependent)

155

Continued

156 SECTION II Cardiovascular Disease

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TABLE 12.8 Major Contraindications and Side Effects of Antihypertensive Drugs—cont’d

Drug Class Major Contraindications Side Effects

Rebound hypertension with clonidine withdrawal Coombs positive hemolytic anemia and elevated LFTs

with α-methyldopa

Direct vasodilators Orthostatic hypotension Reﬂex tachycardia

Fluid retention Hirsutism, pericardial effusion with minoxidil Lupus with hydralazine

ACE, Angiotensin-converting enzyme; ARBs, angiotensin-receptor blockers; AV, arteriovenous; CCBs, calcium channel blockers; CHF, congestive heart failure; GFR, glomerular ﬁltration rate; LFTs, liver function tests; MI, myocardial infarction; NSAIDs, nonsteroidal anti-inﬂammatory drugs; PDE5, phosphodiesterase type 5.

Hypertensive Patients With Diabetes

Compared with its 25% prevalence in the general adult population, hypertension is present in 75% of patients with diabetes and is a major factor contributing to excessive risk of myocardial infarction, stroke, heart failure, microvascular complications, and diabetic nephropathy progressing to end-stage renal disease. The Action to Control Cardiovascular Risk in Diabetes blood pressure trial (ACCORD BP) failed to show beneﬁt of lowering systolic BP below 120 mm Hg in patients with type 2 diabetes mellitus in terms of reducing overall mortality or cardiovascular mortality. However, the risk of stroke was reduced by 60% in these patients. ACCORD trial also tested intensive versus standard glycemic targets (glycated hemoglobin <6% versus 7.0% to 7.9%). A more recent analysis has demonstrated beneﬁt of intensive BP lowering in lowering cardiovascular events in diabetic patients in the standard glycemia arm but not in the intensive glycemic arm. Increased hypoglycemic events associated with intensive glycemic control may negate potential cardiovascular beneﬁt of intensive BP lowering in this population. The Systolic Blood Pressure Intervention Trial (SPRINT), which was conducted in nondiabetic patients and has similar study design to the ACCORD trial, showed beneﬁt of intensive BP lowering in patients with prediabetes. Consequently, the 2017 ACC/AHA guideline endorses a BP target of less than 130/80 mm Hg for diabetic patients. The 2019 American Diabetes Association endorses lower targets only in diabetic patients with 10-year ASCVD risk of greater than 15%. In general, an ACEI or ARB plus a CCB is an excellent combination to treat hypertension in patients with diabetes. Thiazide diuretics and standard β-blockers exacerbate glucose intolerance, whereas the vasodilating β-blockers such as carvedilol and nebivolol have neutral or possibly beneﬁcial effects.

Hypertensive Patients With Coronary Artery Disease

To lower myocardial oxygen demands in patients with coronary disease, the antihypertensive regimen should reduce BP without causing reﬂex tachycardia. For this reason, a β-blocker is often prescribed in conjunction with a dihydropyridine CCB such as amlodipine. β-Block- ers are indicated for patients with hypertension who have sustained a myocardial infarction and for most heart failure patients with reduced ejection fraction (HFrEF). In contrast, diuretics are recommended as the ﬁrst therapy in heart failure patients with preserved ejection fraction (HFpEF) with evidence of volume overload. After euvolemia is achieved, ACEIs, ARBs, or spironolactone may be considered in patients with persistently elevated BP. In patients with stable coronary artery disease, a cardioprotective effect of ACE inhibition has also been demonstrated in patients with moderate cardiovascular risk proﬁles but not in those with lower risk proﬁles.

Isolated Systolic Hypertension in Older Adults

In developed countries, systolic pressure rises progressively with age; if individuals live long enough, then almost all (>90%) develop hypertension. Diastolic pressure rises until the age of 50 years and decreases thereafter, producing a progressive rise in pulse pressure (i.e., systolic pressure minus diastolic pressure) (Fig. 12.12).

Different hemodynamic faults underlie hypertension in younger and older persons. Patients who develop hypertension before 50 years of age typically have combined systolic and diastolic hypertension: systolic pressure greater than 140 mm Hg and diastolic pressure greater than 90 mm Hg. The main hemodynamic fault is vasoconstriction at the level of the resistance arterioles. In contrast, the majority of patients who develop hypertension after 50 years of age have isolated systolic hypertension: systolic pressure greater than 140 mm Hg but diastolic pressure less than 90 mm Hg (often less than 80 mm Hg). In isolated systolic hypertension, the primary hemodynamic fault is decreased distensibility of the aorta and other large conduit arteries (see Fig. 12.12). Collagen replaces elastin in the elastic lamina of the aorta, an age-dependent process that is accelerated by atherosclerosis and hypertension. The cardiovascular risk associated with isolated systolic hypertension is related to pulsatility, the repetitive pounding of the blood vessels with each cardiac cycle and a more rapid return of the arterial pulse wave from the periphery, both begetting more systolic hypertension. In the United States and Europe, the majority of uncontrolled hypertension occurs in older patients with isolated systolic hypertension. A BP of 160/60 mm Hg (pulse pressure of 100 mm Hg) carries twice the risk of fatal coronary heart disease as 140/110 mm Hg (pulse pressure of 30 mm Hg) (Fig. 12.13).

In older persons with isolated systolic hypertension, lowering systolic pressure from higher than 160 to lower than 150 mm Hg reduces the risks of stroke, myocardial infarction, and overall cardiovascular mortality; it also reduces heart failure admissions and slows the progression of dementia. Trial data do not yet exist in older persons to determine whether the treatment of isolated elevations in systolic pressure below 140 mm Hg is beneﬁcial; however, in the absence of such data, treatment may be warranted to prevent progression of systolic hypertension if patients can tolerate treatment without side effects such as orthostatic hypotension.

The combination of a low-dose thiazide diuretic with a dihydropyridine CCB or with an ACEI reduces the risk of CV events in older patients with isolated systolic hypertension. According to the 2017 ACC/AHA high BP guideline, chlorthalidone is the preferred thiazide diuretic given its long half-life and more consistent reduction in cardiovascular events in clinical trials than other thiazide diuretics. To prevent orthostatic hypotension, medication should be titrated to standing BP and one low-dose medication should be started at a time.

CHAPTER 12 Vascular Diseases and Hypertension

Diastolic BP mm Hg

(160/60)

157

Relative risk for

coronary disease

≥100

90–99

Fig. 12.13 Joint inﬂuences of systolic blood pressure (SBP) and dia-

stolic BP on coronary heart disease (CHD) risk in the Multiple Risk Factor Intervention Trial. (Neaton JD, Wentworth D: Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart disease: Overall ﬁndings and differences by age for 316,099 white men. Arch Intern Med 152:56-64, 1992.)

Blood Pressure Lowering for Secondary Prevention of Stroke

Most neurologists do not recommend BP reduction during an acute stroke unless BP is extremely elevated (see section Acute Severe Hypertension). After the acute phase, BP should be lowered with a thiazide diuretic, adding an ACEI or additional drugs as needed to achieve BP lower than 140/90 mm Hg; whether BP should be lowered

150

Systolic blood pressure

130

110

mm Hg

Diastolic blood pressure

10–29 30–39 40–49 50–59 60–69 70–79 ≥80

Age (years)

Fig. 12.12 Age-dependent changes in systolic and diastolic blood pressure (BP) in the United States (left

panel). Schematic diagram explains the relation between aortic compliance and pulse pressure (right panel).

(Left panel, From Burt V, Whelton P, Rocella EJ, et al: Prevalence of hypertension in the U.S. adult popu- lation: Results from the Third National Health and Nutrition Examination Survey, 1988–1991. Hypertension 25:305-313, 1995. Right panel, Courtesy of Dr. Stanley Franklin University of California at Irvine. Used with permission.)

death

(140/110)

80–89

75–79

70–74

<70

<120

Men Women

140–159

120–139

Systolic BP mm Hg

≥160

Compliant

Systole Diastole

Constant stroke volume

Aorta

Pulse pressure

Noncompliant

Systole Diastole

further remains unsettled. Lower BP target of less than 130/80 mm Hg for patients may be reasonable for patients with transient ischemic attack or lacuna infarct to prevent intracranial hemorrhage.

Blood Pressure Lowering for Prevention of Cognitive Impairment

Increasing number of studies have shown that high BP and other cardiovascular risk factors such as hyperlipidemia predisposes not only to increased cardiovascular damage but also brain injury and cognitive impairment in older adults, which is independent of stroke (i.e., what is good for the heart is good for the brain). The recent SPRINT MIND clinical trial showed that intensive lowering of systolic BP to below 120 mm Hg in adults with high cardiovascular risk but without history of stroke prevents development of cognitive impairment. There was no signiﬁcant reduction in new cases of dementia but the trial was limited by short duration of follow-up. Additional studies are needed to clarify optimal BP target to prevent cognitive dysfunction in hypertensive adults.

Hypertensive Disorders of Women

Oral contraceptives cause a small increase in BP in most women but rarely cause a large increase into the hypertensive range. If hypertension develops, oral contraceptive therapy should be discontinued in favor of other methods of contraception. Oral estrogen replacement therapy seems to cause a small increase in BP. In contrast, transdermal estrogen (which bypasses ﬁrst-pass hepatic metabolism) seems to avoid this side effect.

Hypertension, the most common nonobstetric complication of pregnancy, is present in 10% of all pregnancies. Of these women, one third are caused by chronic hypertension and two thirds are due to preeclampsia, which is deﬁned as an increase in BP to 140/90 mm Hg or greater after the twentieth week of gestation accompanied by proteinuria (>300 mg/24 hr) and pathologic edema. This is sometimes accompanied by seizures (eclampsia) and the multisystem HELLP syndrome of hemolysis (H), elevated liver enzymes (EL), and low

158 SECTION II Cardiovascular Disease

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platelets (LP). Although the cause remains an enigma, preeclampsia is the most common cause of maternal mortality and perinatal mortality. Nifedipine and α-methyldopa are considered to be ﬁrst-line drug therapy for preeclampsia and chronic hypertension in pregnancy. Labetalol is also effective in lowering BP but may result in intrauterine growth restriction.

Resistant Hypertension

Deﬁned as persistence of usual BP above 140/90 mm Hg despite treatment with full doses of three or more different classes of medications in rational combination and including a diuretic, resistant hypertension is the most common reason for referral to a hypertension specialist. In practice, the majority of these patients have pseudoresistant hypertension due to: (1) white coat aggravation, a white coat reaction superimposed on chronic hypertension that is well-controlled with medication outside the physician’s ofﬁce; (2) an inadequate medical regimen; (3) nonadherence to medication, which is present in 30% to 60% of patients using direct measurement of drugs levels in the plasma or urine; and (4) ingestion of pressor substances. Common shortcomings of the medical regimen include under-treatment of hypertension with monotherapy and clonidine, a potent central sympatholytic that causes rebound hypertension between doses particularly with PRN dosing. Several common causes of pseudoresistant hypertension are related to the patient’s behavior: medication nonadherence, recidivism with lifestyle modiﬁcation (e.g., obesity, a high-salt diet, excessive alcohol intake), or habitual use of pressor substances such as sympathomimetics (e.g., tobacco, cocaine, methamphetamine, phenylephrine-containing cold or herbal remedies) or NSAIDs, with the latter causing renal sodium retention. Once these behavioral factors have been excluded, the search should begin for secondary hypertension.

The most common forms of secondary hypertension include obstructive sleep apnea, chronic kidney disease, and primary aldosteronism. Either a loop diuretic such a furosemide or a potent thiazide-type diuretic such as chlorthalidone may be required to control hypertension in patients with resistant hypertension and chronic kidney disease. The treatment of primary aldosteronism was discussed earlier. After excluding pseudoresistant hypertension and secondary hypertension, some patients have severe drug-resistant primary hypertension. Fourth- and ﬁfth-line therapy includes a vasodilating β-blocker and spironolactone (even in the absence of primary aldosteronism). Percutaneous catheter-based renal denervation is proposed as a novel interventional approach to treat drug-resistant hypertension. Although the initial results raised enormous enthusiasm, subsequent randomized controlled trials have been disappointing as the magnitude of reduction in BP is modest (less than 10 mm Hg) when compared to the sham control arm. A number of studies that use other neuromodulation techniques, such as baroreﬂex activation, to reduce overall sympathetic tone beyond renal sympathetic activity alone, are being conducted to determine BP outcome in this population.

headaches, confusion, blurred vision, nausea and vomiting, seizures, heart failure, oliguria, and grade III or IV hypertensive retinopathy (Fig. 12.14). Hypertensive emergencies require immediate admission in an intensive care unit (ICU) for intravenous therapy and continuous BP monitoring, whereas hypertensive urgencies can often be managed with oral medications and appropriate outpatient follow-up in 24 to 72 hours. The most common hypertensive cardiac emergencies include hypertension associated with acute aortic dissection, coronary artery bypass graft surgery, acute myocardial infarction, and unstable angina. Other hypertensive emergencies include those accompanying eclampsia, head trauma, severe body burns, postoperative bleeding from vascular suture lines, and epistaxis that cannot be controlled with anterior and posterior nasal packing. Neurologic hypertensive emergencies, which include acute ischemic stroke, hemorrhagic stroke, subarachnoid hemorrhage, and hypertensive encephalopathy, can be difﬁcult to distinguish from one another. Hypertensive encephalopathy is characterized by severe hypertensive retinopathy (i.e., retinal hemorrhages and exudates, with or without papilledema) and a posterior leukoencephalopathy affecting mainly the white matter of the parieto-occipital regions as seen on cerebral MR imaging or CT scanning. A new focal neurologic deﬁcit suggesting a stroke-in-evolution demands a much more conservative approach to correcting the elevated BP.

Acute Severe Hypertension

Of all the patients in the emergency department, 25% have an elevated BP. Hypertensive emergencies are acute, often severe elevations in BP that are accompanied by acute or rapidly progressive target organ dysfunction such as myocardial or cerebral ischemia or infarction, pulmonary edema, or renal failure. Hypertensive urgencies are severe elevations in BP without severe symptoms and without evidence of acute or progressive target organ dysfunction. Thus, the key distinction and approach to the patient depends on the state of the patient and the assessment of target organ damage, not simply the absolute level of BP. The full-blown clinical picture of a hypertensive emergency is a critically ill patient with a BP greater than 220/140 mm Hg,

Fig. 12.14 Hypertensive retinopathy is traditionally divided into four

grades. (A) Grade 1 shows very early and minor changes in a young patient; increased tortuosity of a retinal vessel and increased reﬂectiveness (silver wiring) of a retinal artery are seen at the 1-o’clock position in this view. Otherwise, the fundus is completely normal. (B) Grade 2 also shows increased tortuosity and silver wiring (arrowheads). In addition, nipping of the venules at arteriovenous (AV) crossings is visualized (arrow). (C) Grade 3 shows the same changes as grade 2 plus ﬂameshaped retinal hemorrhages and soft cotton-wool exudates. (D) In grade 4, swelling of the optic disc (papilledema) is observed, retinal edema is present, and hard exudates may collect around the fovea, producing a typical macular star. (From Forbes CD, Jackson WF: Color atlas and text of clinical medicine, 3rd ed. London, Mosby, 2003, with permission.)

CHAPTER 12 Vascular Diseases and Hypertension

159

In most other hypertensive emergencies, the goal of parenteral therapy is to achieve a controlled and gradual lowering of BP. The rapidity of BP reduction is highly dependent on clinical presentation. Patients with acute aortic dissection require rapid reduction to the 120/80 mm Hg range almost immediately to reduce shear stress and prevent further intimal tear in the aortic wall, which could be life-threatening. On the other hand, patients with acute ischemic stroke who are not candidates for intravenous thrombolysis or endovascular treatment should not be treated with antihypertensive agents unless BP is 220/120 mm Hg or higher. Following initial therapy, a more conservative BP reduction goal to no more than 15% during the first 24 hours after onset of stroke is recommended. In those who are candidates for thrombolysis, however, BP should be less than 185/110 mm Hg before administration of intravenous tissue plasminogen activator and should be maintained below 180/105 mm Hg for at least the first 24 hours after initiating drug therapy. The widely cited goal of BP lowering by 10% in the first hour and by an additional 15% over the next 3 to 12 hours is limited to patients who present with hypertensive encephalopathy or other presentations. Unnecessarily rapid correction of the elevated BP to completely normal values places the patient at high risk for worsening cerebral, cardiac, and renal ischemia. In chronic hypertension, cerebral autoregulation is reset to higher-than-normal BPs. This compensatory adjustment prevents tissue overperfusion (i.e., increased intracranial pressure) at very high BPs, but it also predisposes the patient to tissue underperfusion (i.e., cerebral ischemia) when an elevated BP is lowered too quickly.

Parenteral agents for the treatment of hypertensive emergency are summarized in Table 12.9. Sodium nitroprusside, a nitric oxide donor, is the most popular agent because it can be titrated rapidly

to control BP. Intravenous nitroglycerin, another nitric oxide donor, is indicated mainly for hypertension in the setting of acute coronary syndrome or decompensated heart failure. Nicardipine is a parenteral dihydropyridine CCB that is particularly useful in the postoperative cardiac patient and patients with renal failure to avoid the thiocyanate toxicity with nitroprusside. Clevidipine is another intravenous CCB with shorter half-life than nicardipine of only 1 minute. Fenoldopam is a selective dopamine-1receptor agonist that causes both systemic and renal vasodilation, as well as increased glomerular filtration, natriuresis, and diuresis. Intravenous labetalol is an effective treatment of a hypertensive crisis particularly in the setting of myocardial ischemia with preserved ventricular function.

Most patients in the emergency department with hypertensive urgencies are either nonadherent with their medical regimen or are being treated with an inadequate regimen. To expedite the necessary changes in medications, outpatient follow-up should be arranged within 72 hours. To manage the patient during the short-interim period, effective oral medication includes labetalol, clonidine, or captopril, which is a short-acting ACEI.

BPs greater than 160/110 mm Hg are a common incidental ﬁnding among patients in emergency departments and other acute care settings for urgent medical or surgical care of symptoms that are unrelated to BP (e.g., musculoskeletal pain, orthopedic injury). In these settings, the elevated BP is more often the ﬁrst indication of chronic hypertension than a simple physiologic stress reaction, providing an important opportunity to initiate primary care referral for formal evaluation and treatment of chronic hypertension. Home and ambulatory BP monitoring are indicated to determine whether the patient’s BP normalizes completely once the acute illness has resolved.

TABLE 12.9 Parenteral Agents for Management of Hypertensive Emergencies

Agent Dose Onset of Action Precautions Parenteral Vasodilators

Sodium nitroprusside 0.25-10 mcg/kg/min IV infusion Immediate Thiocyanate toxicity with prolonged use Nitroglycerin 5-100 mcg/min IV infusion 2-5 min Headache, tachycardia, tolerance Nicardipine 5-15 mg/hr IV infusion 1-5 min Protracted hypotension after prolonged

use Clevidipine 1-21 mg/hr IV infusion 2-4 min Tachycardia Fenoldopam mesylate 0.01-0.3 mcg/kg/min IV infusion 1-5 min Headache, tachycardia, increased

intraocular pressure Hydralazine 5-10 mg as IV bolus or 10-40 mg IM;

repeat every 4-6 hrs

Enalaprilat 0.625-1.25 mg every 6 hr IV bolus 15-60 min Unpredictable and excessive falls in

Parenteral Adrenergic Inhibitors

Labetalol 20-80 mg as slow IV injection every 10

min, or 0.5-2.0 mg/min IV as infusion

Metoprolol 5 mg IV every 10 min for three doses 5-10 min Bronchospasm, heart block, heart fail-

Esmolol 500 mcg/kg IV over 3 min; then 25-100

mg/kg/min as IV infusion

Phentolamine 5-10 mg IV bolus every 5-15 min 1-2 min Tachycardia, orthostatic hypotension

IM, Intramuscular; IV, intravenous.

10 min IV 20 min IM

5-10 min Bronchospasm, heart block, orthostatic

1-5 min Bronchospasm, heart block, heart failure

Unpredictable and excessive falls in

tachycardia; angina exacerbation;

blood pressure

blood pressure; acute renal failure in

patients with stenosis bilateral renal

artery

hypotension

ure, exacerbation of cocaine-induced

myocardial ischemia

160 SECTION II Cardiovascular Disease

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PROGNOSIS

One of the most important prognostic factors in hypertension is ECG or echocardiographic LVH, with the latter already present in as many as 25% of patients with newly diagnosed hypertension. LVH predisposes the patient to heart failure, atrial ﬁbrillation, and sudden cardiac death.

Because of their relatively short duration (typically <5 years),

randomized controlled trials underestimate the lifetime protection against premature disability and death afforded by several decades of antihypertensive therapy in clinical practice. In the Framingham Heart Study, treating hypertension for 20 years in middle-aged adults reduced total cardiovascular mortality by 60%, which is considerably greater than the results of most randomized trials despite the less intense treatment guidelines when therapy was initiated in the 1950s through the 1970s.

PROSPECTS FOR THE FUTURE

•  Further delineation of genetic causes of hypertension and appli-

cation of this research to the treatment and prevention of hypertension, including development of pharmacologic and nonpharmacologic therapy that target the various signaling pathways in hypertension

•  Determination of antihypertensive drug classes that are most effec-

tive in preventing dementia and cognitive decline

•  Evaluation of the comparative efﬁcacy and safety of DOACs

against LMWH in preventing VTE in patients with active malignancy

•  Further assessment of safety and efficacy of combination of

direct anticoagulants and antiplatelet therapy in patients with atrial fibrillation, venous thromboembolism, and vascular disease