Joseph J. Saseen and Eric J. MacLaughlin
The risk of cardiovascular (CV) morbidity and mortality is directly correlated with blood pressure (BP).
Evidence from clinical trials have shown that antihypertensive drug therapy substantially reduces the risks of CV events and death in patients with high BP.
Essential hypertension is usually an asymptomatic disease. A diagnosis cannot be made based on one elevated BP measurement. An elevated value from the average of two or more measurements, present during two or more clinical encounters, is needed to diagnose hypertension.
The overall goal of treating hypertension is to reduce hypertension-associated morbidity and mortality from CV events. These are considered hypertension-associated complications. The selection of specific drug therapy should be based on evidence that demonstrates CV risk reduction.
A goal BP of <140/90 mm Hg is appropriate for general prevention of CV events and CV risk reduction in most patients. For some patients (e.g., diabetes and/or significant chronic kidney disease) lower goal BP values may be appropriate on a patient-specific basis.
Magnitude of BP elevation should be used to guide determination of the number of agents to start when implementing drug therapy. Most patients with stage 1 hypertension should be started on one drug, with the option of starting two for some patients. However, most patients presenting with stage 2 hypertension should be started on two drugs.
Lifestyle modifications should be prescribed in all patients, especially those with prehypertension and hypertension. However, they should never be used as a replacement for antihypertensive drug therapy for patients with hypertension, especially in those with additional CV risk factors.
Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs), and thiazide diuretics are all first-line agents for most patients with hypertension for general prevention of CV events and CV risk reduction. These first-line options are for patients with hypertension who do not have any compelling indications for a specific antihypertensive drug class.
For general prevention of CV events and CV risk reduction in most patients with hypertension, β-blockers do not reduce CV events to the extent that has been proven with thiazide-type diuretics, ACE inhibitors, ARBs, CCBs, or thiazide diuretics.
Compelling indications are comorbid conditions where specific antihypertensive drug classes have been shown in clinical trials to provide unique long-term benefits (reducing the risk of CV events).
Patients with diabetes are at high risk for CV events. All patients with diabetes and hypertension should ideally be managed with either an ACE inhibitor or an ARB. These are typically in combination with one or more other antihypertensive agents because multiple agents frequently are needed to control BP.
Older patients are often at risk for orthostatic hypotension when antihypertensive drug therapy is started. Although overall antihypertensive drug therapy should be the same as in younger patients, low initial doses should be used and dosage titrations should be gradual to minimize risk of orthostatic hypotension.
Alternative antihypertensive agents have not been proven to reduce the risk of CV events to the same extent compared with first-line antihypertensive agents. They should be used primarily in combination with first-line agents to provide additional BP lowering.
Initial therapy with the combination of two antihypertensive agents should be used in most patients presenting with stage 2 hypertension. This is also an option for patients presenting with stage 1 hypertension. Most patients require combination therapy to achieve goal BP.
Patients have resistant hypertension when they fail to attain goal BP values while adherent to a regimen that includes at least three agents at maximum dose, one of which includes a diuretic, or when four or more agents are needed to treat hypertension.
Hypertensive urgency is ideally managed by adjusting maintenance therapy, adding a new antihypertensive, and/or increasing the dose of a present medication. This provides a gradual reduction in BP, which is a safer treatment approach than rapid reductions in BP.
Hypertension is a common disease that is simply defined as persistently elevated arterial blood pressure (BP). Although elevated BP was perceived to be “essential” for adequate perfusion of vital organs during the early and middle 1900s, it is now identified as one of the most significant risk factors for cardiovascular (CV) disease. Increasing awareness and diagnosis of hypertension, and improving control of BP with appropriate treatment are considered critical public health initiatives to reduce CV morbidity and mortality.
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) is the most prominent evidence-based clinical guideline in the United States for the management of hypertension.1 The Eighth Report of the Joint National Committee was under development for several years. In 2013, the sponsoring organization (National Heart Lung and Blood Institute [NHLBI]) decided that the work of the JNC8 groups will be published as evidentiary reviews, not a guideline. However, the NHLBI will subsequently collaborate with another organization to prepare and issue an updated hypertension clinical practice guideline sometime after 2013. Once available, this will likely be viewed as the preeminent hypertension clinical guideline in the United States. The 2007 American Heart Association (AHA) Scientific Statement on the treatment of hypertension provides additional insight regarding pharmacotherapy for hypertension.2 This chapter reviews relevant components of both these consensus documents and additional evidence from clinical trials, with a focus on the pharmacotherapy of hypertension.
The National Health and Nutrition Examination Survey and the National Center for Health Statistics regularly assess hypertension in the United States.3 Data from 2007 to 2010 indicate that 77.9 million Americans aged 20 years and above have hypertension. Predictions indicate that by 2030 the prevalence of hypertension will increase by 7.2%. Approximately half of all patients with hypertension are at their goal BP value. While this control rate is substantially higher than in the past, there remain many opportunities for clinicians to improve the care of patients with hypertension.
Approximately 1 in 3 adult Americans (77.9 million people) have elevated BP, defined as ≥140/90 mm Hg.3 The overall incidence is similar between men and women, but varies depending on age. The percentage of men with high BP is higher than that of women before the age of 55 and is similar to that of women between the ages 55 and 64. However, after the age of 64, a much higher percentage of women have high BP than men.3 Prevalence rates are highest in non-Hispanic blacks (47% in women, 43% in men), followed by non-Hispanic whites (31% in women, 33% in men), and Mexican Americans (29% in women, 30% in men).3 With regard to BP control, 54.9% of non-Hispanic whites have controlled hypertension in contrast to 47.6% of non-Hispanic blacks and 39.3% in Mexican Americans.3
BP values increase with age, and hypertension (persistently elevated BP values) is very common in the elderly. The lifetime risk of developing hypertension among those 55 years of age and older who are normotensive is 90%.1Most patients have prehypertension before they are diagnosed with hypertension, with most diagnoses occurring between the third and fifth decades of life.
In most patients, hypertension results from unknown pathophysiologic etiology (essential or primary hypertension). This form of hypertension cannot be cured, but it can be controlled. A small percentage of patients have a specific cause of their hypertension (secondary hypertension). There are many potential secondary causes that either are concurrent medical conditions or are endogenously induced. If the cause can be identified, hypertension in these patients can be mitigated or potentially be cured.
Over 90% of individuals with high BP have essential hypertension.1 Numerous mechanisms have been identified that may contribute to the pathogenesis of this form of hypertension, so identifying the exact underlying abnormality is not possible. Genetic factors may play an important role in the development of essential hypertension. There are monogenic and polygenic forms of BP dysregulation that may be responsible for essential hypertension.4 Many of these genetic traits feature genes that affect sodium balance, but genetic mutations altering urinary kallikrein excretion, nitric oxide release, and excretion of aldosterone, other adrenal steroids, and angiotensinogen are also documented.4 In the future, genetic testing for these traits could lead to alternative approaches to preventing or treating hypertension; however, this is not currently recommended.
Fewer than 10% of patients have secondary hypertension where either a comorbid disease or a drug (or other product) is responsible for elevating BP (see Table 3-1).1,5 In most of these cases, renal dysfunction resulting from severe chronic kidney disease (CKD) or renovascular disease is the most common secondary cause. Certain drugs (or other products), either directly or indirectly, can cause hypertension or exacerbate hypertension by increasing BP. The most common agents are listed in Table 3-1. When a secondary cause is identified, removing the offending agent (when feasible) or treating/correcting the underlying comorbid condition should be the first step in management.
TABLE 3-1 Secondary Causes of Hypertension
Multiple factors that control BP are potential contributing components in the development of essential hypertension.4,6 These include malfunctions in either humoral (i.e., the renin–angiotensin–aldosterone system [RAAS]) or vasodepressor mechanisms, abnormal neuronal mechanisms, defects in peripheral autoregulation, and disturbances in sodium, calcium, and natriuretic hormone. Many of these factors are cumulatively affected by the multifaceted RAAS, which ultimately regulates arterial BP. It is probable that no one factor is solely responsible for essential hypertension.
Arterial BP is the pressure in the arterial wall measured in millimeters of mercury (mm Hg). The two typical arterial BP values are systolic BP (SBP) and diastolic BP (DBP). SBP represents the peak value, which is achieved during cardiac contraction. DBP is achieved after contraction when the cardiac chambers are filling, and represents the nadir value. The difference between SBP and DBP is called the pulse pressure and is a measure of arterial wall tension. Mean arterial pressure (MAP) is the average pressure throughout the cardiac cycle of contraction. It is sometimes used clinically to represent overall arterial BP, especially in hypertensive emergency. During a cardiac cycle, two thirds of the time is spent in diastole and one third in systole. Therefore, the MAP is calculated by using the following equation:
Arterial BP is hemodynamically generated by the interplay between blood flow and the resistance to blood flow. It is mathematically defined as the product of cardiac output (CO) and total peripheral resistance (TPR) according to the following equation:
CO is the major determinant of SBP, whereas TPR largely determines DBP. In turn, CO is a function of stroke volume, heart rate, and venous capacitance. Table 3-2 lists physiologic causes of increased CO and TPR and correlates them to potential mechanisms of pathogenesis.
TABLE 3-2 Potential Mechanisms of Pathogenesis
Under normal physiologic conditions, arterial BP fluctuates throughout the day following a circadian rhythm. BP decreases to its lowest daily values during sleep followed by a sharp rise starting a few hours prior to awakening with the highest values occurring midmorning. BP is also increased acutely during physical activity or emotional stress.
The classification of BP in adults (age 18 years and older) is based on the average of two or more properly measured BP values from two or more clinical encounters (Table 3-3).1 It includes four categories: normal, prehypertension, stage 1 hypertension, and stage 2 hypertension. Prehypertension is not considered a disease category but identifies patients whose BP is likely to increase into the classification of hypertension in the future.
TABLE 3-3 Classification of Blood Pressure in Adults (Age ≥18 Years)a
Hypertensive crises are clinical situations where BP values are very elevated, typically >180/120 mm Hg.6 They are categorized as either hypertensive emergency or hypertensive urgency. Hypertensive emergencies are extreme elevations in BP that are accompanied by acute or progressing target-organ damage. Hypertensive urgencies are high elevations in BP without acute or progressing target-organ injury.
Cardiovascular Risk and Blood Pressure
Epidemiologic data demonstrate a strong correlation between BP and CV morbidity and mortality.7 Risk of stroke, myocardial infarction (MI), angina, heart failure, kidney failure, or early death from a CV cause is directly correlated with BP. Starting at a BP of 115/75 mm Hg, risk of CV disease doubles with every 20/10 mm Hg increase.1 Even patients with prehypertension have an increased risk of CV disease.
Treating patients with hypertension with antihypertensive drug therapy provides significant clinical benefits. Evidence from large-scale placebo-controlled clinical trials have shown that the increased risks of CV events and death associated with elevated BP are reduced substantially by antihypertensive therapy.8–11 This is discussed in Treatment section of this chapter.
SBP is a stronger predictor of CV disease than DBP in adults aged 50 years and older; it is the most important clinical BP parameter for most patients.1 Patients are considered to have isolated systolic hypertension when their SBP values are elevated (i.e., ≥140 mm Hg) and DBP values are not (i.e., <90 mm Hg, but commonly <80 mm Hg). Isolated systolic hypertension is believed to result from pathophysiologic changes in the arterial vasculature consistent with aging. These changes decrease the compliance of the arterial wall and portend an increased risk of CV morbidity and mortality. The elevated pulse pressure (SBP minus DBP) is believed to reflect extent of atherosclerotic disease in the elderly and is a measure of increased arterial stiffness. Higher pulse pressure values seen in those with isolated systolic hypertension are directly correlated with risk of CV mortality.
Several humoral abnormalities involving the RAAS, natriuretic hormone, and hyperinsulinemia may be involved in the development of essential hypertension.
The Renin–Angiotensin–Aldosterone System
The RAAS is a complex endogenous system involved with most regulatory components of arterial BP. Activation and regulation is primarily governed by the kidney (see Fig. 3-1). The RAAS regulates sodium, potassium, and blood volume. Therefore, this system significantly influences vascular tone and sympathetic nervous system activity, and is the most influential contributor to the homeostatic regulation of BP.
FIGURE 3-1 Diagram representing the renin–angiotensin–aldosterone system. The interrelationship between the kidney, angiotensin II, and regulation of blood pressure is depicted. Renin secretion from the juxtaglomerular cells in the afferent arterioles is regulated by three major factors to trigger conversion of angiotensinogen to angiotensin 1. The primary sites of action for major antihypertensive agents are included: ACE inhibitors; angiotensin II receptor blockers; β-blockers; calcium channel blockers; diuretics; aldosterone antagonists; direct renin inhibitor.
Renin is an enzyme that is stored in the juxtaglomerular cells, which are located in the afferent arterioles of the kidney. The release of renin is modulated by several factors: intrarenal factors (e.g., renal perfusion pressure, catecholamines, angiotensin II) and extrarenal factors (e.g., sodium, chloride, and potassium).
Juxtaglomerular cells function as a baroreceptor-sensing device. Decreased renal artery pressure and kidney blood flow is sensed by these cells and stimulates secretion of renin. The juxtaglomerular apparatus also includes a group of specialized distal tubule cells referred to collectively as the macula densa. A decrease in sodium and chloride delivered to the distal tubule stimulates renin release. Catecholamines increase renin release probably by directly stimulating sympathetic nerves on the afferent arterioles that in turn activate the juxtaglomerular cells.
Renin catalyzes the conversion of angiotensinogen to angiotensin I in the blood. Angiotensin I is then converted to angiotensin II by angiotensin-converting enzyme (ACE). After binding to specific receptors (classified as either angiotensin II type 1 [AT1] or angiotensin II type 2 [AT2] subtypes), angiotensin II exerts biologic effects in several tissues. The AT1 receptor is located in brain, kidney, myocardium, peripheral vasculature, and the adrenal glands. These receptors mediate most responses that are critical to CV and kidney function. The AT2 receptor is located in adrenal medullary tissue, uterus, and brain. Stimulation of the AT2 receptor does not influence BP regulation.
Circulating angiotensin II can elevate BP through pressor and volume effects. Pressor effects include direct vasoconstriction, stimulation of catecholamine release from the adrenal medulla, and centrally mediated increases in sympathetic nervous system activity. Angiotensin II also stimulates aldosterone synthesis from the adrenal cortex. This leads to sodium and water reabsorption that increases plasma volume, TPR, and ultimately BP. Aldosterone also has a deleterious role in the pathophysiology of other CV diseases (e.g., heart failure, MI, kidney disease) by promoting tissue remodeling leading to myocardial fibrosis and vascular dysfunction. Clearly, any disturbance in the body that leads to activation of the RAAS could explain chronic hypertension.
The heart and brain contain a local RAAS. In the heart, angiotensin II is also generated by angiotensin I convertase (human chymase). This enzyme is not blocked by ACE inhibition. Activation of the myocardial RAAS increases cardiac contractility and stimulates cardiac hypertrophy. In the brain, angiotensin II modulates the production and release of hypothalamic and pituitary hormones, and enhances sympathetic outflow from the medulla oblongata.
Natriuretic hormone inhibits sodium and potassium-ATPase and thus interferes with sodium transport across cell membranes. Inherited defects in the kidney’s ability to eliminate sodium can cause increased blood volume. A compensatory increase in the concentration of circulating natriuretic hormone theoretically could increase urinary excretion of sodium and water. However, this hormone might block the active transport of sodium out of arteriolar smooth muscle cells. The increased intracellular sodium concentration ultimately would increase vascular tone and BP.
Insulin Resistance and Hyperinsulinemia
The combination of multiple CV and metabolic abnormalities is referred to as the metabolic syndrome.12 Hypothetically, increased insulin concentrations may lead to hypertension because of increased renal sodium retention and enhanced sympathetic nervous system activity. Moreover, insulin has growth hormone–like actions that can induce hypertrophy of vascular smooth muscle cells. Insulin also may elevate BP by increasing intracellular calcium, which leads to increased vascular resistance. The exact mechanism by which insulin resistance and hyperinsulinemia occur in hypertension is unknown. However, this association is strong because many of the criteria used to define this population (i.e., elevated BP, abdominal obesity, high triglycerides, low high-density lipoprotein cholesterol, and elevated fasting glucose) are often present in patients with hypertension.12
Central and autonomic nervous systems are intricately involved in the regulation of arterial BP. Many receptors that either enhance or inhibit norepinephrine release are located on the presynaptic surface of sympathetic terminals. The α and β presynaptic receptors play a role in negative and positive feedback to the norepinephrine-containing vesicles. Stimulation of presynaptic α-receptors (α2) exerts a negative inhibition on norepinephrine release. Stimulation of presynaptic β-receptors facilitates norepinephrine release.
Sympathetic neuronal fibers located on the surface of effector cells innervate the α- and β-receptors. Stimulation of postsynaptic α-receptors (α1) on arterioles and venules results in vasoconstriction. There are two types of postsynaptic β-receptors, β1 and β2. Both are present in all tissues innervated by the sympathetic nervous system. However, in some tissues β1-receptors predominate (e.g., heart), and in other tissues β2-receptors predominate (e.g., bronchioles). Stimulation of β1-receptors in the heart results in an increase in heart rate (chronotropy) and force of contraction (ionotropy), whereas stimulation of β2-receptors in the arterioles and venules causes vasodilation.
The baroreceptor reflex system is the major negative feedback mechanism that controls sympathetic activity. Baroreceptors are nerve endings lying in the walls of large arteries, especially in the carotid arteries and aortic arch. Changes in arterial BP rapidly activate baroreceptors that then transmit impulses to the brain stem through the ninth cranial nerve and vagus nerve. In this reflex system, a decrease in arterial BP stimulates baroreceptors, causing reflex vasoconstriction and increased heart rate and force of cardiac contraction. These baroreceptor reflex mechanisms may be less responsive in the elderly and those with diabetes.
Stimulation of certain areas within the central nervous system (e.g., nucleus tractus solitarius, vagal nuclei, vasomotor center, area postrema) can either increase or decrease BP. For example, α2-adrenergic stimulation within the central nervous system decreases BP through an inhibitory effect on the vasomotor center. However, angiotensin II increases sympathetic outflow from the vasomotor center, which increases BP.
The purpose of these neuronal mechanisms is to regulate BP and maintain homeostasis. Pathologic disturbances in any of the four major components (autonomic nerve fibers, adrenergic receptors, baroreceptors, central nervous system) could chronically elevate BP. These systems are physiologically interrelated. A defect in one component may alter normal function in another. Therefore, cumulative abnormalities may explain the development of essential hypertension.
Peripheral Autoregulatory Components
Abnormalities in renal or tissue autoregulatory systems could cause hypertension. It is possible that a renal defect in sodium excretion may develop, which can then cause resetting of tissue autoregulatory processes resulting in a higher BP. The kidney usually maintains a normal BP through a volume–pressure adaptive mechanism. When BP drops, the kidneys respond by increasing retention of sodium and water, which leads to plasma volume expansion that increases BP. Conversely, when BP rises above normal, renal sodium and water excretion are increased to reduce plasma volume and CO.
Local autoregulatory processes maintain adequate tissue oxygenation. When tissue oxygen demand is normal to low, the local arteriolar bed remains relatively vasoconstricted. However, increase in metabolic demand triggers arteriolar vasodilation that lowers peripheral vascular resistance (PVR) and increases blood flow and oxygen delivery.
Intrinsic defects in renal adaptive mechanisms could lead to plasma volume expansion and increased blood flow to peripheral tissues, even when BP is normal. Local tissue autoregulatory processes that vasoconstrict would then be activated to offset the increased blood flow. This effect would result in increased PVR and, if sustained, would also result in thickening of the arteriolar walls. This pathophysiologic component is plausible because increased TPR is a common underlying finding in patients with essential hypertension.
Vascular Endothelial Mechanisms
Vascular endothelium and smooth muscle play important roles in regulating blood vessel tone and BP. These regulating functions are mediated by vasoactive substances that are synthesized by endothelial cells. It has been postulated that a deficiency in local synthesis of vasodilating substances (e.g., prostacyclin and bradykinin) or excess vasoconstricting substances (e.g., angiotensin II and endothelin I) contribute to essential hypertension, atherosclerosis, and other CV diseases.
Nitric oxide is produced in the endothelium, relaxes the vascular epithelium, and is a very potent vasodilator. The nitric oxide system is an important regulator of arterial BP. Patients with hypertension may have an intrinsic nitric oxide deficiency, resulting in inadequate vasodilation.
Epidemiologic and clinical data have associated excess sodium intake with hypertension. Population-based studies indicate that high-sodium diets are associated with a high prevalence of stroke and hypertension. Conversely, low-sodium diets are associated with a lower prevalence of hypertension. Clinical studies have shown that dietary sodium restriction lowers BP in many (but not all) patients with elevated BP. The exact mechanisms by which excess sodium leads to hypertension are not known.
Altered calcium homeostasis also may play an important role in the pathogenesis of hypertension. A lack of dietary calcium hypothetically can disturb the balance between intracellular and extracellular calcium, resulting in an increased intracellular calcium concentration. This imbalance can alter vascular smooth muscle function by increasing PVR. Some studies have shown that dietary calcium supplementation results in a modest BP reduction for patients with hypertension.
The role of potassium fluctuations is also inadequately understood. Potassium depletion may increase PVR, but the clinical significance of small serum potassium concentration changes is unclear. Furthermore, data demonstrating reduced CV risk with dietary potassium supplementation are very limited.
The clinical presentation of hypertension is described in Box 3-1.
BOX 3-1 CLINICAL PRESENTATION Hypertension
General: The patient may appear healthy or may have the presence of additional CV risk factors:
• Age (≥55 years for men, ≥65 years for women)
• Diabetes mellitus
• Family history of premature CV disease
• Obesity (body mass index [BMI] ≥30 kg/m2)
• Physical inactivity
• Tobacco use
Symptoms: Usually none related to elevated BP.
Signs: Previous BP values in either the prehypertension or the hypertension category.
Routine laboratory tests: Blood urea nitrogen (BUN)/serum creatinine, fasting lipid panel, fasting blood glucose, serum electrolytes (sodium, potassium), hemoglobin and hematocrit, and spot urine albumin-to-creatinine ratio. The patient may have normal values and still have hypertension. However, some may have abnormal values that are consistent with either additional CV risk factors or hypertension-related damage.
Other tests: 12-Lead electrocardiogram, estimated glomerular filtration rate (GFR; using modification of diet in renal disease [MDRD] equation).
Hypertension-related target-organ damage: The patient may have a previous medical history or diagnostic findings that indicate the presence of hypertension-related target-organ damage:
• Brain (stroke, transient ischemic attack, dementia)
• Eyes (retinopathy)
• Heart (left ventricular hypertrophy [LVH], angina, prior MI, prior coronary revascularization, heart failure)
• Kidney chronic kidney disease (CKD)
• Peripheral vasculature (peripheral arterial disease [PAD])
Hypertension is called the silent killer because most patients do not have symptoms. The primary physical finding is elevated BP. The diagnosis of hypertension cannot be made based on one elevated BP measurement. The average of two or more measurements taken during two or more clinical encounters is required to diagnose hypertension.1 This BP average should be used to establish a diagnosis, and then classify the stage of hypertension using Table 3-3.
The measurement of BP is a common routine medical screening tool that should be conducted at every healthcare encounter.1
Cuff Measurement Using Sphygmomanometry The most common procedure to measure BP in clinical practice is the indirect measurement of BP using sphygmomanometry.13 The appropriate procedure to indirectly measure BP using sphygmomanometry has been described by the AHA.13 It is imperative that the measurement equipment (inflation cuff, stethoscope, and manometer) meet certain national standards to ensure maximum quality and precision with measurement.
The AHA stepwise technique is recommended:
1. Patients should ideally refrain from nicotine and caffeine ingestion for 30 minutes and sit with lower back supported in a chair. Bare arm should be supported and resting near heart level. Feet should be flat on the floor (with legs not crossed). The measurement environment should be relatively quiet and provide privacy. Measuring BP in a position other than seated (supine or standing position) may be required under special circumstances (e.g., suspected orthostatic hypotension, or dehydration).
2. Measurement should begin only after a 5-minute period of rest.
3. A properly sized cuff (pediatric, small, regular, large, or extra large) should be used. The inflatable rubber bladder should be at least 80% and a width that is at least 40% of arm circumference.
4. The palpatory method should be used to estimate the SBP:
a. Place the cuff on the upper arm 2 to 3 cm above the antecubital fossa and attach it to the manometer (either a mercury or an aneroid).
b. Close the inflation valve and inflate the cuff to 70 mm Hg.
c. Palpate the radial pulse with the index and middle fingers of the opposite hand.
d. Inflate further in increments of 10 mm Hg until the radial pulse is no longer palpated.
e. Note the pressure at which the radial pulse is no longer palpated; this is the estimated SBP.
f. Release the pressure in the cuff by opening the valve.
5. The bell (not the diaphragm) of the stethoscope should be placed on the skin of the antecubital fossa, directly over where the brachial artery is palpated. The stethoscope earpieces should be inserted appropriately. The valve should be closed with the cuff, and then inflated to 30 mm Hg above the estimated SBP from the palpatory method. The valve should be slightly opened to slowly release pressure at a rate of 2 to 3 mm Hg/s.
6. The clinician should listen for Korotkoff sounds with the stethoscope. The first phase of Korotkoff sounds is the initial presence of clear tapping sounds. Note the pressure at the first recognition of these sounds. This is the SBP. As pressure deflates, note the pressure when all sounds disappear, right at the last sound. This is the DBP.
7. Measurements should be rounded to the nearest 2 mm Hg.
8. A second measurement should be obtained after at least 1 minute. If these values differ by more than 5 mm Hg, additional measurements should be obtained.
9. Neither the patient nor the observer should talk during measurement.
10. When first establishing care with a patient, BP should be measured in both arms. If consistent interarm differences exist, the arm with the higher value should be used.
Inaccuracies with indirect measurements result from inherent biologic variability of BP, inaccuracies related to suboptimal technique, and the white coat effect.13 Variations in BP occur with environmental temperature, the time of day and year, meals, physical activity, posture, alcohol, nicotine, and emotions. In the clinic setting, standard BP measurement procedures (e.g., appropriate rest period, correct technique, minimal number of measurements) are often not followed, which results in poor estimation of true BP. It is recommended that the stethoscope bell, rather than the diaphragm, be used for measurement, although some studies suggest little difference between two.13
Approximately 15% to 20% of patients have white coat hypertension, where BP values rise in a clinical setting but return to normal in nonclinical environments using home or ambulatory BP (ABP) measurements.13Interestingly, the rise in BP dissipates gradually over several hours after leaving the clinical setting. It may or may not be precipitated by other stresses in the patient’s daily life. This is in contrast to masked hypertension, where a decrease in BP occurs in the clinical setting.14 With masked hypertension, home BP is hypertensive, while the in-office BP is normotensive or substantially lower than that at home. This situation may lead to undertreatment or lack of treatment for hypertension. Moreover, patients with either white coat or masked hypertension have a high risk of progressing to develop sustained hypertension, which can result in a higher risk of CV events compared with normotensive patients.15
Pseudohypertension is a falsely elevated BP measurement. It may be seen in the elderly, those with long-standing diabetes, or those with CKD due to rigid, calcified brachial arteries.13 In these patients, the true arterial BP when measured directly with intraarterial measurement (the most accurate measurement of BP) is much lower than that measured using the indirect cuff method. The Osler’s maneuver can be used to test for pseudohypertension. In this maneuver, the BP cuff is inflated above peak SBP. If the radial artery remains palpable, the patient has a positive Osler’s sign (rigid artery), which may indicate pseudohypertension.
Elderly patients with a wide pulse pressure may have an auscultatory gap that can lead to underestimated SBP or overestimated DBP measurements.13 In this situation, as the cuff pressure falls from the true SBP value, the Korotkoff sound may disappear (indicating a false DBP measurement), reappear (a false SBP measurement), and then disappear again at the true DBP value. When an auscultatory gap is present, Korotkoff sounds are usually heard when pressure in the cuff first starts to decrease after inflation. This may be eliminated by raising the arm overhead by 30 seconds before bringing it to the proper position and inflating the cuff. This maneuver decreases the intravascular volume and improves inflow thereby allowing Korotkoff sounds to be heard.13
Ambulatory and Self-BP Monitoring Ambulatory BP (ABP) monitoring using an automated device can document BP at frequent time intervals (e.g., every 15 to 30 minutes) throughout a 24-hour period.13 ABP values are usually lower than clinic-measured values. The definition of hypertension for ABP is ≥135/85 mm Hg during the day, ≥120/75 mm Hg nighttime (or asleep), and ≥130/80 mm Hg over 24 hours.13For self BP monitoring, a BP ≥135/85 mm Hg is considered hypertensive. Self-BP measurements are collected by patients, preferably in the morning, using home monitoring devices.
Neither ABP nor self-BP monitoring is needed for the routine diagnosis of hypertension according to JNC7 guidelines; however, these modalities can enhance the ability to identify patients with white coat and masked hypertension.14 ABP and self-BP measurements may also be useful in evaluating and optimizing BP control for patients on antihypertensive drug therapy.14,16 ABP monitoring may be helpful for patients with apparent drug resistance, hypotensive symptoms while on antihypertensive therapy, episodic hypertension (e.g., white coat hypertension), autonomic dysfunction, and in identifying “nondippers” whose BP does not decrease by >10% during sleep and who may portend increased risk of BP-related complications.1,13
Limitations of ABP and self-BP measurements may prohibit routine use of such technology. These include complexity of use, costs, and lack of prospective outcome data describing normal ranges for these measurements. Although self-monitoring of BP at home is less complicated and less costly than ambulatory monitoring, patients may omit or fabricate readings, or have poor technique (e.g., not resting for adequate period of time, improper placement, wrong cuff size).
Frequently, the only sign of essential hypertension is elevated BP. The rest of the physical examination may be completely normal. However, a complete medical evaluation (a comprehensive medical history, physical examination, and laboratory and/or diagnostic tests) is recommended after diagnosis to (a) identify secondary causes, (b) identify other CV risk factors or comorbid conditions that may define prognosis and/or guide therapy, and (c) assess for the presence or absence of hypertension-associated target-organ damage.1 All patients with hypertension should have the tests described in Box 3-1 measured prior to initiating therapy.1 For patients without a history of coronary artery disease, noncoronary atherosclerotic vascular disease, left ventricular dysfunction, or diabetes, it is also important to estimate future risk of CV disease. The 10-year risk of fatal coronary heart disease or nonfatal MI can be estimated using Framingham risk scoring (http://www.nhlbi.nih.gov/guidelines/cholesterol/risk_tbl.htm).2
The most common secondary causes of hypertension are listed in Table 3-1. A complete medical evaluation should provide clues for identifying secondary hypertension.
Patients with secondary hypertension might have signs or symptoms suggestive of the underlying disorder. Patients with pheochromocytoma may have a history of paroxysmal headaches, sweating, tachycardia, and palpitations. Over half of these patients suffer from episodes of orthostatic hypotension. In primary hyperaldosteronism symptoms related to hypokalemia usually include muscle cramps and muscle weakness. Patients with Cushing’s syndrome may complain of weight gain, polyuria, edema, menstrual irregularities, recurrent acne, or muscular weakness and have several classic physical features (e.g., moon face, buffalo hump, hirsutism). Patients with coarctation of the aorta may have higher BP in the arms than in legs and diminished or even absent femoral pulses. Patients with renal artery stenosis may have an abdominal systolic–diastolic bruit.
Routine laboratory tests may also help identify secondary hypertension. Baseline hypokalemia may suggest mineralocorticoid-induced hypertension. Protein, red blood cells, and casts in the urine may indicate renovascular disease. Some laboratory tests are used specifically to diagnose secondary hypertension. These include plasma norepinephrine and urinary metanephrine for pheochromocytoma, plasma and urinary aldosterone concentrations for primary hyperaldosteronism, and plasma renin activity, captopril stimulation test, renal vein renin, and renal artery angiography for renovascular disease.
Certain drugs and other products can result in drug-induced hypertension (see Table 3-1). For some patients, the addition of these agents can be the cause of elevated BP or can exacerbate underlying hypertension. Identifying a temporal relationship between starting the suspected agent and developing elevated BP is most suggestive of drug-induced BP elevation.
Natural Course of Disease
Essential hypertension is usually preceded by elevated BP values that are in the prehypertension category. BP values may fluctuate between elevated and normal levels for an extended period of time. As the disease progresses, PVR increases, and BP elevation becomes chronic.
Hypertension-Associated Target-Organ Damage
Target-organ damage (see Box 3-1) can develop as a complication of hypertension. CV events (e.g., MI, cerebrovascular accidents, kidney failure) are clinical end points of hypertension-associated target-organ damage and are the primary causes of CV morbidity and mortality for patients with hypertension. The probability of CV events and CV morbidity and mortality in patients with hypertension is directly correlated with the severity of BP elevation.
Hypertension accelerates atherosclerosis and stimulates left ventricular and vascular dysfunction. These pathologic changes are thought to be secondary to both a chronic pressure overload and a variety of nonhemodynamic stimuli. Several nonhemodynamic disturbances have been implicated in these effects (e.g., the adrenergic system, RAAS, increased synthesis and secretion of endothelin I, and a decreased production of prostacyclin and nitric oxide). Atherosclerosis in hypertension is accompanied by proliferation of smooth muscle cells, lipid infiltration into the vascular endothelium, and enhancement of vascular calcium accumulation.
Cerebrovascular disease is a consequence of hypertension. A neurologic assessment can detect either gross neurologic deficits or a slight hemiparesis with some incoordination and hyperreflexia that are indicative of cerebrovascular disease. Stroke can result from lacunar infarcts caused by thrombotic occlusion of small vessels or intracerebral hemorrhage resulting from ruptured microaneurysms. Transient ischemic attacks secondary to atherosclerotic disease in the carotid arteries can also happen in patients with hypertension.
Retinopathies can occur in hypertension and may manifest as a variety of different findings. A funduscopic examination can detect hypertensive retinopathy, and the result can be categorized according to the Keith-Wagener-Barker retinopathy classification. Retinopathy manifests as arteriolar narrowing, focal arteriolar constrictions, arteriovenous crossing changes (nicking), retinal hemorrhages and exudates, and disk edema. Accelerated arteriosclerosis, a long-term consequence of essential hypertension, can cause nonspecific changes such as increased light reflex, increased tortuosity of vessels, and arteriovenous nicking. Focal arteriolar narrowing, retinal infarcts, and flame-shaped hemorrhages usually are suggestive of accelerated or malignant phase of hypertension. Papilledema is swelling of the optic disk caused by a breakdown in autoregulation of capillary blood flow in the presence of high pressure. It is usually only present in hypertensive emergencies.
Heart disease is the most well-identified form of target-organ damage. A thorough cardiac and pulmonary examination can identify cardiopulmonary abnormalities. Clinical manifestations include LVH, coronary heart disease (angina, prior MI, and prior coronary revascularization), and heart failure. These complications may lead to cardiac arrhythmias, angina, MI, and sudden death. Coronary disease (also called coronary heart disease) and associated CV events are the most common causes of death in patients with hypertension.
The kidney damage caused by hypertension is characterized pathologically by hyaline arteriosclerosis, hyperplastic arteriosclerosis, arteriolar hypertrophy, fibrinoid necrosis, and atheroma of the major renal arteries. Glomerular hyperfiltration and intraglomerular hypertension are early stages of hypertensive nephropathy. Albuminuria is followed by a gradual decline in renal function. The primary renal complication in hypertension is nephrosclerosis, which is secondary to arteriosclerosis. Atheromatous disease of a major renal artery may give rise to renal artery stenosis. Although overt kidney failure is an uncommon complication of essential hypertension, it is an important cause of end-stage kidney disease, especially in African Americans, Hispanics, and Native Americans.
The peripheral vasculature is a target organ. Physical examination of the vascular system can detect evidence of atherosclerosis, which may present as arterial bruits (aortic, abdominal, or peripheral), distended veins, diminished or absent peripheral arterial pulses, or lower extremity edema. PAD is a clinical condition that can result from atherosclerosis, which is accelerated in hypertension. Other CV risk factors (e.g., smoking) can increase the likelihood of PAD as well as all other forms of target-organ damage.
Overall Goal of Treatment
The overall goal of treating hypertension is to reduce hypertension-associated morbidity and mortality.1 This morbidity and mortality is related to hypertension-associated target-organ damage (e.g., CV events, cerebrovascular events, heart failure, kidney disease). Reducing CV risk is the primary purpose of hypertension therapy and the specific choice of drug therapy should be determined by evidence demonstrating such CV risk reduction.
Surrogate Targets—Blood Pressure Goals
Treating patients with hypertension to achieve a desired target BP value is simply a surrogate goal of therapy. Reducing BP to goal does not guarantee prevention of hypertension-associated target-organ damage, but is associated with a lower risk of hypertension-associated target-organ damage.1 Targeting a goal BP value is a tool that clinicians use to evaluate response to therapy. It is the primary method used to determine the need for titration and regimen modification.
The JNC7 guidelines recommend BP goals for the management of hypertension (Box 3-2). A goal BP of <140/90 mm Hg is recommended for most patients for general prevention of CV events or CV disease (e.g., coronary artery disease).1 The JNC7, published in 2003, recommends a lower BP goal of <130/80 mm Hg for patients with diabetes or significant CKD. However, data supporting that this goal provides better reductions in CV events than a goal of <140/90 mm Hg are lacking. In 2013 the American Diabetes Association changed their recommended goal BP in patients with diabetes to <140/80 mm Hg.17 This was a significant change from their long-standing recommendation of <130/80 mm Hg. They do recommend that a SBP goal of <130 mm Hg may be appropriate for certain individuals (e.g., younger patients) if achieved without undue treatment burden, but the recommendation for most patients with diabetes is <140/80 mm Hg. Similarly, the Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend a BP goal of 140/90 mm Hg for patients with hypertension and CKD (nondialysis), with a lower BP goal of <130/80 mm Hg only for those patients who have persistent albuminuria (>30 mg urine albumin excretion per 24 hours or equivalent).18,19
BOX 3-2 Goal BP Values Recommended by the JNC7 in 2003, American Diabetes Association, and KDIGO
• <140/90 mm Hg for most patients
American Diabetes Association (2013)
• <140/80 mm Hg for patients with diabetes.
• SBP goal of <130 mm Hg may be appropriate for certain individuals (e.g., younger patients) if achieved without undue treatment burden.
• <130/80 mm Hg only for patients with CKD (nondialysis) who have persistent urine albumin excretion of >30 mg per 24 hours (or equivalent)
Until a new clinical guideline based on the NHLBI evidentiary review is published, clinicians should use the most recent recommended BP goals from these consensus statements of <140/90 mm Hg for most patients, <140/80 mm Hg for patients with diabetes, and <130/80 mm Hg for patients with persistent increased urinary albumin excretion (see Box 3-2).
Evidence Supporting <140/90 mm Hg in Most Patients Lower goal DBP values have been evaluated prospectively in the Hypertension Optimal Treatment (HOT) study.20 In this study, over 18,700 patients were randomized to target DBP values of ≤90, ≤85, or ≤80 mm Hg. Although the actual DBP values achieved were 85.2, 83.2, and 81.1 mm Hg, respectively, there were no significant differences in risk of major CV events when the three treatment groups were compared with each other among the total population. This lack of a benefit in reducing risk of CV events is consistent with findings from a 2009 Cochrane Collaboration systematic review that included seven clinical trials that evaluated different goal DBP values in hypertension.21 When the relationship between actual BP values and risk of CV events was evaluated, there was a trend that lower was better. The risk of major CV events was the lowest with a BP of 139/83 mm Hg, and lowest risk of stroke was with a BP of 142/80 mm Hg.
A major limitation of the HOT study and the 2009 Cochrane Collaboration review is the use of DBP goal values. SBP is more directly correlated to CV risk than DBP in most patients with hypertension, especially those above the age of 50. Therefore, data from the HOT study cannot answer this question. It is important to note that no J-curve relationship was seen. The J-curve hypothesis suggests that lowering BP too much might increase the risk of CV events.22 This theoretical hypothesis was described many years ago and was originally suggested in observational studies. Therefore, it remains an unproven hypothesis.
Limited data suggest lower is better when SBP goal values are targeted. The Cardio-Sys trial was a small open-label study in 1,111 patients with hypertension and without a history of diabetes.23 These patients had additional CV risk factors and roughly reflect a population with a Framingham risk score of 10% or greater. Patients were randomized to SBP goals of <140 mm Hg or <130 mm Hg. After a median of 2 years, the incidence of LVH was lower in the group randomized to a SBP goal of <130 mm Hg. Interestingly, the incidence of CV events, which was a secondary end point, was also significantly lower in the <130 mm Hg group. These data suggest that the optional lower BP goals may be better. However, LVH is only a surrogate end point for CV events, and the open-label nature of this study limits broad application to patient care.
How low to go in most patients?
A standard BP goal of <140/90 mm Hg is recommended for most patients with hypertension. Lower goals are recommended in specific patient populations (e.g., diabetes, CKD with persistent albuminuria). However, some clinicians believe that lower BP goals are better, even for patients who do not have one of the aforementioned higher-risk conditions. One ongoing trial sponsored by the NHLBI, the Systolic Pressure Intervention Trial (SPRINT), is a prospective randomized trial that is evaluating standard BP goals with lower BP goals for patients without a history of diabetes or a history of stroke. Once this trial is completed, hopefully the controversy of how low to go in most patients will be resolved.
Evidence Supporting Lower BP Goals in Diabetes A BP goal of <130/80 mm Hg was historically recommended for patients with diabetes for many years, by multiple organizations.1,2 The primary evidence supporting this recommendation was from the HOT study, where the only subgroup to show a lower risk of major CV events in the <80 mm Hg group versus the <90 mm Hg group was in patients with diabetes (n = 1,501).
The NHLBI-sponsored Action to Control Cardiovascular Risk in Diabetes Blood Pressure (ACCORD-BP) study questioned the benefit of lower BP goals for patients with diabetes.24 The ACCORD-BP was an open-label study that randomized 4,733 patients with type 2 diabetes to intensive therapy targeting a SBP of <120 mm Hg, or to standard therapy targeting a SBP <140 mm Hg for a mean followup of 4.7 years. After 1 year, an average of 3.4 medications was needed in the intensive therapy group to attain a mean SBP of 119.3 mm Hg, compared with an average of 2.1 medications in the standard therapy group to attain a mean SBP of 133.5 mm Hg. This difference was generally maintained throughout the study duration. However, there was no significant difference in the annual rate of the primary end point (nonfatal MI, nonfatal stroke, or CV death) between the two groups. The annual incidence of the secondary end point of stroke was lower with the intensive therapy group versus the standard therapy group, and this was the only prespecified end point that was different between the two groups.
Despite consensus guidelines historically recommending a BP goal of <130/80 mm Hg for patients with diabetes, evidence supporting this approach over a standard goal of <140/90 mm Hg is marginal, and comes at the cost of increased side effects (e.g., hypotension, hyperkalemia, bradycardia). While the ACCORD-BP provided additional evidence regarding BP goals for patients with diabetes, these data do not provide all of the clinical answers that are needed. The ACCORD-BP was open label, and those in the standard group (SBP <140 mm Hg) actually had SBP values that were closer to 130 mm Hg than to 140 mm Hg. Based on these data, in 2013 American Diabetes Association changed their recommendation to a goal BP of <140/80 mm Hg for most patients with hypertension and diabetes.17 The KDIGO guidelines recommend a BP goal of <140/90 mm Hg for patients with hypertension and CKD (non-dialysis) and a BP goal of <130/80 mm Hg only for those patients who have persistently increased urine albumin excretion.18
Avoiding Clinical Inertia
Although hypertension is one of the most common medical conditions, BP control rates are poor. Clinical inertia in hypertension has been defined as an office visit at which no therapeutic move was made to lower BP in a patient with uncontrolled hypertension.25 Clinical inertia is not the entire reason why many patients with hypertension do not achieve goal BP values. However, it is certainly a major reason that can be remedied simply through more aggressive treatment with drug therapy. This can involve initiating, titrating, or changing drug therapy.
General Approach to Treatment
Most patients should be placed on both lifestyle modifications and drug therapy concurrently after a diagnosis of hypertension is made. Lifestyle modification alone is appropriate for most patients with prehypertension. However, lifestyle modifications alone may not be adequate for patients with hypertension and either additional CV risk factors or hypertension-associated target-organ damage.
The choice of initial drug therapy depends on the degree of BP elevation and presence of compelling indications (discussed in the Pharmacotherapy section below). Most patients with stage 1 hypertension should be initially treated with a first-line antihypertensive drug or the combination of two agents. Combination drug therapy is recommended for patients with more severe BP elevation (stage 2 hypertension), using preferably two first-line antihypertensive drugs. This general approach is outlined in Figure 3-2. There are six compelling indications where specific antihypertensive drug classes have evidence showing unique benefits in patients with hypertension and the listed compelling indication (Fig. 3-3).
FIGURE 3-2 Algorithm for treatment of hypertension. Drug therapy recommendations are graded with strength of recommendation and quality of evidence in brackets. Strength of recommendations: A, B, and C are good, moderate, and poor evidence to support recommendation, respectively. Quality of evidence: (1) evidence from more than one properly randomized controlled trial; (2) evidence from at least one well-designed clinical trial with randomization, from cohort or case-controlled studies, or dramatic results from uncontrolled experiments or subgroup analyses; (3) evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert communities.
FIGURE 3-3 Compelling indications for individual drug classes. Compelling indications for specific drugs are evidenced-based recommendations from outcome studies or existing clinical guidelines. The order of drug therapies serves as a general guidance that should be balanced with clinical judgment and patient response; however, standard pharmacotherapy should be considered first-line recommendations, preferably in the order depicted. Then add-on pharmacotherapy recommendations are intended to further reduce risk of cardiovascular events when additional pharmacotherapy is needed to lower blood pressure to goal values. Blood pressure control should be managed concurrently with the compelling indication. Drug therapy recommendations are graded with strength of recommendation and quality of evidence in brackets. Strength of recommendations: A, B, and C are good, moderate, and poor evidence to support recommendation, respectively. Quality of evidence: (1) evidence from more than one properly randomized controlled trial; (2) evidence from at least one well-designed clinical trial with randomization, from cohort or case-controlled analytic studies or multiple time series, or dramatic results from uncontrolled experiments or subgroup analyses; (3) evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert communities.
All patients with prehypertension and hypertension should be prescribed lifestyle modifications. Recommended modifications that have been shown to lower BP are listed in Table 3-4.1,26 They can provide small to moderate reductions in SBP. Aside from lowering BP in patients with known hypertension, lifestyle modification can decrease the progression to hypertension in patients with prehypertension BP values.26
TABLE 3-4 Lifestyle Modifications to Prevent and Manage Hypertension
A sensible dietary program is one that is designed to reduce weight gradually (for overweight and obese patients) and one that restricts sodium intake with only moderate alcohol consumption. Successful implementation of dietary lifestyle modifications by clinicians requires aggressive promotion through reasonable patient education, encouragement, and continued reinforcement. Patients may better understand the rationale for dietary intervention in hypertension if they are provided the following three observations and facts26:
1. Weight loss, as little as 10 lb (4.5 kg), can decrease BP significantly in overweight patients.
2. Diets rich in fruits and vegetables and low in saturated fat have been shown to lower BP in patients with hypertension.
3. Most people experience some degree of BP reduction with sodium restriction.
The Dietary Approaches to Stop Hypertension (DASH) eating plan is a diet that is rich in fruits, vegetables, and low-fat dairy products with a reduced content of saturated and total fat. It is recommended as a reasonable and feasible diet that is proven to lower BP. Intake of sodium should be minimized as much as possible, ideally to 1.5 g/day, although an interim goal of <2.3 g/day may be reasonable considering the difficulty in achieving these low intakes. Patients should be aware of the multiple sources of dietary sodium (e.g., processed foods, soups, table salt) so that they may follow these recommendations. Potassium intake should be encouraged through fruits and vegetables with high content (ideally 4.7 g/day) in those with normal kidney function or without impaired potassium excretion. Excessive alcohol use can either cause or worsen hypertension. Patients with hypertension who drink alcoholic beverages should restrict their daily intake.
Carefully designed programs of physical activity can lower BP. Regular physical activity for at least 30 minutes most days of the week is recommended for all adults, with at least 60 minutes recommended for adults attempting to lose weight or maintain weight loss.27 Studies have shown that aerobic exercise can reduce BP, even in the absence of weight loss. Patients should consult their physicians before starting an exercise program, especially those with CV and/or hypertension-associated target-organ disease.
Cigarette smoking is not a secondary cause of essential hypertension; it is a major, independent, modifiable risk factor for CV disease. Patients with hypertension who smoke should be counseled regarding the additional health risks that result from smoking. Moreover, the potential benefits that cessation can provide should be explained to encourage cessation.
ACE inhibitors, angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs), and thiazide diuretics are considered primary antihypertensive agents that may be acceptable first-line options (Table 3-5). These agents should be used to treat the majority of patients with hypertension because evidence from outcome data have demonstrated CV risk reduction benefits with these classes. Several have subclasses where significant differences in mechanism of action, clinical use, side effects, or evidence from outcome studies exist. β-Blockers are effective antihypertensive agents that previously were considered primary agents. They are now preferred either to treat a specific compelling indication or in combination with one or more of the aforementioned primary antihypertensive agents for patients without a compelling indication. Other antihypertensive drug classes are considered alternative drug classes that may be used in select patients after first-line agents (Table 3-6).
TABLE 3-5 First-Line and Other Common Antihypertensive Agents
TABLE 3-6 Alternative Antihypertensive Agents
Thiazide Diuretics as Historical First-Line Agents
Landmark placebo-controlled clinical trials demonstrate that thiazide diuretic therapy irrefutably reduces risk of CV morbidity and mortality.28 The Systolic Hypertension in the Elderly Program (SHEP),8Swedish Trial in Old Patients with Hypertension (STOP-Hypertension),9 and Medical Research Council (MRC)10 studies showed significant reductions in stroke, MI, all-cause CV disease, and mortality with thiazide diuretic–based therapy versus placebo. These trials allowed for β-blockers as add-on therapy for BP control. Newer agents (e.g., ACE inhibitors, ARBs, and CCBs) were not available at the time of these studies. However, subsequent clinical trials have compared these newer antihypertensive agents with thiazide diuretics.29–34 These data show similar effects, but most trials used a prospective open-label, blinded end point (PROBE) study methodology that is not double-blinded and limited their ability to prove equivalence of newer drugs to diuretics. Other prospective trials have compared different primary antihypertensive agents with each other.35,36 Although these studies used head-to-head comparisons, they did not use a thiazide diuretic as their comparator treatment.
The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) The results of the ALLHAT were the deciding evidence that the JNC7 used to justify thiazide diuretics as first-line therapy.32 It was designed to test the hypothesis that newer antihypertensive agents (an α-blocker, ACE inhibitor, or dihydropyridine CCB) would be superior to thiazide diuretic–based therapy. The primary objective was to compare the combined end point of fatal CHD and nonfatal MI. Other hypertension-related complications (e.g., heart failure, stroke) were evaluated as secondary end points. This was the largest prospective hypertension trial ever conducted and included 42,418 patients aged 55 and older with hypertension and one additional CV risk factor. This double-blind trial randomized patients to chlorthalidone-, amlodipine-, doxazosin-, or lisinopril-based therapy for a mean of 4.9 years.
The doxazosin arm was terminated early when a significantly higher risk of heart failure versus chlorthalidone was observed.37 The other arms were continued as scheduled and no significant differences in the primary end point was seen between the chlorthalidone and lisinopril or amlodipine treatment groups. However, chlorthalidone had statistically fewer secondary end points than amlodipine (heart failure) and lisinopril (combined CV disease, heart failure, and stroke). The study conclusions were that chlorthalidone-based therapy was superior in preventing one or more major forms of CV disease and was less expensive than amlodipine- or lisinopril-based therapy.
ALLHAT was designed as a superiority study with the hypothesis that amlodipine, doxazosin, and lisinopril would be better than chlorthalidone.38 It did not prove this hypothesis because the primary end point was no different between chlorthalidone, amlodipine, and lisinopril. Many subgroup analyses of specific populations (e.g., black patients, CKD, diabetes) from the ALLHAT have been conducted to assess response in certain unique patient populations.39–41 Surprisingly, none of these analyses demonstrated superior CV event reductions with lisinopril or amlodipine versus chlorthalidone. Overall, thiazide diuretics remain unsurpassed in their ability to reduce CV morbidity and mortality in most patients.
JNC7 guidelines (from 2003) recommend thiazide diuretics as a first-line therapy option for most patients, and are consistent with the historical treatment of hypertension.1 The AHA 2007 guidelines clearly identify thiazide diuretics as a first-line therapy option, comparable to an ACE inhibitor, ARB, or CCB for first-line therapy. Contrary to the historical preference to use a thiazide diuretic as the preferred first-line agent for treating most patients with hypertension, they are simply one of four first-line drug therapy options. Figure 3-2 displays the algorithm for the treatment of hypertension and highlights that four drug classes are considered first-line agents for patients without a compelling indication for a specific drug class.
Is chlorthalidone superior to hydrochlorothiazide?
Chlorthalidone (thiazide-like) undisputedly reduces CV morbidity and mortality. It was used in the most influential landmark long-term placebo-controlled trials in hypertension, and is almost twice as potent in lowering BP on a milligram-per-milligram basis as hydrochlorothiazide, which has not been as extensively studied in major long-term hypertension clinical trials. In clinical practice, it is well accepted that CV benefits in hypertension apply to all thiazide diuretics, and benefits are considered a class effect. However, it is not definitively known if the clinical benefits of reducing CV morbidity and mortality that have been proven with chlorthalidone can be extrapolated to hydrochlorothiazide.
ACE Inhibitors, ARBs, and CCBs as First-Line Agents
Clinical trial data cumulatively demonstrate that ACE inhibitor–, CCB-, or ARB-based antihypertensive therapy reduces CV events. These agents may be used for patients without compelling indications as a first-line therapy. The Blood Pressure Lowering Treatment Trialists’ Collaboration has evaluated the incidence of major CV events and death among different antihypertensive drug classes from 29 major randomized trials in 162,341 patients.42 In placebo-controlled trials, the incidences of major CV events were significantly lower with ACE inhibitor– and CCB-based regimens versus placebo. Although there were differences in the incidences of certain CV events in some comparisons (e.g., stroke was lower with diuretic or CCB-based regiments versus ACE inhibitor–based regimens), there were no differences in total major CV events when ACE inhibitors, CCBs, or diuretics were compared with each other. In studies evaluating ARB-based therapy to control regimens, the incidence of major CV events was lower with ARB-based therapy. However, the control regimens used in these comparisons included both active antihypertensive drug therapies and placebo.
Data from meta-analyses may not be as influential as data from well-designed, prospective, randomized controlled trials (e.g., the ALLHAT). However, they provide clinically useful data that support using ACE inhibitor–, CCB-, or ARB-based treatment for hypertension as first-line antihypertensive agents. Clinicians can use meta-analyses data as supporting evidence when selecting a first-line antihypertensive regimen for hypertension in most patients.
Other major consensus guidelines recommend multiple first-line options for treating hypertension in most patients. The 2013 European Society of Hypertension/European Society of Cardiology guidelines and the 2011 UK’s National Institute for Health and the Clinical Excellence guidelines list more than one drug therapy option as an acceptable first-line treatment approach.43,44 The European Society of Hypertension/European Society of Cardiology guidelines are founded on the principle that CV risk reduction is a function of BP control that is largely independent of specific antihypertensives.43 The UK guidelines stratify patients based on age and race; they recommend an ACE inhibitor or ARB first line for patients under the age of 55, and a CCB first line for patients age 55 or older or for black patients.44
β-Blockers Versus First-Line Agents Clinical trial data cumulatively suggest that β-blockers may not reduce CV events to the extent that ACE inhibitors, ARBs, CCBs, or thiazide diuretics do. These data are from three meta-analyses of clinical trials evaluating β-blocker–based therapy for hypertension.45–48 Overall, these analyses demonstrated fewer reductions in CV events with β-blocker–based antihypertensive therapy compared mostly with ACE inhibitor– and CCB-based therapy. Although comparative data with ARB-based therapy are more limited, a similar trend was observed.
Meta-analyses data evaluating β-blockers and their ability to reduce CV events have limitations. Most studies that were included used atenolol as the β-blocker studied. Therefore, it is possible that atenolol is the only β-blocker that reduces CV events less than the other primary antihypertensive drug classes. However, consensus guidelines do extrapolate these findings to the β-blocker drug class in general.2 In the absence of a compelling indication, the 2011 UK guidelines recommend a β-blocker as fourth-line therapy, only after other primary antihypertensive agents (e.g., ACE inhibitor or ARB, CCB, thiazide diuretic) have been used.44 These findings also call in question the validity of results from prominent prospective, controlled clinical trials evaluating antihypertensive drug therapy that use β-blocker–based therapy, especially atenolol, as the primary comparator.31,36 Of note, these studies used once-daily atenolol, which may be inadequate based on the shorter half-life of this agent.
β-Blocker therapy for patients without compelling indications still has a role in the management of hypertension. It is important for clinicians to remember that β-blocker–based antihypertensive therapy does not increase risk of CV events; β-blocker–based therapy reduces risk of CV events compared with no antihypertensive therapy. Using a β-blocker as a primary antihypertensive agent is optimal when an ACE inhibitor, ARB, CCB, or thiazide diuretic cannot be used as the primary agent. β-Blockers still have an important add-on role after first-line agents to reduce BP in patients with hypertension but without compelling indications.
Is atenolol the reason that β-blockers should not be used first-line?
Many of the clinical trials included in the meta-analyses that suggest β-blocker–based therapy may not reduce CV events as well as these other agents used atenolol dosed once daily. Atenolol has a half-life of 6 to 7 hours and is nearly always dosed once daily, while immediate-release forms of carvedilol and metoprolol have half-lives of 6 to 10 and 3 to 7 hours, respectively, and are always dosed at least twice daily. Therefore, it is possible that these findings might only apply to atenolol and also that these findings may be a result of using atenolol once daily instead of twice daily.
Patients with Compelling Indications
The JNC7 report identifies six compelling indications.1 Compelling indications represent specific comorbid conditions where evidence from clinical trials supports using specific antihypertensive classes to treat both the compelling indication and hypertension. Drug therapy recommendations typically consist of combination drug therapies (see Fig. 3-3). Data from these clinical trials have demonstrated reduction in CV morbidity and/or mortality that justify use for patients with hypertension and with such a compelling indication. Some compelling indications include recommendations that are provided by other national treatment guidelines, or from newer clinical trials, which are complementary to the JNC7 guidelines.
Heart Failure with Reduced Ejection Fraction Five drug classes are listed as compelling indications for heart failure with reduced ejection fraction (HFrEF), also known as systolic heart failure or left ventricular dysfunction.49The primary physiologic abnormality in this compelling indication is decreased CO resulting from a decrease left ventricular ejection fraction. An evidence-based pharmacotherapy regimen for HFrEF, sometimes called standard pharmacotherapy, consists of three to four drugs: an ACE inhibitor or ARB plus diuretic therapy, followed by the addition of an appropriate β-blocker, and possibly an aldosterone receptor antagonist.
Evidence from clinical trials shows that ACE inhibitors significantly modify disease progression by reducing morbidity and mortality. Although HFrEF was the primary disease in these studies, ACE inhibitor therapy will also control BP in patients with systolic heart failure and hypertension. ARBs are acceptable as an alternative therapy for patients who cannot tolerate ACE inhibitors based on data from the Candesartan in Heart Failure—Assessment of Reduction in Mortality and Morbidity (CHARM) studies.50 An ACE inhibitor or ARB should be started with low doses for patients with HFrEF, especially those in acute exacerbation. Heart failure induces a compensatory high-renin condition, and starting ACE inhibitors or ARBs under these conditions can cause a pronounced first-dose effect and possible orthostatic hypotension.
Diuretics are also a part of standard pharmacotherapy primarily to control symptoms. They provide symptomatic relief of edema by inducing diuresis. Loop diuretics are often needed, especially for patients with more advanced heart failure. However, some patients with well-controlled heart failure and without significant CKD may be managed with a thiazide diuretic.
β-Blocker therapy is appropriate to further modify disease in HFrEF and is a component of standard therapy for these patients. For patients on an initial regimen of diuretics and ACE inhibitors, β-blockers have been shown to reduce CV morbidity and mortality.51,52 It is of paramount importance that β-blockers be dosed appropriately due to the risk of inducing an acute exacerbation of heart failure. They must be started in very low doses, doses much lower than that used to treat hypertension, and titrated slowly to high doses based on tolerability. Bisoprolol, carvedilol, and sustained-release metoprolol succinate are the only β-blockers proven to be beneficial in HFrEF.
After implementation of a standard three-drug regimen (diuretic, ACE inhibitor or ARB, and β-blocker), other agents may be added to further reduce CV morbidity and mortality, and reduce BP if needed. The addition of an aldosterone antagonist can reduce CV morbidity and mortality in HFrEF.53,54 Spironolactone has been studied in severe HFrEF and has shown benefit in addition to diuretic and ACE inhibitor therapy.53 Eplerenone has been studied in patients with symptomatic HFrEF within 3 to 14 days after an acute MI in addition to a standard three-drug regimen and in patients with mild left ventricular dysfunction.54,55 Spironolactone and eplerenone are similar in their ability to lower risk of CV events in HFrEF.56 For patients self-described as African Americans, the combination of a fixed dose of isosorbide dinitrate and hydralazine to standard three-drug regimen is recommended as an option to improve CV outcomes.49
Post-MI β-Blockers (those without intrinsic sympathomimetic activity [ISA]) and ACE inhibitor or ARB therapy are recommended in the AHA/American College of Cardiology Foundation and JNC7 guidelines.1,2,57 β-Blockers decrease cardiac adrenergic stimulation and have been shown in clinical trials to reduce the risk of a subsequent MI or sudden cardiac death. ACE inhibitors have been shown to improve cardiac remodeling and cardiac function and to reduce CV events post-MI. These two drug classes, with β-blockers first, are considered the first drugs of choice for patients who have experienced an MI. One study, the Valsartan in Acute MI (VALIANT) trial, demonstrated that ARB therapy is similar to ACE inhibitor therapy for patients post-MI with heart failure and/or left ventricular systolic dysfunction.58
Coronary Artery Disease Chronic stable angina and acute coronary syndrome (unstable angina and acute MI) are forms of coronary artery disease (aka ischemic heart disease).57,59 These are the most common forms of hypertension-associated target-organ disease. This compelling indication is also referred to as high coronary disease risk and high CV disease risk in the JNC7.1 This compelling indication does not refer to patients without established CV disease (primary prevention patients) even if they have very high Framingham risk score (e.g., >20% over 10 years). β-Blocker therapy has been considered a standard of care for treating patients with coronary artery disease and hypertension. β-Blockers are first-line therapy in chronic stable angina and have the ability to reduce BP and improve ischemic symptoms by decreasing myocardial oxygen consumption and demand. β-Blocker therapy seems to be most effective in reducing the risk of CV events in patients with recent MI and/or ischemic symptoms. However, recent evidence indicates that the long-term risk of CV events and mortality may not be reduced with β-blocker in patients with very stable coronary artery disease (i.e., do not have ischemic symptoms or have a distant history of MI).60
Long-acting CCBs may considered alternatives to β-blockers (the nondihydropyridine CCBs diltiazem and verapamil) or as add-on therapy (dihydropyridine CCBs) in chronic stable angina for patients with ischemic symptoms.59The International Verapamil–Trandolapril Study (INVEST) demonstrated no difference in CV risk reduction when β-blocker–based therapy was compared with nondihydropyridine CCB-based therapy in this population.61Nonetheless, the preponderance of data is with β-blockers and they remain the therapy of choice.1,57,59
For acute coronary syndromes (ST-elevation MI and unstable angina/non–ST-segment MI), first-line therapy should consist of a β-blocker and ACE inhibitor.62,63 An ARB is a reasonable alternative to an ACE inhibitor. This regimen will lower BP, control acute ischemia, and reduce CV risk.
CCBs (especially nondihydropyridine CCBs) and β-blockers provide antiischemic effects; they lower BP and reduce myocardial oxygen demand in patients with hypertension and coronary artery disease. However, cardiac stimulation may occur with dihydropyridine CCBs (particularly immediate release formulations) or β-blockers with ISA, making these agents less desirable. Therefore, β-blockers with ISA should be avoided. Nondihydropyridine CCBs should be used as alternatives to β-blockers, and dihydropyridines should be add-on therapy to β-blockers.
Once ischemic symptoms are controlled with β-blocker and/or CCB therapy, other antihypertensive drugs can be added to provide additional CV risk reduction. Clinical trials have demonstrated that the addition of an ACE inhibitor further reduces CV events in patients with chronic stable angina.64 ARBs may provide similar benefits but have not been as extensively studied as ACE inhibitors.64 Therefore, in coronary artery disease, ARBs are generally considered an alternative to ACE inhibitor therapy. Thiazide diuretics can be added thereafter to provide additional BP lowering and to further reduce CV risk; they do not provide antiischemic effects.
Diabetes Mellitus The primary cause of mortality in diabetes is CV disease, and hypertension management is a very important risk reduction strategy.1,17 Five antihypertensive agents have evidence supporting their compelling indications in diabetes (see Fig. 3-3). All of these agents have been shown to reduce CV events in patients with diabetes. However, risk reduction may not be equal when comparing these agents.
All patients with diabetes and hypertension should ideally be treated with an ACE inhibitor or an ARB.17 Pharmacologically, both of these agents should provide nephroprotection due to vasodilation in the efferent arteriole of the kidney. Moreover, ACE inhibitors have overwhelming data demonstrating CV risk reduction in patients with established forms of heart disease. Evidence from clinical studies have demonstrated reductions in both CV risk (mostly with ACE inhibitors) and reduction in risk of progressive kidney dysfunction (mostly with ARBs) in patients with diabetes.17 There is debate surrounding which agent is better because data support both drug classes. Nonetheless, either drug class should be used to control BP as one of the drugs in the antihypertensive regimen for patients with diabetes, and multiple agents are often needed to attain goal BP values.
CCBs are the most appropriate add-on agents for BP control for patients with diabetes. Data indicate that these are the most optimal second agent added to either an ACE inhibitor or an ARB. Specifically, in the cohort of patients with diabetes from the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial, the combination of an ACE inhibitor with a CCB was better at reducing CV events than the combination of an ACE inhibitor with a thiazide.65 The ACCOMPLISH trial is discussed later in this chapter.
A thiazide diuretic is recommended as an add-on agent to lower BP and provide additional CV risk reduction. A subgroup analysis of patients with diabetes from the ALLHAT trial showed no difference in long-term risk of CV events in the chlorthalidone and lisinopril treatment groups.40 Therefore, some argue that thiazide diuretics, used in low doses, are equally effective for patients with hypertension and diabetes. Nonetheless, the entire body of evidence evaluating pharmacotherapy for patients with hypertension and diabetes supports an ACE inhibitor or ARB first line.1,17,18,66
β-Blockers, similar to CCBs, are useful add-on agents for BP control for patients with diabetes. These agents should also be used to treat another compelling indication (e.g., post-MI). β-Blockers (especially nonselective agents) can possibly mask the signs and symptoms of hypoglycemia in patients with tightly controlled diabetes because most of the symptoms of hypoglycemia (e.g., tremor, tachycardia, and palpitations) are mediated through the sympathetic nervous system. Sweating, a cholinergically mediated symptom of hypoglycemia, should still occur during a hypoglycemic episode despite β-blocker therapy. Patients may also have a delay in hypoglycemia recovery time because compensatory recovery mechanisms need the catecholamine inputs that are antagonized by β-blocker therapy. Finally, unopposed α-receptor stimulation during the acute hypoglycemic recovery phase (due to endogenous epinephrine release intended to reverse hypoglycemia) may result in acutely elevated BP due to vasoconstriction. Despite these potential problems, β-blockers can be safely used for patients with diabetes.
Based on the weight of all evidence, ACE inhibitors or ARBs are preferred first-line agents for controlling hypertension in diabetes. The need for combination therapy should be anticipated, and a CCB should be the second agent added. Thiazide diuretics, and even β-blockers, are useful evidence-based agents in this population, but are considered add-on therapies to the aforementioned agents.
Chronic Kidney Disease Patients with hypertension may develop damage to either the renal tissue (parenchyma) or the renal arteries.19 CKD initially presents as moderately increased albuminuria (urine albumin-to-creatinine ratio 30 to 299 mg/g [3.4 to 33.8 mg/mmol] on a spot urine sample or ≥30 mg albumin in a 24-hour urine collection) that can progress to overt kidney failure. The rate of kidney function deterioration is accelerated when both hypertension and diabetes are present. Once patients have an estimated GFR <60 mL/min/1.73 m2 or albuminuria, they have significant CKD and risk of CV disease and progression to severe CKD increases.1 BP control can slow the decline in kidney function.
In addition to lowering BP, ACE inhibitors and ARBs reduce intraglomerular pressure, which can theoretically provide additional benefits by further reducing the decline in kidney function. ACE inhibitors and ARBs have been shown to reduce progression of CKD in diabetes17,18 and in those without diabetes.19,67 It is difficult to differentiate whether the kidney protection benefits are from RAAS blockade versus BP lowering. A meta-analysis failed to demonstrate any unique long-term kidney protective effects of RAAS-blocking drugs compared with other antihypertensive drugs.68 Moreover, a subgroup analysis of patients from the ALLHAT stratified by different baseline GFR values also did not show a difference in long-term outcomes with chlorthalidone versus lisinopril.39 Nonetheless, consensus guidelines recommend either an ACE inhibitor or an ARB as first-line therapy to control BP and preserve kidney function in CKD, and patients with urine albumin excretion >30 to 300 mg per 24 hours (or equivalent) should be treated to a goal BP of 130/80 mm Hg.
Patients may experience a rapid and profound drop in BP or acute kidney failure when given an ACE inhibitor or ARB. The potential to produce acute kidney failure is particularly problematic in patients with bilateral renal artery stenosis or a solitary functioning kidney with stenosis. Patients with renal artery stenosis are usually older, and the condition is more common in patients with diabetes or those who smoke. Patients with renal artery stenosis do not always have evidence of kidney disease unless sophisticated tests are performed. Starting with low dosages and evaluating serum creatinine soon after starting the drug can minimize this risk.
Recurrent Stroke Prevention Ischemic stroke (not hemorrhagic stroke) and transient ischemic attack are considered a form of hypertension-associated target-organ damage.69 Attaining goal BP values in patients who have experienced an ischemic stroke is considered a primary modality to reduce risk of a second stroke. A thiazide diuretic, either in combination with an ACE inhibitor or as monotherapy, is considered an evidence-based antihypertensive regimen for patients with a history of stroke or transient ischemic attack.1,69,70 ARBs have also been studied in this population.71,72 Antihypertensive drug therapy should only be implemented after patients have stabilized following an acute cerebrovascular event.
Alternative Drug Treatments
It is necessary to use other agents such as a direct renin inhibitor, α-blockers, central α2-agonists, adrenergic inhibitors, and arterial vasodilators in some patients. Although these agents are effective in lowering BP, they do not have compelling outcome data showing reduced morbidity and mortality in hypertension. Moreover, there is a much greater incidence of adverse effects with some of these agents (i.e., α-blockers, central α2-agonists, and arterial vasodilators) than with first-line agents. They are generally reserved for patients with resistant hypertension or as add-on therapy with multiple other primary antihypertensive agents.
Special Populations Selection of drug therapy should follow the guidelines provided by established guidelines, which are summarized in Figures 3-2 and 3-3.1 These should be maintained as the guiding principles of drug therapy. However, there are some patient populations where the approach to drug therapy may be slightly different, or utilize recommended agents using tailored dosing strategies. In some cases, this is because other agents have unique properties that benefit a coexisting condition, but may not be based on evidence from outcome studies in hypertension.
Hypertension in Older People Hypertension often presents as isolated systolic hypertension in the elderly.73 Epidemiologic data indicate that CV morbidity and mortality are more directly correlated to SBP than to DBP for patients aged 50 and older, so this population is at high risk for hypertension-related target-organ damage.1 Although several placebo-controlled trials have specifically demonstrated risk reduction in this form of hypertension, many older people with hypertension are either not treated, or treated but not controlled.
The SHEP was a landmark double-blind, placebo-controlled trial that evaluated chlorthalidone-based treatment (with atenolol or reserpine as add-on therapy) for isolated systolic hypertension.8 A 36% reduction in total stroke, a 27% reduction in coronary artery disease, and 55% reduction in heart failure were demonstrated versus placebo. The Systolic Hypertension in Europe (Syst-Eur) trial was another placebo-controlled trial that evaluated treatment with a long-acting dihydropyridine CCB.11 Treatment resulted in a 42% reduction in stroke, 26% reduction in coronary artery disease, and 29% reduction in heart failure. These data clearly demonstrate reductions in CV morbidity and mortality in older patients with isolated systolic hypertension, especially with thiazide diuretics and long-acting dihydropyridine CCBs.
The very elderly population (i.e., ≥80 years of age) were underrepresented in the SHEP and Syst-Eur studies. Historically, this population often was not treated to goal either because of a fear of side effects or because of limited data demonstrating benefit. However, the Hypertension in the Very Elderly Trial (HYVET) provided definitive evidence that antihypertensive drug therapy provides significant clinical benefits in the very elderly.74 The HYVET was a prospective controlled clinical trial that randomized patients 80 years and older with hypertension to placebo or antihypertensive drug therapy. It was stopped early after a median of only 1.8 years because the incidence of death was 21% higher in placebo-treated patients. Based on these results, hypertension should be treated in the very elderly. This is also recommended by the AHA in a 2011 consensus statement on hypertension in the elderly.73
Thiazide diuretics or β-blockers have been compared with either ACE inhibitors or CCBs in elderly patients with either systolic hypertension, diastolic hypertension, or both in the Swedish Trial in Old Patients with Hypertension-2 (STOP-2) study.75 In this trial no significant differences were seen between conventional drugs and either ACE inhibitors or CCBs. However, there were significantly fewer MIs and cases of heart failure in the ACE inhibitor group compared with the CCB group. These data suggest that overall treatment may be more important than specific antihypertensive agents in this population.
Elderly patients are more sensitive to volume depletion and sympathetic inhibition than younger patients. This may lead to orthostatic hypotension (see next section). In the elderly, this can increase the risk of falls due to the associated dizziness. Centrally acting agents and α1-blockers should generally be avoided or used with caution in the elderly because they are frequently associated with dizziness and orthostatic hypotension. Diuretics, ACE inhibitors, and ARBs provide significant benefits and can safely be used in the elderly, but smaller-than-usual initial doses must be used for initial therapy.
The JNC7 and 2007 AHA goal BP recommendations are independent of age.1,2 However, the AHA published an expert consensus on hypertension in the elderly in 2011.73 Although age-adjusted goals are generally not recommended, for patients aged 80 years and older, a SBP of 140 to 145 mm Hg is recommended as appropriate for patients who do not tolerate treatment with a goal SBP of <140 mm Hg. The treatment of hypertension in older patients should follow the same principles that are outlined for general care of hypertension. However, initial drug doses may be lower, and dosage titrations over a longer period of time are usually needed to minimize the risk of hypotension.
How aggressively should BP be lowered in the very elderly?
It has been advocated for several years to target standard BP goals in the elderly population, regardless of age. This is a well-accepted standard of care for patients with hypertension who continue to have elevated BP as they age, meaning that a patient with a history of hypertension should not have his or her BP goal adjusted just because he or she has become older. However, for patients who initially develop hypertension when they are very elderly, it is less clear what their BP goal should be. The HYVET trial established that treating hypertension in patients aged 80 years or older reduces mortality, but the treatment goal in that population was <150/80 mm Hg with a mean SBP and DBP achieved of 145 and 79 mm Hg, respectively, at 2 years.
Patients at Risk for Orthostatic Hypotension Orthostatic hypotension is a significant drop in BP when standing and can be associated with dizziness and/or fainting. It is defined as a SBP decrease of >20 mm Hg or DBP decrease of >10 mm Hg when changing from supine to standing.1 The risk of orthostatic hypotension is increased in older patients (especially those with isolated systolic hypotension) and those with diabetes, severe volume depletion, baroreflex dysfunction, autonomic insufficiency, and on concomittant venodilators (α-blockers, mixed α-/β-blockers, nitrates, and phosphodiesterase inhibitors). For patients with these risks factors, antihypertensive agents should be started in low doses, especially diuretics, ACE inhibitors, and ARBs.
Hypertension in Children and Adolescents Detecting hypertension in children requires special attention to BP measurement, which is defined as SBP and/or DBP that is >95th percentile for sex, age, and height on at least 3 occasions.76 BP between the 90th and 95th percentile, or >120/80 mm Hg in adolescents, is considered prehypertension. Hypertensive children often have a family history of high BP, and many are overweight predisposing them to insulin resistance and associated CV disease. Unlike hypertension in adults, secondary hypertension is more common in children and adolescents. An appropriate workup for secondary causes is required if elevated BP is identified. Kidney disease (e.g., pyelonephritis, glomerulonephritis) is the most common cause of secondary hypertension in children. Coarctation of the aorta can also produce secondary hypertension. Medical or surgical management of the underlying disorder usually normalizes BP.
Nonpharmacologic treatment, particularly weight loss in those overweight, is the cornerstone of therapy for essential hypertension in children.76 The goal is to reduce the BP to <95th percentile for sex, age, and height, or <90th percentile if concurrent conditions such as CKD, diabetes, or target-organ damage are present. ACE inhibitors, ARBs, β-blockers, CCBs, and thiazide diuretics are all acceptable choices in children and have data supporting their use. ACE inhibitors, ARBs, and direct renin inhibitors are contraindicated in sexually active girls due to potential teratogenic effect. As with adults, selection of initial agents should be based on the presence of compelling indications or concurrent conditions that may warrant their use (e.g., ACE inhibitor or ARB for those with diabetes or CKD).
Pregnancy Hypertension during pregnancy is a major cause of maternal and neonatal morbidity and mortality.1,77 Hypertension during pregnancy is categorized as preeclampsia, eclampsia, gestational, chronic, and superimposition of preeclampsia on chronic hypertension. Preeclampsia, defined as an elevated BP >140/90 mm Hg that appears after 20 weeks’ gestation accompanied by new-onset proteinuria (≥300 mg/24 hours), can lead to life-threatening complications for both mother and fetus. Eclampsia, the onset of convulsions in preeclampsia, is a medical emergency. Gestational hypertension is defined as new-onset hypertension arising after midpregnancy in the absence of proteinuria, and chronic hypertension is elevated BP that is noted before the pregnancy began. It is controversial whether treating elevated BP for patients with chronic hypertension in pregnancy is beneficial. However, women with chronic hypertension prior to pregnancy are at increased risk of a number of complications including superimposed preeclampsia, preterm delivery, fetal growth restriction or demise, placental abruption, heart failure, and acute kidney failure.77
Definitive treatment of preeclampsia is delivery. Delivery is indicated if pending or frank eclampsia is present. Otherwise, management consists of restricting activity, bedrest, and close monitoring. Salt restriction, or any other measures that contract blood volume, should not be employed. Antihypertensive agents are used prior to induction of labor if DBP is greater than 105 mm Hg with a target DBP of 95 to 105 mm Hg. IV hydralazine is most commonly used, and IV labetalol is also effective. Immediate-release oral nifedipine has been used in the past, but it is not approved by the FDA for hypertension, and untoward fetal and maternal effects (hypotension with fetal distress) have been reported.
Many agents can be used to treat chronic hypertension in pregnancy (Table 3-7). Unfortunately, there is little consensus and few data regarding the most appropriate therapy in pregnancy. Methyldopa is still considered the drug of choice.1 It is viewed as very safe based on long-term followup data (7.5 years) that have not demonstrated adverse effects on childhood development. β-Blockers (other than atenolol), labetalol, and CCBs are also reasonable alternatives. ACE inhibitors and ARBs are known teratogens and are absolutely contraindicated.78
TABLE 3-7 Treatment of Chronic Hypertension in Pregnancy
African Americans Hypertension affects African American patients at a disproportionately higher rate, and hypertension-related target-organ damage is more prevalent than in other populations.1,79 Reasons for these differences are not fully understood, but may be related to differences in electrolyte homeostasis, GFR, sodium excretion and transport mechanisms, plasma renin activity, and BP response to plasma volume expansion.
African Americans have an increased need for combination therapy to attain and maintain BP goals.79 The International Society on Hypertension in Blacks consensus statement recommendations aggressively promote combination therapy. They recommend starting with two drugs for patients with SBP values ≥15 mm Hg from goal. This aggressive approach is reasonable considering that overall goal BP attainment rates are low in African Americans.
BP-lowering effects of antihypertensive classes vary in African Americans, primarily when used as monotherapy. Thiazide diuretics and CCBs are most effective at lowering BP in African Americans. When either of these two classes (especially thiazide diuretics) are used in combination with a β-blocker, ACE inhibitor, or ARB (which are three classes known to be less effective at lowering BP in African Americans), antihypertensive response is significantly increased. This may be due to the low-renin pattern of hypertension in African Americans, which can result in less BP lowering with β-blockers, ACE inhibitors, or ARBs when used as monotherapy compared with white patients. Interestingly, African Americans have a higher risk of angioedema and cough from ACE inhibitors compared with whites.79
Despite potential differences in antihypertensive effects, drug therapy selection should be based on evidence, no different from what is recommended for the hypertensive population in general. Drug therapies should be used if a compelling indication is present, even if the antihypertensive effect may not be as great as with another drug class (e.g., a β-blocker is first line for BP control in an African American patient who is post-MI).
Other Concomitant Conditions
Most patients with hypertension have some other coexisting conditions that may influence selection or utilization of drug therapy. The influence of concomitant conditions should only be complementary to, and never in replacement of, drug therapy choices indicated by compelling indications. Under some circumstances, these considerations are helpful in deciding on a particular antihypertensive agent when more than one antihypertensive class is recommended to treat a compelling indication. In some cases, an agent should be avoided because it may aggravate a concomitant disorder. In other cases, an antihypertensive can be used to treat hypertension, a compelling indication, and another concomitant condition. These are briefly summarized in Table 3-5.
Pulmonary Disease and Peripheral Arterial Disease β-Blockers, especially nonselective agents, have been generally avoided for patients with hypertension and reactive airway disease (asthma or chronic obstructive pulmonary disease [COPD] with a reversible obstructive component) due to a fear of inducing bronchospasm.80 This precaution is more of a myth than a fact. Data suggest that cardioselective β-blockers can safely be used in patients with asthma or COPD.81 Therefore, cardioselective β-blockers should be used to treat a compelling indication (i.e., post-MI, coronary disease, or heart failure) for patients with reactive airway disease.
PAD is considered a noncoronary form of atherosclerotic vascular disease and is a coronary artery disease risk equivalent.57,80 β-Blockers can theoretically be problematic for patients with PAD due to possible decreased peripheral blood flow secondary to unopposed stimulation of α1-receptors that results in vasoconstriction. If problematic, this can be mitigated by using a β-blocker that also has α1-blocking properties (e.g., carvedilol). However, β-blockers are not contraindicated in PAD and have not been shown to adversely affect walking capacity.82
Metabolic Syndrome Metabolic syndrome is a cluster of multiple cardiometabolic risk factors.12 It has been most recently defined as the presence of three of the following five criteria: abdominal obesity (based on waist circumference measurements), elevated triglycerides, low HDL cholesterol, elevated BP (≥130/≥85 mm Hg or receiving drug treatment for high BP), and elevated fasting blood glucose.12
Despite the debate regarding whether or not metabolic syndrome is a true “disease” or rather simply a cluster of risk factors, it is widely accepted that patients with metabolic syndrome have increased risk of developing CV disease and/or type 2 diabetes. Using an ACE inhibitor or ARB is associated with the lowest rate of developing new-onset diabetes in patients with hypertension.83 However, studies specifically evaluating the most effective antihypertensive regimen for patients with metabolic syndrome have not been done. In addition, an ALLHAT subgroup analysis of patients with impaired fasting glucose showed that CV events were reduced more with chlorthalidone compared with lisinopril.40 Thus, thiazide diuretics can be used first line for patients with metabolic syndrome, similar to ACE inhibitors, ARBs, or CCBs, but treated patients will have a higher risk of developing elevated fasting glucose.
Erectile Dysfunction Most antihypertensive agents have been associated with erectile dysfunction in men.84 However, it is not clear if erectile dysfunction associated with antihypertensive treatment is solely a result of drug therapy or rather a symptom of underlying vascular disease. β-Blockers have traditionally been labeled as agents that significantly cause sexual dysfunction, and many practitioners have avoided prescribing them as a result. However, data supporting this notion are limited. A systematic review of 15 studies involving 35,000 patients assessing β-blocker use for MI, heart failure, and hypertension found only a very slight increased risk for erectile dysfunction.85 In addition, prospective long-term data from the Treatment of Mild Hypertension Study (TOMHS) and the Veterans Administration Cooperative trial show no difference in the incidence of erectile dysfunction between diuretics and β-blockers versus ACE inhibitors and CCBs.86,87 Centrally acting agents are associated with higher rates of sexual dysfunction and should be avoided in men with erectile dysfunction.
Hypertensive men frequently have atherosclerotic vascular disease, which frequently results in erectile dysfunction. Therefore, erectile dysfunction is associated with chronic arterial changes resulting from elevated BP, and lack of control may increase the risk of erectile dysfunction. These changes are even more pronounced in hypertensive men with diabetes.
Individual Antihypertensive Agents
ACE Inhibitors ACE inhibitors are a first-line therapy option in most patients with hypertension.1,2,6 The ALLHAT demonstrated less heart failure and stroke with chlorthalidone versus lisinopril.31 However, another outcome study has demonstrated similar, if not better, outcomes with ACE inhibitors versus hydrochlorothiazide.34 It is possible that the different thiazide diuretics have different abilities to reduce hypertension-associated target-organ damage. Nonetheless, most clinicians will agree that if ACE inhibitors are not the first agent used in most patients with hypertension, they should be the second agent used.
ACE facilitates production of angiotensin II that has a major role in arterial BP regulation as depicted in Figure 3-1. ACE is distributed in many tissues and is present in several different cell types, but its principal location is in endothelial cells. Therefore, the major site for angiotensin II production is in the blood vessels, not the kidney. ACE inhibitors block the ACE, thus inhibiting conversion of angiotensin I to angiotensin II. Angiotensin II is a potent vasoconstrictor that stimulates aldosterone secretion, causing an increase in sodium and water reabsorption with accompanying potassium loss. By blocking the ACE, vasodilation and a decrease in aldosterone occur.
ACE inhibitors also block degradation of bradykinin and stimulate the synthesis of other vasodilating substances (prostaglandin E2 and prostacyclin). The observation that ACE inhibitors lower BP in patients with normal plasma renin activity suggests that bradykinin and perhaps tissue production of ACE are important in hypertension. Increased bradykinin enhances the BP-lowering effects of ACE inhibitors, but also is responsible for the side effect of dry cough. ACE inhibitors effectively prevent or regress LVH by reducing direct stimulation by angiotensin II on myocardial cells.
There are many evidence-based uses for ACE inhibitors (see Fig. 3-3). ACE inhibitors reduce CV morbidity and mortality in patients with HFrEF,49 and decrease progression of CKD.66 They should be first line as disease-modifying therapy in all of these patients unless absolutely contraindicated. ACE inhibitors (or ARBs in certain patients) are first line for patients with diabetes and hypertension because of demonstrated CV disease and kidney benefits. A regimen including an ACE inhibitor with a thiazide diuretic is considered first line in recurrent stroke prevention based on proven benefits from the PROGRESS trial showing reduced risk of secondary stroke.33 In combination with β-blocker therapy, evidence shows that ACE inhibitors further reduce CV risk in coronary disease and in patients post-MI.57,59,62,63 These benefits of ACE inhibitors occur in patients with atherosclerotic vascular disease even in the absence of left ventricular dysfunction and have the potential to reduce the development of new-onset type 2 diabetes.88
Most ACE inhibitors can be dosed once daily in hypertension (Table 3-5). In some patients, especially when higher doses are used, twice-daily dosing is needed to maintain 24-hour effects with enalapril, benazepril, moexipril, quinapril, and ramipril.
ACE inhibitors are well tolerated,89 but are not absent of side effects. They decrease aldosterone and can increase potassium serum concentrations. While this increase is usually small, hyperkalemia is possible. Patients with CKD or those on concomitant potassium supplements, potassium-sparing diuretics, ARBs, or a direct renin inhibitor are at risk for hyperkalemia. Judicious monitoring of serum potassium and creatinine values within 4 weeks of starting or increasing the dose of an ACE inhibitor can often identify these abnormalities early before they evolve into serious adverse events.
The most worrisome adverse effect of ACE inhibitor therapy is acute kidney failure. This serious adverse effect is rare, occurring in less than 1% of patients. Preexisting kidney disease increases the risk of this side effect. Bilateral renal artery stenosis or unilateral stenosis of a solitary functioning kidney renders patients dependent on the vasoconstrictive effect of angiotensin II on the efferent arteriole of the kidney, thus explaining why these patients are particularly susceptible to acute kidney failure from ACE inhibitors. Slow titration of the ACE inhibitor dose and judicious kidney function monitoring can minimize risk and allow for early detection of those with renal artery stenosis.
It is important to note that GFR does decrease somewhat in patients when started on ACE inhibitors or ARBs.90 This is attributed to the inhibition of angiotensin II vasoconstriction on the efferent arteriole. This decrease in GFR often increases serum creatinine, and small increases should be anticipated when monitoring patients on ACE inhibitors. Either modest elevations of ≤35% (for baseline creatinine values ≤3 mg/dL [265 μmol/L]) or absolute increases <1 mg/dL (88 μmol/L) do not warrant changes. If larger increases occur, ACE inhibitor therapy should be stopped or the dose reduced.
Angioedema is a serious potential complication of ACE inhibitor therapy. It occurs in <1% of the population, and it is more likely in African Americans and smokers. Symptoms include lip and tongue swelling and possibly difficulty breathing. Drug withdrawal is appropriate for treating patients with angioedema. However, angioedema associated with laryngeal edema and/or pulmonary symptoms occasionally occurs and requires additional treatment with epinephrine, corticosteroids, antihistamines, and/or emergent intubations to support respiration. A history of angioedema, even if not from an ACE inhibitor, precludes use of another ACE inhibitor (it is a contraindication). Cross-reactivity between ACE inhibitors and ARBs does not appear to be a significant concern. The Telmisartan Randomized Assessment Study in ACE-Intolerant Subjects with Cardiovascular Disease (TRANSCEND) trial enrolled 75 patients with a history of ACE inhibitor–induced angioedema, and randomized these patients to either placebo or ARB therapy.91 There were no cases of repeat angioedema among these patients. These data suggest the cross-reactivity is very low. Hence, an ARB can be used in a patient with a history of ACE inhibitor–induced angioedema when it is needed. However, clinicians should monitor for repeat occurrences, since idiopathic angioedema may still occur.
A persistent dry cough develops in up to 20% of patients treated with an ACE inhibitor. It is pharmacologically explained by the inhibition of bradykinin breakdown. This cough does not cause respiratory illness but is annoying to patients and can compromise adherence. It should be clearly differentiated from a wet cough due to pulmonary edema, which may be a sign of uncontrolled heart failure versus an ACE inhibitor–induced cough.
ACE inhibitors, as well as ARBs and direct renin inhibitors, are absolutely contraindicated in pregnancy.1,78 Female patients of childbearing age should be counseled regarding effective forms of birth control as ACE inhibitors have been associated with major congenital malformations when exposed in the first trimester and fetopathy (group of conditions that includes renal failure, renal dysplasia, hypotension, oligohydramnios, pulmonary hypotension, hypocalvaria, and death) has occurred when exposed in the second and third trimesters.78 Similar to diuretics, ACE inhibitors can increase lithium serum concentrations in patients on lithium therapy. Concurrent use of an ACE with a potassium-sparing diuretic (including aldosterone antagonists), potassium supplements, an ARB, or a direct renin inhibitor may result in hyperkalemia.
Starting doses of ACE inhibitors should be low, with even lower doses for patients at risk for orthostatic hypotension or severe renal dysfunction (e.g., elderly, CKD). Acute hypotension may occur at the onset of ACE inhibitor therapy. Patients who are sodium or volume depleted, in a heart failure exacerbation, very elderly, or on concurrent vasodilators or diuretics are at high risk for this effect. It is important to start with half the normal dose of an ACE inhibitor for all patients with these risk factors and to use slow dose titration.
ARBs Angiotensin II is generated by two enzymatic pathways: the RAAS, which involves ACE, and an alternative pathway that uses other enzymes such as chymase (aka “tissue ACE”). ACE inhibitors inhibit only the effects of angiotensin II produced through the RAAS, whereas ARBs inhibit angiotensin II from all pathways. It is unclear how these differences affect tissue concentrations of ACE. ACE inhibitors only partially block the effects of angiotensin II, although the clinical significance of this is not known.
ARBs directly block the AT1 receptor that mediates the known effects of angiotensin II in humans: vasoconstriction, aldosterone release, sympathetic activation, antidiuretic hormone release, and constriction of the efferent arterioles of the glomerulus. They do not block the AT2 receptor. Therefore, beneficial effects of AT2 receptor stimulation (vasodilation, tissue repair, and inhibition of cell growth) remain intact when ARBs are used. Unlike ACE inhibitors, ARBs do not block the breakdown of bradykinin. Therefore, some of the beneficial effects of bradykinin, such as vasodilation, regression of myocyte hypertrophy and fibrosis, and increased levels of tissue plasminogen activator, are not present with ARB therapy.
ARB therapy has been directly compared with ACE inhibitor therapy in the management of hypertension.92 The Ongoing Telmisartan Alone and in Combination with Ramipril Global End Point Trial (ON-TARGET) was a double-blind trial that randomized 25,620 patients with hypertension to ACE inhibitor–based therapy, ARB-based therapy, or the combination of an ACE inhibitor with an ARB. The primary end point was a composite end point of CV death or hospitalization for heart failure. After a median followup of 56 months, there was no difference in the primary end point between any of the three treatment groups. Therefore, these data establish that the CV event–lowering benefits of ARB therapy are similar to ACE inhibitor therapy in hypertension. Moreover, the combination of an ACE inhibitor with an ARB had no additional CV event lowering but was associated with a higher risk of side effects (renal dysfunction, hypotension). Therefore, there is no reason to use an ACE inhibitor with an ARB for the management of hypertension.
For patients with certain compelling indications, ARBs have outcome data showing long-term reductions in progression of target-organ damage. For patients with type 2 diabetes and nephropathy, progression of nephropathy has been shown to be significantly reduced with ARB therapy.17 Some benefits appear to be independent of BP lowering, suggesting that the pharmacologic effects of ARBs on the efferent arteriole may result in attenuated progression of kidney disease. For patients with HFrEF, the CHARM study showed that ARB therapy reduces risk of hospitalization for heart failure when used as an alternative therapy in ACE-intolerant patients.50
ARBs have been compared head-to-head with CCBs. The Morbidity and Mortality After Stroke: Eprosartan Versus Nitrendipine in Secondary Prevention (MOSES) trial demonstrated that eprosartan reduced the occurrence of recurrent stroke greater than nitrendipine in patients with a past medical history of cerebrovascular disease.71 Using nitrendipine was a reasonable comparator because the Syst-Eur had already demonstrated that nitrendipine reduces the occurrence of CV events, particularly stroke, in older patients with isolated systolic hypertension compared with placebo.11 These data support the common notion that ARBs may have cerebroprotective effects that may explain CV event reductions.93 Another outcome study, the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial, showed that valsartan-based therapy is equivalent to amlodipine-based therapy for the primary composite outcome of first CV event in patients with hypertension and additional CV risk factors.35 However, occurrence of certain components of the primary end point (stroke and MI) and new-onset type 2 diabetes was lower in the valsartan group. Although patients treated with amlodipine had slightly lower mean BP values than valsartan-treated patients, there was no difference in the primary end point.
The addition of low doses of a CCB or thiazide diuretic to an ARB significantly increases antihypertensive efficacy. Similar to ACE inhibitors, most ARBs have long enough half-lives to allow for once-daily dosing. However, candesartan, eprosartan, losartan, and valsartan have the shortest half-lives and may require twice-daily dosing for sustained BP lowering.
ARBs have the lowest incidence of side effects compared with other antihypertensive agents.89 Because they do not affect bradykinin, they do not illicit a dry cough like ACE inhibitors. While these drugs have been referred to as “ACE inhibitors without the cough,” pharmacologic differences highlight that they could have very different effects on vascular smooth muscle and myocardial tissue that can correlate to different effects on target-organ damage and CV risk reduction when compared with ACE inhibitors. Data from the Randomized Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) trial have demonstrated that ARB therapy delays the onset of albuminuria in patients with type 2 diabetes.94 Regardless, their first-line role for patients with type 2 diabetic nephropathy is well established, and they also are very reasonable alternatives for patients requiring an ACE inhibitor but who experience an intolerable cough.
Like ACE inhibitors, ARBs may cause renal insufficiency, hyperkalemia, and orthostatic hypotension. The same precautions that apply to ACE inhibitors for patients with suspected bilateral renal artery stenosis, those on drugs that can raise potassium, and those on drugs that increase risk of hypotension apply to ARBs. As discussed in ACE Inhibitors, ARBs, and CCBs as First-Line Agents above, patients with a history of ACE inhibitor angioedema can be treated with an ARB when needed.91 ARBs should not be used in pregnancy.
CCBs CCBs, both dihydropyridine CCBs and nondihydropyridine CCBs, are first-line therapy options and are very effective antihypertensive agents.1,2 They also have compelling indications in coronary artery disease and in diabetes. However, with these compelling indications, they are in addition to, or instead of, other first-line antihypertensive drug classes.
Contraction of cardiac and smooth muscle cells requires an increase in free intracellular calcium concentrations from the extracellular fluid. When cardiac or vascular smooth muscle is stimulated, voltage-sensitive channels in the cell membrane are opened, allowing calcium to enter the cells. The influx of extracellular calcium into the cell releases stored calcium from the sarcoplasmic reticulum. As intracellular free calcium concentration increases, it binds to a protein, calmodulin, which then activates myosin kinase enabling myosin to interact with actin to induce contraction. CCBs work by inhibiting influx of calcium across the cell membrane. There are two types of voltage-gated calcium channels: a high-voltage channel (L-type) and a low-voltage channel (T-type). Currently available CCBs only block the L-type channel, which leads to coronary and peripheral vasodilation.
The two subclasses of CCBs, dihydropyridines and nondihydropyridines (see Table 3-5), are pharmacologically very different from each other. Antihypertensive effectiveness is similar with both subclasses, but they differ somewhat in other pharmacodynamic effects. Nondihydropyridines (verapamil and diltiazem) decrease heart rate and slow atrioventricular nodal conduction. Similar to β-blockers, these drugs may also treat supraventricular tachyarrhythmias (e.g., atrial fibrillation). Verapamil produces negative inotropic and chronotropic effects that are responsible for its propensity to precipitate or cause systolic heart failure in high-risk patients. Diltiazem also has these effects but to a lesser extent than verapamil. All CCBs (except amlodipine and felodipine) have negative inotropic effects. Dihydropyridines may cause a baroreceptor-mediated reflex tachycardia because of their potent peripheral vasodilating effects. This effect appears to be more pronounced with the first-generation dihydropyridines (e.g., nifedipine) and is significantly diminished with the newer agents (e.g., amlodipine) and when given in sustained-release dosage forms. Dihydropyridines do not alter conduction through the atrioventricular node and thus are not effective agents in supraventricular tachyarrhythmias.
Dihydropyridine CCBs CCBs, both dihydropyridines and nondihydropyridines, are as effective at lowering CV events as other first-line agents in most patients with hypertension. The dihydropyridine CCBs have been extensively studied. In ALLHAT there was no difference in the primary outcome between chlorthalidone and amlodipine, and only the secondary outcome of heart failure was higher with amlodipine.32 A subgroup analysis of ALLHAT directly compared amlodipine with lisinopril and demonstrated that there was no difference in the primary outcome.95 However, amlodipine was superior to lisinopril for BP control in blacks, and for stroke reduction in blacks and in women. There was a lower risk of heart failure in the lisinopril group. As discussed previously, the VALUE study also showed no difference between valsartan and amlodipine in the primary outcome of first CV event in high-risk patients.35
Dihydropyridine CCBs are very effective in older patients with isolated systolic hypertension. The placebo-controlled Syst-Eur trial demonstrated that a long-acting dihydropyridine CCB reduced the risk of CV events markedly in isolated systolic hypertension.11 A long-acting dihydropyridine CCB should be strongly considered as preferred add-on therapy when a thiazide diuretic is not controlling BP in a patient with isolated systolic hypertension and no other compelling indications.
Among dihydropyridines, short-acting nifedipine may rarely cause an increase in the frequency, intensity, and duration of angina in association with acute hypotension. This effect is most likely due to a reflex sympathetic stimulation and is likely obviated by using sustained-release formulations of nifedipine. For this reason, all other dihydropyridines have an intrinsically long half-life or are sustained-release formulations. Immediate-release nifedipine has been associated with an increased incidence of adverse CV effects, is not approved for treatment of hypertension, and should not be used to treat hypertension. Other side effects with dihydropyridines include dizziness, flushing, headache, gingival hyperplasia, peripheral edema, mood changes, and various GI complaints. Side effects due to vasodilation such as dizziness, flushing, headache, and peripheral edema occur more frequently with all dihydropyridines than with the nondihydropyridines (i.e., verapamil, diltiazem) because they are less potent vasodilators.
Nondihydropyridine CCBs Diltiazem and verapamil can cause cardiac conduction abnormalities such as bradycardia or atrioventricular block. These problems occur mostly with high doses or when used for patients with preexisting abnormalities in the cardiac conduction system. Heart failure has been reported in otherwise healthy patients due to negative inotropic effects. Both drugs can cause anorexia, nausea, peripheral edema, and hypotension. Verapamil causes constipation in about 7% of patients. This side effect also occurs with diltiazem, but to a lesser extent.
Verapamil and to a lesser extent diltiazem can cause drug interactions due to their ability to inhibit the cytochrome P450 3A4 isoenzyme system. This inhibition can increase serum concentrations of other drugs that are metabolized by this isoenzyme system (e.g., cyclosporine, digoxin, lovastatin, simvastatin, tacrolimus, theophylline). Verapamil and diltiazem should be given very cautiously with a β-blocker because there is an increased risk of heart block with these combinations. When a CCB is needed in combination with a β-blocker for BP lowering, a dihydropyridine should be selected because it will not increase risk of heart block. The hepatic metabolism of CCBs, especially felodipine, nicardipine, nifedipine, and nisoldipine, may be inhibited by ingesting large quantities of grapefruit juice (e.g., ≥1 qt daily).
Many different formulations of verapamil and diltiazem are currently available (see Table 3-5). Although certain sustained-release verapamil and diltiazem products contain the same active drug (e.g., Calan SR and Verelan), they are usually not AB rated by the FDA as interchangeable on a milligram-per-milligram basis due to different biopharmaceutical release mechanisms. However, the clinical significance of these differences is likely negligible.
Two sustained-release verapamil products (Covera-HS and Verelan PM) and one diltiazem product (Cardizem LA) are chronotherapeutically designed to target the circadian BP rhythm. These agents are primarily dosed in the evening (with the exception of Cardizem LA, which may be dosed in the morning or evening) so that drug is released during the early morning hours when BP first starts to increase. The rationale behind chronotherapy in hypertension is that blunting the early morning BP surge may result in greater reductions in CV events than conventional dosing of regular antihypertensive products in the morning. However, evidence from the Controlled Onset Verapamil Investigation of Cardiovascular End-Points (CONVINCE) trial showed that chronotherapeutic verapamil was similar to, but not better than, a thiazide diuretic–β-blocker–based regimen with respect to CV events.30
Diuretics There are four subclasses of diuretics that are used in the treatment of hypertension: thiazide diuretics, loops, potassium-sparing agents, and aldosterone antagonists (see Table 3-5).96 Thiazide diuretics are the preferred type of diuretic for most patients with hypertension.1,2 The best available evidence justifying this recommendation is from the ALLHAT.32 Moreover, when combination therapy is needed in hypertension to control BP, a thiazide diuretic as an add-on agent, but not necessarily the second agent, is very effective in lowering BP.1,97
Loops are more potent agents for inducing diuresis, but they are not ideal antihypertensive agents unless relief of edema is also needed. In general, loops are often preferred over a thiazide diuretic for hypertension in patients with CKD when estimated GFR is <30 mL/min/1.73 m2.96 However, many patients with an estimated GFR of <30 mL/min/1.73 m2 but not on dialysis will still have antihypertensive effects with thiazide diuretics.98 This is especially true with chlorthalidone.96
Potassium-sparing diuretics are very weak antihypertensive agents when used alone and provide minimal additive effect when used in combination with a thiazide or loop diuretic. Their primary use is in combination with another diuretic to counteract the potassium-wasting properties of the other diuretic agent. Aldosterone antagonists (spironolactone and eplerenone) may be technically considered potassium-sparing agents but are more potent as antihypertensives. However, they are viewed as an independent class due to evidence supporting compelling indications.
The exact hypotensive mechanism of action of diuretics is not known, but has been well hypothesized. The drop in BP seen when diuretics are first started is caused by an initial diuresis. Diuresis causes reductions in plasma and stroke volume, which decreases CO and BP. This initial drop in CO causes a compensatory increase in PVR. With chronic diuretic therapy, extracellular fluid and plasma volume return to near pretreatment values. However, PVR decreases to values that are lower than the pretreatment baseline. This reduction in PVR is responsible for chronic antihypertensive effects.
Thiazide diuretics have additional actions that may further explain their antihypertensive effects. They mobilize sodium and water from arteriolar walls. This effect would lessen the amount of physical encroachment on the lumen of the vessel created by excessive accumulation of intracellular fluid. As the diameter of the lumen relaxes and increases, there is less resistance to the flow of blood and PVR further drops. High dietary sodium intake can blunt this effect and a low salt intake can enhance this effect. Thiazide diuretics are also postulated to cause direct relaxation of vascular smooth muscle.
Diuretics should ideally be dosed in the morning if given once daily and in the morning and late afternoon when dosed twice daily to minimize risk of nocturnal diuresis. However, with chronic use, thiazide diuretics, potassium-sparing diuretics, and aldosterone antagonists rarely cause a pronounced diuresis.
The major pharmacokinetic differences between the various thiazide diuretics are serum half-life and duration of diuretic effect. The clinical relevance of these differences is unknown because the serum half-life of most antihypertensive agents does not correlate with the hypotensive duration of action. Moreover, diuretics lower BP primarily through extrarenal mechanisms. Hydrochlorothiazide and particularly chlorthalidone are the two most frequently used thiazide diuretics in landmark clinical trials that have demonstrated reduced morbidity and mortality. Hydrochlorothiazide is considered a “thiazide-type” diuretic while chlorthalidone is a “thiazide-like” diuretic. These agents are not equipotent on a milligram-per-milligram basis; chlorthalidone is 1.5 to 2 times more potent than hydrochlorothiazide.96 This has been attributed to a longer half-life (45 to 60 hours vs. 8 to 15 hours) and longer duration of effect (48 to 72 hours vs. 16 to 24 hours) with chlorthalidone.
Diuretics are very effective in lowering BP when used in combination with most other antihypertensives. This additive response is explained by two independent pharmacodynamic effects. First, when two drugs cause the same overall pharmacologic effect (BP lowering) through different mechanisms of action, their combination usually results in an additive or synergistic effect. This is especially relevant when a β-blocker or ACE inhibitor is indicated in an African American, but does not elicit sufficient antihypertensive effect. Adding a diuretic in this situation can often significantly lower BP. Second, a compensatory increase in sodium and fluid retention may be seen with antihypertensive agents. This problem is counteracted with the concurrent use of a diuretic.
Side effects of thiazide diuretics include hypokalemia, hypomagnesemia, hypercalcemia, hyperuricemia, hyperglycemia, dyslipidemia, and sexual dysfunction. Many of these side effects were identified when high doses of thiazides were used in the past (e.g., hydrochlorothiazide 100 to 200 mg/day). Current guidelines recommend limiting the dose of hydrochlorothiazide or chlorthalidone to 12.5 to 25 mg/day, which markedly reduces the risk for most metabolic side effects. However, the most effective antihypertensive dose of hydrochlorothiazide is 50 mg daily, although many clinicians are dissuaded from this higher dose due to potential higher risk of hypokalemia.99 Loop diuretics may cause the same side effects, although the effect on serum lipids and glucose is not as significant, hypokalemia is more pronounced, and hypocalcemia may occur.
Hypokalemia and hypomagnesemia may cause muscle fatigue or cramps. However, serious cardiac arrhythmias can occur in patients with severe hypokalemia and hypomagnesemia. Patients at greatest risk for this are patients with LVH, coronary disease, post-MI, a history of arrhythmia, or those concurrently receiving digoxin. Low-dose therapy (i.e., 25 mg hydrochlorothiazide or 12.5 mg chlorthalidone daily) causes small electrolyte disturbances. However, the most effective doses of these two thiazide diuretics are hydrochlorothiazide 50 mg daily and chlorthalidone 25 mg daily. Efforts should be made to keep potassium in the therapeutic range by careful monitoring, especially if these higher doses are used.
Diuretic-induced hyperuricemia can precipitate gout. This side effect may be especially problematic for patients with a previous history of gout and is more common with thiazide diuretics. However, acute gout is unlikely in patients with no previous history of gout. If gout does occur in a patient who requires diuretic therapy, allopurinol can be given to prevent gout and will not compromise the antihypertensive effects of the diuretic. High doses of thiazide and loop diuretics may increase fasting glucose and serum cholesterol values. These effects, however, usually are transient and often inconsequential.100
Potassium-sparing diuretics can cause hyperkalemia, especially in patients with CKD or diabetes and in patients receiving concurrent treatment with an ACE inhibitor, ARB, direct renin inhibitor, or potassium supplements. Hyperkalemia is especially problematic for the newest aldosterone antagonist eplerenone. This agent is a very selective aldosterone antagonist, and its propensity to cause hyperkalemia is greater than with the other potassium-sparing agents and even spironolactone. Due to this increased risk of hyperkalemia, eplerenone is contraindicated for patients with impaired kidney function or type 2 diabetes with proteinuria (see Table 3-5). While spironolactone may cause gynecomastia in up to 10% of patients, this occurs rarely with eplerenone.
Diuretics can be used safely with most other agents. However, concurrent administration with lithium may result in increased lithium serum concentrations and can predispose patients to lithium toxicity.
β-Blockers β-Blockers have been used in several large outcome trials in hypertension. However, in most of these trials, a thiazide diuretic was the primary agent with a β-blocker added on for additional BP lowering. Moreover, as previously discussed, for patients with hypertension but without compelling indications, other primary agents (ACE inhibitors, ARBs, CCBs, thiazide diuretics) should be used as the initial first-line agent before β-blockers. While this may be surprising to experienced clinicians, this recommendation is consistent with the 2007 AHA guidelines and the 2011 UK’s National Institute for Health and the Clinical Excellence guidelines.2,44 It is based on meta-analyses that suggest β-blocker–based therapy may not reduce CV events as well as these other agents when used as the initial drug to treat patients with hypertension and without a compelling indication for a β-blocker.45–48
β-Blockers are only considered appropriate first-line agents to treat specific compelling indications (post-MI, coronary artery disease). They are also evidenced-based as additional therapy for other compelling indications (HFrEF and diabetes). Numerous trials have shown a reduced risk of CV events when β-blockers are used following an MI, during an acute coronary syndrome, or in patients with chronic stable angina with ischemic symptoms. Although once contraindicated in heart failure, studies have shown that bisoprolol, carvedilol, and metoprolol succinate reduce mortality in patients with HFrEF who are treated with a diuretic and ACE inhibitor.
Several mechanisms of action have been proposed for β-blockers, but none of them alone has been shown to be consistently associated with a reduction in arterial BP. β-Blockers have negative chronotropic and inotropic effects that reduce CO, which explains some of the antihypertensive effect. However, CO falls equally for patients treated with β-blockers regardless of BP lowering. Additionally, β-blockers with ISA do not reduce CO, yet they lower BP and decrease peripheral resistance.
β-Adrenoceptors are also located on the surface membranes of juxtaglomerular cells, and β-blockers inhibit these receptors and thus the release of renin. However, there is a weak association between plasma renin and antihypertensive efficacy of β-blocker therapy. Some patients with low plasma renin concentrations do respond to β-blockers. Therefore, additional mechanisms likely also account for the antihypertensive effect of β-blockers. However, the ability of β-blockers to reduce plasma renin and thus angiotensin II concentrations may play a major role in their ability to reduce CV risk.
There are important pharmacodynamic and pharmacokinetic differences among β-blockers, but all agents provide a similar degree of BP lowering. There are three pharmacodynamic properties of the β-blockers that differentiate this class: cardioselectivity, ISA, and membrane-stabilizing effects. β-Blockers that possess a greater affinity for β1-receptors than for β2-receptors are cardioselective.
β1-Adrenoceptors and β2-adrenoceptors are distributed throughout the body, but they concentrate differently in certain organs and tissues. There is a preponderance of β1-receptors in the heart and kidney, and a preponderance of β2-receptors in the lungs, liver, pancreas, and arteriolar smooth muscle. β1-Receptor stimulation increases heart rate, contractility, and renin release. β2-Receptor stimulation results in bronchodilation and vasodilation. Cardioselective β-blockers are not likely to provoke bronchospasm and vasoconstriction. Insulin secretion and glycogenolysis are mediated by β2-receptors. Blocking β2-receptors may reduce these processes and cause hyperglycemia or blunt recovery from hypoglycemia.
Cardioselective β-blockers (e.g., atenolol, bisoprolol, metoprolol, nebivolol) have clinically significant advantages over nonselective β-blockers (e.g., propranolol, nadolol), and are preferred when using a β-blocker to treat hypertension. Cardioselective agents are safer than nonselective agents for patients with asthma or diabetes who have a compelling indication for a β-blocker. However, cardioselectivity is a dose-dependent phenomenon; at higher doses, cardioselective agents lose their relative selectivity for β1-receptors and block β2-receptors as effectively as they block β1-receptors. The dose at which cardioselectivity is lost varies from patient to patient.
Some β-blockers (e.g., acebutolol, pindolol) have ISA and act as partial β-receptor agonists. When they bind to the β-receptor, they stimulate it, but far less than a pure β-agonist. If sympathetic tone is low, as it is during resting states, β-receptors are partially stimulated by ISA β-blockers. Therefore, resting heart rate, CO, and peripheral blood flow are not reduced when these types of β-blockers are used. Theoretically, ISA agents would appear to have advantages over β-blockers in certain patients with heart failure or sinus bradycardia. Unfortunately, they do not appear to reduce CV events as well as other β-blockers. In fact, they may increase CV risk post-MI or in those with coronary artery disease. Thus, agents with ISA are rarely needed.
All β-blockers exert a membrane-stabilizing action on cardiac cells when large doses are given. This activity is needed when β-blockers are used as an antiarrhythmic agent.
Pharmacokinetic differences among β-blockers relate to first-pass metabolism, route of elimination, degree lipophilicity, and serum half-lives. Propranolol and metoprolol undergo extensive first-pass metabolism, so the dose needed to attain β-blockade with either drug varies from patient to patient. Atenolol and nadolol are renally excreted. The dose of these agents may need to be reduced for patients with moderate-to-severe CKD.
β-Blockers, especially those with high lipophilic properties, penetrate the central nervous system and may cause other effects. Propranolol is the most lipophilic drug and atenolol is the least lipophilic. Therefore, higher brain concentrations of propranolol compared with atenolol are seen after equivalent doses are given. It is thought that higher lipophilicity is associated with more central nervous system side effects (dizziness, drowsiness). However, the lipophilic properties can provide better effects for non-CV conditions such as migraine headache prevention, essential tremor, and thyrotoxicosis. BP lowering is equal among β-blockers regardless of lipophilicity.
Most side effects of β-blockers are an extension of their ability to antagonize β-adrenoceptors. β-Blockade in the myocardium can be associated with bradycardia, atrioventricular conduction abnormalities (e.g., second- or third-degree heart block), and the development of acute heart failure. The decrease in heart rate may actually benefit certain patients with atrial arrhythmias (atrial fibrillation, atrial flutter) and hypertension by both providing rate control and BP lowering. β-Blockers usually only produce heart failure if they are used in high initial doses for patients with preexisting left ventricular dysfunction or if started in these patients during an acute heart failure exacerbation. Blocking β2-receptors in arteriolar smooth muscle may cause cold extremities and may aggravate intermittent claudication or Raynaud’s phenomenon as a result of decreased peripheral blood flow. In addition, there is an increase of sympathetic tone during periods of hypoglycemia in patients with diabetes that may result in a significant increase in BP because of unopposed α-receptor–mediated vasoconstriction.
Abrupt cessation of β-blocker therapy can produce unstable angina, MI, or even death in patients with coronary disease. Abrupt cessation may also lead to rebound hypertension (a sudden increase in BP to or above pretreatment values). To avoid this, β-blockers should always be tapered gradually over 1 to 2 weeks before eventually discontinuing the drug. This acute withdrawal syndrome is believed to be secondary to progression of underlying coronary disease, hypersensitivity of β-adrenergic receptors due to upregulation, and increased physical activity after withdrawal of a drug that decreases myocardial oxygen requirements. For patients without coronary disease, abrupt discontinuation may present as tachycardia, sweating, and generalized malaise in addition to increased BP.
Like diuretics, β-blockers have been shown to increase serum cholesterol and glucose values, but these effects are transient and of little clinical significance. For patients with diabetes, the reduction in CV events was as great with β-blockers as with an ACE inhibitor in the United Kingdom Prospective Diabetes Study (UKPDS)101 and far superior to placebo in the SHEP trial.8 In the Glycemic Effects in Diabetes Mellitus: Carvedilol–Metoprolol Comparison in Hypertensives (GEMINI) trial, patients with diabetes and hypertension who were randomized to metoprolol had an increase in hemoglobin A1C values, while patients randomized to carvedilol did not.102 This suggests that mixed α- and β-blocking effects of carvedilol may be preferential to metoprolol for patients with uncontrolled diabetes. However, differences in hemoglobin A1C values were small. Nebivolol is considered a third-generation β-blocker. Similar to carvedilol and labetalol, this β-blocker results in vasodilation. However, carvedilol and labetalol cause vasodilation because of their ability to block α1-receptors, while nebivolol causes vasodilation through release of nitric oxide. The long-term clinical benefits of the nitric oxide effects seen with nebivolol are currently unknown, but this might explain a lower risk of β-blocker–associated fatigue, erectile dysfunction, and metabolic side effects (e.g., hyperglycemia) with this agent.
Alternative Agents The primary role of an alternative antihypertensive agent is to provide additional BP lowering in patients who are already treated with antihypertensive agents from a drug class proven to reduce hypertension-associated CV events (ACE inhibitors, ARBs, CCBs, diuretics, and/or β-blockers).
α1-Blockers Prazosin, terazosin, and doxazosin are selective α1-receptor blockers.37 They work in the peripheral vasculature and inhibit the uptake of catecholamines in smooth muscle cells resulting in vasodilation and BP lowering.
Doxazosin was one of the original treatment arms of the ALLHAT. However, it was stopped prematurely when statistically more secondary end points of stroke, heart failure, and CV events were seen with doxazosin compared with chlorthalidone.37 There were no differences in the primary end point of fatal coronary heart disease and nonfatal MI. These data suggest that thiazide diuretics are superior to α1-blockers in preventing CV events in patients with hypertension. Therefore, α1-blockers are alternative agents that should be used in combination with first-line antihypertensive agents.
α1-Blockers can provide symptomatic benefits in men with benign prostatic hypertrophy. These agents block postsynaptic α1-adrenergic receptors located on the prostate capsule, causing relaxation and decreased resistance to urinary outflow. However, when used to lower BP, they should only be in addition to other first-line antihypertensive agents.
A potentially severe side effect of α1-blockers is a “first-dose” phenomenon that is characterized by transient dizziness or faintness, palpitations, and even syncope within 1 to 3 hours of the first dose. This adverse reaction can also happen after dose increases. These episodes are accompanied by orthostatic hypotension and can be obviated by taking the first dose and subsequent first increased doses at bedtime. Because orthostatic hypotension and dizziness may persist with chronic administration, these agents should be used very cautiously in elderly patients. Even though antihypertensive effects are achieved through a peripheral α1-receptor antagonism, these agents cross the blood–brain barrier and may cause central nervous system side effects such as lassitude, vivid dreams, and depression. α1-Blockers also may cause priapism. Sodium and water retention can occur with higher doses, and sometimes even with chronic administration of low doses. Therefore, these agents are most effective when given in combination with a diuretic to maintain antihypertensive efficacy and minimize potential edema.
Aliskiren Aliskiren is the only agent that is a direct renin inhibitor. This drug blocks the RAAS at its point of activation, which results in reduced plasma renin activity and BP lowering. It has a 24-hour half-life, is primarily eliminated through biliary excretion unchanged, and provides 24-hour antihypertensive effects with once-daily dosing.
The exact role of this drug class in the management of hypertension is unclear. Aliskiren is approved as monotherapy or in combination therapy. However, because of the lack of long-term studies evaluating CV event reduction and significant drug cost compared with older generic agents with outcome data, it should clearly be used as an alternative therapy for the treatment of hypertension. Moreover, aliskiren is considered a RAAS blocker. Therefore, it should not be used in combination with an ACE inhibitor or an ARB because of a higher risk of adverse effects without providing additional reduction in CV events.103
Many of the cautions and adverse effects seen with ACE inhibitors and ARBs apply to direct renin inhibitors (e.g., aliskiren). Aliskiren should never be used in pregnancy due to the known teratogenic effects of using other drugs that block the RAAS system. Angioedema has also been reported for patients treated with aliskiren. Increases in serum creatinine and serum potassium values have been observed. The mechanisms of these adverse effects are likely similar to those with ACE inhibitors and ARBs. It is reasonable to utilize similar monitoring strategies by measuring serum creatinine and serum potassium in patients treated with aliskiren.
Central α2-Agonists Clonidine, guanabenz, guanfacine, and methyldopa lower BP primarily by stimulating α2-adrenergic receptors in the brain. This stimulation reduces sympathetic outflow from the vasomotor center in the brain and increases vagal tone. It is also believed that peripheral stimulation of presynaptic α2-receptors may further reduce sympathetic tone. Reduced sympathetic activity together with enhanced parasympathetic activity can decrease heart rate, CO, TPR, plasma renin activity, and baroreceptor reflexes. Clonidine is often used in resistant hypertension, and methyldopa is a first-line agent for pregnancy-induced hypertension.
Chronic use of centrally acting α2-agonists results in sodium and water retention, which is most prominent with methyldopa. Low doses of clonidine (and guanfacine or guanabenz) can be used to treat hypertension without the addition of a diuretic. However, methyldopa should be given in combination with a diuretic to avoid the blunting of antihypertensive effect that happens with prolonged use when used to treat chronic hypertension (not necessary in pregnancy-induced hypertension). Sedation and dry mouth are common anticholinergic side effects that typically improve with chronic use of low doses, but they are more troublesome in the elderly. As with other centrally acting antihypertensives, depression can occur, especially with high doses. The incidence of orthostatic hypotension and dizziness is higher than with other antihypertensive agents, so they should be used very cautiously in the elderly. Lastly, clonidine has a relatively high incidence of anticholinergic side effects (sedation, dry mouth, constipation, urinary retention, and blurred vision). Thus, it should generally be avoided for chronic antihypertensive therapy in the elderly.
Abrupt cessation of central α2-agonists may lead to rebound hypertension. This effect is thought to be secondary to a compensatory increase in norepinephrine release after abrupt discontinuation. In addition, other effects such as nervousness, agitation, headache, and tremor can also occur, which may be exacerbated by concomitant β-blocker use, particularly with clonidine. Thus, if clonidine is to be discontinued, it should be tapered. For patients who are receiving concomitant β-blocker therapy, the β-blocker should be gradually discontinued first several days before gradual discontinuation of clonidine.
Methyldopa can cause hepatitis or hemolytic anemia, although this is rare. Transient elevations in serum hepatic transaminases are occasionally seen with methyldopa therapy but are clinically irrelevant unless they are greater than three times the upper limit or normal. Methyldopa should be quickly discontinued if persistent increases in serum hepatic transaminases or alkaline phosphatase are detected because this may indicate the onset of fulminant life-threatening hepatitis. A Coombs-positive hemolytic anemia occurs in <1% of patients receiving methyldopa, although 20% exhibit a positive direct Coombs test without anemia. For these reasons, methyldopa has limited use in routine management of hypertension, except in pregnancy.
Reserpine Reserpine lowers BP by depleting norepinephrine from sympathetic nerve endings and blocking transport of norepinephrine into its storage granules. Norepinephrine release into the synapse following nerve stimulation is reduced and results in reduced sympathetic tone, PVR, and BP. Reserpine also depletes catecholamines in the brain and the myocardium, which may lead to sedation, depression, and decreased CO.
Reserpine has a slow onset of action and long half-life that allows for once-daily dosing. However, it may take 2 to 6 weeks before the maximal antihypertensive effect is seen. Because reserpine can cause significant sodium and water retention, it should be given in combination with a diuretic (preferably a thiazide). Reserpine’s strong inhibition of sympathetic activity results in increased parasympathetic activity. This effect explains why side effects such as nasal stuffiness, increased gastric acid secretion, diarrhea, and bradycardia can occur. Depression has been reported, which is a consequence of central nervous system depletion of catecholamines and serotonin. The initial reports of depression with reserpine were in the 1950s and are not consistent with current definitions of depression. Regardless, reserpine-induced depression is dose related. Moreover, very high doses (above 1 mg daily) were frequently used in the 1950s, resulting in more depression. When reserpine is dosed between 0.05 and 0.25 mg daily (recommended doses), the rate of depression is equal to that seen with β-blockers, diuretics, or placebo.8
Reserpine was used as a third-line agent in many of the landmark clinical trials that have documented the benefit in treating hypertension, including the Veterans Administration Cooperative trials and the SHEP trial.8 An analysis of the SHEP data found that reserpine was very well tolerated and that the combination of a thiazide diuretic and reserpine is very effective at lowering BP.
Direct Arterial Vasodilators Hydralazine and minoxidil directly relax arteriolar smooth muscle resulting in vasodilation and BP lowering. They exert little to no venous vasodilation. Both agents cause potent reductions in perfusion pressure that activates the baroreceptor reflexes. Activation of baroreceptors results in a compensatory increase in sympathetic outflow, which leads to an increase in heart rate, CO, and renin release. Consequently, tachyphylaxis can develop resulting in a loss of hypotensive effect with continued use. This compensatory baroreceptor response can be counteracted by concurrent use of a β-blocker.
All patients receiving hydralazine or minoxidil long-term for hypertension should first receive both a diuretic and a β-blocker. Direct arterial vasodilators can precipitate angina in patients with underlying coronary disease unless the baroreceptor reflex mechanism is completely blocked with a β-blocker. Nondihydropyridine CCBs can be used as an alternative to β-blockers in these patients, but a β-blocker is preferred. The side effect of sodium and water retention is significant but is minimized by using a diuretic concomitantly.
One side effect unique to hydralazine is a dose-dependent drug-induced lupus-like syndrome. Hydralazine is eliminated by hepatic N-acetyltransferase. This enzyme displays genetic polymorphism, and “slow acetylators” are especially prone to develop drug-induced lupus with hydralazine. This syndrome is more common in women and is reversible on discontinuation. Drug-induced lupus may be avoided by using less than 200 mg of hydralazine daily. Because of side effects, hydralazine has limited clinical use for chronic management of hypertension. However, it is especially useful for patients with severe CKD and in kidney failure on hemodialysis. Hydralazine, when used in combination with isosorbide dinitrate, has been shown to reduce the risk of CV events in black patients with HFrEF when added to a standard regimen of a diuretic, ACE inhibitor or ARB, and appropriate β-blocker therapy.104
Minoxidil is a more potent vasodilator than hydralazine. Therefore, the compensatory increases in heart rate, CO, renin release, and sodium retention are even more dramatic. Sodium and water retention can be so severe with minoxidil that heart failure can be precipitated. It is even more important to coadminister a β-blocker and a diuretic with minoxidil. A loop diuretic is often more effective than a thiazide in patients treated with minoxidil. A troublesome side effect of minoxidil is hypertrichosis (hirsutism), presenting as increased hair growth on the face, arms, back, and chest. This usually ceases when the drug is discontinued. Other minoxidil side effects include pericardial effusion and a nonspecific T-wave change on the electrocardiogram. Minoxidil is reserved for very-difficult-to-control hypertension and for patients requiring hydralazine that experience drug-induced lupus.
The cost of effectively treating hypertension is substantial. It is projected that the direct costs of treating hypertension will rise from $91.4 billion in 2015 to $200.3 billion in 2030.105 However, these costs are offset by savings that would be realized by reducing CV morbidity and mortality. Cost related to treating target-organ damage (e.g., MI, end-stage kidney failure) can drastically increase healthcare costs.
Antihypertensive drug costs are a major portion of the total cost of hypertensive care. First-line drug classes (i.e., ACE inhibitors, ARBs, CCBs, and diuretics) are predominantly generic.1,2 Using these agents to treat hypertension results in lower drug acquisition costs. There are even multiple generic fixed-dose combinations of these agents. A comparative analysis of 133,624 patients with hypertension aged 65 and older from a state prescription drug assistance program demonstrated that 40% of patients were prescribed pharmacotherapy that was not necessarily according to JNC7 guideline recommendations.106 If these 40% had drug therapy modifications made to follow evidence-based treatment, a reduction in costs of $11.6 million would have been realized in the 2001 calendar year based on discounted prices. This was projected to increase to $20.5 million using usual Medicaid pricing limits.
It is crucial to identify ways to control the cost of care without increasing the morbidity and mortality associated with uncontrolled hypertension. Using evidence-based pharmacotherapy will save costs. ACE inhibitors, ARBs, CCBs, and diuretics are first-line treatment options in most patients without compelling indications and most are very inexpensive. Just utilizing generic agents, either as monotherapy or in combination, is appropriate under most circumstances in hypertension management. Brand name drugs should also be used when needed. However, considerations to implement once-daily options and even fixed-dose combination options that are economical should be considered.
Team-Based Collaborative Care
Team-based care for patients with hypertension is a proven strategy that improves goal BP attainment rates.107,108 These patient care models are interprofessional and utilize physicians, pharmacists, nurses, and other healthcare professionals. With the advent of healthcare reform, such approaches to chronic diseases are being viewed as high-quality and cost-effective improvement modalities. Within these models, pharmacists have been proven to be an effective component of team-based models both in ambulatory clinic settings107 and in community pharmacist settings.109 In addition to optimizing selection and implementation of antihypertensive drug therapy, clinical interventions by pharmacists have been proven to reduce the risk of adverse drug events and medication errors in ambulatory patients with CV disease.110
EVALUATION OF THERAPEUTIC OUTCOMES
Monitoring the Pharmacotherapy Plan
Routine ongoing monitoring to assess disease progression, the desired effects of antihypertensive therapy (efficacy, including BP goal attainment), and undesired adverse side effects (toxicity) is needed in all patients treated with antihypertensive drug therapy.
Patients should be monitored for signs and symptoms of progressive hypertension-associated target-organ disease. A careful history for ischemic chest pain (or pressure), palpitations, dizziness, dyspnea, orthopnea, headache, sudden change in vision, one-sided weakness, slurred speech, and loss of balance should be taken to assess the presence of CV and cerebrovascular hypertensive complications. Other clinical monitoring parameters that may be used to assess target-organ disease include funduscopic changes on eye exam, LVH on electrocardiogram, proteinuria, and changes in kidney function. These parameters should be monitored periodically because any sign of deterioration requires immediate assessment and followup.
The most important strategy to prevent CV morbidity and mortality in hypertension is BP control to goal values (see Box 3-2). Routine goal BP values should be attained in elderly patients and in those with isolated systolic hypertension, but actual BP lowering can occur at a gradual pace over a period of several months to avoid orthostatic hypotension. Modifying other CV risk factors (e.g., smoking, dyslipidemia, and diabetes) is also important.
Clinic-based BP monitoring remains the standard for managing hypertension. BP response should be evaluated 2 to 4 weeks after initiating or making changes in therapy. With some agents, monitoring BP 4 to 6 weeks later may better represent steady-state BP values (e.g., thiazide diuretics, reserpine). Once goal BP values are attained, assuming no signs or symptoms of acute target-organ disease are present, BP monitoring can be done every 3 to 6 months. More frequent evaluations are required for patients with a history of poor control, nonadherence, progressive target-organ damage, or symptoms of adverse drug effects.
Self-measurements of BP or automated ABP monitoring can be useful clinically to establish effective 24-hour control. This type of monitoring may become the standard of care in the future because evolving data have demonstrated significant benefits of using these types of measurements to both diagnose hypertension111,112 and optimize the use of antihypertensive drug therapy.16 Currently, ABP monitoring is used in select situations such as suspected white coat hypertension.14 If patients are measuring their BP at home, it is important that they measure during the early morning hours for most days and then at different times of the day on alternative days of the week. It is also of paramount importance that clinicians remember self-BP and ABP measurements are lower than clinic BP measurements.14 Goal BP values should be lowered accordingly when clinicians use self-BP or ABP measurements to monitor and/or adjust antihypertensive pharmacotherapy.
Patients should be monitored routinely for adverse drug effects. The most common side effects associated with each class of antihypertensive agents were discussed in Individual Antihypertensive Agents above, and laboratory parameters for primary agents are listed in Table 3-8. Laboratory monitoring should typically occur 2 to 4 weeks after starting a new agent or dose increase, and then every 6 to 12 months in stable patients. Additional monitoring may be needed for other concomitant diseases if present (e.g., diabetes, dyslipidemia, gout). Moreover, patients treated with an aldosterone antagonist (eplerenone or spironolactone) should have potassium concentrations and kidney function assessed within 3 days of initiation and again at 1 week to detect potential hyperkalemia. The occurrence of an adverse drug event may require dosage reduction or substitution with an alternative antihypertensive agent.
TABLE 3-8 Select Monitoring for Antihypertensive Pharmacotherapy
Adherence and Persistence
Nonadherence and lack of persistence with hypertension treatment is a major problem in the United States and is associated with significant increases in costs due to development of complications. Since hypertension is a relatively asymptomatic disease, poor adherence is frequent, particularly in patients newly treated. It has been estimated that up to 50% of patients with newly diagnosed hypertension are continuing treatment at 1 year.113 It has also been demonstrated that long-term risk of CV events is significantly reduced when newly diagnosed patients are adherent with their antihypertensive drug therapy.114 Therefore, it is imperative to assess patient adherence on a regular basis.
The American Society of Hypertension has outlined four global practical considerations and recommendations for adherence in patients with hypertension.115 These include: (a) focus on clinical outcomes (e.g., following national guidelines, simplifying drug regimens, encouraging self-monitoring of BP), (b) empowering informed activated patients (e.g., problem-solving and behavior change interventions, urge the use of pill boxes, help patients develop a system for refilling prescriptions), (c) implement a team approach (e.g., implementing collaborative models of care, using office practice policies and procedures to improve BP control), and (d) advocating for health policy reform (e.g., elevate medication adherence as a critical healthcare issue, structure/finance healthcare that stimulates behavioral aspects).
Identification of nonadherence should be followed up with appropriate patient education, counseling, and intervention. Once-daily regimens are preferred in most patients to improve adherence. Although some may believe that aggressive treatment may negatively impact quality of life and thus adherence, several studies have found that most patients actually feel better once their BP is controlled. Patients on antihypertensive therapy should be questioned periodically about changes in their general health perception, energy level, physical functioning, and overall satisfaction with treatment. Lifestyle modifications should always be recommended to provide additional BP lowering and other potential health benefits. Persistence with lifestyle modifications should be continually encouraged for patients engaging in such endeavors.
Initial therapy with a combination of two drugs is highly recommended for patients with stage 2 hypertension and is an option for treating patients with stage 1 hypertension.116 Using a fixed-dose combination product is an option for these types of patients and has been shown to improve adherence.117 Initial two-drug combination therapy may also be appropriate for patients with multiple compelling indications for different antihypertensive agents. Moreover, combination therapy is often needed to control BP in patients who are already on drug therapy and most patients require two or more agents.1,43,116
The Avoiding Cardiovascular Events Through Combination Therapy for Patients Living with Systolic Hypertension Trial
Long-term safety and efficacy of initial two-drug therapy for hypertension has been evaluated in the ACCOMPLISH trial.118 This was a prospective, randomized, double-blind trial in 11,506 patients with hypertension and other CV risk factors. All of these patients either had stage 2 hypertension or were on antihypertensive drug therapy on enrollment. Patients were randomized to receive either benazepril-with-hydrochlorothiazide or benazepril-with-amlodipine as initial drug therapy. Treatment was titrated to a goal BP of <140/90 mm Hg for most patients and <130/80 mm Hg for patients with diabetes or CKD.
The trial was terminated early after a mean of 36 months because the incidence of CV events was 20% lower in the benazepril-with-amlodipine group compared with the benazepril-with-hydrochlorothiazide group. What is most important for clinical practice is that this trial established that initial two-drug therapy, as is recommended in JNC and AHA guidelines, was safe and highly effective in lowering BP. Mean BP measurements were 132/73 and 133/74 mm Hg in the benazepril-with-amlodipine and the benazepril-with-hydrochlorothiazide groups, respectively. However, rates of attaining a BP of <140/90 mm Hg were 75.4% and 72.4% (benazepril-with-amlodipine and benazepril-with-hydrochlorothiazide, respectively). These goal attainment rates are higher than in any other long-term prospective study and are higher than what is seen in clinical practice.
The ACCOMPLISH trial established initial two-drug antihypertensive therapy as an evidence-based strategy to treat hypertension. Clinicians should consider this study as positive justification for implementing initial two-drug therapy antihypertensive regimens in appropriate patients.
Why is the most effective two-drug combination for reducing CV events not as frequently used as other combinations?
The ACCOMPLISH trial demonstrated that the combination of an ACE inhibitor with a dihydropyridine CCB was more effective in reducing risk of CV events than the combination of an ACE inhibitor with a thiazide diuretic. However, thiazide diuretics are very effective at lowering BP, especially when used in combination with other agents, and hydrochlorothiazide is easily available in many fixed-dose combination products. Therefore, the most ideal two-drug combination for the treatment of hypertension in the absence of compelling indications is an ACE inhibitor (an ARB is a reasonable alternative) with a dihydropyridine CCB. However, because of traditional habits and common availability of combination products, many clinicians use an ACE inhibitor with hydrochlorothiazide.
Optimal Use of Combination Therapy
Clinicians should anticipate the need for combination drugs to control BP in most patients. Using low-dose combinations also provides greater reductions in BP compared with high doses of single agents, with fewer drug-related side effects.89 Contrary to popular myth, appropriately increasing the number of antihypertensive medications to attain goal BP values does not increase the risk of adverse effects.119 The American Society of Hypertension has recommended three categories of combination therapy (see Box 3-3).116 Preferred combinations are ideal for lowering BP, have complementary mechanisms of action, and use first-line drugs that have been shown to lower risk of CV events. Acceptable combinations may not provide all of the benefits that preferred combinations do, and may have additive side effect profiles. Less effective combinations are limited in their overall benefits, and should only be used when absolutely necessary.
BOX 3-3 Recommendations for Combination Therapy
• ACE inhibitor/CCB
• ACE inhibitor/diuretic
• CCB (dihydropyridine)/β-blocker
• Renin inhibitor/diuretic
• Thiazide diuretics/potassium-sparing diuretics
• ACE inhibitor/β-blocker
• CCB (nondihydropyridine)/β-blocker
• Centrally acting agent/β-blocker
Some combinations are not effective long-term in treating hypertension. As previously discussed, the ON-TARGET demonstrated that the use of an ACE inhibitor with an ARB in the management of hypertension results in no additional reduction in incidence of CV events.92 Moreover, this combination results in a higher risk of adverse events. These same effects are seen when aliskiren is used in combination with an ARB.103 These combinations (using two RAAS blockers together) should not be used for the purpose of managing hypertension. Other combinations such as a thiazide diuretic with a potassium-sparing agent, both of which appear to have overlapping mechanisms of action, should be implemented primarily to minimize side effects. The combination of two CCBs, a dihydropyridine with a nondihydropyridine, might provide additional BP lowering120,121 but has limited use in the routine management of most patients with hypertension. Under no circumstance should two drugs from the same exact class of medications (e.g., two β-blockers, two ACE inhibitors) be used to treat hypertension.
Fixed-Dose Combination Products Many fixed-dose combination products are commercially available, and some are generic (see Table 3-9). Most of these products contain a thiazide diuretic and have multiple dose strengths available. Individual dose titration is more complicated with fixed-dose combination products, but this strategy can reduce the number of daily tablets/capsules and can simplify regimens to improve adherence by decreasing pill burden.116,117 This alone may increase the likelihood of achieving or maintaining goal BP values. Depending on the product, some may be less expensive to patients and to health systems. Nonadherence rates are 24% lower when fixed-dose combination products are used to treat hypertension compared with using free drug components (separate pills) to treat hypertension.117
TABLE 3-9 Fixed-Dose Combination Products
Resistant hypertension is defined as patients who are uncontrolled (failure to achieve goal BP of <140/90 mm Hg, or lower when indicated) with the use of three or more drugs.122 Ideally, these should be patients who are adhering to full doses of an appropriate three-drug regimen that includes a diuretic.1 This also includes patients who are controlled but require the use of four or more medications.122 Patients with newly diagnosed hypertension or who are not receiving drug therapy should not be considered to have resistant hypertension.123 Difficult-to-control hypertension is persistently elevated BP despite treatment with two or three drugs that does not meet the criteria for resistant hypertension (e.g., maximum doses that include a diuretic).
Several causes of resistant hypertension are listed in Table 3-10. Volume overload is a common cause, thus highlighting the importance of diuretic therapy in the management of hypertension. Pseudoresistance should also be ruled out by assuring adherence with prescribed therapy and possibly use of home BP measurements (by using a self-monitoring device or 24-hour ABP monitor).122 Patients should be closely evaluated to see if any of these causes can be reversed.
TABLE 3-10 Causes of Resistant Hypertension
Treatment of patients with resistant hypertension should ultimately follow the principle of drug therapy selection from the JNC and AHA guidelines. Compelling indications, if present, should guide selection assuming these patients are on a diuretic. However, there are treatment philosophies that are germane to the management of resistant hypertension: (a) assuring adequate diuretic therapy, (b) appropriate use of combination therapies, and (c) using alternative antihypertensive agents when needed.
Assuring Appropriate Diuretic Therapy
Diuretics have a large role in the pharmacotherapy of resistant hypertension. Thiazide diuretics are the mainstay of treatment, but chlorthalidone (thiazide-like) should be preferentially used instead of hydrochlorothiazide, especially for patients with resistant hypertension, because it is more potent on a milligram-per-milligram basis.96,122 Clinicians should identify that chlorthalidone therapy, like all thiazide diuretics, has dose-dependent metabolic side effects (hypokalemia and hyperglycemia) and that appropriate monitoring should be implemented. An aldosterone antagonist (e.g., spironolactone) is also very effective as an add-on agent.122 Evolving data indicate that many patients with resistant hypertension have some degree of underlying hyperaldosteronism, emphasizing the role of adding an aldosterone antagonist. Clinicians should consider using a loop diuretic, even in place of a thiazide diuretic, for patients with resistant hypertension who have very compromised kidney function (estimated GFR <30 mL/min/1.73 m2). Torsemide can be dosed once daily while furosemide must be dosed twice daily or three times daily.
Hypertensive Urgencies and Emergencies
Both hypertensive urgencies and emergencies are characterized by the presence of very elevated BP, typically >180/120 mm Hg.1,6 However, the need for urgent or emergent antihypertensive therapy must be determined based on the presence of acute or immediately progressing target-organ injury, not elevated BP alone. Urgencies are not associated with acute or immediately progressing target-organ injury, while emergencies are. Examples of acute target-organ injury include encephalopathy, intracranial hemorrhage, acute left ventricular failure with pulmonary edema, dissecting aortic aneurysm, unstable angina, and eclampsia or severe hypertension during pregnancy.
A common error with hypertensive urgency is overly aggressive antihypertensive therapy. This treatment has likely been perpetrated by the classification terminology “urgency.” Hypertensive urgencies are ideally managed by adjusting maintenance therapy, by adding a new antihypertensive, and/or by increasing the dose of a present medication. This is the preferred approach to these patients as it provides a more gradual reduction in BP. Very rapid reductions in BP to goal values should be discouraged due to potential risks. Because autoregulation of blood flow in patients with hypertension occurs at a much higher range of pressure than in normotensive persons, the inherent risks of reducing BP too precipitously include cerebrovascular accidents, MI, and acute kidney failure. Hypertensive urgency requires BP reductions with oral antihypertensive agents to stage 1 values over a period of several hours to several days. All patients with hypertensive urgency should be reevaluated within and no later than 7 days (preferably after 1 to 3 days).
Acute administration of a short-acting oral antihypertensive (e.g., captopril, clonidine, or labetalol) followed by careful observation for several hours to assure a gradual reduction in BP is an option for hypertensive urgency. However, there are no data supporting this approach as being absolutely needed. Oral captopril is one of the agents of choice and can be used in doses of 25 to 50 mg at 1- to 2-hour intervals. The onset of action of oral captopril is 15 to 30 minutes, and a marked fall in BP is unlikely to occur if no hypotensive response is observed within 30 to 60 minutes. For patients with hypertensive rebound following withdrawal of clonidine, 0.2 mg can be given initially, followed by 0.2 mg hourly until the DBP falls below 110 mm Hg or a total of 0.7 mg clonidine has been administered. A single dose may be all that is necessary. Labetalol can be given in a dose of 200 to 400 mg, followed by additional doses every 2 to 3 hours.
Oral or sublingual immediate-release nifedipine has been used for acute BP lowering in the past but is potentially dangerous. This approach produces a rapid reduction in BP. Immediate-release nifedipine should never be used for hypertensive urgencies due to risk of causing severe adverse events such as MIs and strokes.124
Hypertensive emergencies are those rare situations that require immediate BP reduction to limit new or progressing target-organ damage (see Classification under Arterial BP above). Hypertensive emergencies require parenteral therapy, at least initially, with one of the agents listed in Table 3-11. The goal in hypertensive emergencies is not to lower BP to <140/90 mm Hg; rather, the initial target is a reduction in MAP of up to 25% within minutes to hours. If the patient is then stable, DBP can be reduced to 100–110 mm Hg within the next 2 to 6 hours. Precipitous drops in BP may lead to end-organ ischemia or infarction. If patients tolerate this reduction well, additional gradual reductions toward goal BP values can be attempted after 24 to 48 hours. The exception to this guideline is for patients with an acute ischemic stroke where maintaining an elevated BP is needed for a longer period of time.
TABLE 3-11 Parenteral Antihypertensive Agents for Hypertensive Emergency
The clinical situation should dictate which IV medication is used to treat hypertensive emergencies. Regardless, therapy should be provided in a hospital or emergency room setting with intraarticular BP monitoring. Table 3-11lists special indications for agents that can be used.
Nitroprusside is widely considered the agent of choice for most cases, but it can be problematic for patients with CKD. It is a direct-acting vasodilator that decreases PVR but does not increase CO unless left ventricular failure is present. Nitroprusside can be given to treat most hypertensive emergencies, but in aortic dissection, propranolol should be given first to prevent reflex sympathetic activation. Nitroprusside is metabolized to cyanide and then to thiocyanate, which is eliminated by the kidneys. Therefore, serum thiocyanate levels should be monitored when infusions are continued longer than 72 hours. Nitroprusside should be discontinued if the concentration exceeds 12 mg/dL (∼2 mmol/L). The risk of thiocyanate accumulation and toxicity is increased for patients with impaired kidney function.
IV nitroglycerin dilates both arterioles and venous capacitance vessels, thereby reducing both cardiac afterload and cardiac preload, which can decrease myocardial oxygen demand. It also dilates collateral coronary blood vessels and improves perfusion to ischemic myocardium. These properties make IV nitroglycerin ideal for the management of hypertensive emergency in the presence of myocardial ischemia. IV nitroglycerin is associated with tolerance when used over 24 to 48 hours and can cause severe headache.
Fenoldopam, nicardipine, and clevidipine are newer and more expensive agents. Fenoldopam is a dopamine-1 agonist. It can improve renal blood flow and may be especially useful for patients with kidney insufficiency. Nicardipine and clevidipine are dihydropyridine CCBs that provide arterial vasodilation and can treat cardiac ischemia similar to nitroglycerin, but they may provide more predictable reductions in BP.
The hypotensive response of hydralazine is less predictable than with other parenteral agents. Therefore, its major role is in the treatment of eclampsia or hypertensive encephalopathy associated with renal insufficiency.
Hypertension is a very common medical condition in the United States. Treatment of patients with hypertension should include both lifestyle modifications and pharmacotherapy. Evidence from outcome-based clinical trials have definitively demonstrated that treating hypertension reduces the risk of CV events and subsequently reduces morbidity and mortality. Moreover, evidence evaluating individual drug classes has resulted in an evidence-based approach to selecting pharmacotherapy in an individual patient ACE inhibitors, ARBs, CCBs, and thiazide diuretics are all first-line agents. Data suggest that using a β-blocker as the primary agent to treat patients with hypertension, without the presence of a compelling indication, may not be as beneficial in reducing risk of CV events compared with ACE inhibitor–, ARB-, CCB-, or thiazide diuretic–based therapy. Therefore, they are not first-line therapy options unless an appropriate compelling indication is present.
Patients should be treated to a goal BP value. In addition to selecting the most appropriate agent, attaining a goal BP is also of paramount importance to ensure maximum reduction in risk for CV events is provided. A BP goal of <140/90 mm Hg is recommended for most patients with hypertension and some patients are candidates for lower goal values. Most patients with hypertension require more than one drug to attain goal BP values; therefore, combination therapy should be anticipated.
Optimizing hypertension management can be achieved many ways. Team-based approaches to implement care and attain goal BP values are effective. Judicious use of cost-effective treatments and fixed-dose combination products should always be considered to improve sustainability of treatment. Lastly, interventions to reinforce adherence and lifestyle modifications also are highly recommended in the comprehensive management of hypertension.
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