CHAPTER 11

Hypertension

Judy Cheng, PharmD, MPH, BCPS, FCCP

Hypertension is one of the most common and most important risk factors in developing cardiovascular diseases such as coronary artery, cerebrovascular, and renal diseases. Prevention and proper control of hypertension can reduce the risk of developing such diseases. Since the inception of the National High Blood Pressure Education Program in 1972, remarkable progress has been made in detecting, treating, and controlling hypertension (James et al., 2013). Management of hypertension to date thus revolves around primary prevention via lifestyle modifications, early detection, and optimal treatment, with consideration of patients’ other concurrent medical problems. This chapter discusses the primary prevention strategy for hypertension as well as the proper therapeutic management once the diagnosis is established. Issues related to the implementation and dissemination of these approaches are emphasized.

ANATOMY, PHYSIOLOGY, AND PATHOLOGY

Anatomy and Physiology

Arterial blood pressure is defined hemodynamically as the product of the cardiac output and the total peripheral resistance. It reaches its peak during cardiac systole (systolic blood pressure [SBP]) and its nadir at the end of diastole (diastolic blood pressure [DBP]). The cardiac output is the major determinant of SBP, and total peripheral resistance determines DBP. Cardiac output, in turn, depends on stroke volume, heart rate, and venous capacitance. Factors that increase stroke volume and heart rates will increase cardiac output and subsequently SBP. Alternatively, venous capacitance affects the volume of venous blood (preload) that is returned to the heart. Venous dilatation increases venous capacitance and decreases preload, thus decreasing SBP. Total peripheral resistance is regulated by contraction and dilation of the arterioles. Other factors that may also affect intravascular resistance include the elasticity of arteries and blood viscosity.

The difference between SBP and DBP (pulse pressure) is an indicator of the tone of the vessel walls. The mean arterial pressure, which is defined as one third of the pulse pressure plus DBP, is the average pressure throughout the cardiac cycle.

Blood pressure can be regulated by the kidneys, which control blood volume, and the sympathomimetic nervous system. Increased sympathomimetic activity stimulates vasoconstriction of arterioles, thus raising total peripheral resistance, and increases cardiac output, thus elevating blood pressure. For blood pressure to remain within normal limits, specialized receptors (baroreceptors) are used. These stretch receptors are located in the aortic arch and in the carotid sinuses. An increase in blood pressure causes these receptors to stretch and stimulate the activity of the sensory nerve. Sensory nerve activity from the baroreceptors is transmitted via the vagus and glossopharyngeal nerves to the medulla oblongata, which directs the autonomic system to respond appropriately. An effective baroreceptor reflex helps to maintain adequate blood flow to the brain on standing.

Pathophysiology

The vast majority of patients who have hypertension have essential (primary) hypertension. Secondary hypertension makes up only about 10% of the hypertensive population (James et al., 2013). Some possible causes of secondary hypertension include kidney disease, pheochromocytoma, primary aldosteronism, hyperthyroidism, or drug-induced hypertension (e.g., cyclosporine, erythropoietin, sympathomimetic agents). Primary hypertension, in contrast, may be caused by multiple factors, including abnormal neural mechanisms; defects in peripheral autoregulation; disturbances in sodium, calcium, and natriuretic hormone levels; and malfunctions in either humoral or vasodepressor mechanisms.

Abnormal Neural Mechanisms

The central and the autonomic nervous systems are intricately involved in the maintenance of arterial blood pressure. Located in the presynaptic and postsynaptic nervous endings are alpha and beta receptors. Stimulation of presynaptic alpha and beta receptors will lead to inhibition and enhancement, respectively, of norepinephrine release. Stimulation of postsynaptic alpha-1 receptors leads to vasoconstriction. Stimulation of postsynaptic beta-2 receptors leads to vasodilation. Stimulation of beta-1 receptors in the heart enhances cardiac contractility and increases heart rate. The major negative feedback system of the sympathetic nervous system is the baroreceptor reflex. A pathological disturbance in any of these neural components could lead to sustained elevations of blood pressure.

Peripheral Autoregulation

A defect in renal adaptive mechanisms can lead to plasma volume expansion and increased blood flow to peripheral tissues, even when blood pressure is normal. To offset such increases in blood flow, local tissue autoregulatory processes would induce arteriolar constriction to raise the peripheral vascular resistance.

Disturbances in Sodium, Calcium, and Natriuretic Hormone

Increased sodium intake, together with an inherited defect in the kidney’s ability to excrete sodium, leads to an increase in the level of circulating natriuretic hormones. Natriuretic hormones inhibit intracellular sodium transport, causing increased vascular reactivity and a rise in blood pressure.

Calcium homeostasis also contributes to the pathogenesis of hypertension. Lack of calcium in the blood circulation leads to a relative elevation of calcium concentration intracellularly, which leads to altered vascular smooth muscle function and increased peripheral vascular resistance.

Potassium depletion may also cause an increase in peripheral vascular resistance, but its clinical impact is not clearly defined.

Malfunction of Humoral Mechanism

The renin–angiotensin system’s involvement in hypertension has been well described. Renin is synthesized in the kidney and stored in the juxtaglomerular cells. Decreases in perfusion pressure to the kidney and the flux of sodium and chloride across the renal tubule trigger renin release. In blood, renin catalyzes the conversion of angiotensinogen to angiotensin I, which is then converted by angiotensin-converting enzymes (ACE) to angiotensin II. Angiotensin II is a direct vasoconstrictor. It also stimulates catecholamine and aldosterone release from the adrenal gland. These neurohormones (catecholamine and aldosterone) can further increase blood pressure. Angiotensin is also produced by the tissue of various organs other than the kidney, such as the heart and the brain. Local angiotensin may interact with other humoral regulators and endothelium-derived growth factors to stimulate vascular smooth muscle growth. Components of the local angiotensin system may be responsible for long-term adaptation to hypertension (e.g., left ventricular hypertrophy, smooth muscle hypertrophy of blood vessels, and glomerular hypertrophy).

Other neurohormonal mechanisms involved in hypertension include hyperinsulinemia and insulin resistance. Elevation in the serum insulin concentration may induce renal sodium retention, enhance sympathetic nervous system activity, and cause vascular smooth muscle hypertrophy. The vascular endothelium also plays an important role in blood vessel tone. Vasoactive substances produced by the endothelium, such as prostacyclin, bradykinin, endothelium-derived relaxing factor, and endothelin I, interact with each other to maintain normal vessel tone. Imbalances of these vasoactive substances may contribute to hypertension.

EPIDEMIOLOGY

The American Heart Association reported that the prevalence of hypertension in the United States between 2007 and 2010 was approximately 78 million adults (or one in every four adults; American Heart Association, 2013). Hypertension is associated with an increased risk of developing coronary artery disease, stroke, heart failure, renal insufficiency, and peripheral vascular disease. There is no gender discrimination for such risk throughout the entire adult age range. However, the prevalence of hypertension increases progressively with increasing age. The risk of morbidity and mortality from cardiovascular disease increases in a curvilinear fashion with progressively higher levels of SBP and DBP.

Research over the years has helped in identifying environmental, cultural, and social factors that may contribute to the current hypertension pattern. The following factors have been identified as the most important contributors to age-related increases in blood pressure (Joint National Committee [JNC], 2004):

High sodium intake (beyond human physiological needs)

Overweight

Lack of physical activity

Excessive alcohol consumption

Smoking

Excessive stress

Inadequate potassium intake

Positive family history

Membership in minority population (e.g., African Americans)

In a culture with a high level of stress, low physical activity, and excessive consumption of salt and alcohol, the prevalence of hypertension may increase. Socioeconomic status can also be a determinant of blood pressure. In economically developed countries, only a relatively small proportion of the general population has a blood pressure within the optimal range (<120/80 mmHg). This is, however, the norm in less-developed societies, where age-related increases in blood pressure are uncommon (Pereira et al., 2012). Reasons that may explain this phenomenon include differences in lifestyle (e.g., activity level) and diet (e.g., alcohol consumption) among different societies.

DIAGNOSTIC CRITERIA

The JNC on prevention, detection, evaluation, and treatment of high blood pressure has provided guidelines for hypertension management since the release of its first report in 1976. Hypertension management begins with early detection. Primary care providers should measure a patient’s blood pressure at every clinic visit. Table 11.1 provides the Seventh Report of the Joint National Committee (JNC7) classification of adult blood pressure based on the risk of developing cardiovascular events (JNC, 2004). All stages of hypertension are associated with an elevated risk of cardiovascular events and renal disease, but the higher the blood pressure, the greater the risk. In the eighth report of the JNC’s hypertension management guideline (JNC8; James et al., 2013), the definition of hypertension was not readdressed, but thresholds for pharmacological treatment were defined and are discussed later in this chapter.

Hypertension should never be diagnosed based on a single measurement because various factors, such as coffee consumption and the medical white coat, may affect a patient’s blood pressure. An initial elevated reading should be confirmed on at least two subsequent visits over one to several weeks, except if SBP is >180 mmHg, DBP is >110 mmHg, or signs and symptoms of end organ damage are present. In these situations, patients need to be referred for emergency care. An overall average SBP >140 mmHg or a DBP >90 mmHg will require further diagnosis and treatment. In some patient populations, such as those with suspected white coat hypertension and no target organ damage, apparent drug resistance, hypotensive symptoms with antihypertensive medications, episodic hypertension and autonomic dysfunction, continuous ambulatory blood pressure monitoring may be more helpful than clinical blood pressure monitoring in making a diagnosis.

TABLE 11.1

Classification of Blood Pressure for Patients >18 Years of Age

CATEGORY	SYSTOLIC (mmHg)	DIASTOLIC (mmHg)
Normal	<120	<80
Pre-hypertensive	120–139	80–89
Hypertension
Stage 1	140–159	90–99
Stage 2	≥160	≥100

Note: When systolic blood pressure and diastolic blood pressure fall into different categories, the higher category should be used.

HISTORY AND PHYSICAL EXAMINATION

A complete medical history and physical examination should be performed in all hypertensive patients during their initial evaluation. This examination should include:

Family history of high blood pressure, premature coronary heart disease, stroke, cerebrovascular disease, diabetes, and hypercholesterolemia

Patient history or symptoms of cardiovascular disease, cerebrovascular disease, renal disease, diabetes, hypercholesterolemia, or gout

Known duration and levels of elevated blood pressure

History of weight gain, stress, physical activity, and smoking

Dietary assessment, including sodium intake, alcohol use, and intake of cholesterol and saturated fat

Complete medication history, including the use of over-the-counter products as well as the results and side effects of previous antihypertensive agents

Symptoms suggesting secondary hypertension

Psychosocial and environmental factors that may influence blood pressure control (e.g., family and employment situations, educational level)

Verification of blood pressure by two or more blood pressure measurements separated by 2 minutes with the patient either supine or seated and after standing for at least 2 minutes