Hypertension

Over the past several decades, health professionals and public officials have increased efforts to educate the public about the hazards of untreated hypertension, and this has led to a significant increase in the number of hypertensive individuals who are aware of their condition and treat it effectively with lifestyle changes and drug therapy. The effective treatment of high blood pressure appears to be one of the factors that has contributed to a nearly 60% reduction in the incidence of stroke and at least a 50% reduction in the mortality rate from coronary artery disease since 1970.

About 95% of the cases of hypertension are considered to be primary hypertension that cannot be attributed to a specific cause. The other 5% of cases are classified as secondary hypertension, which results from an identifiable cause such as chronic kidney disease or hyperaldosteronism. In some cases, secondary hypertension can be corrected by medication or surgery.

Although the cause of primary hypertension in any specific patient is usually unknown, numerous genetic and lifestyle factors are associated with it. These include obesity, lack of exercise, the so-called metabolic syndrome (abdominal obesity, hyperlipidemia, and insulin resistance), elevated dietary sodium intake, and excessive consumption of alcohol.

Vascular endothelial cell dysfunction also contributes to the development of hypertension. The endothelium regulates vascular smooth muscle tone through the synthesis and release of relaxing factors such as nitric oxide and prostacyclin, and vasoconstricting factors such as endothelin-1 and angiotensin II. Angiotensin II may cause vascular injury by activating growth factors that cause vascular smooth muscle proliferation and hypertrophy as well as fibrotic changes in the vascular wall. Oxidative stress increases vasoconstrictive factors but decreases relaxing factors, thereby contributing to the development of hypertension. Several antihypertensive drugs, including carvedilol and the angiotensin inhibitors, appear to counteract endothelial cell dysfunction and reduce some of the adverse consequences of hypertensive disease.

Classification of Blood Pressure

Blood pressure is classified as shown in Table 10-1. This classification uses the term prehypertension for those with blood pressures ranging from 120 to 139 mm Hg systolic, 80 to 89 mm Hg diastolic blood pressure, or both. This designation helps identify persons in whom early adoption of lifestyle changes that decrease blood pressure could prevent the progression of blood pressure to hypertensive levels (see later). These persons are not candidates for drug therapy unless they have diabetes and a trial of lifestyle changes fails to reduce their blood pressure to the desired level of 130/80 mm Hg or less for diabetics.

The classification includes two stages of hypertension that confer differences in follow-up recommendations and management. In addition to providing information about lifestyle modifications, stage 1 hypertension should be confirmed within 2 months and then treated appropriately. Stage 2 hypertension should be treated immediately if blood pressure is greater than 180/110 mm Hg. For lower blood pressures, stage 2 hypertension should be evaluated and treated within 1 month.

Regulation of Blood Pressure

From a systemic hemodynamic perspective, blood pressure is regulated primarily by the sympathetic nervous system and the kidneys through their influence on cardiac output and peripheral vascular resistance (PVR). Vasoactive and other substances produced within the blood vessel wall also have a substantial role in the regulation of blood pressure and in the pathophysiology of hypertension.

Cardiac output, which is the product of stroke volume and heart rate, is increased by sympathetic stimulation via activation of β₁-adrenoceptors in the heart, and it is influenced by the kidneys through their regulation of blood volume, which is one of the factors determining the cardiac filling pressure and stroke volume.

PVR is chiefly determined by the resistance to blood flow through the arterioles, whose cross-sectional area depends on arteriolar smooth muscle tone in the various vascular beds. Via activation of α₁-adrenoceptors, the sympathetic nervous system stimulates arteriolar smooth muscle contraction, and this leads to vasoconstriction. Blood-borne substances such as vasopressin and angiotensin II also cause vasoconstriction, whereas locally released adenosine, serotonin, endothelin, and prostaglandins also affect arteriolar smooth muscle tone. These substances serve to regulate blood flow through the tissues and influence arterial pressure.

The sympathetic nervous system provides short-term control of blood pressure through the baroreceptor reflex. This reflex modulates sympathetic stimulation of cardiac output and PVR and adjusts blood pressure in response to postural changes and altered physical activity. The kidneys are responsible for the long-term control of blood pressure, via regulation of plasma volume and the renin-angiotensin-aldosterone axis. By these mechanisms, the sympathetic system and kidneys maintain arterial blood pressure within a fairly narrow range when a person is at rest, and they adjust blood pressure appropriately in response to postural changes and physical activity.

In normotensive individuals, an increase in blood pressure leads to a proportional increase in sodium and water excretion by the kidneys, so that blood volume is reduced and blood pressure returns to its normal set point. In hypertensive patients, the set point at which blood pressure is controlled is higher than normal; the regulation of blood pressure is defective; and an increase in blood pressure is not followed by a proportional increase in sodium and water excretion by the kidneys. Although studies have shown that PVR is elevated in most hypertensive patients, it is not clear whether this is the cause or the result of hypertension.

Sites and Effects of Antihypertensive Drug Action

The four major categories of antihypertensive drugs are the diuretics, sympatholytic drugs, angiotensin inhibitors, and other vasodilators. These drugs lower blood pressure through actions exerted at one or more of the following sites: kidneys, sympathetic nervous system, renin-angiotensin-aldosterone axis, or vascular smooth muscle (Fig. 10-1).

Antihypertensive drugs can be characterized in terms of their cardiovascular effects (Table 10-2) and their effects on serum potassium and cholesterol measurements (Table 10-3). They can also be characterized in terms of the compensatory mechanisms invoked by their hypotensive effect. Compensatory reactions serve to return blood pressure to the pretreatment level and include reflex tachycardia, fluid retention by the kidneys, and activation of the renin-angiotensin-aldosterone axis. Whereas most antihypertensive drugs are taken orally on a long-term basis, some are administered parenterally for the management of hypertensive emergencies. The treatment of this condition is discussed at the end of the chapter.

Thiazide and Related Diuretics

Thiazide and related diuretics reduce blood pressure by two mechanisms, both stemming from their ability to increase sodium and water excretion. When they are first administered to a patient, the drugs decrease blood volume and thereby decrease cardiac output (Fig. 10-2; see Table 10-2). With continued administration over weeks and months, they also decrease PVR, and this appears to account for much of their long-term antihypertensive effect. The decreased PVR may result from a reduction in the sodium content of arteriolar smooth muscle cells, which decreases muscle contraction in response to vasopressor agents such as norepinephrine and angiotensin. This relationship is supported by the finding that the effect of a thiazide on PVR is reduced if patients ingest enough dietary sodium to counteract the natriuretic effect of the drug.