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CARDIOVASCULAR-RENAL DRUGS

11. Antihypertensive Agents ¾ Neal L. Benowitz, MD

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INTRODUCTION

Hypertension is the most common cardiovascular disease. In a survey carried out in 2000, hypertension was found in 28% of American adults. According to a Framingham study of blood pressure trends in middle-aged and older individuals, approximately 90% of Caucasian Americans will develop hypertension in their lifetime. The prevalence varies with age, race, education, and many other variables. Sustained arterial hypertension damages blood vessels in kidney, heart, and brain and leads to an increased incidence of renal failure, coronary disease, cardiac failure, and stroke. Effective pharmacologic lowering of blood pressure has been shown to prevent damage to blood vessels and to substantially reduce morbidity and mortality rates. Unfortunately, several surveys indicate that only one third of Americans with hypertension have adequate blood pressure control. Many effective drugs are available. Knowledge of their antihypertensive mechanisms and sites of action allows accurate prediction of efficacy and toxicity. As a result, rational use of these agents, alone or in combination, can lower blood pressure with minimal risk of serious toxicity in most patients.

HYPERTENSION & REGULATION OF BLOOD PRESSURE

Diagnosis

The diagnosis of hypertension is based on repeated, reproducible measurements of elevated blood pressure. The diagnosis serves primarily as a prediction of consequences for the patient; it seldom includes a statement about the cause of hypertension.

Epidemiologic studies indicate that the risks of damage to kidney, heart, and brain are directly related to the extent of blood pressure elevation. Even mild hypertension (blood pressure 140/90 mm Hg) increases the risk of eventual end organ damage. Starting at 115/75 mm Hg cardiovascular disease risk doubles with each increment of 20/10 mm Hg throughout the blood pressure range. The risks¾and therefore the urgency of instituting therapy¾increase in proportion to the magnitude of blood pressure elevation. The risk of end organ damage at any level of blood pressure or age is greater in African-Americans and relatively less in premenopausal women than in men. Other positive risk factors include smoking, hyperlipidemia, diabetes, manifestations of end organ damage at the time of diagnosis, and a family history of cardiovascular disease.

It should be noted that the diagnosis of hypertension depends on measurement of blood pressure and not on symptoms reported by the patient. In fact, hypertension is usually asymptomatic until overt end organ damage is imminent or has already occurred.

Etiology of Hypertension

A specific cause of hypertension can be established in only 10-15% of patients. It is important to consider specific causes in each case, however, because some of them are amenable to definitive surgical treatment: renal artery constriction, coarctation of the aorta, pheochromocytoma, Cushing's disease, and primary aldosteronism.

Patients in whom no specific cause of hypertension can be found are said to have essential hypertension.*

In most cases, elevated blood pressure is associated with an overall increase in resistance to flow of blood through arterioles, while cardiac output is usually normal. Meticulous investigation of autonomic nervous system function, baroreceptor reflexes, the renin-angiotensin-aldosterone system, and the kidney has failed to identify a primary abnormality as the cause of increased peripheral vascular resistance in essential hypertension.

Elevated blood pressure is usually caused by a combination of several (multifactorial) abnormalities. Epidemiologic evidence points to genetic inheritance, psychological stress, and environmental and dietary factors (increased salt and decreased potassium or calcium intake) as perhaps contributing to the development of hypertension. Increase in blood pressure with aging does not occur in populations with low daily sodium intake. Patients with labile hypertension appear more likely than normal controls to have blood pressure elevations after salt loading.

The heritability of essential hypertension is estimated to be about 30%. Mutations in several genes have been linked to various rare causes of hypertension. Functional variations of the genes for angiotensinogen, angiotensin-converting enzyme (ACE), the b2 adrenoceptor, and a adducin (a cytoskeletal protein) appear to contribute to some cases of essential hypertension.

        *The adjective originally was intended to convey the now abandoned idea that blood pressure elevation was essential for adequate perfusion of diseased tissues.

Normal Regulation of Blood Pressure

According to the hydraulic equation, arterial blood pressure (BP) is directly proportionate to the product of the blood flow (cardiac output, CO) and the resistance to passage of blood through precapillary arterioles (peripheral vascular resistance, PVR):

BP = CO ´ PVR

Physiologically, in both normal and hypertensive individuals, blood pressure is maintained by moment-to-moment regulation of cardiac output and peripheral vascular resistance, exerted at three anatomic sites (Figure 11-1): arterioles, postcapillary venules (capacitance vessels), and heart. A fourth anatomic control site, the kidney, contributes to maintenance of blood pressure by regulating the volume of intravascular fluid. Baroreflexes, mediated by autonomic nerves, act in combination with humoral mechanisms, including the renin-angiotensin-aldosterone system, to coordinate function at these four control sites and to maintain normal blood pressure. Finally, local release of vasoactive substances from vascular endothelium may also be involved in the regulation of vascular resistance. For example, endothelin-1 (see Chapter 17) constricts and nitric oxide (see Chapter 19) dilates blood vessels.

Blood pressure in a hypertensive patient is controlled by the same mechanisms that are operative in normotensive subjects. Regulation of blood pressure in hypertensive patients differs from healthy patients in that the baroreceptors and the renal blood volume-pressure control systems appear to be "set" at a higher level of blood pressure. All antihypertensive drugs act by interfering with these normal mechanisms, which are reviewed below.

A. POSTURAL BAROREFLEX (FIGURE 11-2)
Baroreflexes are responsible for rapid, moment-to-moment adjustments in blood pressure, such as in transition from a reclining to an upright posture. Central sympathetic neurons arising from the vasomotor area of the medulla are tonically active. Carotid baroreceptors are stimulated by the stretch of the vessel walls brought about by the internal pressure (arterial blood pressure). Baroreceptor activation inhibits central sympathetic discharge. Conversely, reduction in stretch results in a reduction in baroreceptor activity. Thus, in the case of a transition to upright posture, baroreceptors sense the reduction in arterial pressure that results from pooling of blood in the veins below the level of the heart as reduced wall stretch, and sympathetic discharge is disinhibited. The reflex increase in sympathetic outflow acts through nerve endings to increase peripheral vascular resistance (constriction of arterioles) and cardiac output (direct stimulation of the heart and constriction of capacitance vessels, which increases venous return to the heart), thereby restoring normal blood pressure. The same baroreflex acts in response to any event that lowers arterial pressure, including a primary reduction in peripheral vascular resistance (eg, caused by a vasodilating agent) or a reduction in intravascular volume (eg, due to hemorrhage or to loss of salt and water via the kidney).

B. RENAL RESPONSE TO DECREASED BLOOD PRESSURE
By controlling blood volume, the kidney is primarily responsible for long-term blood pressure control. A reduction in renal perfusion pressure causes intrarenal redistribution of blood flow and increased reabsorption of salt and water. In addition, decreased pressure in renal arterioles as well as sympathetic neural activity (via b adrenoceptors) stimulates production of renin, which increases production of angiotensin II (see Figure 11-1 and Chapter 17). Angiotensin II causes (1) direct constriction of resistance vessels and (2) stimulation of aldosterone synthesis in the adrenal cortex, which increases renal sodium absorption and intravascular blood volume. Vasopressin released from the posterior pituitary gland also plays a role in maintenance of blood pressure through its ability to regulate water reabsorption by the kidney (see Chapters 15 and 17).

 Figure 11-1. Anatomic sites of blood pressure control. 0 
 Figure 11-2. Baroreceptor reflex arc. 0 

I. BASIC PHARMACOLOGY OF ANTIHYPERTENSIVE AGENTS

INTRODUCTION

All antihypertensive agents act at one or more of the four anatomic control sites depicted in Figure 11-1 and produce their effects by interfering with normal mechanisms of blood pressure regulation. A useful classification of these agents categorizes them according to the principal regulatory site or mechanism on which they act (Figure 11-3). Because of their common mechanisms of action, drugs within each category tend to produce a similar spectrum of toxicities. The categories include the following:

(1) Diuretics, which lower blood pressure by depleting the body of sodium and reducing blood volume and perhaps by other mechanisms.

(2) Sympathoplegic agents, which lower blood pressure by reducing peripheral vascular resistance, inhibiting cardiac function, and increasing venous pooling in capacitance vessels. (The latter two effects reduce cardiac output.) These agents are further subdivided according to their putative sites of action in the sympathetic reflex arc (see below).

(3) Direct vasodilators, which reduce pressure by relaxing vascular smooth muscle, thus dilating resistance vessels and¾to varying degrees¾increasing capacitance as well.

(4) Agents that block production or action of angiotensin and thereby reduce peripheral vascular resistance and (potentially) blood volume.

The fact that these drug groups act by different mechanisms permits the combination of drugs from two or more groups with increased efficacy and, in some cases, decreased toxicity. (See Box: Monotherapy Versus Polypharmacy in Hypertension, p. 172 .)

 Figure 11-3. Sites of action of the major classes of antihypertensive drugs. 0 

DRUGS THAT ALTER SODIUM & WATER BALANCE

Introduction

Dietary sodium restriction has been known for many years to decrease blood pressure in hypertensive patients. With the advent of diuretics, sodium restriction was thought to be less important. However, there is now general agreement that dietary control of blood pressure is a relatively nontoxic therapeutic measure and may even be preventive. Several studies have shown that even modest dietary sodium restriction lowers blood pressure (although to varying extents) in many hypertensive individuals.

Mechanisms of Action & Hemodynamic Effects of Diuretics

Diuretics lower blood pressure primarily by depleting body sodium stores. Initially, diuretics reduce blood pressure by reducing blood volume and cardiac output; peripheral vascular resistance may increase. After 6-8 weeks, cardiac output returns toward normal while peripheral vascular resistance declines. Sodium is believed to contribute to vascular resistance by increasing vessel stiffness and neural reactivity, possibly related to increased sodium-calcium exchange with a resultant increase in intracellular calcium. These effects are reversed by diuretics or sodium restriction.

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