hypertention selective

139 C H A P T E R 15 Hypertension JOSEPH J. SASEEN AND ERIC J. MACLAUGHLIN KEY CONCEPTS � The risk of cardiovascular (CV) morbidity and mortality is direct- ly correlated with blood pressure (BP). Even patients with pre- hypertension have an increased risk of CV disease. � Outcome trials have shown that antihypertensive drug therapy substantially reduces the risks of CV events and death in pa- tients with hypertension. � Essential hypertension is usually an asymptomatic condition. A diagnosis cannot be made based on one elevated BP measure- ment. Elevated values from the average of two or more mea- surements on two or more clinical encounters are needed to diagnose hypertension. � The overall goal of treating hypertension is to reduce hypertension- associated morbidity and mortality from CV events. The selection of specific drug therapy is based on evidence that demonstrates CV risk reduction. � A goal BP of less than 140/90 mm Hg is appropriate for general prevention of CV events or CV disease. However, achieving BP of less than 130/80 mm Hg goal is recommended in patients with diabetes, significant chronic kidney disease, known coronary artery disease (myocardial infarction, stable angina, unstable angina), noncoronary atherosclerotic vascular disease (ischemic stroke, transient ischemic attack, peripheral arterial disease, abdominal aortic aneurism), or a 10% or greater 10-year risk of fatal coronary heart disease or nonfatal myocardial infarction based on Framing- ham risk scoring. Patients with left ventricular dysfunction (systolic heart failure) have a BP goal of less than 120/80 mm Hg. � Lifestyle modifications should be prescribed in all patients with hypertension and prehypertension. However, they should never be used as a replacement for antihypertensive drug therapy in patients with hypertension, especially patients with additional CV risk factors. � Thiazide-type diuretics have traditionally been classified as first-line agents for treating most patients with hypertension. This recommendation is supported by clinical trials showing reduced CV morbidity and mortality with thiazide diuretic ther- apy. Comparative data from the landmark Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) confirm the first-line role of thiazide-type diuretics. An angiotensin-converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB), or calcium channel blocker (CCB) may be used as first-line agents in patients without compelling indications. Clinical trials have demonstrated that these agents reduce the risk of CV events when used to treat hypertension. β-Blockers do not reduce CV events to the extent that thiazide- type diuretics, ACE inhibitors, ARBs, or CCBs do when used as the primary antihypertensive agent in patients with hyperten- sion but without a compelling indication for β-blocker therapy. � Compelling indications are comorbid conditions where specific drug therapies have been shown in outcome trials to provide unique long-term benefits (reducing the risk of CV events). � Patients with diabetes are at very high risk for CV events. All pa- tients with diabetes and hypertension should be managed with either an ACE inhibitor or an ARB. These are typically in combi- nation with one or more other antihypertensive agents because multiple agents frequently are needed to lower BP to less than 130/80 mm Hg. Older patients with isolated systolic hypertension are often at risk for orthostatic hypotension when antihypertensive drug therapy is started, particularly with diuretics, ACE inhibitors, and ARBs. Although overall treatment should be the same, low ini- tial doses should be used and dosage titrations should be grad- ual to minimize risk of orthostatic hypotension. � Alternative antihypertensive agents have not been proven to reduce the risk of CV events compared with first-line antihyper- tensive agents. They should be used primarily in combination with first-line agents to provide additional BP lowering. � Hypertensive urgency is ideally managed by adjusting mainte- nance therapy (adding a new antihypertensive and/or increas- ing the dose of a present medication). This provides a gradual reduction in BP, which is a safer treatment approach than very rapid reductions in BP. � Most patients require combination therapy to achieve goal BP values. Combination regimens should include a diuretic, pref- erably a thiazide-type. If a diuretic was not the first drug used, it should be the second drug add-on therapy for most patients. � Patients have resistant hypertension when they fail to attain goal BP values while adherent with an appropriate three drug- regimen. This three-drug regimen must include full doses and include a diuretic. Hypertension is a common disease that is simply defined as persis- tently elevated arterial blood pressure (BP). Although elevated BP was perceived to be “essential” for adequate perfusion of essential Learning objectives, review questions, and other resources can be found at www.pharmacotherapyonline.com. Copyright © 2008, 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use. 140 SEC TIO N 2 C ardiovascular D isorders 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 the 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 supple- mented by the 2007 American Heart Association (AHA) Scientific Statement on the treatment of hypertension.2 This chapter reviews relevant components of these guidelines and additional evidence from clinical trials, with a focus on the pharmacotherapy of hyper- tension. Data from the National Health and Nutrition Examination Survey from 1999 to 2000 indicate that of the population of Ameri- cans with hypertension, 68.9% are aware that they have hyperten- sion, only 58.4% are on some form of antihypertensive treatment, and only 34% of all patients have controlled BP.3 Therefore, there are ample opportunities for clinicians to improve the care of patients with hypertension. EPIDEMIOLOGY Approximately 31% of the population (72 million Americans) have high BP (≥140/90 mm Hg).4 The percentage of men with high BP is higher than that of women before the age of 45 years, but between the ages of 45 and 54 years the percentage is slightly higher with women.4 After age 55 years, a much higher percentage of women have high BP than men.4 Prevalence rates are highest in non- Hispanic blacks (33.5%) followed by non-Hispanic whites (28.9%) and Mexican Americans (20.7%).3 BP values increase with age, and hypertension (persistently ele- vated 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%.1 Most patients have prehypertension before they are diagnosed with hypertension, with most diagnoses occurring between the third and fifth decades of life. In the popula- tion age ≥60 years, the prevalence of hypertension in 2000 was estimated at 65.4%, which is significantly higher than the 57.9% prevalence estimated in 1988.3 ETIOLOGY In most patients, hypertension results from an unknown patho- physiologic 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 are either concurrent medical conditions or are endoge- nously induced. If the cause can be identified, hypertension in these patients has the potential to be cured. ESSENTIAL HYPERTENSION More than 90% of individuals with hypertension 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 hyperten- sion.5 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.5 In the future, identifying individuals with these genetic traits could lead to alter- native approaches to preventing or treating hypertension; however, this is not currently recommended. SECONDARY HYPERTENSION Fewer than 10% of patients have secondary hypertension where either a comorbid disease or drug is responsible for elevating BP (Table 15–1).1,6 In most of these cases, renal dysfunction resulting from severe chronic kidney disease or renovascular disease is the most common secondary cause. Certain drugs, either directly or indirectly, can cause hypertension or exacerbate hypertension by increasing BP. Table 15–1 lists the most common agents. Some of these agents are herbal products. Although these are not technically drugs, they have been identified as secondary causes. 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. PATHOPHYSIOLOGY5,7 Multiple factors that control BP are potential contributing compo- nents in the development of essential hypertension. These include malfunctions in either humoral (i.e., the renin–angiotensin–aldos- terone system [RAAS]) or vasodepressor mechanisms, abnormal TABLE 15-1 Secondary Causes of Hypertension Diseases Drugs Associated with Hypertension in Humans a Chronic kidney disease Prescription drugs Cushing’s syndrome • Adrenal steroids (e.g., prednisone, fludrocortisone, triamcinolone)Coarctation of the aorta Obstructive sleep apnea • Amphetamines/anorexiants (e.g., phendimetrazine, phentermine, sibutramine)Parathyroid disease Pheochromocytoma • Antivascular endothelin growth factor agents (bevaci- zumab, sorafenib, sunitinib), estrogens (usually oral contraceptives) Primary aldosteronism Renovascular disease Thyroid disease • Calcineurin inhibitors (cyclosporine and tracolimus) • Decongestants (phenylpropanolamine and analogs) • Erythropoiesis stimulating agents (erythropoietin and darbepoietin) • Nonsteroidal antiinflammatory drugs, cyclooxygenase-2 inhibitors • Others: venlafaxine, bromocriptine, bupropion, bus- pirone, carbamazepine, clozapine, desulfrane, ket- amine, metoclopramide Situations: β-blocker or centrally acting α-agonists (when abruptly discontinued); β-blocker without α- blocker first when treating pheochromocytoma Street drugs and other natural products Cocaine and cocaine withdrawal Ephedra alkaloids (e.g., Ma-huang), “herbal ecstasy,” other phenylpropanolamine analogsa Nicotine withdrawal, anabolic steroids, narcotic withdrawal, methylphenidate, phencyclidine, ketamine, ergotamine and other ergot-containing herbal products, St. John’s wort Food substances Sodium Ethanol Licorice Tyramine-containing foods if taking a monoamine oxi- dase inhibitor aAgents of most clinical importance. Data from Kaplan NM, Kaplan’s Clinical Hypertension. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2002:1–550. 141 C H APTER 15 H ypertension neuronal mechanisms, defects in peripheral autoregulation, and disturbances in sodium, calcium, and natriuretic hormones. Many of these factors are cumulatively affected by the multifaceted RAAS, which ultimately regulates arterial BP. It is probable that none of these factors is solely responsible for essential hypertension; how- ever, most antihypertensives specifically target these mechanisms and components of the RAAS. ARTERIAL BLOOD PRESSURE Arterial BP is the pressure in the arterial wall measured in millime- ters of mercury (mm Hg). The two typical arterial BP values are systolic BP (SBP) and diastolic BP (DBP). SBP is achieved during cardiac contraction and represents the peak value. DBP is achieved after contraction when the cardiac chambers are filling, and repre- sents 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 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. Consequently, the mean arterial pressure can be estimated by using the following equation: mean arterial pressure = (SBP × 1/3) + (DBP × 2/3) Arterial BP is hemodynamically generated by the interplay between blood flow and the resistance to blood flow. It is mathe- matically defined as the product of cardiac output and total periph- eral resistance according to the following equation: BP = cardiac output × total peripheral resistance Cardiac output is the major determinant of SBP, whereas total peripheral resistance largely determines DBP. In turn, cardiac out- put is a function of stroke volume, heart rate, and venous capaci- tance. Table 15–2 lists physiologic causes of increased cardiac output and total peripheral resistance and correlates them to poten- tial mechanisms of pathogenesis. Under normal physiologic conditions, arterial BP fluctuates throughout the day. It typically follows a circadian rhythm, where it decreases to its lowest daily values during sleep. This is 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. Classification The JNC7 classification of BP in adults (age ≥18 years) is based on the average of two or more properly measured BP readings from two or more clinical encounters (Table 15–3).1 It includes four categories: normal, prehypertension, stage 1 hypertension, and stage 2 hypertension. Prehypertension is not considered a disease cate- gory, but identifies patients whose BP is likely to increase into the classification of hypertension in the future. Hypertensive crises are clinical situations where BP values are very elevated, typically greater than 180/120 mm Hg.7 They are catego- rized as either a hypertensive emergency or hypertensive urgency. Hypertensive emergencies are extreme elevations in BP that are accompanied by acute or progressing target-organ damage. Hyper- tensive urgencies are high elevations in BP without acute or pro- gressing target-organ injury. Recommendations for managing hypertensive crises are described later in this chapter. � Cardiovascular Risk and Blood Pressure Epidemiologic data clearly indicate a strong correlation between BP and CV morbidity and mortality.8 Risk of stroke, myocardial infarc- tion, angina, heart failure, kidney failure, or early death from a CV cause are 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 benefits. Large-scale, placebo- controlled, outcome trials show that the increased risks of CV events and death associated with elevated BP are reduced substan- tially by antihypertensive drug therapy.9–12 SBP is a stronger predictor of CV disease than DBP in adults ≥50 years of age and is the most important clinical BP parameter for most patients.1 Patients with DBP values less than 90 mm Hg and SBP values ≥140 mm Hg have isolated systolic hypertension. Isolated sys- tolic 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. Pulse pressure is the difference between the SBP and the DBP. It is believed to reflect extent of atherosclerotic disease in the elderly and is a measure of increased arterial stiffness. Higher pulse pressure values are correlated with an increased risk of CV mortality, especially in those with isolated systolic hypertension. TABLE 15-2 Potential Mechanisms of Pathogenesis Blood pressure is the mathematical product of cardiac output and peripheral resistance. Elevated blood pressure can result from increased cardiac output and/ or increased total peripheral resistance. Increased cardiac output Increased cardiac preload: • Increased fluid volume from excess sodium intake or renal sodium retention (from reduced number of nephrons or decreased glomerular filtration) Venous constriction: • Excess stimulation of the RAAS • Sympathetic nervous system overactivity Increased peripheral resistance Functional vascular constriction: • Excess stimulation of the RAAS • Sympathetic nervous system overactivity • Genetic alterations of cell membranes • Endothelial-derived factors Structural vascular hypertrophy: • Excess stimulation of the RAAS • Sympathetic nervous system overactivity • Genetic alterations of cell membranes • Endothelial-derived factors • Hyperinsulinemia resulting from obesity or the metabolic syndrome RAAS, renin–angiotensin–aldosterone system. TABLE 15-3 Classification of Blood Pressure in Adults (Age ≥18 Years)a Classification Systolic Blood Pressure (mm Hg) Diastolic Blood Pressure (mm Hg) Normal <120 and <80 Prehypertensionb 120–139 or 80–89 Stage 1 hypertension 140–159 or 90–99 Stage 2 hypertension ≥160 or ≥100 aClassification determined based on the average of two or more properly measured seated blood pressure measurements from two or more clinical encounters. If systolic and diastolic blood pressure values yield different classifications, the highest category is used for the purpose of determining a classification. bFor patients with diabetes mellitus, significant chronic kidney disease, known coronary artery disease (myocardial infarction, stable angina, unstable angina), noncoronary atherosclerotic vascular disease (ischemic stroke, transient ischemic attack, peripheral arterial disease, abdominial aortic aneurism), or a Framingham risk score of 10% or greater, values ≥130/80 mm Hg are considered above goal; patients with left ventricular dysfuction have a blood pressure goal of less than 120/80 mm Hg. 142 SEC TIO N 2 C ardiovascular D isorders HUMORAL MECHANISMS Several humoral abnormalities may be involved in the development of essential hypertension. These abnormalities may involve the RAAS, natriuretic hormones, and hyperinsulinemia. The Renin–Angiotensin–Aldosterone System The RAAS is a complex endogenous system that is involved with most regulatory components of arterial BP. Activation and regula- tion are primarily governed by the kidney (Fig. 15–1). The RAAS regulates sodium, potassium, and fluid balance. Consequently, this system significantly influences vascular tone and sympathetic ner- vous system activity and is the most influential contributor to the homeostatic regulation of BP. 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