Hypertension
Hypertension is the most important modifiable risk factor for coronary heart disease (the leading cause of death in North America), stroke (the third leading cause), congestive heart failure, end-stage renal disease, and peripheral vascular disease. Therefore, health care professionals must not only identify and treat patients with hypertension but also promote a healthy lifestyle and preventive strategies to decrease the prevalence of hypertension in the general population.
Historical perspectives
Blood pressure was measured for the first time by Stephen Hales in 1773. Hales also described the importance of blood volume in blood pressure regulation. The contribution of peripheral arterioles in maintaining blood pressure, described as "tone," was first described by Lower in 1669 and subsequently by Sénac in 1783. The role of vasomotor nerves in the regulation of blood pressure was observed by such eminent investigators as Claude Bernard, Charles E. Edouard, Charles Brown-Séquard, and Augustus Waller. William Dayliss advanced this concept in a monograph published in 1923. Cannon and Rosenblueth developed the concept of humoral control of blood pressure and investigated pharmacologic effects of epinephrine. Three contributors who advanced the knowledge of humoral mechanisms of blood pressure control are TR Elliott, Sir Henry Dale, and Otto Loew.
Richard Bright, a physician who practiced in the first half of the 19th century, observed the changes of hypertension on the cardiovascular system in patients with chronic renal disease. George Johnson in 1868 postulated that the cause of left ventricular hypertrophy (LVH) in Bright disease was the presence of muscular hypertrophy in the smaller arteries throughout the body. Further clinical pathologic studies by Sir William Gull and HG Sutton (1872) led to further description of the cardiovascular changes of hypertension. Frederick Mahomed was one of the first physicians to systematically incorporate blood pressure measurement as a part of a clinical evaluation.
The recognition of primary, or essential, hypertension is credited to the work of Huchard, Vonbasch, and Albutt. Observations of Janeway and Walhard led to the recognition of target organ damage, which branded hypertension as the "silent killer." The concepts of renin, angiotensin, and aldosterone were advanced by several investigators in the late 19th and early 20th centuries. The names of Irwine, Page, van Slyke, Goldblatt, Laragh, and Tuttle prominently appear throughout the hypertension literature, and their work enhances our understanding of the biochemical basis of essential hypertension. Cushman and Ondetti developed an orally acting converting enzyme inhibitor from snake venom peptides and are credited with the successful synthesis of the modern antihypertensive captopril.
Definition
Defining abnormally high blood pressure is extremely difficult and arbitrary. Furthermore, the relationship between systemic arterial pressure and morbidity appears to be quantitative rather than qualitative. A level for high blood pressure must be agreed upon in clinical practice for screening patients with hypertension and for instituting diagnostic evaluation and initiating therapy. Because the risk to an individual patient may correlate with the severity of hypertension, a classification system is essential for making decisions about aggressiveness of treatment or therapeutic interventions.
Based on recommendations of the Seventh Report of the Joint National Committee of Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII), the classification of blood pressure (expressed in mm Hg) for adults aged 18 years or older is as follows*:1
†Normal blood pressure with respect to cardiovascular risk is less than 120/80 mm Hg. However, unusually low readings should be evaluated for clinical significance.
Prehypertension, a new category designated in the JNC VII report, emphasizes that patients with prehypertension are at risk for progression to hypertension and that lifestyle modifications are important preventive strategies.
Hypertension may be either essential or secondary. Essential hypertension is diagnosed in the absence of an identifiable secondary cause. Approximately 95% of the 50 million American adults with hypertension have essential hypertension, while secondary hypertension accounts for fewer than 5% of the cases. However secondary forms of hypertension, such as primary hyperaldosteronism, account for 20% of resistant hypertension (hypertension that requires 4 or more medications to control).
Regulation of blood pressure
Regulation of normal blood pressure is a complex process. Although a function of cardiac output and peripheral vascular resistance, both of these variables are influenced by multiple factors.
The factors affecting cardiac output include sodium intake, renal function, and mineralocorticoids; the inotropic effects occur via extracellular fluid volume augmentation and an increase in heart rate and contractility. Peripheral vascular resistance is dependent upon the sympathetic nervous system, humoral factors, and local autoregulation. The sympathetic nervous system produces its effects via the vasoconstrictor alpha effect or the vasodilator beta effect. The humoral actions on peripheral resistance are also mediated by other mediators such as vasoconstrictors (angiotensin and catecholamines) or vasodilators (prostaglandins and kinins).
Autoregulation of blood pressure occurs by way of intravascular volume contraction and expansion regulated by the kidney, as well as via transfer of transcapillary fluid. Through the mechanism of pressure natriuresis, salt and water balance is achieved at heightened systemic pressure, as proposed by Guyton. Interactions between cardiac output and peripheral resistance are autoregulated to maintain a set blood pressure in an individual. For example, constriction of the arterioles elevates arterial pressure by increasing total peripheral resistance, whereas venular constriction leads to redistribution of the peripheral intravascular volume to the central circulation, thereby increasing preload and cardiac output.
Pathogenesis of hypertension
The pathogenesis of essential hypertension is multifactorial and highly complex. Multiple factors modulate the blood pressure for adequate tissue perfusion and include humoral mediators, vascular reactivity, circulating blood volume, vascular caliber, blood viscosity, cardiac output, blood vessel elasticity, and neural stimulation. A possible pathogenesis of essential hypertension has been proposed in which multiple factors, including genetic predisposition, excess dietary salt intake, and adrenergic tone, may interact to produce hypertension. Although genetics appears to contribute to essential hypertension, the exact mechanism has not been established.The natural history of essential hypertension evolves from occasional to established hypertension. After a long invariable asymptomatic period, persistent hypertension develops into complicated hypertension, in which target organ damage to the aorta and small arteries, heart, kidneys, retina, and central nervous system is evident. The progression begins with prehypertension in persons aged 10-30 years (by increased cardiac output) to early hypertension in persons aged 20-40 years (in which increased peripheral resistance is prominent) to established hypertension in persons aged 30-50 years, and, finally, to complicated hypertension in persons aged 40-60 years.
One mechanism of hypertension has been described as high-output hypertension. High-output hypertension results from decreased peripheral vascular resistance and concomitant cardiac stimulation by adrenergic hyperactivity and altered calcium homeostasis. A second mechanism manifests with normal or reduced cardiac output and elevated systemic vascular resistance due to increased vasoreactivity. Another (and overlapping) mechanism is increased salt and water reabsorption (salt sensitivity) by the kidney, which increases circulating blood volume.
The vasoreactivity of the vascular bed, an important phenomenon mediating changes of hypertension, is influenced by the activity of vasoactive factors, reactivity of the smooth muscle cells, and structural changes in the vessel wall and vessel caliber, expressed by a lumen-to-wall ratio. Patients who develop hypertension are known to develop a systemic hypertensive response secondary to vasoconstrictive stimuli. Alterations in structural and physical properties of resistance arteries, as well as changes in endothelial function, are probably responsible for this abnormal behavior of vasculature. Furthermore, vascular remodeling occurs over the years as hypertension evolves, thereby maintaining increased vascular resistance irrespective of the initial hemodynamic pattern.
Genetic factors
Hypertension develops secondary to environmental factors, as well as to multiple genes, whose inheritance appears to be complex.2,3 Very rare secondary causes are related to single genes and include Liddle syndrome, glucocorticoid remediable hyperaldosteronism, 11 beta-hydroxylase and 17 alpha-hydroxylase deficiencies, the syndrome of apparent mineralocorticoid excess, and pseudohypoaldosteronism type II.
Role of the vascular endothelium
The vascular endothelium is presently considered a vital organ, where synthesis of various vasodilating and constricting mediators occurs. The interaction of autocrine and paracrine factors takes place in the vascular endothelium, leading to growth and remodeling of the vessel wall and to the hemodynamic regulation of blood pressure.
Numerous hormonal, humeral vasoactive, and growth and regulating peptides are produced in the vascular endothelium. These mediators include angiotensin II, bradykinin, endothelin, nitric oxide, and several other growth factors. Endothelin is a potent vasoconstrictor and growth factor that likely plays a major role in the pathogenesis of hypertension. Angiotensin II is a potent vasoconstrictor synthesized from angiotensin I with the help of an angiotensin-converting enzyme (ACE). Another vasoactive substance manufactured in the endothelium is nitric oxide. Nitric oxide is an extremely potent vasodilator that influences local autoregulation and other vital organ functions. Additionally, several growth factors are manufactured in the vascular endothelium; each of these plays an important role in atherogenesis and target organ damage. These factors include platelet-derived growth factor, fibroblast growth factor, insulin growth factor, and many others.
Pathophysiology of target organ damage
Hypertension and the cardiovascular system
Cardiac involvement in hypertension manifests as LVH, left atrial enlargement, aortic root dilatation, atrial and ventricular arrhythmias, systolic and diastolic heart failure, and ischemic heart disease. LVH is associated with an increased risk of premature death and morbidity. A higher frequency of cardiac atrial and ventricular dysrhythmias and sudden cardiac death may exist. Possibly, increased coronary arteriolar resistance leads to reduced blood flow to the hypertrophied myocardium, resulting in angina despite clean coronary arteries. Hypertension, along with reduced oxygen supply and other risk factors, accelerates the process of atherogenesis, thereby further reducing oxygen delivery to the myocardium.
Hypertension remains the most common cause of congestive heart failure. Antihypertensive therapy has been demonstrated to significantly reduce the risk of death from stroke and coronary heart disease. Two published meta-analyses have shown 14% and 26% reductions in cardiovascular mortality rates.
Left ventricular hypertrophy
The myocardium undergoes structural changes in response to increased afterload. Cardiac myocytes respond by hypertrophy, allowing the heart to pump more strongly against the elevated pressure. However, the contractile function of the left ventricle remains normal until later stages. Eventually, LVH lessens the chamber lumen, limiting diastolic filling and stroke volume. The left ventricular diastolic function is markedly compromised in long-standing hypertension.
The mechanisms of diastolic dysfunction have been elucidated only recently. An aberration in the passive relaxation of the left ventricle during diastole appears to exist. Over time, fibrosis may occur, further contributing to the poor compliance of the ventricle. As the left ventricle does not relax during early diastole, left ventricular end-diastolic pressure increases, further increasing left atrial pressure in late diastole. The exact determinants of left ventricular diastolic dysfunction have not been well studied; possibly, the abnormality is governed by abnormal calcium kinetics.
The central nervous system
Long-standing hypertension may manifest as hemorrhagic and atheroembolic stroke or encephalopathy. Both the high systolic and diastolic pressures are harmful; a diastolic pressure of more than 100 mm Hg and a systolic pressure of more than 160 mm Hg have led to a significant incidence of strokes. Other cerebrovascular manifestations of complicated hypertension include hypertensive hemorrhage, hypertensive encephalopathy, lacunar-type infarctions, and dementia.
Renal disease
Despite widespread treatment of hypertension in the United States, the incidence of end-stage renal disease continues to rise. The explanation for this rise may be concomitant diabetes mellitus, the progressive nature of hypertensive renal disease despite therapy, or a failure to reduce blood pressure to a protective level. A reduction in renal blood flow in conjunction with elevated afferent glomerular arteriolar resistance increases glomerular hydrostatic pressure secondary to efferent glomerular arteriolar constriction. The result is glomerular hyperfiltration, followed by development of glomerulosclerosis and further impairment of renal function.
Two studies have demonstrated that a reduction in blood pressure may result in improved renal function. Therefore, earlier detection of hypertensive nephrosclerosis using means to detect microalbuminuria and aggressive therapeutic interventions, particularly with ACE inhibitor drugs, may prevent progression to end-stage renal disease.4
Nephrosclerosis is one of the possible complications of long-standing hypertension. The risk of hypertension-induced end-stage renal disease is higher in black patients, even when blood pressure is under good control. Furthermore, patients with diabetic nephropathy who are hypertensive are also at high risk for developing end-stage renal disease.
The renin-angiotensin system activity influences the progression of renal disease. Angiotensin II acts at the afferent and the efferent arterioles, but more so on the efferent arteriole, which leads to an increase of the intraglomerular pressure. The excess glomerular pressure leads to microalbuminuria. Reducing intraglomerular pressure using an ACE inhibitor has been shown to be beneficial in patients with diabetic nephropathy, even in those who are not hypertensive. The beneficial effect of ACE inhibitors on the progression of renal insufficiency in patients who are nondiabetic is less clear. The benefit of ACE inhibitors is greater in patients with more pronounced proteinuria.
Hypertension in renal disease
Hypertension is commonly observed in patients with kidney disease. Volume expansion is the main cause of hypertension in patients with glomerular disease (nephrotic and nephritic syndrome). Hypertension in patients with vascular disease is the result of the activation of the renin-angiotensin system, which is often secondary to ischemia. Most patients with chronic renal failure are hypertensive (80-90%). The combination of volume expansion and the activation of the renin-angiotensin system is believed to be the main factor behind hypertension in patients with chronic renal failure.
Metabolic syndrome
The metabolic syndrome is an assemblage of metabolic risk factors that directly promote the development of atherosclerotic cardiovascular disease.5,6 Dyslipidemia, hypertension, and hyperglycemia are the most widely recognized metabolic risk factors. The combination of these risk factors leads to a prothrombotic, proinflammatory state in humans and identifies individuals who are at elevated risk for atherosclerotic cardiovascular disease.
The predominant underlying risk factors for the metabolic syndrome appear to be abdominal obesity and insulin resistance. Other associated conditions are physical inactivity, aging, hormonal imbalance, and atherogenic diet. Insulin resistance, an essential cause of the metabolic syndrome, predisposes to hyperglycemia and type 2 diabetes mellitus. Individuals who insulin resistant may not be clinically obese, but they commonly have an abnormal fat distribution that is characterized by predominant upper body fat. Upper body obesity can occur either intraperitoneally (visceral fat) or subcutaneously, both of which correlate strongly with insulin resistance and the metabolic syndrome.
The rising prevalence of the metabolic syndrome is secondary to the increasing burden of obesity in our society. The adipose tissue in people who are obese is insulin resistant, raises nonesterified fatty acid levels, alters hepatic metabolism, and produces several adipokines. These include increased production of inflammatory cytokines, plasminogen activator inhibitor-1, and other bioactive products, while the synthesis of potentially protective adipokine, adiponectin, is reduced. This syndrome has been noted to be associated with a state of chronic, low-grade inflammation. Although the metabolic syndrome unequivocally predisposes to type 2 diabetes mellitus, this syndrome is multidimensional risk factor for atherosclerotic cardiovascular disease.
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*Includes racial/ethnic groups not shown separately because of small sample sizes
At any given visit, an average of 3 blood pressure readings taken 2 minutes apart using a mercury manometer is preferable. Blood pressure should be measured in both the supine and sitting positions, auscultating with the bell of the stethoscope. On the first visit, blood pressure should be checked in both arms and in one leg to avoid missing the diagnosis of coarctation of aorta or subclavian artery stenosis.
As the improper cuff size may influence blood pressure measurement, a wider cuff is preferable, particularly if the patient's arm circumference exceeds 30 cm.
The patient should rest quietly for at least 5 minutes before the measurement.
Although somewhat controversial, the common practice is to document phase V (a disappearance of all sounds) of Korotkoff sounds as the diastolic pressure.
Ambulatory blood pressure monitoring provides a more accurate prediction of cardiovascular risk than does office blood pressure.14
"Non-dipping" is the loss of the usual physiologic nocturnal drop in blood pressure and is associated with an increased cardiovascular risk.
Home blood pressure predicts cardiovascular events much better than do office readings and can be a useful clinical tool.
Clinical trials Multiple clinical trials suggest that most antihypertensive drugs provide the same degree of cardiovascular protection for the same level of blood pressure control. Well-designed prospective randomized trials, such as the Swedish Trial in Old Patients with Hypertension (STOP-2), the Nordic Diltiazem (NORDIL) trial, and the Intervention as a Goal in Hypertension Treatment (INSIGHT) trial, have shown a similar outcome with older drugs (eg, diuretics, beta blockers) compared to the newer antihypertensive agents (eg, ACE inhibitors, calcium channel blockers).
No consensus exists regarding optimal drug therapy for treatment of hypertension; most clinicians recommend initiating therapy with a single agent and advancing to the low-dose combination therapy. Any of the first-line medications decrease blood pressure in 40-60% of patients with mild-to-moderate hypertension. In unresponsive patients, switching to a second drug (rather than combining it with the first drug) or switching to a third drug if the second drug is not effective may allow a 70-80% response rate to monotherapy. Therefore, attempt to identify a particular class of drug to which the patient responds rather than adding multiple drugs (as in combination therapy).
The JNC VII report recommends either a thiazide diuretic or a beta blocker as the initial therapy of uncomplicated hypertension.1 A low dose of thiazide diuretic (12.5-25 mg hydrochlorothiazide) is a low-cost therapy with fewer complications, and it provides equivalent cardiovascular protection.20,21 Patients unresponsive to low-dose thiazide therapy should try an ACE inhibitor, beta blocker, or calcium channel blocker, sequentially. Patients unresponsive to a diuretic may not respond to a calcium channel blocker, and an ACE inhibitor or a beta blocker should be tried as a second-line agent in these patients. Calcium channel blocking agents and diuretics may be more effective in hypertensive black patients.
Initial therapy based on the JNC VII report recommendations is as follows:1
Two randomized controlled trials, the Hypertension Detection and Follow-up Program (HDFP) and the Medical Research Council (MRC) trials, randomized patients with elevated levels of diastolic blood pressure to either diuretic-based stepped-care treatment or usual care. The usual care group received some form of therapy from their own physicians, whereas the stepped-care group received systematic care. In both studies, stepped-care treatment reduced diastolic blood pressure by 5 mm more than that reduced in the control group. Both trials showed a benefit from stepped-care therapy compared to the control group. In the HDFP trial, stepped-care led to relative risk reduction of 17% for total mortality; 76 hypertensive patients needed to be treated with stepped-care therapy for 5 years to prevent one death.
A meta-analysis published in the Journal of the American Medical Association (JAMA) in 1997 included several randomized controlled clinical trials. The total number of participants randomized to active therapy was 24,294, and the number for the control therapy was 23,926. Active treatment reduced diastolic blood pressure by at least 5 mm Hg. The meta-analysis showed a risk reduction of coronary heart disease of 8-14% and the reduction in stroke incidence of 35-40%. Subsequent meta-analysis reported that benefits of active treatment are similar in men and women.
Recommendations for management of hypertension
The JNC recommends certain situations for which a specific class of drug may be administered.1 An ACE inhibitor should be the initial treatment in situations in which hypertension is associated with congestive heart failure, diabetes mellitus with proteinuria, and postmyocardial infarction with systolic left ventricular dysfunction. In patients who develop persistent cough while on ACE inhibitor therapy, an angiotensin II receptor antagonist may be substituted. A beta blocker should be prescribed following an acute myocardial infarction. A diuretic or a long-acting calcium channel blocker may be more effective in elderly patients with isolated systolic hypertension.
The 2004 Canadian Hypertension Society recommendations (similar to JNC VII guidelines) for the management of hypertension in specific patient groups are listed in Table 2 and Table 3, as follows:22
Table 2. Synopsis of Considerations in the Use of Antihypertensive Drug Classes*
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*CMAJ 1999, 161:S1-S22
Table 3. Considerations in the Individualization of Antihypertensive Therapy*
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*Short-acting calcium channel blockers are not recommended in the treatment of hypertension
Several situations demand the addition of a second drug because 2 drugs may be used at lower doses to avoid adverse effects, which may occur with higher doses of an individual agent. Diuretics generally potentiate the effects of other antihypertensive drugs by minimizing volume expansion. Specifically, the use of the diuretic thiazide in conjunction with a beta blocker or an ACE inhibitor has an additive effect, controlling blood pressure in up to 85% of patients.
Most drug combinations using agents that act by different mechanisms have an additive effect. The combination of a calcium channel blocker with either an ACE inhibitor or a dihydropyridine calcium channel blocker and a beta blocker has additive effects. An ACE inhibitor may be combined with an angiotensin II receptor antagonist because the blocking of angiotensin I receptors may lead to increased plasma angiotensin II concentration, which may compete with a drug for the receptor. Some combinations may not be additive, including a beta blocker and ACE inhibitor, a beta blocker and an alpha1-blocker and an alpha2 stimulant, and, more controversially, a diuretic and a calcium channel blocker. Some combinations may have additive adverse effects; these include a beta blocker combined with verapamil or diltiazem, which leads to cardiac depression, bradycardia, or heart block.
Clinical trials have shown that the effective control of blood pressure reduces the risk of cardiovascular events in high-risk patients. In the patients who achieved optimal blood pressure control compared with those with uncontrolled hypertension, significant reductions in the incidence of cardiac events, stroke, and all-cause mortality occurred (according to the Valsartan Antihypertensive Long-term Use Evaluation [VALUE] Trial). The lack of significant difference in cardiovascular mortality and morbidity among patients receiving diuretics, calcium channel blockers, or ACE inhibitors in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) possibly occurred due to confounding because of differences in the blood pressure reductions achieved with the 3 treatments.23
Studies have consistently shown that newer antihypertensive agents, such as ACE inhibitors and calcium channel blockers, reduce cardiovascular events to a similar, or possibly greater, extent than do older therapies, such as diuretics and beta blockers. ACE inhibitors specifically offer additional benefits beyond blood pressure reduction, including renal protection and reduction of cardiovascular events. Similarly, ARBs have demonstrated beneficial effects in heart failure, stroke, and renal protection.
A 2007 research summary by the Agency for Healthcare Research and Quality (AHRQ) noted that despite the relative importance of ACE inhibitors and ARBs for treatment of essential hypertension, few large, long-term, head-to-head studies have been published.24 Consequently, there is insufficient comparative evidence for the long-term beneficial or deleterious effects of these 2 classes of agents. On the basis of existing evidence, the AHRQ concluded that ACE inhibitors and ARBs appear to have similar long-term effects on blood pressure; the only significant difference between them is that ACE inhibitors have been consistently associated with a greater risk of cough.
>6 months: 2 mg/kg/d PO divided bid
Alternatively, 1 mg/kg IV/IM slowly under close supervision; not to exceed 6 mg/kg
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Not suitable for emergency treatment of hypertension. Do not give IV in hypertensive emergencies.
Inderal LA: 80 mg PO qd; usual maintenance dose is 120-160 mg PO qd; not to exceed 640 mg/d
InnoPran XL: 80 mg PO hs initially; may increase dose at 2-3 wk intervals; not to exceed 120 mg hs
Inderal LA: Not established
InnoPran XL: Not established
CrCl <30 mL/min: 2.5 mg PO qd initially
Moderate hepatic impairment: 2.5 mg PO qd initially
Maintenance dose: 10-40 mg/d PO qd or divided bid; not to 100 mg/d
Dilacor XR: 180-240 mg PO qd; may adjust dose after 14 days; dose range is 180-420 mg/day; not to exceed 540 mg/day
30-60 mg SR tab PO qd; not to exceed 90-120 mg/d
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Helps control blood pressure and proteinuria. Decreases pulmonary-to-systemic flow ratio in the catheterization laboratory and increases systemic blood flow in patients with relatively low pulmonary vascular resistance. Has favorable clinical effect when administered over a long period. Helps prevent potassium loss in distal tubules. Body conserves potassium; thus, less oral potassium supplementation needed.
Dosing range: 10-40 mg/d PO in 1-2 divided doses
Alternatively, 1.25 mg/dose IV over 5 min q6h
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
>6 years: 1.3 mg/kg PO qd initially, not to exceed 40 mg/d; may adjust dose according to blood pressure response up to 2.7 mg/kg/d (not to exceed 160 mg/d)
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Note: Lower dose in volume- or salt-depleted patients
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Historical perspectives
Blood pressure was measured for the first time by Stephen Hales in 1773. Hales also described the importance of blood volume in blood pressure regulation. The contribution of peripheral arterioles in maintaining blood pressure, described as "tone," was first described by Lower in 1669 and subsequently by Sénac in 1783. The role of vasomotor nerves in the regulation of blood pressure was observed by such eminent investigators as Claude Bernard, Charles E. Edouard, Charles Brown-Séquard, and Augustus Waller. William Dayliss advanced this concept in a monograph published in 1923. Cannon and Rosenblueth developed the concept of humoral control of blood pressure and investigated pharmacologic effects of epinephrine. Three contributors who advanced the knowledge of humoral mechanisms of blood pressure control are TR Elliott, Sir Henry Dale, and Otto Loew.
Richard Bright, a physician who practiced in the first half of the 19th century, observed the changes of hypertension on the cardiovascular system in patients with chronic renal disease. George Johnson in 1868 postulated that the cause of left ventricular hypertrophy (LVH) in Bright disease was the presence of muscular hypertrophy in the smaller arteries throughout the body. Further clinical pathologic studies by Sir William Gull and HG Sutton (1872) led to further description of the cardiovascular changes of hypertension. Frederick Mahomed was one of the first physicians to systematically incorporate blood pressure measurement as a part of a clinical evaluation.
The recognition of primary, or essential, hypertension is credited to the work of Huchard, Vonbasch, and Albutt. Observations of Janeway and Walhard led to the recognition of target organ damage, which branded hypertension as the "silent killer." The concepts of renin, angiotensin, and aldosterone were advanced by several investigators in the late 19th and early 20th centuries. The names of Irwine, Page, van Slyke, Goldblatt, Laragh, and Tuttle prominently appear throughout the hypertension literature, and their work enhances our understanding of the biochemical basis of essential hypertension. Cushman and Ondetti developed an orally acting converting enzyme inhibitor from snake venom peptides and are credited with the successful synthesis of the modern antihypertensive captopril.
Definition
Defining abnormally high blood pressure is extremely difficult and arbitrary. Furthermore, the relationship between systemic arterial pressure and morbidity appears to be quantitative rather than qualitative. A level for high blood pressure must be agreed upon in clinical practice for screening patients with hypertension and for instituting diagnostic evaluation and initiating therapy. Because the risk to an individual patient may correlate with the severity of hypertension, a classification system is essential for making decisions about aggressiveness of treatment or therapeutic interventions.
Based on recommendations of the Seventh Report of the Joint National Committee of Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII), the classification of blood pressure (expressed in mm Hg) for adults aged 18 years or older is as follows*:1
- Normal† - Systolic lower than 120, diastolic lower than 80
- Prehypertension - Systolic 120-139, diastolic 80-99
- Stage 1 - Systolic 140-159, diastolic 90-99
- Stage 2 - Systolic equal to or more than 160, diastolic equal to or more than 100
†Normal blood pressure with respect to cardiovascular risk is less than 120/80 mm Hg. However, unusually low readings should be evaluated for clinical significance.
Prehypertension, a new category designated in the JNC VII report, emphasizes that patients with prehypertension are at risk for progression to hypertension and that lifestyle modifications are important preventive strategies.
Hypertension may be either essential or secondary. Essential hypertension is diagnosed in the absence of an identifiable secondary cause. Approximately 95% of the 50 million American adults with hypertension have essential hypertension, while secondary hypertension accounts for fewer than 5% of the cases. However secondary forms of hypertension, such as primary hyperaldosteronism, account for 20% of resistant hypertension (hypertension that requires 4 or more medications to control).
Pathophysiology
Arterial blood pressure is a product of cardiac output and systemic vascular resistance. Therefore, determinants of blood pressure include factors that affect cardiac output and arteriolar vascular physiology. Blood viscosity, vascular wall sheer conditions (rate and stress), and blood flow velocity (mean and pulsatile components) have potential relevance with regard to the regulation of blood pressure in humans by vascular and endothelial function. Furthermore, changes in vascular wall thickness affect the amplification of peripheral vascular resistance in hypertensive patients and result in reflection of waves back to the aorta, increasing systolic blood pressure. Circulating blood volume is regulated by renal salt and water handling, a phenomenon that plays a particularly important role in salt-sensitive hypertension.Regulation of blood pressure
Regulation of normal blood pressure is a complex process. Although a function of cardiac output and peripheral vascular resistance, both of these variables are influenced by multiple factors.
The factors affecting cardiac output include sodium intake, renal function, and mineralocorticoids; the inotropic effects occur via extracellular fluid volume augmentation and an increase in heart rate and contractility. Peripheral vascular resistance is dependent upon the sympathetic nervous system, humoral factors, and local autoregulation. The sympathetic nervous system produces its effects via the vasoconstrictor alpha effect or the vasodilator beta effect. The humoral actions on peripheral resistance are also mediated by other mediators such as vasoconstrictors (angiotensin and catecholamines) or vasodilators (prostaglandins and kinins).
Autoregulation of blood pressure occurs by way of intravascular volume contraction and expansion regulated by the kidney, as well as via transfer of transcapillary fluid. Through the mechanism of pressure natriuresis, salt and water balance is achieved at heightened systemic pressure, as proposed by Guyton. Interactions between cardiac output and peripheral resistance are autoregulated to maintain a set blood pressure in an individual. For example, constriction of the arterioles elevates arterial pressure by increasing total peripheral resistance, whereas venular constriction leads to redistribution of the peripheral intravascular volume to the central circulation, thereby increasing preload and cardiac output.
Pathogenesis of hypertension
The pathogenesis of essential hypertension is multifactorial and highly complex. Multiple factors modulate the blood pressure for adequate tissue perfusion and include humoral mediators, vascular reactivity, circulating blood volume, vascular caliber, blood viscosity, cardiac output, blood vessel elasticity, and neural stimulation. A possible pathogenesis of essential hypertension has been proposed in which multiple factors, including genetic predisposition, excess dietary salt intake, and adrenergic tone, may interact to produce hypertension. Although genetics appears to contribute to essential hypertension, the exact mechanism has not been established.The natural history of essential hypertension evolves from occasional to established hypertension. After a long invariable asymptomatic period, persistent hypertension develops into complicated hypertension, in which target organ damage to the aorta and small arteries, heart, kidneys, retina, and central nervous system is evident. The progression begins with prehypertension in persons aged 10-30 years (by increased cardiac output) to early hypertension in persons aged 20-40 years (in which increased peripheral resistance is prominent) to established hypertension in persons aged 30-50 years, and, finally, to complicated hypertension in persons aged 40-60 years.
One mechanism of hypertension has been described as high-output hypertension. High-output hypertension results from decreased peripheral vascular resistance and concomitant cardiac stimulation by adrenergic hyperactivity and altered calcium homeostasis. A second mechanism manifests with normal or reduced cardiac output and elevated systemic vascular resistance due to increased vasoreactivity. Another (and overlapping) mechanism is increased salt and water reabsorption (salt sensitivity) by the kidney, which increases circulating blood volume.
The vasoreactivity of the vascular bed, an important phenomenon mediating changes of hypertension, is influenced by the activity of vasoactive factors, reactivity of the smooth muscle cells, and structural changes in the vessel wall and vessel caliber, expressed by a lumen-to-wall ratio. Patients who develop hypertension are known to develop a systemic hypertensive response secondary to vasoconstrictive stimuli. Alterations in structural and physical properties of resistance arteries, as well as changes in endothelial function, are probably responsible for this abnormal behavior of vasculature. Furthermore, vascular remodeling occurs over the years as hypertension evolves, thereby maintaining increased vascular resistance irrespective of the initial hemodynamic pattern.
Genetic factors
Hypertension develops secondary to environmental factors, as well as to multiple genes, whose inheritance appears to be complex.2,3 Very rare secondary causes are related to single genes and include Liddle syndrome, glucocorticoid remediable hyperaldosteronism, 11 beta-hydroxylase and 17 alpha-hydroxylase deficiencies, the syndrome of apparent mineralocorticoid excess, and pseudohypoaldosteronism type II.
Role of the vascular endothelium
The vascular endothelium is presently considered a vital organ, where synthesis of various vasodilating and constricting mediators occurs. The interaction of autocrine and paracrine factors takes place in the vascular endothelium, leading to growth and remodeling of the vessel wall and to the hemodynamic regulation of blood pressure.
Numerous hormonal, humeral vasoactive, and growth and regulating peptides are produced in the vascular endothelium. These mediators include angiotensin II, bradykinin, endothelin, nitric oxide, and several other growth factors. Endothelin is a potent vasoconstrictor and growth factor that likely plays a major role in the pathogenesis of hypertension. Angiotensin II is a potent vasoconstrictor synthesized from angiotensin I with the help of an angiotensin-converting enzyme (ACE). Another vasoactive substance manufactured in the endothelium is nitric oxide. Nitric oxide is an extremely potent vasodilator that influences local autoregulation and other vital organ functions. Additionally, several growth factors are manufactured in the vascular endothelium; each of these plays an important role in atherogenesis and target organ damage. These factors include platelet-derived growth factor, fibroblast growth factor, insulin growth factor, and many others.
Pathophysiology of target organ damage
Hypertension and the cardiovascular system
Cardiac involvement in hypertension manifests as LVH, left atrial enlargement, aortic root dilatation, atrial and ventricular arrhythmias, systolic and diastolic heart failure, and ischemic heart disease. LVH is associated with an increased risk of premature death and morbidity. A higher frequency of cardiac atrial and ventricular dysrhythmias and sudden cardiac death may exist. Possibly, increased coronary arteriolar resistance leads to reduced blood flow to the hypertrophied myocardium, resulting in angina despite clean coronary arteries. Hypertension, along with reduced oxygen supply and other risk factors, accelerates the process of atherogenesis, thereby further reducing oxygen delivery to the myocardium.
Hypertension remains the most common cause of congestive heart failure. Antihypertensive therapy has been demonstrated to significantly reduce the risk of death from stroke and coronary heart disease. Two published meta-analyses have shown 14% and 26% reductions in cardiovascular mortality rates.
Left ventricular hypertrophy
The myocardium undergoes structural changes in response to increased afterload. Cardiac myocytes respond by hypertrophy, allowing the heart to pump more strongly against the elevated pressure. However, the contractile function of the left ventricle remains normal until later stages. Eventually, LVH lessens the chamber lumen, limiting diastolic filling and stroke volume. The left ventricular diastolic function is markedly compromised in long-standing hypertension.
The mechanisms of diastolic dysfunction have been elucidated only recently. An aberration in the passive relaxation of the left ventricle during diastole appears to exist. Over time, fibrosis may occur, further contributing to the poor compliance of the ventricle. As the left ventricle does not relax during early diastole, left ventricular end-diastolic pressure increases, further increasing left atrial pressure in late diastole. The exact determinants of left ventricular diastolic dysfunction have not been well studied; possibly, the abnormality is governed by abnormal calcium kinetics.
The central nervous system
Long-standing hypertension may manifest as hemorrhagic and atheroembolic stroke or encephalopathy. Both the high systolic and diastolic pressures are harmful; a diastolic pressure of more than 100 mm Hg and a systolic pressure of more than 160 mm Hg have led to a significant incidence of strokes. Other cerebrovascular manifestations of complicated hypertension include hypertensive hemorrhage, hypertensive encephalopathy, lacunar-type infarctions, and dementia.
Renal disease
Despite widespread treatment of hypertension in the United States, the incidence of end-stage renal disease continues to rise. The explanation for this rise may be concomitant diabetes mellitus, the progressive nature of hypertensive renal disease despite therapy, or a failure to reduce blood pressure to a protective level. A reduction in renal blood flow in conjunction with elevated afferent glomerular arteriolar resistance increases glomerular hydrostatic pressure secondary to efferent glomerular arteriolar constriction. The result is glomerular hyperfiltration, followed by development of glomerulosclerosis and further impairment of renal function.
Two studies have demonstrated that a reduction in blood pressure may result in improved renal function. Therefore, earlier detection of hypertensive nephrosclerosis using means to detect microalbuminuria and aggressive therapeutic interventions, particularly with ACE inhibitor drugs, may prevent progression to end-stage renal disease.4
Nephrosclerosis is one of the possible complications of long-standing hypertension. The risk of hypertension-induced end-stage renal disease is higher in black patients, even when blood pressure is under good control. Furthermore, patients with diabetic nephropathy who are hypertensive are also at high risk for developing end-stage renal disease.
The renin-angiotensin system activity influences the progression of renal disease. Angiotensin II acts at the afferent and the efferent arterioles, but more so on the efferent arteriole, which leads to an increase of the intraglomerular pressure. The excess glomerular pressure leads to microalbuminuria. Reducing intraglomerular pressure using an ACE inhibitor has been shown to be beneficial in patients with diabetic nephropathy, even in those who are not hypertensive. The beneficial effect of ACE inhibitors on the progression of renal insufficiency in patients who are nondiabetic is less clear. The benefit of ACE inhibitors is greater in patients with more pronounced proteinuria.
Hypertension in renal disease
Hypertension is commonly observed in patients with kidney disease. Volume expansion is the main cause of hypertension in patients with glomerular disease (nephrotic and nephritic syndrome). Hypertension in patients with vascular disease is the result of the activation of the renin-angiotensin system, which is often secondary to ischemia. Most patients with chronic renal failure are hypertensive (80-90%). The combination of volume expansion and the activation of the renin-angiotensin system is believed to be the main factor behind hypertension in patients with chronic renal failure.
Metabolic syndrome
The metabolic syndrome is an assemblage of metabolic risk factors that directly promote the development of atherosclerotic cardiovascular disease.5,6 Dyslipidemia, hypertension, and hyperglycemia are the most widely recognized metabolic risk factors. The combination of these risk factors leads to a prothrombotic, proinflammatory state in humans and identifies individuals who are at elevated risk for atherosclerotic cardiovascular disease.
The predominant underlying risk factors for the metabolic syndrome appear to be abdominal obesity and insulin resistance. Other associated conditions are physical inactivity, aging, hormonal imbalance, and atherogenic diet. Insulin resistance, an essential cause of the metabolic syndrome, predisposes to hyperglycemia and type 2 diabetes mellitus. Individuals who insulin resistant may not be clinically obese, but they commonly have an abnormal fat distribution that is characterized by predominant upper body fat. Upper body obesity can occur either intraperitoneally (visceral fat) or subcutaneously, both of which correlate strongly with insulin resistance and the metabolic syndrome.
The rising prevalence of the metabolic syndrome is secondary to the increasing burden of obesity in our society. The adipose tissue in people who are obese is insulin resistant, raises nonesterified fatty acid levels, alters hepatic metabolism, and produces several adipokines. These include increased production of inflammatory cytokines, plasminogen activator inhibitor-1, and other bioactive products, while the synthesis of potentially protective adipokine, adiponectin, is reduced. This syndrome has been noted to be associated with a state of chronic, low-grade inflammation. Although the metabolic syndrome unequivocally predisposes to type 2 diabetes mellitus, this syndrome is multidimensional risk factor for atherosclerotic cardiovascular disease.
Frequency
United States
Forty-three million people are estimated to have hypertension, defined by a systolic blood pressure of 140 mm Hg or greater and/or diastolic blood pressure of 90 mm Hg or greater or defined as those taking antihypertensive medications. The age-adjusted prevalence of hypertension varies from 18-32%, according to data from the National Health Examination Surveys. According to the National Center for Health Statistic Surveys, the awareness for hypertension increased from 53% in 1960-1962 to 89% in 1988-1991. The percentage of patients engaged in hypertension treatment increased from 35% to 79% during this period.7- The National High Blood Pressure Education Program (NHBPEP) has reported estimates of hypertension prevalence in United States.8 The hypertension survey was conducted from 1989-1994, and actual blood pressure and self-reported information was used. Hypertension was defined as systolic blood pressure equal to or more than 140 mm Hg, diastolic blood pressure equal or more than 90 mm Hg, or taking medication for hypertension. The data estimated 43.3 million adults with hypertension in November 1991. The prevalence according to age group, sex, and race is shown in Table 1.
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Table
| Age Groups | All Races | White | Black | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Men (%) | Women (%) | Total (%) | Men (%) | Women (%) | Total (%) | Men (%) | Women (%) | Total (%) | |
| 18-24 | 2.6 | 4.6 | 0.7 | 2.5 | 4.6 | 0.5 | 2.6 | 4.1 | 1.4 |
| 25-34 | 5.4 | 8.4 | 2.4 | 4.9 | 8.1 | 1.6 | 8.2 | 10.6 | 6.2 |
| 35-44 | 13.0 | 16.0 | 10.2 | 11.3 | 14.3 | 8.5 | 25.9 | 29.5 | 22.9 |
| 45-54 | 27.6 | 30.0 | 25.2 | 25.8 | 29.1 | 22.6 | 46.9 | 44.3 | 48.8 |
| 55-64 | 43.7 | 44.2 | 43.2 | 42.1 | 43.0 | 41.4 | 60.0 | 58.0 | 63.0 |
| 65-74 | 59.6 | 55.8 | 62.7 | 58.6 | 54.9 | 61.7 | 71.0 | 65.2 | 75.6 |
| 75+ | 70.3 | 60.5 | 76.2 | 69.7 | 59.0 | 76.1 | 75.5 | 71.3 | 77.9 |
| Total | 23.4 | 23.5 | 23.3 | 23.2 | 23.4 | 23.1 | 28.1 | 27.9 | 28.2 |
| Age Groups | All Races | White | Black | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Men (%) | Women (%) | Total (%) | Men (%) | Women (%) | Total (%) | Men (%) | Women (%) | Total (%) | |
| 18-24 | 2.6 | 4.6 | 0.7 | 2.5 | 4.6 | 0.5 | 2.6 | 4.1 | 1.4 |
| 25-34 | 5.4 | 8.4 | 2.4 | 4.9 | 8.1 | 1.6 | 8.2 | 10.6 | 6.2 |
| 35-44 | 13.0 | 16.0 | 10.2 | 11.3 | 14.3 | 8.5 | 25.9 | 29.5 | 22.9 |
| 45-54 | 27.6 | 30.0 | 25.2 | 25.8 | 29.1 | 22.6 | 46.9 | 44.3 | 48.8 |
| 55-64 | 43.7 | 44.2 | 43.2 | 42.1 | 43.0 | 41.4 | 60.0 | 58.0 | 63.0 |
| 65-74 | 59.6 | 55.8 | 62.7 | 58.6 | 54.9 | 61.7 | 71.0 | 65.2 | 75.6 |
| 75+ | 70.3 | 60.5 | 76.2 | 69.7 | 59.0 | 76.1 | 75.5 | 71.3 | 77.9 |
| Total | 23.4 | 23.5 | 23.3 | 23.2 | 23.4 | 23.1 | 28.1 | 27.9 | 28.2 |
- A 2005 survey in the United States found that in the population aged 20 years or older, an estimated 41.9 million men and 27.8 million women have prehypertension, 12.8 million men and 12.2 million women have stage 1 hypertension, and 4.1 million men and 6.9 million women have stage 2 hypertension.7 Age- and sex-adjusted rates of prehypertension and stage I hypertension increased among non-Hispanic white, African American, and Hispanic persons between 1988-1992 and 1999-2000. Age- and sex-adjusted rates of stage 2 hypertension decreased among non-Hispanic whites between 1988-1992 and 1999-2000, but they were unchanged for African American and Hispanic persons.9
International
National health surveys in various countries have shown a high prevalence of poor control of hypertension.10 These studies have reported that prevalence of hypertension is 22% in Canada, of which 16% is controlled; 26.3% in Egypt, of which 8% is controlled; and 13.6% in China, of which 3% is controlled. Hypertension is a worldwide epidemic; in many countries, 50% of the population older than 60 years has hypertension. Overall, approximately 20% of the world's adults are estimated to have hypertension. The 20% prevalence is for hypertension defined as blood pressure in excess of 140/90 mm Hg. The prevalence dramatically increases in patients older than 60 years.Mortality/Morbidity
- In the Framingham Heart Study, the age-adjusted risk of congestive heart failure was 2.3 times higher in men and 3 times higher in women when highest blood pressure was compared to the lowest.11 Multiple Risk Factor Intervention Trial (MRFIT) data showed that the relative risk for coronary heart disease mortality varied from 2.3-6.9 times higher for persons with mild to severe hypertension compared to persons with normal blood pressure.12
- The relative risk for stroke ranged from 3.6-19.2. The population-attributable risk percentage for coronary artery disease varied from 2.3-25.6%, whereas the population-attributable risk for stroke ranged from 6.8-40%.
Race
Blacks have a higher prevalence and incidence of hypertension than whites.13 The prevalence of hypertension was increased by 50% in African Americans. In Mexican Americans, the prevalence and incidence of hypertension is similar to or lower than in whites. The National Health and Nutrition Examination Survey (NHANES) III reported an age-adjusted prevalence of hypertension at 20.6% in Mexican Americans and 23.3% in non-Hispanic whites.9- Are there ethnic differences in the pathogenesis of hypertension, and do these differences influence the choice of treatment? To understand ethnic influence, an understanding of the renin angiotensin system is essential. Renin secretion is suppressed when the kidney detects that the amount of sodium excretion is increased; thus, a clue to the excess sodium in the circulation. Black people tend to develop hypertension at an earlier age and have lower renin activity; target organ damage also differs in black people from that in white people.
- Most studies in the United Kingdom and the United States report a higher prevalence and lower awareness of hypertension in black people than in white people. Mortality from hypertension in African-Caribbean–born people is 3.5 times the national rate; similar data have been published for African American citizens. Strokes are more common in black people, but coronary heart disease is more common in Asians. Both groups have a higher incidence of chronic renal failure than white people, but this is more due to hypertension in black people and diabetes in Asians.
- Black people have a poorer response to treatment with ACE inhibitors compared to white people; the evidence for beta-blockers being less effective in black people is also clear. However, diuretics are more effective at a young age in black people.
Sex
The age-adjusted prevalence of hypertension was 34%, 25.4%, and 23.2% for men and 31%, 21%, and 21.6% for women among African Americans, whites, and Mexican Americans, respectively. In the NHANES III study, the prevalence of hypertension was 12% for white men and 5% for white women aged 18-49 years. However, the age-related blood pressure rise for women exceeds that of men. The prevalence of hypertension was reported at 50% for white men and 55% for white women aged 70 years or older.9Age
A progressive rise in blood pressure with increasing age is observed. The third NHANES survey reported that the prevalence of hypertension grows significantly with increasing age in all sex and race groups. The age-specific prevalence was 3.3% in white men (aged 18-29 y); this increased to 13.2% in the group aged 30-39 years. The prevalence further increased to 22% in the group aged 40-49 years, to 37.5% in the group aged 50-59 years, and to 51% in the group aged 60-74 years. In another study, the incidence of hypertension appeared to increase approximately 5% for each 10-year interval of age. Age-related hypertension appears to be predominantly systolic rather than diastolic. The systolic blood pressure rises into the eighth or ninth decade, while the diastolic blood pressure remains constant or declines after age 40 years.9Clinical
History
- Following the documentation of hypertension, which is confirmed after an elevated blood pressure, properly measured, has been documented on at least 3 separate occasions (based on the average of 2 or more readings taken at each of 2 or more visits after initial screening), a detailed history should extract the following information:
- Extent of target organ damage
- Assessment of patients' cardiovascular risk status
- Exclusion of secondary causes of hypertension
- Patients may have undiagnosed hypertension for years without having had their blood pressure checked. Therefore, a careful history of end organ damage should be obtained.
- A history of cardiovascular risk factors includes hypercholesterolemia, diabetes mellitus, and tobacco use (including chewing tobacco).
- Obtain a history of the patient's use of over-the-counter medications and herbal medicines, such as herbal tea containing licorice, ephedrine, current and previous unsuccessful antihypertensive medication trials, oral contraceptives, ethanol, and illicit drugs, such as cocaine.
- The historical and physical findings that suggest the possibility of secondary hypertension are a history of known renal disease, abdominal masses, anemia, and urochrome pigmentation.
- A history of sweating, labile hypertension, and palpitations suggests the diagnosis of pheochromocytoma.
- A history of cold or heat tolerance, sweating, lack of energy, and bradycardia or tachycardia may indicate hypothyroidism or hyperthyroidism.
- A history of obstructive sleep apnea
- A history of weakness suggests hyperaldosteronism.
- Kidney stones raise the possibility of hyperparathyroidism.
Physical
An accurate measurement of blood pressure is the key to diagnosis. Several determinations should be made over a period of several weeks.At any given visit, an average of 3 blood pressure readings taken 2 minutes apart using a mercury manometer is preferable. Blood pressure should be measured in both the supine and sitting positions, auscultating with the bell of the stethoscope. On the first visit, blood pressure should be checked in both arms and in one leg to avoid missing the diagnosis of coarctation of aorta or subclavian artery stenosis.
As the improper cuff size may influence blood pressure measurement, a wider cuff is preferable, particularly if the patient's arm circumference exceeds 30 cm.
The patient should rest quietly for at least 5 minutes before the measurement.
Although somewhat controversial, the common practice is to document phase V (a disappearance of all sounds) of Korotkoff sounds as the diastolic pressure.
Ambulatory blood pressure monitoring provides a more accurate prediction of cardiovascular risk than does office blood pressure.14
"Non-dipping" is the loss of the usual physiologic nocturnal drop in blood pressure and is associated with an increased cardiovascular risk.
Home blood pressure predicts cardiovascular events much better than do office readings and can be a useful clinical tool.
- A funduscopic evaluation of the eyes should be performed to detect any evidence of hypertensive retinopathy. These are flame-shaped hemorrhages and cotton wool exudates.
- Palpation of all peripheral pulses should be performed. Absence of femoral pulses suggests coarctation of the aorta or severe peripheral vascular disease.
- Look for renal artery bruit over the upper abdomen; the presence of a unilateral bruit with both a systolic and diastolic component suggests renal artery stenosis.
- A careful cardiac examination is performed to evaluate signs of LVH. These include displacement of apex, a sustained and enlarged apical impulse, and the presence of an S4. Occasionally, a tambour S2 is heard with aortic root dilatation.
Causes
- Primary or essential hypertension (90-95%)
- Secondary hypertension: A small percentage of patients (2-10%) have a secondary cause. The following is a list of secondary causes of hypertension:
- Renal (2.5-6%)
- Renal parenchymal disease
- Polycystic kidney disease
- Urinary tract obstruction
- Renin-producing tumor
- Liddle syndrome
- Renovascular hypertension (0.2-4%)
- Vascular
- Coarctation of aorta
- Vasculitis
- Collagen vascular disease
- Endocrine (1-2%) - Oral contraceptives
- Adrenal
- Primary hyperaldosteronism
- Cushing syndrome
- Pheochromocytoma
- Congenital adrenal hyperplasia
- Hyperthyroidism and hypothyroidism
- Hypercalcemia
- Hyperparathyroidism
- Acromegaly
- Neurogenic
- Brain tumor
- Bulbar poliomyelitis
- Intracranial hypertension
- Obstructive sleep apnea
- Pregnancy-induced hypertension
- Drugs and toxins
- Alcohol
- Cocaine
- Cyclosporin, tacrolimus
- Erythropoietin
- Adrenergic medications
- Decongestants containing ephedrine
- Herbal remedies containing licorice or ephedrine
Differential Diagnoses
Workup
Laboratory Studies
- Unless a secondary cause for hypertension is suspected, only the following routine laboratory studies should be performed:
- CBC count, serum electrolytes, serum creatinine, serum glucose, uric acid, and urinalysis
- Lipid profile (total cholesterol, low-density lipoprotein [LDL], high-density lipoprotein [HDL], and triglycerides)
- Additional tests described below are indicated when specific clinical situations warrant further investigation.
- Microalbuminuria is an early indication of diabetic nephropathy and is also a marker for a higher risk of cardiovascular morbidity and mortality. Present recommendations suggest that individuals with type I diabetes should be screened for microalbuminuria. Usefulness of this screening in hypertensive patients without diabetes has not been established.4
- Measurement of the aldosterone /plasma renin activity ratio is performed to detect evidence of primary hyperaldosteronism. A ratio of more than 20-30 is suggestive of this condition. Hypokalemia and metabolic alkalosis are relatively late manifestations of this disorder. A 24-hour urinary excretion of aldosterone under salt-loading conditions confirms the diagnosis.
- Determination of a sensitive thyroid-stimulating hormone (TSH) level excludes hypothyroidism or hyperthyroidism as a cause of hypertension.
- If pheochromocytoma is suspected, urinary catecholamines and fractionated metanephrines are the tests of choice. Plasma fractionated metanephrines have specificity, but their sensitivity is too low for screening purposes. Urinary vanillylmandelic acid (VMA) is no longer recommended because of its poor sensitivity and specificity.
Imaging Studies
- Renal (2.5-6%)
- Echocardiography: The limited echocardiography study, rather than the complete examination, may detect LVH more frequently than electrocardiography. The main indication for limited echocardiography is evaluation for end organ damage in a patient with borderline high blood pressure.15 Therefore, the presence of LVH despite normal or borderline high blood pressure measurements requires antihypertensive therapy.
- Imaging studies for renovascular stenosis: If the patient's history suggests renal artery stenosis and if a corrective procedure is considered, further radiologic investigations are performed, such as computed tomography (CT) angiography and magnetic resonance angiography (MRA). Concern over the risk of nephrogenic systemic fibrosis due to gadolinium has reduced the use of MRA, particularly in patients with chronic kidney disease who have a GFR of less than 30 mL/min. This is a rare debilitating, life threatening disorder associated with gadolinium. CT angiography carries the risk of dye nephropathy, particularly in persons with diabetes who have chronic kidney disease.
- Doppler ultrasonography: This modality is very operator dependent.16
- Captopril radionuclide scanning: This imaging technique does not give anatomic detail and is less often used.
- Digital subtraction angiography with arterial injection of radiocontrast dye: This technique is the gold standard, but it carries the risk of dye nephropathy and atheroemboli in patients with diabetes or chronic kidney disease.
Other Tests
- Routine testing includes electrocardiograms.
- Ambulatory blood pressure monitoring: Indications for ambulatory blood pressure monitoring include labile blood pressure, a discrepancy between blood pressure measurement inside and outside the physician's office, and poor blood pressure control. Ambulatory monitoring also identifies patients who have the distinct syndrome called white coat hypertension.14
Treatment
Medical Care
Consider lifestyle modifications. As the cardiovascular disease risk factors are assessed in individuals with hypertension, pay attention to the lifestyles that favorably affect blood pressure level and reduce overall cardiovascular disease risk. A relatively small reduction in blood pressure may affect the incidence of cardiovascular disease on a population basis. A decrease in blood pressure of 2 mm Hg reduces the risk of stroke by 15% and the risk of coronary artery disease by 6% in a given population.JNC VII recommendations to lower blood pressure and decrease cardiovascular disease risk include the following:1- Lose weight if overweight. This can be accomplished with the DASH (Dietary Approaches to Stop Hypertension) diet, which is rich in fruits and vegetables and encourages the use of fat-free or low-fat milk and milk products.17,18
- Limit alcohol intake to no more than 1 oz (30 mL) of ethanol per day in men (ie, 24 oz [720 mL] of beer, 10 oz [300 mL] of wine, 2 oz [60 mL] of 100-proof whiskey) or 0.5 (15 mL) of ethanol per day for women and people of lighter weight.
- Increase aerobic activity (30-45 min most days of the week).
- Reduce sodium intake to no more than 100 mmol/d (2.4 g sodium or 6 g sodium chloride).
- Maintain adequate intake of dietary potassium (approximately 90 mmol/d).
- Maintain adequate intake of dietary calcium and magnesium for general health.
- Stop smoking and reduce intake of dietary saturated fat and cholesterol for overall cardiovascular health.
Clinical trials Multiple clinical trials suggest that most antihypertensive drugs provide the same degree of cardiovascular protection for the same level of blood pressure control. Well-designed prospective randomized trials, such as the Swedish Trial in Old Patients with Hypertension (STOP-2), the Nordic Diltiazem (NORDIL) trial, and the Intervention as a Goal in Hypertension Treatment (INSIGHT) trial, have shown a similar outcome with older drugs (eg, diuretics, beta blockers) compared to the newer antihypertensive agents (eg, ACE inhibitors, calcium channel blockers).
No consensus exists regarding optimal drug therapy for treatment of hypertension; most clinicians recommend initiating therapy with a single agent and advancing to the low-dose combination therapy. Any of the first-line medications decrease blood pressure in 40-60% of patients with mild-to-moderate hypertension. In unresponsive patients, switching to a second drug (rather than combining it with the first drug) or switching to a third drug if the second drug is not effective may allow a 70-80% response rate to monotherapy. Therefore, attempt to identify a particular class of drug to which the patient responds rather than adding multiple drugs (as in combination therapy).
The JNC VII report recommends either a thiazide diuretic or a beta blocker as the initial therapy of uncomplicated hypertension.1 A low dose of thiazide diuretic (12.5-25 mg hydrochlorothiazide) is a low-cost therapy with fewer complications, and it provides equivalent cardiovascular protection.20,21 Patients unresponsive to low-dose thiazide therapy should try an ACE inhibitor, beta blocker, or calcium channel blocker, sequentially. Patients unresponsive to a diuretic may not respond to a calcium channel blocker, and an ACE inhibitor or a beta blocker should be tried as a second-line agent in these patients. Calcium channel blocking agents and diuretics may be more effective in hypertensive black patients.
Initial therapy based on the JNC VII report recommendations is as follows:1
- Prehypertension (systolic 120-139, diastolic 80-89): No antihypertensive drug is indicated.
- Stage 1 hypertension (systolic 140-159, diastolic 90-99): Thiazide-type diuretics are recommended for most. ACE inhibitor, angiotensin II receptor blocker (ARB), beta blocker, calcium channel blocker, or a combination may be considered.
- Stage 2 hypertension (systolic more than 160, diastolic more than 100): Two-drug combination (usually thiazide-type diuretic and ACE inhibitor or ARB or beta blocker or calcium channel blocker) is recommended for most.
- For the compelling indications, other antihypertensive drugs (eg, diuretics, ACE inhibitor, ARB, beta blocker, calcium channel blocker) may be considered as needed.
Two randomized controlled trials, the Hypertension Detection and Follow-up Program (HDFP) and the Medical Research Council (MRC) trials, randomized patients with elevated levels of diastolic blood pressure to either diuretic-based stepped-care treatment or usual care. The usual care group received some form of therapy from their own physicians, whereas the stepped-care group received systematic care. In both studies, stepped-care treatment reduced diastolic blood pressure by 5 mm more than that reduced in the control group. Both trials showed a benefit from stepped-care therapy compared to the control group. In the HDFP trial, stepped-care led to relative risk reduction of 17% for total mortality; 76 hypertensive patients needed to be treated with stepped-care therapy for 5 years to prevent one death.
A meta-analysis published in the Journal of the American Medical Association (JAMA) in 1997 included several randomized controlled clinical trials. The total number of participants randomized to active therapy was 24,294, and the number for the control therapy was 23,926. Active treatment reduced diastolic blood pressure by at least 5 mm Hg. The meta-analysis showed a risk reduction of coronary heart disease of 8-14% and the reduction in stroke incidence of 35-40%. Subsequent meta-analysis reported that benefits of active treatment are similar in men and women.
Recommendations for management of hypertension
The JNC recommends certain situations for which a specific class of drug may be administered.1 An ACE inhibitor should be the initial treatment in situations in which hypertension is associated with congestive heart failure, diabetes mellitus with proteinuria, and postmyocardial infarction with systolic left ventricular dysfunction. In patients who develop persistent cough while on ACE inhibitor therapy, an angiotensin II receptor antagonist may be substituted. A beta blocker should be prescribed following an acute myocardial infarction. A diuretic or a long-acting calcium channel blocker may be more effective in elderly patients with isolated systolic hypertension.
The 2004 Canadian Hypertension Society recommendations (similar to JNC VII guidelines) for the management of hypertension in specific patient groups are listed in Table 2 and Table 3, as follows:22
Table 2. Synopsis of Considerations in the Use of Antihypertensive Drug Classes*
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Table
| Class of Medication | When to Use | When Not to Use | |
|---|---|---|---|
| Diuretics | Loop diuretics | Renal insufficiency (additional therapy) | Gout |
| Potassium-sparing | Primary hyperaldosteronism (additional therapy in combination with thiazide diuretics) | Renal insufficiency | |
| Thiazides | Uncomplicated hypertension (preferred therapy), systolic hypertension in elderly people (preferred therapy), for older diabetic patients without nephropathy | Gout, dyslipidemia (high-dose) | |
| Beta-adrenergic antagonists | Post–myocardial infarction, uncomplicated hypertension (preferred therapy), diabetes (without nephropathy) | Asthma, peripheral vascular disease (severe) | |
| ACE inhibitors | Diabetes, post–myocardial infarction, heart failure, renal disease, uncomplicated hypertension (preferred therapy) | Bilateral renovascular disease, pregnancy | |
| Angiotensin II antagonists | Diabetes (alternative therapy), heart failure (alternative therapy), uncomplicated hypertension (preferred therapy) | Bilateral renovascular disease, pregnancy | |
| Calcium channel blockers | Nondihydropyridines | Uncomplicated hypertension (alternative therapy) | Heart block, heart failure |
| Dihydropyridines | Systolic hypertension (preferred therapy), uncomplicated therapy (alternative therapy) | Heart block, heart failure | |
| Alpha-adrenergic antagonists/central acting agents | Uncomplicated hypertension (alternative therapy) | Autonomic dysfunction | |
| Class of Medication | When to Use | When Not to Use | |
|---|---|---|---|
| Diuretics | Loop diuretics | Renal insufficiency (additional therapy) | Gout |
| Potassium-sparing | Primary hyperaldosteronism (additional therapy in combination with thiazide diuretics) | Renal insufficiency | |
| Thiazides | Uncomplicated hypertension (preferred therapy), systolic hypertension in elderly people (preferred therapy), for older diabetic patients without nephropathy | Gout, dyslipidemia (high-dose) | |
| Beta-adrenergic antagonists | Post–myocardial infarction, uncomplicated hypertension (preferred therapy), diabetes (without nephropathy) | Asthma, peripheral vascular disease (severe) | |
| ACE inhibitors | Diabetes, post–myocardial infarction, heart failure, renal disease, uncomplicated hypertension (preferred therapy) | Bilateral renovascular disease, pregnancy | |
| Angiotensin II antagonists | Diabetes (alternative therapy), heart failure (alternative therapy), uncomplicated hypertension (preferred therapy) | Bilateral renovascular disease, pregnancy | |
| Calcium channel blockers | Nondihydropyridines | Uncomplicated hypertension (alternative therapy) | Heart block, heart failure |
| Dihydropyridines | Systolic hypertension (preferred therapy), uncomplicated therapy (alternative therapy) | Heart block, heart failure | |
| Alpha-adrenergic antagonists/central acting agents | Uncomplicated hypertension (alternative therapy) | Autonomic dysfunction | |
Table 3. Considerations in the Individualization of Antihypertensive Therapy*
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Table
| Risk Factor/Disease | Preferred Therapy | Alternative Therapy | Avoid Therapy |
|---|---|---|---|
| Uncomplicated hypertension (<60 y) | Low-dose thiazidelike diuretics, beta blockers, ACE inhibitors, or long-acting dihydropyridine calcium channel blockers | Combinations of first-line drugs | … |
| Uncomplicated hypertension (³60 y) | Low-dose thiazidelike diuretics, ACE inhibitors, or long-acting dihydropyridine calcium channel blockers | Combinations of first-line drugs | … |
| Dyslipidemia | As for uncomplicated hypertension | … | … |
| Diabetes mellitus with nephropathy | ACE inhibitors | Angiotensin II receptor blockers | High-dose diuretics and centrally acting agents (in the setting of autonomic neuropathy) |
| Diabetes mellitus without nephropathy | ACE inhibitors or beta blockers | … | … |
| Diabetes mellitus without nephropathy, with systolic hypertension | Low-dose thiazidelike diuretics or long-acting dihydropyridine calcium channel blockers | … | … |
| Angina | Beta blockers (ACE inhibitors as add-on therapy) | Long-acting calcium channel blockers | … |
| Prior myocardial infarction | Beta blockers, ACE inhibitors | … | … |
| Systolic dysfunction | ACE inhibitors (thiazide or loop diuretics, beta blockers, spironolactone is additive therapy) | Angiotensin II receptor blockers, hydralazine/isosorbide dinitrate, amlodipine | Nondihydropyridine calcium channel blockers (diltiazem, verapamil) |
| Left ventricular hypertrophy | Most antihypertensives reduce LVH | … | Hydralazine, minoxidil |
| Peripheral arterial disease | As for uncomplicated hypertension | As for uncomplicated hypertension | Beta blockers (with severe disease) |
| Renal disease | ACE inhibitors (diuretics as additive therapy) | Dihydropyridine calcium channel blockers | ACE inhibitors in cases of bilateral renal artery stenosis |
| Risk Factor/Disease | Preferred Therapy | Alternative Therapy | Avoid Therapy |
|---|---|---|---|
| Uncomplicated hypertension (<60 y) | Low-dose thiazidelike diuretics, beta blockers, ACE inhibitors, or long-acting dihydropyridine calcium channel blockers | Combinations of first-line drugs | … |
| Uncomplicated hypertension (³60 y) | Low-dose thiazidelike diuretics, ACE inhibitors, or long-acting dihydropyridine calcium channel blockers | Combinations of first-line drugs | … |
| Dyslipidemia | As for uncomplicated hypertension | … | … |
| Diabetes mellitus with nephropathy | ACE inhibitors | Angiotensin II receptor blockers | High-dose diuretics and centrally acting agents (in the setting of autonomic neuropathy) |
| Diabetes mellitus without nephropathy | ACE inhibitors or beta blockers | … | … |
| Diabetes mellitus without nephropathy, with systolic hypertension | Low-dose thiazidelike diuretics or long-acting dihydropyridine calcium channel blockers | … | … |
| Angina | Beta blockers (ACE inhibitors as add-on therapy) | Long-acting calcium channel blockers | … |
| Prior myocardial infarction | Beta blockers, ACE inhibitors | … | … |
| Systolic dysfunction | ACE inhibitors (thiazide or loop diuretics, beta blockers, spironolactone is additive therapy) | Angiotensin II receptor blockers, hydralazine/isosorbide dinitrate, amlodipine | Nondihydropyridine calcium channel blockers (diltiazem, verapamil) |
| Left ventricular hypertrophy | Most antihypertensives reduce LVH | … | Hydralazine, minoxidil |
| Peripheral arterial disease | As for uncomplicated hypertension | As for uncomplicated hypertension | Beta blockers (with severe disease) |
| Renal disease | ACE inhibitors (diuretics as additive therapy) | Dihydropyridine calcium channel blockers | ACE inhibitors in cases of bilateral renal artery stenosis |
Several situations demand the addition of a second drug because 2 drugs may be used at lower doses to avoid adverse effects, which may occur with higher doses of an individual agent. Diuretics generally potentiate the effects of other antihypertensive drugs by minimizing volume expansion. Specifically, the use of the diuretic thiazide in conjunction with a beta blocker or an ACE inhibitor has an additive effect, controlling blood pressure in up to 85% of patients.
Most drug combinations using agents that act by different mechanisms have an additive effect. The combination of a calcium channel blocker with either an ACE inhibitor or a dihydropyridine calcium channel blocker and a beta blocker has additive effects. An ACE inhibitor may be combined with an angiotensin II receptor antagonist because the blocking of angiotensin I receptors may lead to increased plasma angiotensin II concentration, which may compete with a drug for the receptor. Some combinations may not be additive, including a beta blocker and ACE inhibitor, a beta blocker and an alpha1-blocker and an alpha2 stimulant, and, more controversially, a diuretic and a calcium channel blocker. Some combinations may have additive adverse effects; these include a beta blocker combined with verapamil or diltiazem, which leads to cardiac depression, bradycardia, or heart block.
Clinical trials have shown that the effective control of blood pressure reduces the risk of cardiovascular events in high-risk patients. In the patients who achieved optimal blood pressure control compared with those with uncontrolled hypertension, significant reductions in the incidence of cardiac events, stroke, and all-cause mortality occurred (according to the Valsartan Antihypertensive Long-term Use Evaluation [VALUE] Trial). The lack of significant difference in cardiovascular mortality and morbidity among patients receiving diuretics, calcium channel blockers, or ACE inhibitors in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) possibly occurred due to confounding because of differences in the blood pressure reductions achieved with the 3 treatments.23
Studies have consistently shown that newer antihypertensive agents, such as ACE inhibitors and calcium channel blockers, reduce cardiovascular events to a similar, or possibly greater, extent than do older therapies, such as diuretics and beta blockers. ACE inhibitors specifically offer additional benefits beyond blood pressure reduction, including renal protection and reduction of cardiovascular events. Similarly, ARBs have demonstrated beneficial effects in heart failure, stroke, and renal protection.
A 2007 research summary by the Agency for Healthcare Research and Quality (AHRQ) noted that despite the relative importance of ACE inhibitors and ARBs for treatment of essential hypertension, few large, long-term, head-to-head studies have been published.24 Consequently, there is insufficient comparative evidence for the long-term beneficial or deleterious effects of these 2 classes of agents. On the basis of existing evidence, the AHRQ concluded that ACE inhibitors and ARBs appear to have similar long-term effects on blood pressure; the only significant difference between them is that ACE inhibitors have been consistently associated with a greater risk of cough.
- Key messages of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII) are as follows:1
- In those older than 50 years, systolic blood pressure (BP) of greater than 140 mm Hg is a more important cardiovascular disease risk factor than diastolic BP.
- Beginning at 115/75 mm Hg, the cardiovascular disease risk doubles for each increment of 20/10 mm Hg.
- Individuals who are normotensive at 55 years will have a 90% lifetime risk of developing hypertension.
- Prehypertension (systolic 120-139, diastolic 80-89) requires health-promoting lifestyle modifications to prevent the progressive rise in blood pressure and cardiovascular disease.
- In uncomplicated hypertension, a thiazide diuretic, either alone or combined with drugs from other classes, should be used for the drug treatment of most.
- In specific high-risk conditions, there are compelling indications for the use of other antihypertensive drug classes (eg, ACE inhibitors, angiotensin-receptor blockers, beta blockers, calcium channel blockers).
- Two or more antihypertensive medications will be required to achieve goal BP (<140/90 mm Hg or <130/80 mm Hg) for patients with diabetes and chronic kidney disease.
- For patients whose blood pressure is more than 20 mm Hg above the systolic BP goal or more than 10 mm Hg above the diastolic BP goal, initiation of therapy using 2 agents, one of which usually will be a thiazide diuretic, should be considered.
- Regardless of therapy or care, hypertension will be controlled only if patients are motivated to stay on their treatment plan.
- Resistant hypertension: Some patients may have a persistent diastolic blood pressure above 100 mm Hg despite the use of 3 or more different classes of antihypertensive medications.25 Patients who require 4 or more medications to control their blood pressure should be considered resistant to treatment. A study has shown that the addition of low-dose spironolactone provides significant additive blood pressure reduction in African-American and white patients who have resistant hypertension with or without primary hyperaldosteronism These patients may be experiencing one of the following factors as the cause of resistant hypertension:
- Inadequate treatment was described as the most common cause of resistant hypertension in several published series. Patients may not be on an effective drug, or concomitant volume expansion may occur as a side effect of the drug.
- Extracellular volume expansion: Volume expansion may contribute to the inability to lower systemic blood pressure. The volume expansion may occur because of renal insufficiency, sodium retention due to treatment with vasodilators, high-salt diet, or insufficient dosing of diuretic. This situation can be treated with more aggressive diuretic therapy until clinical signs of extracellular volume depletion (eg, orthostatic hypotension) develop.
- Poor compliance: Noncompliance with medical therapy or dietary modifications (eg, salt restriction) may play a role in causing resistant hypertension. Address noncompliance with extensive patient education, simplification of the drug regimen, and use of drugs with the fewest adverse effects.
- Secondary hypertension: Whenever confronted with resistant hypertension, try to exclude any secondary causes of hypertension. A reevaluation of the patient's history, physical examination, and laboratory results may provide clues to secondary hypertension (eg, renal artery stenosis, primary hyperaldosteronism, obstructive sleep apnea). Primary hyperaldosteronism has a prevalence of 20% in this population. Obstructive sleep apnea is also associated with resistant hypertension, with 85% of patients with resistant hypertension having an elevated apnea/hypopnea index.26
- White coat hypertension: Blood pressure rise secondary to anxiety may be observed in 20-30% of patients.27 This may be avoided by having patients rest prior to measurement, having a nurse check the blood pressure, or arranging to have the blood pressure monitored at home. Development of hypotensive symptoms on medications is an indication of white coat hypertension. White coat hypertension can also be evaluated by the use of a 24-hour ambulatory monitor.
- Pseudohypertension may be observed in elderly individuals who have thickened, calcified arteries. Much higher cuff pressure may be required to occlude a thickened brachial artery, and diastolic pressure may also be overestimated. Consider pseudohypertension in situations in which no organ damage occurs despite marked hypertension, when patients develop hypotensive symptoms on medications, and when calcification of the brachial artery is observed on radiologic examination. Direct measurement of intra-arterial pressure may be required in this setting.
- Vasoactive substances: Resistant hypertension may be encountered in patients who are ingesting vasoactive substances despite taking antihypertensive drugs regularly. Use of salt and alcohol are the common examples; others include use of cocaine, amphetamines, anabolic steroids, oral contraceptives, cyclosporine, antidepressants, and nonsteroidal anti-inflammatory drugs.
- Hypertension in special populations
- Age
- The systolic pressure continues to progressively rise throughout life, reaching the highest levels in later stages of life. Isolated systolic hypertension may be present in 10% of the population aged 70 years and in 24% of those aged 80 years. Furthermore, severe arteriosclerosis may lead to pseudohypertension. Isolated hypertension results in low cardiac output because of the decreased stroke volume and high peripheral resistance. This may reduce glomerular filtration further, which is why low activity of renal angiotensin aldosterone cascade is encountered in elderly individuals who are hypertensive.
- Despite low PRA, blood pressure responds well to ACE inhibitor and angiotensin receptor inhibitor therapy. Low doses of diuretics may also be effective. Calcium antagonists are quite useful because of their strong antihypertensive effects.28 Often, combining 2 drugs at a lower dose may be preferable to using a single drug at a high dose that has the potential for adverse effects.
- Sex: The prevalence of hypertension is similar between men and women, but women are protected from coronary heart disease prior to menopause. Premenopausal women have a higher resting heart rate, a higher cardiac index, and a lower peripheral resistance than men. These changes are not encountered in postmenopausal females. Therefore, in premenopausal situations, a medication such as beta blocker may be effective. However, postmenopausal hypertension is treated similarly to that in men.
- Race
- Blacks have a higher prevalence of hypertension and a much higher frequency of end organ damage, such as occurs in end-stage renal disease, strokes, and heart failure. Black patients also develop more severe LVH than white patients. Renal function in hypertensive black patients continues to deteriorate over time despite aggressive management of the blood pressures.
- Black patients respond less well to beta blockers, ACE inhibitors, and angiotensin receptor blockers than white patients. At times, this relative lack of efficacy may be overcome by increasing the dosage of the medications. Blacks may respond well to treatment with calcium antagonists, diuretics, and postsynaptic alpha-blockers.
- Obesity29
- Hypertensive patients who are obese have a sympathetic overdrive, higher cardiac output, and a rise in peripheral vascular resistance due to reduced endothelium-dependent vasodilation. Plasma aldosterone and endothelin are increased. The increase in cardiac output manifests secondary to increased preload. The end-diastolic volume and pressure are elevated, leading to left ventricular dilatation. Left ventricular wall thickening occurs secondary to increased afterload, increasing the risk of congestive heart failure. The concomitant diabetes that is often present in patients who are obese produces a devastating effect on the kidneys and leads to a much higher incidence of renal failure. Obstructive sleep apnea confers additional risk of resistant hypertension.
- No class of drugs seems to be of particular advantage in hypertensive patients who are obese, but thiazide diuretics may be helpful, unless the patient also has coexisting diabetes. In patients who are diabetic and who may have microalbuminuria, ACE inhibitors or calcium antagonists are recommended because they may slow declining renal function.4 Because of the high preload and afterload, drugs that have negative inotropic effects, such as beta blockers, should be avoided. In obese patients with obstructive sleep apnea, treatment with positive airway pressure devices can lead to some modest reductions in blood pressure.
- Age
- The management of secondary hypertension may result in cure by the surgical correction of the underlying problem, such as removal of a pheochromocytoma. Surgery may not be feasible in a substantial number of patients for whom medical therapy is instituted to control hypertension.
- Renovascular hypertension
- The goals of therapy are maintenance of normal blood pressure and prevention of end-stage renal disease. The therapeutic options include medical therapy, percutaneous transluminal renal angioplasty and stenting, and surgical revascularization. These options must be individualized because no randomized studies document the superiority of one option over the other. The indications for surgery or angioplasty include an inability to control blood pressure while on a medical regimen, the need to preserve renal function, and intolerable effects of medical therapy.
- With the advent of noninvasive techniques, aortal renal bypass using a saphenous vein or hypogastric artery is not commonly employed for revascularization. Percutaneous transluminal renal angioplasty (PTRA) can be an effective treatment for hypertension and the preservation of renal function in a subset of patients that is difficult to identify.30 PTRA may be the initial choice in younger patients with fibromuscular lesions amenable to balloon angioplasty. Renal artery stenting of osteal lesions has been associated with improved long-term patency.
- PTRA may also be used for arthrosclerotic renal artery stenosis; the outcome may be comparable to that of surgical revascularization. Medical therapy is required in the preoperative phase of interventional therapy. Medical therapy is also indicated for high-risk individuals and for older patients who have easily controlled hypertension. The specific population that will benefit from these techniques has yet to be clearly defined.
- ACE inhibitors are quite effective in patients with unilateral renal artery stenosis; however, avoid ACE inhibitors in patients with bilateral renal artery stenosis or stenosis of a solitary kidney. A diuretic can be combined with an ACE inhibitor. Because of their glomerular vasodilatory effect, calcium antagonists are effective in renal artery stenosis and do not compromise renal function.31
- Pheochromocytoma
- Following suspicion of pheochromocytoma, the presence of a tumor should be confirmed biochemically by measuring urine and plasma concentrations of catecholamine or their metabolites. In most situations, a CT scan or an MRI may be used to localize the tumor in the abdomen. In the absence of abdominal imaging, nuclear scan with metaiodobenzylguanidine (MIBG) may further help with the localization.
- Surgical resection is the treatment of choice because hypertension is cured by tumor resection. In the preoperative phase, combined alpha- and beta-adrenergic blockade is recommended for hypertension control. Alpha-adrenergic blockade is initiated with phenoxybenzamine or prazosin, and, following adequate alpha-adrenergic blockade, beta-adrenergic blockade is initiated. These patients are often volume contracted and require saline or sodium tablets. Catecholamines can be reduced further by metyrosine. For adrenal pheochromocytoma, laparoscopic adrenalectomy is becoming the procedure of choice in suitable patients. Follow-up 24-hour urinary excretion studies of catecholamines should be performed 2 weeks following surgery (and periodically thereafter) to detect recurrence, metastases, or development of second primary lesion.
- Primary hyperaldosteronism
- The prevalence of primary hyperaldosteronism increases with the severity of hypertension, being 2% in Stage 1 and 20% in resistant hypertension. Hypokalemia and metabolic alkalosis are important clues to the presence primary hyperaldosteronism. However, these are relatively late manifestations, and in a large subset of patients, the serum potassium concentration and bicarbonate are within the reference range. Measurement of the plasma aldosterone/renin activity ratio is the best initial screening test for primary hyperaldosteronism. A ratio of over 20-30 suggests that primary hyperaldosteronism may be present. Some labs require a minimum plasma aldosterone level 12 ng/dL.
- The diagnosis of primary hyperaldosteronism can be confirmed by the determination of the aldosterone excretion rate in a 24-hour urine following IV or oral salt loading. If the urinary aldosterone excretion rate is greater than 12-14 μg/24 h, with urine sodium of more than 200 meq/24 h, this confirms the diagnosis of primary hyperaldosteronism.
- The appropriate therapy depends on the cause of excessive aldosterone production. A CT scan may help localize an adrenal mass, indicating adrenal adenoma. If the results of the CT scan are inconclusive, adrenal venous sampling for aldosterone and cortisol levels should be performed. Medical therapy is indicated in patients with adrenal hyperplasia, patients with adenoma who are poor surgical risks, and patients with bilateral adenomas. These patients are best treated with sustained salt and water depletion. Hydrochlorothiazide or furosemide in combination with either spironolactone or amiloride corrects hypokalemia and normalizes the blood pressure. Some patients may require the addition of a vasodilator or a beta blocker for better control of hypertension.
- Adrenal adenomas may be resected via a laparoscopic procedure. Surgical resection often leads to the control of blood pressure and the reversal of biochemical abnormalities. These patients may develop hypoaldosteronism during the postoperative follow-up period and require supplementation with fludrocortisone.
- Renovascular hypertension
Surgical Care
Aortorenal bypass using a saphenous vein graft or a hypogastric artery is a revascularization technique for renovascular hypertension that has become much less common since the advent of renal artery angioplasty with stenting. Surgical resection is the treatment of choice for pheochromocytoma, because hypertension is cured by tumor resection. In patients with fibromuscular renal disease, angioplasty has a 60-80% success rate for improvement or cure of hypertension. See Medical Care for more details.Consultations
Consultations with a nutritionist and exercise specialist are often helpful in changing lifestyle and initiating weight loss. Consultations with an appropriate consultant are indicated for management of secondary hypertension attributable to a specific cause.Diet
A number of studies have documented an association between sodium chloride intake and blood pressure. The effect of sodium chloride is particularly important in individuals who are middle-aged to elderly with a family history of hypertension. A moderate reduction in sodium chloride intake can lead to a small reduction in blood pressure. The American Heart Association recommends that the average daily consumption of sodium chloride not exceed 6 g, this may lower blood pressure by 2-8 mm Hg.- The aforementioned DASH eating plan encompasses a diet rich in fruits, vegetables, and low-fat dairy products and may lower blood pressure by 8-14 mm Hg.17,18
- Dietary potassium, calcium, and magnesium consumption have an inverse association with blood pressures. Lower intake of these elements potentiates the affect of sodium on blood pressure. Oral potassium supplementation may lower both systolic and diastolic pressure. Calcium and magnesium supplementation have elicited small reductions in blood pressures.
- In population studies, low levels of alcohol consumption have shown a favorable effect on blood pressure, with reductions of 2-4 mm Hg. However, the consumption of 3 or more drinks per day is associated with elevation of blood pressure. Alcohol intake should be restricted to less than 1 oz of ethanol in men and 0.5 oz in women.
- Weight reduction may lower blood pressure by 5-20 mm Hg per 10 kg of weight loss in a patient who weighs more than 10% of ideal body weight.
Activity
Up to 60% of all individuals with hypertension are more than 20% overweight. The centripetal fat distribution is associated with insulin resistance and hypertension. Even modest weight loss (5%) can lead to reduction in blood pressure and improved insulin sensitivity. Regular aerobic physical activity can facilitate weight loss, decrease blood pressure, and reduce the overall risk of cardiovascular disease. Blood pressure may be lowered by 4-9 mm Hg with moderately intense physical activity. These activities include brisk walking for 30 minutes a day, 5 days per week. More intense workouts for 20-30 minutes, 3-4 times a week may also lower blood pressure and have additional health benefits.Medication
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.Diuretics
Cause diuresis, which decreases plasma volume and edema, thereby decreasing cardiac output and blood pressure.Hydrochlorothiazide (Esidrix, HydroDIURIL, Microzide)
Inhibits reabsorption of sodium in distal tubules, causing increased excretion of sodium, water, potassium, and hydrogen ions.Adult
25-100 mg PO qd; not to exceed 200 mg/kg/dPediatric
<6 months: 2-3 mg/kg/d PO divided bid>6 months: 2 mg/kg/d PO divided bid
May decrease effects of anticoagulants, antigout agents, and sulfonylureas; may increase toxicity of allopurinol, anesthetics, antineoplastics, calcium salts, loop diuretics, lithium, diazoxide, digitalis, amphotericin B, and nondepolarizing muscle relaxants
Documented hypersensitivity; anuria; renal decompensation
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetusPrecautions
Caution in renal and hepatic disease, gout, diabetes mellitus, and lupus erythematosusSpironolactone (Aldactone)
Used for management of hypertension. May block effects of aldosterone on arteriolar smooth muscles.Adult
25-200 mg/d PO qd or divided bidPediatric
1.5-3.5 mg/kg/d PO in divided doses q6-24hMay decrease effect of anticoagulants; potassium and potassium-sparing diuretics may increase toxicity of spironolactone
Documented hypersensitivity; anuria; renal failure; hyperkalemia
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetusPrecautions
Caution in renal and hepatic impairmentAmiloride (Midamor)
l-carbonyl-guanidine unrelated chemically to other known antikaliuretic or diuretic agents. Potassium-conserving (antikaliuretic) drug that, compared with thiazide diuretics, possesses weak natriuretic, diuretic, and antihypertensive activity.Adult
5-20 mg PO qdPediatric
Not establishedConcomitant therapy with potassium supplementation may increase serum potassium levels (if concomitant use indicated because of demonstrated hypokalemia, use caution and monitor serum potassium frequently); lithium generally should not be administered with diuretics because may reduce renal clearance and increase risk of lithium toxicity; administration of nonsteroidal anti-inflammatory agents can reduce diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics (when used concomitantly, observe patient closely to determine if desired effect of diuretic achieved); indomethacin and potassium-sparing diuretics, including amiloride, may be associated with increased serum potassium levels, so consider potential effects on potassium kinetics and renal function
Documented hypersensitivity; elevated serum potassium levels >5.5 mEq/L; impaired renal function, acute or chronic renal insufficiency, and evidence of diabetic nephropathy
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animalsPrecautions
Potassium retention associated with use of an antikaliuretic agent accentuated in presence of renal impairment and may result in rapid development of hyperkalemia; monitor serum potassium level; mild hyperkalemia usually not associated with abnormal ECG findings; monitor electrolytes closely if evidence of renal functional impairment present, BUN >30 mg/100 mL, or serum creatinine levels >1.5 mg/100 mLFurosemide (Lasix)
Increases excretion of water by interfering with chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in ascending loop of Henle and distal renal tubule. Dose must be individualized to patient. Depending on response, administer at increments of 20-40 mg no sooner than 6-8 h after previous dose until desired diuresis occurs. When treating infants, titrate with 1-mg/kg per dose increments until satisfactory effect achieved.Adult
20-80 mg/d PO/IV/IM; titrate up to 600 mg/d for severe edematous statesPediatric
1-2 mg/kg/dose PO; not to exceed 6 mg/kg/dose; not to administer more often than q6hAlternatively, 1 mg/kg IV/IM slowly under close supervision; not to exceed 6 mg/kg
Metformin decreases furosemide concentrations; furosemide interferes with hypoglycemic effect of antidiabetic agents and antagonizes muscle-relaxing effect of tubocurarine; auditory toxicity appears to be increased with coadministration of aminoglycosides and furosemide; hearing loss of varying degrees may occur; anticoagulant activity of warfarin may be enhanced when taken concurrently with this medication; increased plasma lithium levels and toxicity possible when taken concurrently
Documented hypersensitivity; hepatic coma; anuria; state of severe electrolyte depletion
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetusPrecautions
Perform frequent serum electrolyte, CO2, glucose, creatinine, uric acid, calcium, and BUN determinations during first few mo of therapy and periodically thereafterAlpha1-adrenergic blockers
Selectively block postsynaptic alpha1-adrenergic receptors. Dilate arterioles and veins, thus lowering blood pressure.Prazosin (Minipress)
Treats prostatic hypertrophy. Improves urine flow rates by relaxing smooth muscle, which is caused by blocking alpha1-adrenoceptors in bladder neck and prostate. When increasing dose, administer first dose of each increment at bedtime to reduce syncopal episodes. Although doses >20 mg/d usually do not increase efficacy, some patients may benefit from as much as 40 mg/d.Adult
1 mg PO bid/tid initial; 6-15 mg/d PO bid/tid maintenancePediatric
Not established; suggested dose is 0.5-7 mg PO tidAcute postural hypotensive reaction from beta blockers may worsen; indomethacin may decrease antihypertensive activity; verapamil may increase serum levels and may increase patient's sensitivity to drug-induced postural hypotension; may decrease antihypertensive effects of clonidine
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetusPrecautions
Caution in renal impairment; may cause marked hypotension following first dose and coadministration with beta-blockersTerazosin (Hytrin)
Decreases arterial tone by allowing peripheral postsynaptic blockade. Has minimal alpha2 effect.Adult
1 mg PO hs; increase slowly to effect; not to exceed 20 mg/dPediatric
Not establishedEffects decrease with coadministration of NSAIDs; effects increase with coadministration of diuretics and antihypertensive medications
Documented hypersensitivity
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animalsPrecautions
Caution in renal impairment; may cause marked hypotension following first dose and coadministration with beta blockersBeta-adrenergic blocking agents
Used to treat hypertension as initial agents or in combination with other drugs (eg, thiazides).Atenolol (Tenormin)
Selectively blocks beta1 receptors with little or no effect on beta2 types.Adult
50 mg PO qd; increase to 100 mg/d, if necessaryPediatric
1-2 mg/kg/dose PO qdCoadministration with aluminum salts, barbiturates, calcium salts, cholestyramine, NSAIDs, penicillins, and rifampin may decrease effects; haloperidol, hydralazine, loop diuretics, and MAOIs may increase toxicity; coadministration with myocardial depressants, AV conduction inhibitors (eg, verapamil, diltiazem), or antiarrhythmic agents (eg, disopyramide) may increase risk for bradycardia; if coadministered with clonidine, discontinue nebivolol several days before gradually tapering clonidine
Documented hypersensitivity; congestive heart failure; pulmonary edema; cardiogenic shock; AV conduction abnormalities; heart block (without a pacemaker)
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetusPrecautions
Beta-adrenergic blockade may reduce signs and symptoms of acute hypoglycemia and may decrease clinical signs of hyperthyroidism; abrupt withdrawal may exacerbate symptoms of hyperthyroidism, including thyroid storm; monitor patient closely and withdraw drug slowly; during IV administration, carefully monitor blood pressure, heart rate, and ECGMetoprolol (Lopressor, Toprol XL)
Selective beta1-adrenergic receptor blocker that decreases automaticity of contractions. During IV administration, carefully monitor blood pressure, heart rate, and ECG.Adult
100 mg/d PO qd or divided bid/tid initially and increase at 1 wk interval prn to a total of 450 mg/d if necessaryPediatric
1-5 mg/kg/24h PO divided bidAluminum salts, barbiturates, NSAIDs, penicillins, calcium salts, cholestyramine, and rifampin may decrease bioavailability and plasma levels of metoprolol, possibly resulting in decreased pharmacologic effects; toxicity of metoprolol may increase with coadministration of sparfloxacin, phenothiazines, astemizole, calcium channel blockers, quinidine, flecainide, and contraceptives; metoprolol may increase toxicity of digoxin, flecainide, clonidine, epinephrine, nifedipine, prazosin, verapamil, and lidocaine
Documented hypersensitivity; uncompensated congestive heart failure, bradycardia, asthma, cardiogenic shock, and A-V conduction abnormalities
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetusD - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Pregnancy category D in second or third trimester; beta-adrenergic blockade may reduce signs and symptoms of acute hypoglycemia and may decrease clinical signs of hyperthyroidism; abrupt withdrawal may exacerbate symptoms of hyperthyroidism, including thyroid storm; monitor patient closely and withdraw the drug slowly; during IV administration, carefully monitor blood pressure, heart rate, and ECGPropranolol (Inderal, Inderal LA, InnoPran XL)
Has membrane-stabilizing activity and decreases automaticity of contractions.Not suitable for emergency treatment of hypertension. Do not give IV in hypertensive emergencies.
Adult
Inderal: 40-80 mg PO bid initially; increase to 160-320 mg/d; not to exceed 640 mg/dInderal LA: 80 mg PO qd; usual maintenance dose is 120-160 mg PO qd; not to exceed 640 mg/d
InnoPran XL: 80 mg PO hs initially; may increase dose at 2-3 wk intervals; not to exceed 120 mg hs
Pediatric
Inderal: 0.5 mg/kg/d PO divided bid/qid; increase gradually q3-7d; dosage range is 2-4 mg/kg/d divided bid; not to exceed 2 mg/kg/dInderal LA: Not established
InnoPran XL: Not established
Coadministration with aluminum salts, barbiturates, NSAIDs, penicillins, calcium salts, cholestyramine, and rifampin may decrease propranolol effects; calcium channel blockers, cimetidine, loop diuretics, and MAOIs may increase toxicity of propranolol; toxicity of hydralazine, haloperidol, benzodiazepines, and phenothiazines may increase with propranolol
Documented hypersensitivity; uncompensated congestive heart failure; bradycardia, cardiogenic shock; A-V conduction abnormalities
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetusPrecautions
Beta-adrenergic blockade may decrease signs of acute hypoglycemia and hyperthyroidism; abrupt withdrawal may exacerbate symptoms of hyperthyroidism, including thyroid storm; withdraw drug slowly and monitor closelyNebivolol (Bystolic)
Beta-adrenergic blocking agent. In extensive metabolizers (majority of the population) and doses £ 10 mg, preferentially elicits beta1 selective inhibition; whereas in poor metabolizers and at higher doses, inhibits beta1- and beta2-receptors. Lacks intrinsic sympathomimetic and membrane stabilizing activity. Active metabolites contribute to beta-blocking action. Half-life is about 12 h in extensive metabolizers and 19 h in poor metabolizers.Adult
5 PO qd initially; if further blood pressure reduction required after 2 wk, may increase dose at 2 wk intervals, not to exceed 40 mg/dCrCl <30 mL/min: 2.5 mg PO qd initially
Moderate hepatic impairment: 2.5 mg PO qd initially
Pediatric
Not establishedCoadministration with myocardial depressants, AV conduction inhibitors (eg, verapamil, diltiazem), or antiarrhythmic agents (eg, disopyramide) may increase risk for bradycardia; if coadministered with clonidine, discontinue nebivolol several days before gradually tapering clonidine; coadministration with CYP2D6 inhibitors (eg, quinidine, propafenone, fluoxetine, paroxetine) may decrease clearance
Documented hypersensitivity; severe bradycardia; second- or third-degree heart block; cardiogenic shock; decompensated cardiac failure; sick sinus syndrome (unless permanent pacemaker in place); severe hepatic impairment (Child-Pugh >B)
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetusPrecautions
Common adverse effects include headache, fatigue, dizziness, and diarrhea; do not abruptly discontinue, gradual dose reduction over 1-2 wk recommended if discontinued; caution with peripheral vascular disease, thyrotoxicosis, severe renal impairment (decrease dose), any degree of hepatic impairment (decrease dose with moderate hepatic impairment), or in patients undergoing major surgery; may mask manifestations of hypoglycemia (eg, tachycardia) in diabetes mellitus; may exacerbate bronchospastic disease (in general, beta-blockers are not recommended in asthma or other bronchospastic diseases)Alpha/beta-adrenergic blocking agents
Block alpha-, beta1-, and beta2-adrenergic receptor sites, thus decreasing blood pressure.Labetalol (Normodyne, Trandate)
Nonselective beta- and alpha-adrenergic blocker. Does not appear to have intrinsic sympathomimetic activity. May reduce cardiac output and decrease peripheral vascular resistance. Use in aortic dissection not advisable when titratable drugs, such as esmolol and nitroprusside, available.Adult
20-30 mg IV over 2 min followed by 40-80 mg at 10-min intervals; not to exceed 300 mg/dosePediatric
Not established; suggested dose is 0.4-1 mg/kg/h; not to exceed 3 mg/kg/hDecreases effect of diuretics and increases toxicity of methotrexate, lithium, and salicylates; may diminish reflex tachycardia resulting from nitroglycerin use without interfering with hypotensive effects; cimetidine may increase labetalol blood levels; glutethimide may decrease labetalol effects by inducing microsomal enzymes; concurrent administration with clonidine may increase blood pressure and decrease heart rate
Documented hypersensitivity; cardiogenic shock; pulmonary edema; bradycardia; AV block; uncompensated congestive heart failure; reactive airway disease; severe bradycardia
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetusPrecautions
Caution in impaired hepatic function; discontinue therapy if signs of liver dysfunction present; in elderly patients, a lower response rate and higher incidence of toxicity may be observed; caution in congestive heart failure being treated with digitalis, diuretics, or ACE inhibitors (AV conduction may be slowed); caution in peripheral vascular disease, hyperthyroidism, and diabetes mellitusCarvedilol (Coreg)
Nonselective beta- and alpha-adrenergic blocker. Also has antioxidant properties. Does not appear to have intrinsic sympathomimetic activity. May reduce cardiac output and decrease peripheral vascular resistance.Adult
6.25 mg PO bid; maintain for 1-2 wk if tolerated and increase to 12.5 mg bid, to maximum 25 mg bidPediatric
Not establishedRifampin, barbiturates, cholestyramine, colestipol, NSAIDs, salicylates, and penicillins may decrease effects; carvedilol may increase effects of antidiabetic agents, digoxin, and calcium channel blockers; concurrent administration with clonidine may increase blood pressure and decrease heart rate; carvedilol may decrease effect of sulfonylureas; cimetidine, fluoxetine, paroxetine, and propafenone may increase carvedilol levels
Documented hypersensitivity; hypotension; bradycardia; AV/SA node disease; cardiogenic shock; overt cardiac failure
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetusPrecautions
Caution in congestive heart failure being treated with digitalis, diuretics, or ACE inhibitors (A-V conduction may be slowed); discontinue if liver impairment occurs; caution in peripheral vascular disease, hyperthyroidism, and diabetes mellitusPeripheral vasodilators
Relax blood vessels to improve blood flow, thus decreasing blood pressure.Hydralazine (Apresoline)
Hydralazine decreases systemic resistance through direct vasodilation of arterioles.Adult
10-20 mg/dose IV/IM q4-6h prn initial; increase to 40 mg/dose if necessary; change to PO as soon as possiblePediatric
Not establishedMAOIs and beta-blockers may increase hydralazine toxicity; pharmacologic effects of hydralazine may be decreased by indomethacin
Documented hypersensitivity; mitral valve, rheumatic heart disease
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetusPrecautions
Has been implicated in MI; caution in pulmonary hypertension, congestive heart failure, coronary artery disease, and significant renal failureMinoxidil (Rogaine, Loniten)
Relaxes arteriolar smooth muscle, causing vasodilation, which in turn may reduce blood pressure.Adult
5 mg PO qd; increase gradually q3dMaintenance dose: 10-40 mg/d PO qd or divided bid; not to 100 mg/d
Pediatric
Not establishedConcurrent use with guanethidine, diuretics, or hypotensive agents may result in additive hypotension
Documented hypersensitivity; pheochromocytoma
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetusPrecautions
May exacerbate angina pectoris; caution in pulmonary hypertension, congestive heart failure, coronary artery disease, and significant renal failureCalcium channel blockers
May be a more effective class of medication for black patients.32Diltiazem (Cardizem CD, Dilacor XR)
During depolarization, inhibits calcium ion from entering slow channels or voltage-sensitive areas of vascular smooth muscle and myocardium.Adult
Cardizem CD: 180-240 mg PO qd; may adjust dose after 14 days; dose range is 180-420 mg/day; not to exceed 480 mg/dayDilacor XR: 180-240 mg PO qd; may adjust dose after 14 days; dose range is 180-420 mg/day; not to exceed 540 mg/day
Pediatric
Not establishedMay increase carbamazepine, digoxin, cyclosporine, and theophylline levels; when administered with amiodarone, may cause bradycardia and a decrease in cardiac output; when administered with beta-blockers, may increase cardiac depression; cimetidine may increase levels
Documented hypersensitivity; severe CHF; sick sinus syndrome; second- or third-degree AV block; hypotension (<90 mm Hg systolic)
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetusPrecautions
Caution in impaired renal or hepatic function; may increase LFTs, and hepatic injury may occur; nifedipine may cause lower extremity edemaVerapamil (Calan, Covera-HS)
During depolarization, inhibits calcium ions from entering slow channels and voltage-sensitive areas of vascular smooth muscle and myocardium.Adult
240-480 mg/d PO divided tid/qidPediatric
Not establishedVerapamil may increase carbamazepine, digoxin, and cyclosporine levels; coadministration with amiodarone can cause bradycardia and a decrease in cardiac output; when administered concurrently with beta blockers may increase cardiac depression; cimetidine may increase verapamil levels; verapamil may increase theophylline levels
Documented hypersensitivity; severe CHF, sick sinus syndrome or second- or third-degree AV block, and hypotension (<90 mm Hg systolic)
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetusPrecautions
May cause AV block, negative inotropism, and vasodilation, which can result in hypotension, shock, pulmonary edema, and death; hepatocellular injury may occur; transient elevations of transaminases with or without concomitant elevations in alkaline phosphatase and bilirubin have occurred (elevations have been transient and may disappear with continued verapamil treatment), monitor liver function; IV administration discouraged in neonates and young infants due to severe apnea, bradycardia, hypotension, and cardiac arrest periodicallyNifedipine (Adalat)
Relaxes coronary smooth muscle and produces coronary vasodilation, which in turn improves myocardial oxygen delivery. Sublingual administration is generally safe, despite theoretical concerns.Adult
10-30 mg IR cap PO tid; not to exceed 120-180 mg/d30-60 mg SR tab PO qd; not to exceed 90-120 mg/d
Pediatric
0.25-0.5 mg/kg/dose PO tid/qid prnFentanyl and alcohol may increase hypotensive effects; calcium channel blocker may increase cyclosporine levels; H2 blockers (cimetidine), erythromycin, nafcillin, and azole antifungals may increase toxicity (avoid combination or monitor closely); carbamazepine may reduce bioavailability (avoid this combination); rifampin may decrease levels (monitor and adjust dose of calcium channel blocker)
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetusPrecautions
May cause lower extremity edema; allergic hepatitis have occurred but is rareAngiotensin-converting enzyme (ACE) inhibitors
Competitive inhibitors of ACE. Reduces angiotensin II levels, thus decreasing aldosterone secretion.Captopril (Capoten)
Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion.Adult
12.5-25 mg PO bid/tid; may increase by 12.5-25 mg/dose at 1- to 2-wk intervals up to 50 mg tidPediatric
6.25-12.5 mg/dose PO q12-24h; not to exceed 6 mg/kg/dNSAIDs may reduce hypotensive effects; ACE inhibitors may increase digoxin, lithium, and allopurinol levels; rifampin decreases levels; probenecid may increase levels; hypotensive effects of ACE inhibitors may be enhanced when administered concurrently with diuretics
Documented hypersensitivity; history of angioedema
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetusD - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Pregnancy category D in second and third trimesters; caution in renal impairment, valvular stenosis, or severe congestive heart failureEnalapril (Vasotec)
Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion.Helps control blood pressure and proteinuria. Decreases pulmonary-to-systemic flow ratio in the catheterization laboratory and increases systemic blood flow in patients with relatively low pulmonary vascular resistance. Has favorable clinical effect when administered over a long period. Helps prevent potassium loss in distal tubules. Body conserves potassium; thus, less oral potassium supplementation needed.
Adult
2.5-5 mg/d PO (increase as necessary)Dosing range: 10-40 mg/d PO in 1-2 divided doses
Alternatively, 1.25 mg/dose IV over 5 min q6h
Pediatric
Not establishedNSAIDs may reduce hypotensive effects of enalapril; ACE inhibitors may increase digoxin, lithium, and allopurinol levels; rifampin decreases enalapril levels; probenecid may increase enalapril levels; the hypotensive effects of ACE inhibitors may be enhanced when given concurrently with diuretics
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetusD - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Pregnancy category D in second and third trimesters; caution in renal impairment, valvular stenosis, or severe congestive heart failure; IV formulation not recommended in managing neonatal hypertension because of risk of acute renal failure and oliguriaLisinopril (Zestril)
Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion.Adult
10 mg/d PO; increase 5-10 mg/d at 1-2 wk intervals; not to exceed 40 mgPediatric
Not establishedNSAIDs may reduce hypotensive effects of lisinopril; ACE inhibitors may increase digoxin, lithium, and allopurinol levels; rifampin decreases lisinopril levels; probenecid may increase lisinopril levels; the hypotensive effects of ACE inhibitors may be enhanced when given concurrently with diuretics
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetusD - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Pregnancy category D in second and third trimesters; caution in renal impairment, valvular stenosis, or severe congestive heart failureRamipril (Altace)
Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion.Adult
2.5 mg PO bid initially; titrate up to 5 mg bid, when possiblePediatric
Not establishedNSAIDs may reduce hypotensive effects of ramipril; ACE inhibitors may increase digoxin, lithium, and allopurinol levels; rifampin decreases ramipril levels; probenecid may increase ramipril levels; the hypotensive effects of ACE inhibitors may be enhanced when given concurrently with diuretics
Documented hypersensitivity; history of angioedema
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetusD - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Pregnancy category D in second and third trimesters; caution in renal impairment, valvular stenosis, or severe congestive heart failureAngiotensin II receptor antagonists
For patients unable to tolerate ACE inhibitors.Losartan (Cozaar)
Nonpeptide angiotensin II receptor antagonist that blocks vasoconstrictor and aldosterone-secreting effects of angiotensin II. May induce more complete inhibition of renin-angiotensin system than ACE inhibitors, does not affect response to bradykinin, and is less likely to be associated with cough and angioedema.Adult
25-100 mg PO qd/bidPediatric
Not establishedKetoconazole, troleandomycin, sulfaphenazole, and phenobarbital may decrease effects; cimetidine may increase effects
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetusD - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Pregnancy category D in second and third trimester; caution in unilateral or bilateral renal artery stenosis, severe hepatic insufficiency, biliary cirrhosis or obstruction, primary hyperaldosteronism, and hyperkalemiaEprosartan (Teveten)
Angiotensin receptor antagonist that binds to AT1 angiotensin II receptor, blocking vasoconstrictor and aldosterone-secreting effects of angiotensin II. May induce a more complete inhibition of renin-angiotensin system than ACE inhibitors and does not affect response to bradykinin and is therefore less likely to be associated with cough and angioedema. For patients unable to tolerate ACE inhibitors.Adult
400-800 mg PO qd or divided bidPediatric
Not establishedMay increase toxicity of lithium; may decrease angiotensin II antagonist efficacy; may increase risk of hyperkalemia if taken concurrently with potassium supplements
Documented hypersensitivity; bilateral renal artery stenosis and preexisting renal insufficiency; significant aortic/mitral stenosis
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetusD - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Pregnancy category D in second and third trimesters; avoid use or use lower dose in patients who are volume depleted (correct volume depletion first); renal deterioration can occur with initiation of therapy; caution in unilateral renal artery stenosis and preexisting renal insufficiency; caution in aortic/mitral stenosisValsartan (Diovan)
Prodrug that produces direct antagonism of angiotensin II receptors. Displaces angiotensin II from AT1 receptor and may lower blood pressure by antagonizing AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses. May induce more complete inhibition of renin-angiotensin system than ACE inhibitors, does not affect response to bradykinin, and is less likely to be associated with cough and angioedema. For use in patients unable to tolerate ACE inhibitors.Adult
80 mg/d PO; may increase to 160 mg/d if neededPediatric
<6 years: Not established>6 years: 1.3 mg/kg PO qd initially, not to exceed 40 mg/d; may adjust dose according to blood pressure response up to 2.7 mg/kg/d (not to exceed 160 mg/d)
May increase digoxin, lithium, and allopurinol levels; probenecid may increase valsartan levels; coadministration with diuretics increase hypotensive effects; NSAIDs may reduce hypotensive effects of valsartan; may increase risk of hyperkalemia if taken concurrently with potassium supplements or other potassium-sparing diuretics
Documented hypersensitivity; severe hepatic insufficiency, biliary cirrhosis or obstruction, primary hyperaldosteronism, bilateral renal artery stenosis
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetusD - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Pregnancy category D in second and third trimesters; caution in hyperkalemia, suspected bilateral renal artery stenosis, or solitary kidney with unilateral RASOlmesartan (Benicar)
Blocks vasoconstrictor effects of angiotensin II by selectively blocking binding of angiotensin II to AT1 receptor in vascular smooth muscle. Action is independent of pathways for angiotensin II synthesis.Adult
20 mg PO qd initially; may increase to 40 mg/d after 2 wk if further BP reduction requiredNote: Lower dose in volume- or salt-depleted patients
Pediatric
Not establishedDiuretics may enhance hypotensive effect
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetusD - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
May cause injury or even death to the developing fetus, due to effect on renin-angiotensin system, if given in second or third trimesters of pregnancy; serum levels and AUC increase with renal and hepatic insufficiency, respectively; may cause oliguria, azotemia, and acute renal failure; facial edema, angioedema, or decreased hemoglobin or hematocrit occur rarelyAldosterone antagonists
Compete with aldosterone receptor sites, reducing blood pressure and sodium reabsorption.Eplerenone (INSPRA)
Selectively blocks aldosterone at the mineralocorticoid receptors in epithelial (eg, kidney) and nonepithelial (eg, heart, blood vessels, brain) tissues, thus decreasing blood pressure and sodium reabsorption.Adult
50 mg PO qd; may increase dose after 4 wk, not to exceed 100 mg/dPediatric
Not establishedCYP450 3A4 substrate; potent CYP3A4 inhibitors (eg, ketoconazole) increase serum levels about 5-fold, less potent CYP3A4 inhibitors (eg, erythromycin, saquinavir, verapamil, fluconazole) increase serum levels about 2-fold; grapefruit juice increases serum levels about 25%; coadministration with potassium supplements, salt substitutes, or drugs known to increase serum potassium (eg, amiloride, spironolactone, triamterene, ACE inhibitors, angiotensin II inhibitors) increases risk of hyperkalemia
Documented hypersensitivity; hyperkalemia or coadministration with drugs causing increased potassium; type 2 diabetes with microalbuminuria; moderate to severe renal insufficiency (ie, CrCl <50 mL/min or serum creatinine >2 mg/dL [males] or >1.8 mg/dL [females])
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animalsPrecautions
May cause hyperkalemia, headache, or dizziness; caution with hepatic insufficiencyAlpha-adrenergic agonists
Stimulate presynaptic alpha2-adrenergic receptors in the brain stem, which reduces sympathetic nervous activity.Methyldopa (Aldomet)
Stimulates central alpha-adrenergic receptors by a false transmitter, resulting in decreased sympathetic outflow. This results in inhibition of vasoconstriction.Adult
250 mg PO bid/tid; increase q2d prn; not to exceed 3 g/dPediatric
10 mg/kg/d PO divided bid/qid; increase q2d prn to maximum 65 mg/kg/d; not to exceed 3 g/dEffects may decrease with concurrent administration of barbiturates and tricyclic antidepressants; increase in blood pressure may occur with coadministration of iron supplements, MAOIs, sympathomimetics, phenothiazines, and beta blockers
Documented hypersensitivity; acute liver disease
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetusPrecautions
Caution in previous history of liver disease; hemolytic anemia and liver disease may occur; reduce dose in renal diseaseClonidine (Catapres)
Stimulates alpha2-adrenoreceptors in brainstem, activating an inhibitory neuron, which in turn results in reduced sympathetic outflow. These effects result in a decrease in vasomotor tone and heart rate.Adult
0.1 mg PO bid initial; 0.2-1.2 mg/d divided bid/qid maintenance; not to exceed 1.2 mg/dPediatric
Not establishedTricyclic antidepressants inhibit hypotensive effects of clonidine; coadministration of clonidine with beta blockers may potentiate bradycardia; tricyclic antidepressants may enhance hypertensive response associated with abrupt clonidine withdrawal; hypotensive effects of clonidine are enhanced by narcotic analgesics
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetusPrecautions
Caution in cerebrovascular disease, coronary insufficiency, sinus node dysfunction, and renal impairmentRenin inhibitor
Newest class of antihypertensive drugs. Acts by disrupting the renin-angiotensin-aldosterone system feedback loop.Aliskiren (Tekturna)
Direct renin inhibitor. Decreases plasma renin activity and inhibits conversion of angiotensinogen to angiotensin I (as a result, also decreasing angiotensin II) and thereby disrupts the renin-angiotensin-aldosterone system (RAAS) feedback loop. Indicated for hypertension as monotherapy or in combination with other antihypertensive drugs.Adult
150 mg PO qd initially; if needed, may increase to 300 mg/dPediatric
<18 years: Not establishedFollow-up
Further Inpatient Care
- Severe hypertension is defined by a blood pressure above 180/110 without symptoms. Hypertensive urgency is defined as a blood pressure above 180/110 with mild end organ effects, such as headache and dyspnea. Hypertensive emergency is a blood pressure of 220/140 or greater with life-threatening end organ dysfunction. The clinical conditions associated with hypertensive emergency include hypertensive encephalopathy, acute pulmonary edema, acute aortic dissection, intracerebellar hemorrhage, and acute myocardial infarction.
- Malignant hypertension: Malignant hypertension may or may not be associated with clinical conditions present in hypertensive urgency. A patient with malignant hypertension always has retinal papilledema and flame-shaped hemorrhages and exudates. Other clinical features of malignant hypertension may include encephalopathy, confusion, left ventricular failure, intravascular coagulation, and impaired renal function, with hematuria and weight loss. The pathological hallmark of malignant hypertension is fibrinoid necrosis of the arterioles, which occurs systemically, but specifically in the kidneys. These patients develop fatal complications if untreated, and more than 90% will not survive beyond 1-2 years.
- Treatment of hypertensive urgency consists of the acute reduction of blood pressure using aggressive pharmacologic therapy, followed by maintenance therapy with oral medications. The goal is to reduce the mean arterial pressure (MAP) more than 25% in 2 hours or to not less then 160/100 (MAP 120 mmHg)
- Sodium nitroprusside is a commonly used medication. It is a short-acting agent, and the blood pressure response can be titrated from minute to minute. However, patients must have constant monitoring in an intensive care unit. The potential exists for thiocyanate and cyanide toxicity with prolonged use or if the patient has renal or hepatic failure.
- Diazoxide may also be used in hypertensive crisis. Small boluses of 100 mg are administered every 5 minutes, as indicated. Diazoxide is not preferred with concomitant congestive heart failure or low cardiac output.
- Labetalol, an alpha- and beta-blocking agent, has proven to be quite beneficial in the treatment of patients with hypertensive emergencies. Labetalol is particularly preferred in patients with acute dissection. Boluses of 10-20 mg may be administered, or the drug may be infused at 1 mg/min until the desired blood pressure is obtained. Once an adequate blood pressure level is obtained, oral hypertensive therapy should be initiated, and patients are gradually weaned from parenteral agents.
- Fenoldopam, a peripheral dopamine-1 – receptor agonist given IV initial dose of 0.1 μ g/kg/min titrated every 15 minutes.
- Clevidipine, a dihydropyridine calcium channel blocker, is administered intravenously for rapid and precise blood pressure reduction.33 Clevidipine is rapidly metabolized in the blood and tissues and does not accumulate in the body.
- Initiate IV infusion of clevidipine at 1-2 mg/h; titrate the dose at short intervals (ie, 90 seconds) initially by doubling the dose. As blood pressure approaches its goal, increase the dose by less than double and lengthen the time between dose adjustments to every 5-10 minutes. An approximately 1-2 mg/h increase produces an additional 2-4 mm Hg decrease in systolic pressure. Typically, the therapeutic response is achieved with 4-6 mg/h, although severe hypertension may require higher doses. Most patients have received maximum doses of 16 mg/h or less; experience is limited with short-term dosing as high as 32 mg/h. Because of lipid load restrictions, do not exceed 1000 mL or an average of 21 mg/h within a 24-hour period; experience is limited with use beyond 72 hours.
Further Outpatient Care
- Interventions can be used to improve the control of blood pressure in patients with hypertension.
- Various interventions can be implemented to treat uncontrolled hypertension. These interventions include the following: (1) self-monitoring, (2) educational interventions directed to the patient, (3) educational interventions directed to the health professional, (4) health professional (nurse or pharmacist)–led care, (5) organizational interventions that aim to improve the delivery of care, and (6) appointment reminder systems.
- The Cochrane Collaboration has shown that these interventions are associated with large net reductions in blood pressure and that health professional (nurse or pharmacist)–led care may be a promising way of delivering care.34 Their recommendations include that family practices and community-based clinics should have an organized system of regular follow-up and review of their patients with hypertension. Antihypertensive drug therapy should be implemented by means of a vigorous stepped care approach when patients do not reach target blood pressure levels.
Deterrence/Prevention
- A comprehensive strategy for reduction in mortality and morbidity from hypertension must include prevention strategies, earlier detection, and adequate treatment. Ideally, a population strategy should be used in order to lower blood pressure in the community. More intensive efforts are required to lower blood pressure in high-risk population groups, which include individuals with a family history of hypertension, black ancestry, obesity, excessive sodium consumption, physical inactivity, and/or alcohol consumption. Even a small reduction in blood pressure confers significant health benefits. A 2-mm Hg reduction in diastolic pressure is estimated to decrease the risk of stroke by 15% and the risk of coronary heart disease by 6%.
- Prevention of hypertension may be achieved by the following interventions:
- Weight control
- Increased physical activity
- Moderated sodium and alcohol intake
- Increased potassium intake
- A dietary pattern rich in fruits and vegetables and low-fat meat, fish, and dairy products
Complications
- Central nervous system - Intracerebral hemorrhage, lacunar infarcts, encephalopathy, thrombotic stroke, transient ischemic attack
- Ophthalmologic - Fundal hemorrhages, exudates, papilledema
- Cardiac - LVH, congestive heart failure, angina pectoris, myocardial infarction
- Vascular - Aortic dissection, diffuse arthrosclerosis
- Renal - Nephrosclerosis, renal artery stenosis
Prognosis
- Most individuals diagnosed with hypertension will have increasing blood pressure as they age.
- Untreated hypertension is notorious for increasing the risk of mortality and is often described as a silent killer.
- Mild-to-moderate hypertension, if left untreated, is associated with a risk of atherosclerotic disease in 30% of people and organ damage in 50% of people after only 8-10 years of onset.
Patient Education
- Hypertension is a lifelong disorder. For optimal control, a long-term commitment to lifestyle modifications and pharmacological therapy is required. Therefore, repeated in-depth patient education and counseling not only improve compliance with medical therapy but also reduce cardiovascular risk factors.
- Various strategies to decrease cardiovascular disease risk include the following:
- Prevention and treatment of obesity
- Appropriate amounts of aerobic physical activity
- Diets low in salt, total fat, and cholesterol
- Adequate dietary intakes of potassium, calcium, and magnesium
- Limited alcohol consumption
- Avoidance of cigarette smoking
- Avoidance of the use of illicit drugs, such as cocaine
- For excellent patient education resources, visit eMedicine's Diabetes Center and Cholesterol Center. Also, see eMedicine's patient education articles High Blood Pressure, High Cholesterol, Chest Pain, Coronary Heart Disease, and Heart Attack.
Miscellaneous
Medicolegal Pitfalls
- Hypertension is one of the most common modifiable risk factors for atherosclerotic disease.
- According to the JNC VII enrollment report, only 59% of patients with hypertension are being treated in the United States. Of these, only 34% have adequately controlled blood pressure, and only 45% of treated patients have a blood pressure less than 140/90 mm Hg.1
- Despite an array of pharmaceutical agents to treat hypertension, JNC VI recommends diuretics and beta-blockers as the preferred initial agents because of proven efficacy and lower cost.
- Patients with hypertension should be identified and staged based on blood pressure determinations and cardiovascular risk and the presence or absence of target organ damage.
- JNC VII recommends lower target blood pressure goals in 2 select populations: (1) patients with diabetes mellitus (blood pressure <130/80 mm Hg) and (2) patients with renal disease (blood pressure <130/80 mm Hg; if urinary protein is >1 g/d, a blood pressure <125/75 mm Hg).1
- Malignant hypertension is a medical emergency and requires hospitalization and urgent therapy. The blood pressure should be reduced rapidly, but diastolic blood pressure should be maintained at approximately 95 mm Hg.
Special Concerns
- For most patients with renovascular hypertension, with the exception of persons with fibromuscular dysplasia, it is unclear whether revascularization will be beneficial. Fibromuscular dysplasia responds well to angioplasty. The causes of renovascular hypertension include atherosclerosis, fibromuscular dysplasia, coarctation of the aorta, embolic renal artery occlusion, aneurysm of the renal artery, and diffuse arteritis. Additionally, causes of diffuse bilateral renal ischemia, such as accelerated hypertension, vasculitis, hepatitis B, and intravenous drug abuse, may also lead to hypertension.
- Although the true incidence of renovascular hypertension is not known, an incidence of 1% is estimated in patients with hypertension.35 In one study, among hypertensive individuals who had 1 or more clinical features known to be associated with renovascular hypertension, 24% had renal artery stenosis and 14% had renovascular hypertension.36 This study also demonstrated that renovascular hypertension is more common in the white population (18%) than in the black population (9%).
- A workup for renovascular hypertension should be recommended for patients who meet the following criteria:
- Recent onset of moderate-to-severe hypertension
- Sudden unexplained exacerbation of preexisting hypertension
- Hypertension associated with an abdominal bruit
- Onset of hypertension in a young patient (<30 y)
- Severe hypertension resistant to pharmacologic management
- Deterioration of renal function following treatment for hypertension
- The workup for renovascular hypertension is recommended only in patients in whom further interventional therapy, such as angioplasty or surgery, is feasible and will be pursued.
- CT scanning or MRA is performed following intravenous contrast injection, to detect stenosis in the abdominal aorta and its branches, but renal arteriography is required for definitive diagnosis. Duplex ultrasonography of the renal arteries is very operator dependent. Renography using iodohippurate sodium iodine-131 (131 I) or technetium-99m (99m TC) diethylenetriamine penta-acetic acid after administration of the oral ACE inhibitor captopril is not now in wide use. MRA is avoided in patients with chronic kidney disease who have a GFR <30 ml/min because of the increased risk of nephrogenic systemic fibrosis. This is a rare debilitating, life-threatening complication of MRA; it is thought to be due to the gadolinium contrast agent.
- Appropriate management of patients with bilateral or unilateral renal artery stenosis and significant renal dysfunction is controversial. Correction of stenosis may not result in an improvement in renal function or a reduction in blood pressure, because renal dysfunction and hypertension may be caused by renal small vessel and parenchymal disease.
- In the first year of follow-up, a prospective investigation known as the Angioplasty and Stent for Renal Artery Lesions (ASTRAL) study showed no major differences in blood pressure control and renal function between patients with atherosclerotic renovascular disease who underwent revascularization and those who received medical therapy alone.37 In the ASPIRE study, significant risk from revascularization, as high as 19.7%, was found for major adverse events, such as atheroemboli, stent thrombosis, and (least commonly) renal and peripheral infarctions.
- An Agency for the Healthcare Research and Quality (AHRQ) study examined the entire published literature regarding medical therapy compared with revascularization and concluded that the existing data are insufficient to establish whether mortality rates, blood pressure control, and renal function outcomes improved with revascularization.
- Pheochromocytoma is an infrequent cause of hypertension, but cure often is possible with surgical therapy. The incidence is not known, but up to 0.1% of individuals with hypertension may have these lesions. Pheochromocytomas are chromaffin cell tumors, which arise mainly in the adrenal medulla, symptomatic ganglia, and paraganglia along the symptomatic chain. Up to 80-90% of pheochromocytomas are found in one or both adrenal glands. Most patients with pheochromocytoma have headache, sweating, or palpitations. Hypertension may be sustained or paroxysmal. Patients may manifest nervousness, nausea, vomiting, weight loss, and funduscopic changes of hypertension. Headaches are paroxysmal, throbbing, and bilateral. Sweating is quite profuse and generalized. Palpitations are due to the concomitant tachycardia.
- The workup of pheochromocytoma includes measurement of urinary catecholamines and their metabolites. Urinary excretion of metanephrine, normetanephrine, and free catecholamines can be performed. Measurement of catecholamines increases the sensitivity from 70-90%, compared with measuring metanephrine alone. When an abnormal value is detected by metanephrine, measurement of free catecholamines should be performed to confirm the diagnosis.
- Once the diagnosis of pheochromocytoma is confirmed by chemical analysis, the precise location and extent of the tumor is assessed with an imaging study. An abdominal CT scan often allows localization of the tumor, but the absence of a lesion on CT scan requires adrenal venous sampling or exploratory laparotomy. Initial stabilization is with medical therapy. Surgical resection is required because up to 10% of tumors may be malignant. In difficult cases, plasma, catecholamine assays, and a clonidine suppression test may be used. In normal and essential hypertension, clonidine suppresses plasma norepinephrine levels. An inability to suppress catecholamines may indicate pheochromocytoma; however, the sensitivity and specificity of this test is not known.
- A workup for renovascular hypertension should be recommended for patients who meet the following criteria:
- Mineralocorticoid-induced hypertension: Mineralocorticoid excess secondary to primary hyperaldosteronism is infrequently observed and is characterized by excessive production of aldosterone. Renal sodium retention, kaliuresis, hypokalemia, and hypochloremic metabolic alkalosis are the common manifestations. These patients develop increased intravascular volume, resulting in hypertension. The blood pressure increase may vary from mild hypertension to marked elevation in primary hyperaldosteronism. Patients may have underlying adenoma or hyperplasia of the adrenal gland and rarely have an extra-adrenal source for aldosterone.
- Oral contraceptive–associated hypertension: The most common form of secondary hypertension is an endocrine cause: oral contraceptive use. Activation of the renin-angiotensin-aldosterone system is the likely mechanism because hepatic synthesis of angiotensinogen is induced by the estrogen component of oral contraceptives. Approximately 5% of women prescribed oral contraceptives may develop hypertension, which abates within 6 months of discontinuation. The risk factors for oral contraceptive–associated hypertension include mild renal disease, familial history of essential hypertension, age greater than 35 years, and obesity.
- For the patient who has hypertension and is hypokalemic, a 24-hour urine specimen should be collected for sodium and potassium measurement. If the urine sodium level is more than 100 mmol/L and urine potassium is less than 30 mmol/L, hyperaldosteronism is unlikely. If urinary potassium exceeds 30 mmol/L, the patient should have PRA measured. If the PRA is high, the likely causes are estrogen therapy, renovascular hypertension, malignant hypertension, or salt-wasting renal disease. In the presence of low PRA, the serum aldosterone level can be measured. A low aldosterone level indicates licorice ingestion or other mineralocorticoid ingestions. A high aldosterone level indicates primary hyperaldosteronism. A CT scan may identify the presence of an adenoma. In the absence of CT scan findings, differentiating hyperplastic hyperaldosteronism from adenoma is often difficult.
- Advances in understanding of the regulation of blood pressure and pathophysiologic events that result in hypertension have led to the development of new classes of drugs. These agents are in various stages of development and include the following:
- Vasopressin antagonists
- Compounds to enhance the effects of endogenous vasodilators (eg, natriuretic peptides)
- Endothelin antagonists
- Renin inhibitors
- Antagonists of the angiotensin receptors: Several of these have already been marketed.
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