hypertension

Background

Hypertension is one of the most common worldwide diseases afflicting humans. Because of the associated morbidity and mortality and the cost to society, hypertension is an important public health challenge. Over the past several decades, extensive research, widespread patient education, and a concerted effort on the part of health care professionals have led to decreased mortality and morbidity rates from the multiple organ damage arising from years of untreated hypertension.
Approximately 50 million people in the United States are affected by hypertension.^{[1, 2]} Substantial improvements have been made with regard to improving awareness and treatment of hypertension. However, approximately 30% of adults are still unaware of their hypertension; up to 40% of people with hypertension are not receiving treatment; and, of those treated, up to 67% do not have their blood pressure (BP) controlled to less than 140/90 mm Hg.^[1] (See Epidemiology.)
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. (See Treatment and Management.)

Definition and classification

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 BP 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. (See Clinical Presentation.)
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 BP (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 80-90
• Stage 1 - Systolic 140-159, diastolic 90-99
• Stage 2 - Systolic equal to or more than 160, diastolic equal to or more than 100

The classification above is based on the average of 2 or more readings taken at each of 2 or more visits after initial screening. Normal BP 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.
From another perspective, hypertension may be categorized as 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).
Especially severe cases of hypertension may be further categorized. Severe hypertension is defined by a blood pressure above 180/110 without symptoms. Hypertensive urgency is defined as a BP above 180/110 with mild end organ effects, such as headache and dyspnea. Hypertensive emergency is a BP of 220/140 or greater with life-threatening end-organ dysfunction.
Hypertensive emergencies encompass a spectrum of clinical presentations in which uncontrolled BPs lead to progressive or impending end-organ dysfunction; in these conditions, the BP should be lowered aggressively over minutes to hours. Acute end-organ damage in the setting of a hypertensive emergency may include the following^[3] :

• Neurologic - Hypertensive encephalopathy, cerebral vascular accident/cerebral infarction. subarachnoid hemorrhage, intracranial hemorrhage
• Cardiovascular - Myocardial ischemia/infarction, acute left ventricular dysfunction, acute pulmonary edema, aortic dissection
• Other - Acute renal failure/insufficiency, retinopathy, eclampsia, microangiopathic hemolytic anemia

With the advent of antihypertensives, the incidence of hypertensive emergencies has declined from 7% to approximately 1%.^[4] In addition, the 1-year survival rate associated with this condition has increased from only 20% (prior to 1950) to a survival rate of more than 90% with appropriate medical treatment.^[5] (See Medication.)

Pathophysiology

The pathogenesis of essential hypertension is multifactorial and highly complex. Multiple factors modulate the blood pressure (BP) 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.

Etiology

Hypertension may be primary, which may develop as a result of environmental or genetic causes, or secondary, which has multiple etiologies, including renal, vascular, and endocrine causes. Hypertensive emergencies are most often precipitated by inadequate medication or poor compliance.

Environmental and genetic causes

Hypertension develops secondary to environmental factors, as well as to multiple genes, whose inheritance appears to be complex.^{[6, 7]} 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.
Primary or essential hypertension accounts for 90-95% of adult cases, and a small percentage of patients (2-10%) have a secondary cause.

Causes of secondary hypertension

Renal causes (2.5-6%) include the renal parenchymal diseases and renal vascular diseases, as follows:

• Polycystic kidney disease
• Chronic kidney disease
• Urinary tract obstruction
• Renin-producing tumor
• Liddle syndrome

Renovascular hypertension (RVHT) causes 0.2-4% of cases. Since Goldblatt’s seminal experiment in 1934, RVHT has become increasingly recognized as an important cause of clinically atypical hypertension and chronic kidney disease, the latter by virtue of renal ischemia. The coexistence of renal arterial vascular (ie, renovascular) disease and hypertension roughly defines this type of nonessential hypertension. More specific diagnoses are made retrospectively when hypertension is improved after intravascular intervention.
Vascular causes include the following:

• Coarctation of aorta
• Vasculitis
• Collagen-vascular disease

Endocrine causes account for 1-2% and include exogenous or endogenous hormonal imbalances. Exogenous causes include administration of steroids. 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 older than 35 years, and obesity.
Exogenous administration of the other steroids used for therapeutic purposes also increases blood pressure, especially in susceptible individuals, mainly by volume expansion. Nonsteroidal anti-inflammatory drugs (NSAIDs) may also have adverse effects on blood pressure. NSAIDs block both cyclooxygenase-1 (COX-1) and COX-2 enzymes. The inhibition of COX-2 can inhibit its natriuretic effect, which, in turn, increases sodium retention. NSAIDs also inhibit the vasodilating effects of prostaglandins and the production of vasoconstricting factors, namely endothelin-1. These effects can contribute to the induction of hypertension in a normotensive and/or controlled hypertensive patient
Endogenous hormonal causes include the following:

• Primary hyperaldosteronism
• Cushing syndrome
• Pheochromocytoma
• Congenital adrenal hyperplasia

Neurogenic causes include the following:

• Brain tumor
• Bulbar poliomyelitis
• Intracranial hypertension

Drugs and toxins that cause hypertension include the following:

• Alcohol
• Cocaine
• Cyclosporine, tacrolimus
• NSAIDs
• Erythropoietin
• Adrenergic medications
• Decongestants containing ephedrine
• Herbal remedies containing licorice or ephedrine

Other causes include the following:

• Hyperthyroidism and hypothyroidism
• Hypercalcemia
• Hyperparathyroidism
• Acromegaly
• Obstructive sleep apnea
• Pregnancy-induced hypertension

Causes of hypertensive emergencies

The most common hypertensive emergency is a rapid unexplained rise in BP in a patient with chronic essential hypertension. Most patients who develop hypertensive emergencies have a history of inadequate hypertensive treatment or an abrupt discontinuation of their medications.
Other causes of hypertensive emergencies include the use of recreational drugs, abrupt clonidine withdrawal, post pheochromocytoma removal, and systemic sclerosis.
Other causes include the following:

• Renal parenchymal disease - Chronic pyelonephritis, primary glomerulonephritis, tubulointerstitial nephritis (accounts for 80% of all secondary causes)
• Systemic disorders with renal involvement - Systemic lupus erythematosus, systemic sclerosis, vasculitides
• Renovascular disease - Atherosclerotic disease, fibromuscular dysplasia, polyarteritis nodosa
• Endocrine disease - Pheochromocytoma, Cushing syndrome, primary hyperaldosteronism
• Drugs - Cocaine, amphetamines, cyclosporine, clonidine withdrawal, phencyclidine, diet pills, oral contraceptive pills
• Drug interactions - Monoamine oxidase inhibitors with tricyclic antidepressants, antihistamines, or tyramine-containing food
• Central nervous system (CNS) factors - CNS trauma or spinal cord disorders, such as Guillain-Barré syndrome
• Coarctation of the aorta
• Preeclampsia/eclampsia
• Postoperative hypertension

Epidemiology

Hypertension is a worldwide epidemic; accordingly, its epidemiology has been well studied.
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.^[8] 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 BP in excess of 140/90 mm Hg. The prevalence dramatically increases in patients older than 60 years.

Prognosis

Most individuals diagnosed with hypertension will have increasing BP 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.
Death from both ischemic heart disease and stroke increase progressively as BP increases. For every 20 mm Hg systolic or 10 mm Hg diastolic increase in BP above 115/75 mm Hg, the mortality rate for both ischemic heart disease and stroke doubles.
The morbidity and mortality of hypertensive emergencies depend on the extent of end-organ dysfunction on presentation and the degree to which BP is controlled subsequently. With BP control and medication compliance, the 10-year survival rate of patients with hypertensive crises approaches 70%.^[9]
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.^[10] 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 BP.^[11] 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%.
The Framingham Heart Study found a 72% increase in the risk of all-cause death and a 57% increase in the risk of any cardiovascular event in patients with hypertension who were also diagnosed with diabetes mellitus.^[12]
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.
Comparative data from NHANES I and III showed a decrease in mortality over time among hypertensive adults, but the mortality gap between hypertensive and normotensive adults remains high.^[13]

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.

History

Following the documentation of hypertension, which is confirmed after an elevated blood pressure (BP) 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 BP 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; 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 may be noted. A history of weakness suggests hyperaldosteronism. Kidney stones raise the possibility of hyperparathyroidism.

Physical Examination

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. 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.
The patient should rest quietly for at least 5 minutes before the measurement. Blood pressure should be measured in both the supine and sitting positions, auscultating with the bell of the stethoscope. 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. Although somewhat controversial, the common practice is to document phase V (a disappearance of all sounds) of Korotkoff sounds as the diastolic pressure.
Ambulatory or home blood pressure monitoring provides a more accurate prediction of cardiovascular risk than do office blood pressure readings.^[14] "Non-dipping" is the loss of the usual physiologic nocturnal drop in blood pressure and is associated with an increased cardiovascular risk.
A funduscopic evaluation of the eyes should be performed to detect any evidence of early or late, chronic or acute hypertensive retinopathy, including AV nicking or changes in the vessel wall (eg, copper wiring, silver wiring, sot, hard exudates, flame-shaped hemorrhages, papilledema). Ocular changes can be the initial finding in an asymptomatic patient necessitating a primary care referral. Both acute and chronic changes may manifest in the eyes. On the other side, a symptomatic patient may be referred to the ophthalmologist for visual changes due to hypertensive changes.
Palpation of all peripheral pulses should be performed. Absent, weak, or delayed femoral pulses suggests coarctation of the aorta or severe peripheral vascular disease.
Listen for renal artery bruit over the upper abdomen; the presence of a 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.

Hypertension and Cerebrovascular Disease

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.
Hypertensive encephalopathy is one of the clinical manifestations of cerebral edema and microhemorrhages seen with dysfunction of cerebral autoregulation and is characterized by hypertension, altered mentation, and papilledema.^[15]

Hypertensive Emergencies

The history and physical examination determine the nature, severity, and management of the hypertensive event. The history should focus on the presence of end-organ dysfunction, the circumstances surrounding the hypertension, and any identifiable etiology. The physical examination should assess whether end-organ dysfunction is present. BP should be measured in both the supine position and the standing position (assess volume depletion). BP should also be measured in both arms (a significant difference may suggest aortic dissection).
The most common clinical presentations of hypertensive emergencies are cerebral infarction (24.5%), pulmonary edema (22.5%), hypertensive encephalopathy (16.3%), and congestive heart failure (12%). Other clinical presentations associated with hypertensive emergencies include intracranial hemorrhage, aortic dissection, and eclampsia,^[16] as well as acute myocardial infarction.

Hypertensive Heart Disease

Uncontrolled and prolonged BP elevation can lead to a variety of changes in the myocardial structure, coronary vasculature, and conduction system of the heart. These changes in turn can lead to the development of left ventricular hypertrophy (LVH), coronary artery disease, various conduction system diseases, and systolic and diastolic dysfunction of the myocardium, which manifest clinically as angina or myocardial infarction, cardiac arrhythmias (especially atrial fibrillation), and congestive heart failure (CHF). Thus, hypertensive heart disease is a term applied generally to heart diseases—such as LVH, coronary artery disease, cardiac arrhythmias, and CHF—that are caused by direct or indirect effects of elevated BP. Although these diseases generally develop in response to chronically elevated BP, marked and acute elevation of BP can also lead to accentuation of an underlying predisposition to any of the symptoms traditionally associated with chronic hypertension.
In a study by Tymchak et al, patients presenting with acute heart failure as a manifestation of hypertensive emergency were more likely to be African American and have a history of heart failure; they were also more likely to have higher B-type natriuretic peptide (BNP) and creatinine levels and lower left ventricular ejection fraction.^[17]

Hypertension in Pediatric Patients

Recent advances in the ability to identify, evaluate, and care for infants with hypertension, coupled with advances in the practice of neonatology in general, have led to an increased awareness of hypertension in modern neonatal ICUs (NICUs) since its first description in the 1970s.
The true incidence of hypertension in the pediatric population is not known. Hypertension is now commonly discovered in children. The long-term health risks to these children with hypertension may be substantial.
Systemic hypertension is less common in children than in adults, but the incidence of hypertension in children is approximately 1-5%. The presence of hypertension in younger children is usually indicative of an underlying disease process (secondary hypertension). In children, approximately 5-25% of secondary hypertension is attributed to renovascular disease.

Hypertension in Pregnancy

Hypertension is the most common medical problem encountered during pregnancy, complicating 2-3% of pregnancies. Hypertensive disorders during pregnancy are classified into the 4 following categories, as recommended by the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy:

• Chronic hypertension
• Preeclampsia-eclampsia
• Preeclampsia superimposed on chronic hypertension
• Gestational hypertension (transient hypertension of pregnancy or chronic hypertension identified in the latter half of pregnancy); this terminology is preferred over the older but widely used term pregnancy-induced hypertension (PIH) because it is more precise.

Primary Aldosteronism

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 BP 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. 

Diagnostic Considerations

Problems to be considered include the following:

• Steroid use
• Use of over-the-counter or recreational sympathomimetic drugs
• Pheochromocytoma
• Acute vasculitis
• Serotonin syndrome
• Other CNS pathology
• Coarctation of the aorta

Differential Diagnoses

• Anxiety Disorders
• Apnea, Sleep
• Cardiomyopathy, Cocaine
• Cardiomyopathy, Hypertrophic
• Congestive Heart Failure and Pulmonary Edema
• Hyperaldosteronism, Primary
• Hyperthyroidism, Thyroid Storm, and Graves Disease
• Myocardial Infarction
• Stroke, Hemorrhagic
• Stroke, Ischemic
• Toxicity, Amphetamine
• Toxicity, Phencyclidine 

Approach Considerations

Digital subtraction angiography with arterial injection of radiocontrast dye is the criterion standard, but it carries the risk of dye nephropathy and atheroemboli in patients with diabetes or chronic kidney disease.

Routine Laboratory Studies

Unless a secondary cause for hypertension is suspected, only the following routine laboratory studies should be performed:

• Complete blood count (CBC), serum electrolytes, serum creatinine, serum glucose, uric acid, and urinalysis
• Lipid profile (total cholesterol, low-density lipoprotein [LDL], high-density lipoprotein [HDL], and triglycerides)

Laboratory Studies in Hypertensive Emergencies

Electrolytes, blood urea nitrogen (BUN), and creatinine levels to are used to evaluate for renal impairment. CBC count and smear help to exclude microangiopathic anemia. Dipstick urinalysis can be used to detect hematuria or proteinuria (renal impairment), and microscopic urinalysis can be used to detect red blood cells (RBCs) or RBC casts (renal impairment). Optional studies include toxicology screen, pregnancy test, and endocrine testing.

Laboratory Studies for Assessment of Suspected Secondary Causes

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.^[3]
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 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 plasma renin activity (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.
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.

Echocardiography

The limited echocardiography study, rather than the complete examination, may detect left atrial dilatation, left ventricular hypertrophy (LVH), and diastolic or systolic left ventricular dysfunction more frequently than electrocardiography. The main indication for limited echocardiography is evaluation for end organ damage in a patient with borderline high BP.^[18] Therefore, the presence of LVH despite normal or borderline high BP measurements requires antihypertensive therapy. In addition, a stress echocardiogram can provide prognostic information in patients with hypertension and CAD.^[19]

Ultrasonography

This modality is very operator dependent.^[20]

Nuclear Imaging

Captopril radionuclide scanning imaging technique does not give anatomic detail and is less often used.

Imaging Studies for Renovascular Stenosis

If the patient’s history suggests renal artery stenosis and if a corrective procedure is considered, further noninvasive radiologic investigations (eg, CT angiography, magnetic resonance angiography [MRA]) or invasive renal angiography can be performed. 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 glomerular filtration rate lower than 30 mL/min. This is a rare, debilitating, life-threatening disorder associated with gadolinium. CT or invasive angiography carries the risk of dye nephropathy.

Ambulatory Blood Pressure Monitoring

Indications for ambulatory blood pressure monitoring include labile BP, a discrepancy between blood pressure measurements inside the physician’s office and those outside it, and poor BP control. Ambulatory monitoring also identifies patients who have the distinct syndrome called white coat hypertension.

Approach Considerations

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 (BP) level and reduce overall cardiovascular disease risk. A relatively small reduction in BP may affect the incidence of cardiovascular disease on a population basis. A decrease in BP of 2 mm Hg reduces the risk of stroke by 15% and the risk of coronary artery disease by 6% in a given population. In addition, a prospective study showed a reduction of 5 mm Hg in the nocturnal mean blood pressure and a possibly significant (17%) reduction in future adverse cardiovascular events if at least one antihypertensive medication is taken at bedtime.^[21]
The American Diabetes Association (ADA) 2011 standard of medical care states that in individuals with diabetes and mild hypertension, it may be reasonable to begin treatment with a trial of nonpharmacological therapy (diet, exercise, and other lifestyle modifications.) Mild hypertension as defined by the ADA guideline (systolic blood pressure 130-139 mmHg or diastolic blood pressure 80-89 mmHg) may be classified as prehypertension by other organizations.^[22]
Hypertension remains one of the most common causes of congestive heart failure (CHF). 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.
Other studies have demonstrated that a reduction in BP 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.^[3]
According to the ADA 2011 standards of medical care in diabetes, a majority of patients with diabetes mellitus have hypertension. In patients with type 1 diabetes, nephropathy is often the cause of hypertension, while, in type 2 diabetes, hypertension is one of a group of related cardiometabolic factors.^[22]

JNC VII

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]

• 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 cases.
• In specific high-risk conditions, there are compelling indications for the use of other antihypertensive drug classes (eg, angiotensin-converting enzyme [ACE] inhibitors, angiotensin-receptor blockers [ARBs], 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 BP 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.

Lifestyle Modifications

JNC VII recommendations to lower BP 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.^{[23, 24]}
• 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.

The 2010 American Heart Association-American Stroke Association (AHA-ASA) guidelines for the primary prevention of stroke makes the following recommendations:^[25]

• Hypertension: The AHA-ASA guidelines recommend regular blood pressure screening, lifestyle modification, and drug therapy. A lower risk of stroke and cardiovascular events are seen when systolic blood pressure levels are < 140 mm Hg and diastolic blood pressure < 90 mm Hg. In patients that have hypertension with diabetes or renal disease, the blood pressure goal is < 130/80 mm Hg.
• Diet and nutrition: A diet that is low in sodium and high in potassium is recommended to reduce blood pressure. Diets that promote the consumption of fruits, vegetables, and low-fat dairy products such as the DASH-style diet help lower blood pressure and may lower risk of stroke.
• Physical inactivity: Increasing physical activity is associated with a reduction in the risk of stroke. The goal is to engage in ≥30 minutes of moderate intensity activity on a daily basis.
• Obesity and body fat distribution: Weight reduction among overweight and obese persons, is recommended to reduce blood pressure and risk of stroke.

Dietary changes

A number of studies have documented an association between sodium chloride intake and BP. 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.
One randomized controlled trial published found that moderate dietary sodium reduction (approximately 2500 mg Na+/day or 6 g NaCl/day) added to angiotensin-converting enzyme inhibition compared with dual blockade (angiotensin-converting enzyme inhibitor and angiotensin receptor blocker) was more effective in reducing both proteinuria and blood pressure in nondiabetic patients with modest chronic kidney disease. Furthermore, a low sodium diet added to dual therapy yielded additional reductions in both blood pressure and proteinuria, emphasizing the beneficial effect of dietary salt reduction in the management of hypertensive patients with renal insufficiency.^[26]
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.^{[23, 24]}
The 2011 ADA standard of care supports the DASH diet, with the caution that high-quality studies of diet and exercise to lower blood pressure have not been performed on individuals with diabetes.^[22]
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 BP. Alcohol intake should be restricted to less than 1 oz of ethanol in men and 0.5 oz in women. The 2011 ADA standard supports limiting alcohol consumption in patients with diabetes and hypertension.^[22]

Weight loss and exercise

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 BP and improved insulin sensitivity. 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.
Regular aerobic physical activity can facilitate weight loss, decrease BP, 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 BP and have additional health benefits.
Blumenthal et al found that in overweight or obese patients with high BP, adding exercise and weight loss to the DASH diet resulted in even larger reductions in BP and cardiovascular biomarkers of risk. Their randomized, controlled trial in 144 patients showed that after 4 months, clinic-measured blood pressure was reduced by 16.1/9.9 mm Hg in patients in the DASH-plus–weight management group, by 11.2/7.5 mm in patients managed with DASH alone, and by 3.4/3.8 mm in a control group eating a usual diet. Compared with DASH alone, DASH plus weight management also resulted in greater improvement in pulse wave velocity, baroreflex sensitivity, and left ventricular mass.^[27]
The 2011 ADA diabetes standard supports increasing physical activity.^[22]
According to the 2011 ADA standard, patients with diabetes and severe hypertension (systolic BP ≥ 140 or diastolic BP ≥ 90 mmHg) at diagnosis or afterwards should receive drug therapy along with lifestyle modifications.^[22]

Pharmacologic Treatment of Hypertension

Multiple clinical trials suggest that most antihypertensive drugs provide the same degree of cardiovascular protection for the same level of BP 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 with the newer antihypertensive agents (eg, ACE inhibitors, calcium channel blockers).
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.
According to the 2011 ADA standard, two or more antihypertensive drugs at maximal doses should be used to achieve optimal blood pressure targets in patients with diabetes and hypertension. Either an ACE inhibitor or an ARB is usually required in patients with diabetes and hypertension. If the patient cannot tolerate one class of drugs, the other should be tried. If needed to achieve blood pressure goals, a thiazide diuretic is indicated for those patients with an estimated GFR (eGFR) ≥30 mL/min/1.73 m2 and a loop diuretic for those with an eGFR < 30 mL/min/1.73 m2. Regardless of which antihypertensive drugs are used, kidney function and serum potassium levels should be monitored.^[22]
A study by Leung et al found a 30% incidence of hyponatremia (Na < 130 mmol) in a long-term follow-up of patients who were exposed to thiazide diuretics for treatment of hypertension.^[28]
A study by Brown et al compared the combination of aliskiren and amlodipine with the use of monotherapy to control BP.^[29] The study found that combination therapy resulted in a greater reduction in mean systolic BP than monotherapy (6.5 mm Hg; 95% CI, 5.3-7.7).
Ruggenenti et al found that in patients with type 2 diabetes who have hypertension, combined manidipine and delapril therapy helped increase health for cardiovascular disease, retinopathy, and neuropathy and stabilized insulin sensitivity.^[30]
Patients with chronic kidney disease and hypertension were found in one study to have improved BP control and a reduced risk for cardiovascular events by taking at least one antihypertensive medication at bedtime.^[31]

Surgical Treatment of Hypertension

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.

Management of Hypertensive Emergencies

The primary goal of the emergency physician is to determine which patients with acute hypertension are exhibiting symptoms of end-organ damage and require immediate intravenous (IV) parenteral therapy. The fundamental principle in determining the necessary emergency department (ED) care of the hypertensive patient is the presence or absence of end-organ dysfunction.
Approximately 3-45% of adult ED patients have at least one increased BP during their stay in the ED. Many patients present to the ED with elevated BPs; however, only a small proportion of patients will require emergency treatment. In contrast, patients presenting with acutely elevated BPs (systolic BP >200 mm Hg or diastolic BP >120 mm Hg) without symptoms that are sustained throughout the ED stay and stay significantly elevated to this level on discharge should have initiation of medical therapy and close follow-up in the outpatient setting.^[32]

Treatment of Hypertension in Pediatric Patients

Usually, continuous IV infusions are the most appropriate initial therapy, especially in acutely ill infants with severe hypertension. The advantages of IV infusions are numerous, most importantly including the ability to quickly increase or decrease the rate of infusion to achieve the desired BP. As in patients of any age with malignant hypertension, take care to avoid too rapid a reduction in BP in order to avoid cerebral ischemia and hemorrhage; premature infants in particular are already at an increased risk because of the immaturity of their periventricular circulation. Because of the paucity of available data regarding the use of these agents in newborns, the choice of agent depends on the individual clinician’s experience.

Treatment of Hypertension in Pregnancy

In normal pregnancy, women’s MAP drops 10-15 mm Hg over the first half of pregnancy. Most women with mild chronic hypertension (ie, systolic BP 140-160 mm Hg, diastolic BP 90-100 mm Hg) have a similar decrease in BPs and may not require any medication during this period. Conversely, diastolic BP greater than 110 mm Hg has been associated with an increased risk of placental abruption and intrauterine growth restriction, and systolic BP greater than 160 mm Hg increases the risk of maternal intracerebral hemorrhage. Therefore, pregnant patients should be started on antihypertensive therapy if the systolic BP is greater than 160 mm Hg or the diastolic BP is greater than 100-105 mm Hg. The goal of pharmacologic treatment should be a diastolic BP of less than 100-105 mm Hg and a systolic BP less than 160 mm Hg.
Women with preexisting end-organ damage from chronic hypertension should have a lower threshold for starting antihypertensive medication (ie, >139/89) and a lower target BP (< 140/90).^[33]
Although the primary risk of chronic hypertension in pregnancy is development of superimposed preeclampsia, no evidence suggests that pharmacological treatment of mild hypertension reduces the incidence of preeclampsia in this population.^[34]

Treatment of Hypertension in the Elderly

The systolic pressure continues to rise progressively 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 ARB therapy. Low doses of diuretics may also be effective. Calcium antagonists are quite useful because of their strong antihypertensive effects.^[35] 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.
According to the 2011 American College of Cardiology Foundation (ACCF)/AHA Expert Consensus Document on Hypertension in the Elderly, there are insufficient data for strong evidence-based guidelines on managing hypertension in older patients. The ACCF/AHA document provides a consensus of expert opinion on clinical options; however, clinicians should take an individualized approach to the treatment of elderly patients.
The 2011 ACCF/AHA consensus document recommends starting the evaluation of the elderly patient with known or suspected hypertension with 3 measurements of blood pressure, to obtain an accurate BP value. If BP is elevated, the cause should be isolated. Any organ damage should be assessed. Other CVD risk factors or comorbid conditions should be identified, along with any potential barriers to treatment adherence.^[36]
The 2011 ACCF/AHA consensus advises against the routine use of laboratory testing in elderly patients. Instead, it recommends a more deliberative, focused approach. This would include a urinalysis for signs of renal damage (albuminuria/microalbuminuria); blood chemistries (especially potassium and creatinine with eGFR); total cholesterol, LDL, HDL, and triglycerides; fasting blood sugar (A1c if diabetes mellitus is suspected; and an ECG.^[36]
According to the ACCF/AHA consensus, lifestyle modifications may be all that is necessary to treat milder forms of hypertension in elderly patients. However, drug treatment for elderly patients with hypertension is generally recommended and should be started at the lowest dose possible, with gradual increases depending on response.^[36]
The Systolic Hypertension in the Elderly Program (SHEP) trial, a study by Kostis et al, found that chlorthalidone stepped-care therapy for 4.5 years was associated a longer life expectancy at 22 years of follow-up among patients with isolated systolic hypertension.^[37]

Treatment of Ocular Hypertension

In the presence of hypertensive optic neuropathy, a rapid reduction of BP may pose a risk of worsening ischemic damage to the optic nerve. The optic nerve demonstrates autoregulation, so there is an adjustment in perfusion based on the elevated blood pressure. A precipitous reduction in BP will reduce perfusion to the optic nerve and central nervous system as a result of their autoregulatory changes, resulting in infarction of the optic nerve head and, potentially, acute ischemic neurologic lesions of the CNS.

Treatment of Renovascular Hypertension

The goals of therapy for renovascular hypertension (RVHT) are maintenance of normal BP and prevention of end-stage renal disease. The therapeutic options include medical therapy, percutaneous transluminal renal angioplasty (PTRA) and stenting, and surgical revascularization. These options must be individualized, because no randomized studies document the superiority of one option over the other. In a study focusing on patients with atherosclerotic renal artery stenosis, data suggested that revascularization therapy should be confined to patients who have renal ischemia with viable underlying renal function because they will experience the greatest clinical benefit.^[38] The indications for surgery or angioplasty include an inability to control BP 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. PTRA can be an effective treatment for hypertension and the preservation of renal function in a subset of patients that is difficult to identify.^[39] 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.^[40]
For most patients with RVHT, 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 IV drug abuse, may also lead to hypertension.

Treatment of Resistant Hypertension

Some patients may have a persistent diastolic BP above 100 mm Hg despite the use of 3 or more different classes of antihypertensive medications.^[41] Although among more than one third of patients with resistant hypertension, ambulatory BP is normal; this stresses the importance of monitoring patients to achieve correct diagnosis and management.^[42] Patients who require 4 or more medications to control their BP should be considered resistant to treatment. A study has shown that the addition of low-dose spironolactone provides significant additive BP reduction in African-American and white patients who have resistant hypertension with or without primary hyperaldosteronism.
Catheter-based renal sympathetic denervation also lowers BP for an extended period of up to 2 years, according to a study of 153 patients with resistant hypertension in Australia, Europe, and the United States conducted by the American Heart Association.^[43] In addition, data suggest baroreceptor activation treatment (BAT) by an implantable stimulator can potentially safely reduce systolic blood pressure (SBP) over the long term in patients with resistant hypertension.^[44]

Inadequate treatment

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

Extracellular volume expansion may contribute to the inability to lower systemic BP. 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.

Noncompliance

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, use of fixed-dose combinations, and use of drugs with the fewest adverse effects.
Limited data suggests better compliance with ACE inhibitors and ARBs than some other antihypertensive medications.^[45]

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.

Excluding secondary causes

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.^[46]
A study by Pedrosa et al also found that a good predictor for sleep apnea in patients older than 50 years with resistant hypertension is a large neck circumference and snoring.^[47]
Blood pressure rise secondary to anxiety may be observed in 20-30% of patients.^[48] 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 so-called white-coat hypertension. White-coat hypertension can also be evaluated by the use of a 24-hour ambulatory monitor.

Treatment of Pseudohypertension

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 BP 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.

Treatment of 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, computed tomography (CT) or magnetic resonance imaging (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.

Treatment of 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 of 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 of 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 at least 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.

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.

Continuing Care

Various interventions can be implemented to improve BP control in patients with hypertension or to treat uncontrolled hypertension. These interventions include the following:

• Self-monitoring
• Educational interventions directed to the patient
• Educational interventions directed to the health professional
• Health professional (nurse or pharmacist)–led care
• Organizational interventions that aim to improve the delivery of care
• Appointment reminder systems

The Cochrane Collaboration has shown that these interventions are associated with large net BP reductions and that health professional (nurse or pharmacist)–led care may be a promising way of delivering care.^[49] A study by Pezzin et al found that extensive patient education, coupled with nurse-led monitoring and feedback, resulted in significant improvements in 3-month BP control and secondary BP outcomes in high-risk black patients with stage 2 hypertension.^[50] Cochrane 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. A randomized trial looking at home BP management found that systolic BP decreased among individuals with poor BP control at baseline using a combined treatment of nurse-administered behavioral management and nurse-administered and physician-administered medication management.^[51]
Antihypertensive drug therapy should be implemented by means of a vigorous stepped care approach when patients do not reach target BP levels.

Deterrence and 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 BP 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,^[52] excessive sodium consumption, physical inactivity, and/or alcohol consumption. Even a small reduction in BP confers significant health benefits. A 2-mm Hg reduction in diastolic BP 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 (see Lifestyle Modifications)

  Medication Summary

  The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Medications include diuretics, alpha- and beta-adrenergic blockers, antihypertensives, calcium channel blockers, ACE inhibitors, and vasodilators.

  Diuretic, Thiazide

  Class Summary

  Thiazide diuretics inhibit reabsorption of sodium and chloride in the cortical thick ascending limb of the loop of Henle and the distal tubules. They also increase potassium and bicarbonate excretion, decrease calcium excretion, and uric acid retention.
  

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  Hydrochlorothiazide (Esidrix, HydroDIURIL, Microzide)

   

  Hydrochlorothiazide inhibits reabsorption of sodium in distal tubules, causing increased excretion of sodium, water, potassium, and hydrogen ions. Examples of thiazide diuretics are chlorthalidone
  

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  Chlorthalidone (Thalitone)

   

  Chlorthalidone inhibits reabsorption of sodium in distal tubules, causing increased excretion of sodium and water, as well as potassium and hydrogen ions.
  

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  Metolazone (Zaroxolyn)

   

  Metolazone increases excretion of sodium, water, potassium, and hydrogen ions by inhibiting reabsorption of sodium in distal tubules. Metolazone may be more effective in patients with impaired renal function.
  

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  Indapamide (Lozol)

   

  Indapamide is chemically not a thiazide although its structure and function are very similar. The half-life of indapamide is about 14 hour, so the drug can be taken just once daily. Effect on urinary calcium and hypercalciuria is identical to thiazides. Adverse effects tend to be somewhat milder than with thiazides.

  Diuretic, Potassium Sparing

  Class Summary

  The potassium-sparing diuretics interfere with sodium reabsorption at the distal tubules, decreasing potassium secretion. Potassium-sparing diuretics have a weak diuretic and antihypertensive effect when used alone.
  

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  Spironolactone (Aldactone)

   

  Spironolactone may block effects of aldosterone on arteriolar smooth muscles.
  

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  Amiloride (Midamor)

   

  Amiloride is unrelated chemically to other known antikaliuretic or diuretic agents. It is a potassium-conserving (antikaliuretic) drug that, compared with thiazide diuretics, possesses weak natriuretic, diuretic, and antihypertensive activity.
  

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  Triamterene (Dyrenium)

   

  Triamterene is a potassium-sparing diuretic with relatively weak natriuretic properties. It exerts its diuretic effect on the distal renal tubules by inhibiting the reabsorption of sodium in exchange for potassium and hydrogen. Increases sodium excretion and reduces excessive loss of potassium and hydrogen associated with hydrochlorothiazide.

  Diuretic, Loop

  Class Summary

  Loop diuretics act on the ascending limb of the loop of Henle, inhibiting the reabsorption of sodium and chloride. Examples of loop diuretics include furosemide (Lasix), torsemide (Demadex), bumetanide (Bumex), and ethacrynic acid (Edecrin).
  

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  Furosemide (Lasix)

   

  Furosemide increases excretion of water by interfering with the chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle and the distal renal tubule. The dose must be individualized to the patient.
  

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  Torsemide (Demadex)

   

  Acts from within the lumen of the thick ascending portion of the loop of Henle, where it inhibits the sodium, potassium and chloride carrier system. Increases urinary excretion of sodium, chloride, and water, but does not significantly alter glomerular filtration rate, renal plasma flow, or acid-base balance.
  

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  Bumetanide (Bumex)

   

  Increases excretion of water by interfering with chloride-binding cotransport system, which, in turn, inhibits sodium, potassium, and chloride reabsorption in ascending loop of Henle. These effects increase urinary excretion of sodium, chloride, and water, resulting in profound diuresis. Renal vasodilation occurs following administration, renal vascular resistance decreases, and renal blood flow is enhanced.
  

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  Ethacrynic acid (Edecrin)

   

  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.

  Alpha-Adrenergic Blocking Agents

  Class Summary

  These agents selectively block postsynaptic alpha₁ -adrenergic receptors. They dilate arterioles and veins, thus lowering blood pressure (BP).
  

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  Prazosin (Minipress)

   

  Prazosin improves urine flow rates by relaxing smooth muscle, which is caused by blocking alpha1-adrenoceptors in the bladder neck and the prostate. When increasing the dose, administer the 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.
  

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  Terazosin (Hytrin)

   

  Terazosin decreases arterial tone by allowing peripheral postsynaptic blockade. It has minimal alpha2 effect.
  

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  Phentolamine (OraVerse)

   

  Phentolamine is an alpha1- and alpha2-adrenergic blocking agent, effective for pheochromocytoma and hypercatecholaminergic-induced hypertension.
  

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  Doxazosin (Cardura, Cardura XL)

   

  Doxazosin is a selective alpha1-adrenergic antagonist. It inhibits postsynaptic alpha-adrenergic receptors, resulting in vasodilation of veins and arterioles and decrease in total peripheral resistance and blood pressure.

  Beta-Adrenergic Blocking Agents

  Class Summary

  Beta-blockers are used to treat hypertension as initial agents or in combination with other drugs (eg, thiazides). Some examples of beta-blockers are atenolol (Tenormin), metoprolol (Lopressor, Toprol XL), propranolol (Inderal, Inderal LA, InnoPran XL), nebivolol (Bystolic), and esmolol (Brevibloc).
  

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  Atenolol (Tenormin)

   

  Atenolol selectively blocks beta₁ receptors with little or no effect on beta₂ types.
  

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  Metoprolol (Lopressor, Toprol XL)

   

  Metoprolol is a selective beta1-adrenergic receptor blocker that decreases the automaticity of contractions. During intravenous (IV) administration, carefully monitor blood pressure (BP), heart rate, and electrocardiogram (ECG).
  

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  Propranolol (Inderal, Inderal LA, InnoPran XL)

   

  Propranolol has membrane-stabilizing activity and decreases the automaticity of contractions. It is not suitable for emergency treatment of hypertension. Do not give propranolol IV in hypertensive emergencies.
  

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  Nebivolol (Bystolic)

   

  In extensive metabolizers (the majority of the population) and doses ≤10 mg, nebivolol preferentially elicits beta₁ selective inhibition, whereas in poor metabolizers and at higher doses, it inhibits beta₁ - and beta₂ -receptors. Nebivolol lacks intrinsic sympathomimetic and membrane stabilizing activity. Active metabolites contribute to beta-blocking action. The half-life is about 12 h in extensive metabolizers and 19 h in poor metabolizers.
  

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  Esmolol (Brevibloc)

   

  Esmolol is ideal for use in patients at risk for complications from beta-blockers, especially patients with mild to moderately severe left ventricular dysfunction or peripheral vascular disease. It has a short half-life of 8 min and thus is easily titratable to the desired effect. In addition, therapy may be stopped quickly if necessary.

  Alpha/Beta-Adrenergic Blocking Agents

  Class Summary

  These agents block alpha-, beta₁ -, and beta₂ -adrenergic receptor sites, thus decreasing BP.
  

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  Labetalol (Normodyne, Trandate)

   

  Labetalol does not appear to have intrinsic sympathomimetic activity. It may reduce cardiac output and decrease peripheral vascular resistance. Its use in aortic dissection is not advisable when titratable drugs, such as esmolol and nitroprusside, are available.
  

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  Carvedilol (Coreg)

   

  Carvedilol is a nonselective beta- and alpha-adrenergic blocker that also has antioxidant properties. It does not appear to have intrinsic sympathomimetic activity. It may reduce cardiac output and decrease peripheral vascular resistance.

  Peripheral Vasodilators

  Class Summary

  Relax blood vessels to improve blood flow, thus decreasing blood pressure.
  

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  Hydralazine (Apresoline)

   

  Hydralazine decreases systemic resistance through direct vasodilation of arterioles.
  

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  Minoxidil (Rogaine, Loniten)

   

  Minoxidil relaxes arteriolar smooth muscle, causing vasodilation, which in turn may reduce BP.

  Calcium Channel Blockers, Dihydropyridine

  Class Summary

  Dihydropyridines bind to L-type calcium channels in the vascular smooth muscle, which results in vasodilatation and a decrease in blood pressure. Effective as monotherapy in black patients and elderly patients. Some examples of dihydropyridines include amlodipine (Norvasc), nifedipine (Adalat CC, Procardia, Procardia XL, Nifedical XL), clevidipine butyrate (Cleviprex), and felodipine (Plendil).
  

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  Nifedipine (Adalat)

   

  Nifedipine relaxes coronary smooth muscle and produces coronary vasodilation, which in turn improves myocardial oxygen delivery. Sublingual administration is generally safe, despite theoretical concerns.
  

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  Clevidipine butyrate (Cleviprex)

   

  Clevidipine butyrate is rapidly metabolized in blood and tissues and does not accumulate in the body. It is administered IV and is indicated for rapid and precise BP reduction. Clevidipine butyrate is available in a concentration of 0.5 mg/mL as single-use vials (50 mL or 100 mL).
  

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  Amlodipine (Norvasc)

   

  Amlodipine has antianginal and antihypertensive effects. It blocks the postexcitation release of calcium ions into cardiac and vascular smooth muscle, thereby inhibiting the activation of ATPase on myofibril contraction. The overall effect is reduced intracellular calcium levels in cardiac and smooth muscle cells of the coronary and peripheral vasculature, resulting in dilatation of coronary and peripheral arteries. Also increases myocardial oxygen delivery in patients with vasospastic angina.
  

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  Felodipine (Plendil)

   

  Relaxes coronary smooth muscle and produces coronary vasodilation, which, in turn, improves myocardial oxygen delivery.

  Calcium Channel Blockers, Non-Dihydropyridine

  Class Summary

  Non-dihydropyridines bind to L-type calcium channels in the sinoatrial and atrioventricular node, as well as exerting effects in the myocardium and vasculature. These agents may constitute a more effective class of medication for black patients.^[53]
  

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  Diltiazem (Cardizem CD, Dilacor XR)

   

  During depolarization, diltiazem inhibits calcium ion from entering slow channels or voltage-sensitive areas of vascular smooth muscle and myocardium.
  

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  Verapamil (Calan, Covera-HS)

   

  During depolarization, verapamil inhibits calcium ions from entering slow channels and voltage-sensitive areas of vascular smooth muscle and myocardium.

  Angiotensin-Converting Enzyme Inhibitors

  Class Summary

  These agents are competitive inhibitors of angiotensin-converting enzyme (ACE). They reduce angiotensin II levels, thus decreasing aldosterone secretion.
  

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  Captopril (Capoten)

   

  Captopril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion.
  

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  Ramipril (Altace)

   

  Ramipril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion.
  

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  Enalapril (Vasotec)

   

  Enalapril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion. It helps control blood pressure and proteinuria. Enalapril decreases pulmonary-to-systemic flow ratio in the catheterization laboratory and increases systemic blood flow in patients with relatively low pulmonary vascular resistance. It has a favorable clinical effect when administered over a long period. It helps prevent potassium loss in distal tubules. The body conserves potassium; thus, less oral potassium supplementation is needed.
  

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  Lisinopril (Zestril)

   

  Lisinopril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion.

  Angiotensin II Receptor Antagonists

  Class Summary

  Angiotensin II receptor antagonists, or angiotensin receptor blockers (ARBs), are used for patients who are unable to tolerate ACE inhibitors.
  Azilsartan was approved by the FDA in February 2011. In a randomized, double-blind, placebo-controlled trial of nearly 1300 patients, White et al, found azilsartan (80 mg daily) to be superior to maximum daily doses of valsartan (320 mg/day) or olmesartan (40 mg/day). Adverse effects between each group did not differ significantly.^[54]
  A study by Harel et al found an increased risk for hyperkalemia when aliskerin and ACE inhibitors or angiotensin receptor blockers were used together. Careful monitoring of serum potassium levels is warranted when these agents are used in combination.^[55]
  

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  Losartan (Cozaar)

   

  Losartan is a nonpeptide angiotensin II receptor antagonist that blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II. It may induce more complete inhibition of the renin-angiotensin system than ACE inhibitors do, it does not affect response to bradykinin, and it is less likely to be associated with cough and angioedema.
  

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  Valsartan (Diovan)

   

  Valsartan is a prodrug that produces direct antagonism of angiotensin II receptors. It displaces angiotensin II from the AT1 receptor and may lower BP by antagonizing AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses. Valsartan may induce more complete inhibition of renin-angiotensin system than ACE inhibitors do, does not affect response to bradykinin, and is less likely to be associated with cough and angioedema.
  

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  Olmesartan (Benicar)

   

  Olmesartan blocks the vasoconstrictor effects of angiotensin II by selectively blocking binding of angiotensin II to AT1 receptor in vascular smooth muscle. Its action is independent of pathways for angiotensin II synthesis.
  

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  Eprosartan (Teveten)

   

  Eprosartan binds to AT1 angiotensin II receptor, blocking the vasoconstrictor and aldosterone-secreting effects of angiotensin II. It may induce more complete inhibition of the renin-angiotensin system than ACE inhibitors do, it does not affect response to bradykinin, and it is less likely to be associated with cough and angioedema.
  

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  Azilsartan (Edarbi)

   

  Angiotensin II blocker. Displaces angiotensin II from AT1 receptor and may lower blood pressure by antagonizing AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water absorption, and hypertrophic responses. May induce more complete inhibition of renin-angiotensin system compared with ACE inhibitors; does not affect response to bradykinin and is less likely to be associated with cough and angioedema. Indicated for hypertension, either alone or in combination with other antihypertensives

  Aldosterone Antagonists

  Class Summary

  Compete with aldosterone receptor sites, reducing blood pressure and sodium reabsorption.
  

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  Eplerenone (INSPRA)

   

  Eplerenone selectively blocks aldosterone at the mineralocorticoid receptors in epithelial (eg, kidney) and nonepithelial (eg, heart, blood vessels, brain) tissues, thus decreasing BP and sodium reabsorption.

  Alpha-Adrenergic Agonists

  Class Summary

  Stimulate presynaptic alpha₂ -adrenergic receptors in the brain stem, which reduces sympathetic nervous activity.
  

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  Methyldopa (Aldomet)

   

  Methyldopa stimulates central alpha-adrenergic receptors by a false transmitter, resulting in decreased sympathetic outflow. This results in inhibition of vasoconstriction.
  

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  Clonidine (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.
  

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  Guanfacine (Tenex)

   

  Guanfacine stimulates alpha2-adrenergic receptors in brain stem, activating an inhibitory neuron, which, in turn, results in a decrease in vasomotor tone and heart rate.

  Renin Inhibitor

  Class Summary

  Newest class of antihypertensive drugs. Acts by disrupting the renin-angiotensin-aldosterone system feedback loop.
  

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  Aliskiren (Tekturna)

   

  Aliskiren 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 feedback loop. It is indicated for hypertension as monotherapy or in combination with other antihypertensive drugs.

  Vasodilators

  Class Summary

  Nitroglycerin and nitroprusside cause both arterial and venous dilatation. Nitroglycerin primarily affects the venous system and helps to decrease preload. Nitroprusside decreases both preload and afterload, which helps to decrease myocardial oxygen demand.
  

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  Nitroglycerin topical (Nitro-Bid)

   

  Nitroglycerin decreases coronary vasospasm, which increases coronary blood flow. It also induces vessel dilatation, decreasing cardiac workload.
  

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  Sodium nitroprusside (Nitropress)

   

  Sodium nitroprusside reduces peripheral resistance by acting directly on arteriolar and venous smooth muscle.

  Dopamine Agonist

  Class Summary

  Dopamine agonists such as fenoldopam^[39] exert hypotensive effects by decreasing peripheral vasculature resistance, causing increased renal blood flow, diuresis, and natriuresis.
  

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  Fenoldopam (Corlopam)

   

  Fenoldopam is a short-acting dopamine agonist that was recently approved for management of severe hypertension. It increases renal blood flow and sodium excretion. It is 10 times more potent than dopamine as a renal vasodilator.

  Antihypertensive Combinations

  Class Summary

  Drug combinations using agents that act by different mechanisms have an additive effect. Most clinicians recommend initiating therapy with a single agent and advancing to the low-dose combination therapy. Some examples of drug combinations include enalapril/hydrochlorothiazide (Vaseretic), metoprolol/hydrochlorothiazide (Lopressor HCT), triamterene/hydrochlorothiazide (Maxzide, Maxzide-25, Dyazide), valsartan/hydrochlorothiazide (Diovan HCT), and valsartan/amlodipine/hydrochlorothiazide (Exforge HCT).
  

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  Metoprolol/hydrochlorothiazide (Lopressor HCT)

   

  Metoprolol/hydrochlorothiazide is a combination of metoprolol, a beta-blocker, and hydrochlorothiazide, a thiazide diuretic. Metoprolol is a beta1-selective blocker at low doses; at higher doses, it also inhibits beta2-adrenoreceptors. Hydrochlorothiazide inhibits sodium reabsorption in distal renal tubules, resulting in increased excretion of water, sodium, potassium, and hydrogen ions.
  

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  Triamterene/hydrochlorothiazide (Maxzide, Maxzide-25, Dyazide)

   

  Triamterene/hydrochlorothiazide is a fixed-combination indicated for hypertension or edema in patients who are at risk of developing hypokalemia on hydrochlorothiazide alone. Triamterene exerts a diuretic effect on the distal renal tubule, inhibiting the reabsorption of sodium in exchange for potassium and hydrogen ions. Hydrochlorothiazide inhibits sodium and chloride reabsorption in distal renal tubules, resulting in increased excretion of water, sodium, potassium, and hydrogen ions.
  

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  Valsartan/hydrochlorothiazide (Diovan HCT)

   

  Valsartan/hydrochlorothiazide is a combination of valsartan, an angiotensin receptor blocker, and hydrochlorothiazide, a diuretic. Valsartan is a prodrug that produces direct antagonism of angiotensin II receptors. It 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. Hydrochlorothiazide inhibits sodium and chloride reabsorption in distal renal tubules, resulting in increased excretion of water, sodium, potassium, and hydrogen ions.
  

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  Valsartan/amlodipine/hydrochlorothiazide (Exforge HCT)

   

  Valsartan/amlodipine/hydrochlorothiazide is a combination of amlodipine, a dihydropyridine calcium channel blocker, valsartan, an angiotensin receptor blocker, and hydrochlorothiazide, a diuretic. Amlodipine exhibits antianginal and antihypertensive effects by inhibiting the influx of calcium in cardiac and smooth muscle cells of the coronary and peripheral vasculature, resulting in dilatation of coronary and peripheral arteries. Valsartan is a prodrug that produces direct antagonism of angiotensin II receptors. It displaces angiotensin II from the AT1 receptor and may lower blood pressure by antagonizing AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses. Hydrochlorothiazide inhibits sodium and chloride reabsorption in distal renal tubules, resulting in increased excretion of water, sodium, potassium, and hydrogen ions.
  

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  Enalapril/hydrochlorothiazide (Vaseretic)

   

  Enalapril/hydrochlorothiazide is a combination of enalapril, an ACE inhibitor, and hydrochlorothiazide, a diuretic. Hydrochlorothiazide inhibits sodium reabsorption in distal renal tubules, resulting in increased excretion of water, sodium, potassium, and hydrogen ions. Enalapril prevents the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion. It helps control blood pressure and proteinuria.
  

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  Azilsartan/chlorthalidone (Edarbyclor)

   

  This is an angiotensin II receptor blocker (ARB) and thiazide-like diuretic combination. It is indicated as initial hypertension therapy or for the treatment of hypertension in patients whose condition is not adequately controlled with monotherapy.