Hypertension

High blood pressure, or hypertension, is the most common primary diagnosis in the United States,[3]  and it is one of the most common worldwide diseases afflicting humans and is a major risk factor for stroke, myocardial infarction, vascular disease, and chronic kidney disease. Despite extensive research over the past several decades, the etiology of most cases of adult hypertension is still unknown, and control of blood pressure is suboptimal in the general population. Due to the associated morbidity and mortality and cost to society, preventing and treating hypertension is an important public health challenge. Fortunately, recent advances and trials in hypertension research are leading to an increased understanding of the pathophysiology of hypertension and the promise for novel pharmacologic and interventional treatments for this widespread disease.

According to the American Heart Association (AHA), approximately 86 million adults (34%) in the United States are affected by hypertension, which is defined as a systolic blood pressure (SBP) of 140 mm Hg or more or a diastolic blood pressure (DBP) of 90 mm Hg or more, taking antihypertensive medication, or having been told by clinicians on at least 2 occasions as having hypertension.[4] Substantial improvements have been made with regard to enhancing awareness and treatment of hypertension. However, a National Health Examination Survey (NHANES) spanning 2011-2014 revealed that 34% of US adults aged 20 years and older are hypertensive and NHANES 2013-2014 data showed that 15.9% of these hypertensive adults are unaware they are hypertensive; these data have increased from NHANES 2005-2006 data that showed 29% of US adults aged 18 years and older were hypertensive and that 7% of these hypertensive adults had never been told that they had hypertension.[4]

Furthermore, of those with high blood pressure (BP), 78% were aware they were hypertensive, 68% were being treated with antihypertensive agents, and only 64% of treated individuals had controlled hypertension.[4] In addition, previous data from NHANES estimated that 52.6% (NHANES 2009-2010) to 55.8% (NHANES 1999-2000) of adults aged 20 years and older have prehypertension, defined as an untreated SBP of 120-139 mm Hg or untreated DBP of 80-89 mmHg.[4] (See Epidemiology.)

Data from the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), which was released in 2003, were relatively similar to the NHANES data. The JNC 7 noted that approximately 30% of adults were unaware of their hypertension; up to 40% of people with hypertension were not receiving treatment; and, of those treated, up to 67% did not have their BP controlled to less than 140/90 mm Hg.[5]

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.)

Definition and classification

Defining abnormally high blood pressure (BP) 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 Presentation.)

Based on recommendations of the JNC 7, the classification of BP (expressed in mm Hg) for adults aged 18 years or older is as follows[5] :

• Normal: systolic lower than 120 mm Hg, diastolic lower than 80 mm Hg

• Prehypertension: systolic 120-139 mm Hg, diastolic 80-89 mm Hg

• Stage 1: systolic 140-159 mm Hg, diastolic 90-99 mm Hg

• Stage 2: systolic 160 mm Hg or greater, diastolic 100 mm Hg or greater

The classification above is based on the average of 2 or more readings taken at each of 2 or more visits after initial screening.[5, 7] 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 7 report, emphasizes that patients with prehypertension are at risk for progression to hypertension and that lifestyle modifications are important preventive strategies.

However, the 2017 ACC/AHA guidelines eliminate the classification of prehypertension and divides it into two levels[1, 2] : (1) elevated BP, with a systolic pressure (SBP) between 120 and 129 mm Hg and diastolic pressure (DBP) less than 80 mm Hg, and (2) stage 1 hypertension, with an SBP of 130 to 139 mm Hg or a DBP of 80 to 89 mm Hg.

From another perspective, hypertension may be categorized as either essential or secondary. Primary (essential) hypertension is diagnosed in the absence of an identifiable secondary cause. Approximately 90-95% of adults with hypertension have primary hypertension, whereas secondary hypertension accounts for around 5-10% of the cases.[11] However, secondary forms of hypertension, such as primary hyperaldosteronism, account for 20% of resistant hypertension (hypertension in which BP is >140/90 mm Hg despite the use of medications from 3 or more drug classes, 1 of which is a thiazide diuretic).

Especially severe cases of hypertension, or hypertensive crises, are defined as a BP of more than 180/120 mm Hg and may be further categorized as hypertensive emergencies or urgencies. Hypertensive emergencies are characterized by evidence of impending or progressive target organ dysfunction, whereas hypertensive urgencies are those situations without progressive target organ dysfunction.[5]

In hypertensive emergencies, the BP should be aggressively lowered within minutes to an hour by no more than 25%, and then lowered to 160/100-110 mm Hg within the next 2-6 hours.[5] Acute end-organ damage in the setting of a hypertensive emergency may include the following[12] :

• 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, unstable angina pectoris

• 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%.[13] In addition, the 1-year survival rate associated with this condition has increased from only 20% (prior to 1950) to more than 90% with appropriate medical treatment.[14] (See Medication.)

The pathogenesis of essential hypertension is multifactorial and complex.[15] Multiple factors modulate the blood pressure (BP) including 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, the exact mechanisms underlying essential hypertension have not been established.

Investigations into the pathophysiology of hypertension, both in animals and humans, have revealed that hypertension may have an immunological basis. Studies have revealed that hypertension is associated with renal infiltration of immune cells and that pharmacologic immunosuppression (such as with the drug mycophenolate mofetil) or pathologic immunosuppression (such as occurs with HIV) results in reduced blood pressure in animals and humans. Evidence suggests that T lymphocytes and T-cell derived cytokines (eg, interleukin 17, tumor necrosis factor alpha) play an important role in hypertension.[16, 17]

One hypothesis is that prehypertension results in oxidation of lipids such as arachidonic acid that leads to the formation of isoketals or isolevuglandins, which function as neoantigens, which are then presented to T cells, leading to T-cell activation and infiltration of critical organs (eg, kidney, vasculature).[18] This results in persistent or severe hypertension and end organ damage. Sympathetic nervous system activation and noradrenergic stimuli have also been shown to promote T-lymphocyte activation and infiltration and contribute to the pathophysiology of hypertension.[19, 20, 21]

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 end-organ damage to the aorta and small arteries, heart, kidneys, retina, and central nervous system is evident.

The progression of essential hypertension is as follows:

1. Prehypertension in persons aged 10-30 years (by increased cardiac output)

2. Early hypertension in persons aged 20-40 years (in which increased peripheral resistance is prominent)

3. Established hypertension in persons aged 30-50 years

4. Complicated hypertension in persons aged 40-60 years

As evident from the above, younger individuals may present with hypertension associated with an elevated cardiac output (high-output hypertension). High-output hypertension results from volume and sodium retention by the kidney, leading to increased stroke volume and, often, with cardiac stimulation by adrenergic hyperactivity. Systemic vascular resistance is generally not increased at such earlier stages of hypertension. As hypertension is sustained, however, vascular adaptations including remodeling, vasoconstriction, and vascular rarefaction occur, leading to increased systemic vascular resistance. In this situation, cardiac output is generally normal or slightly reduced, and circulating blood volume is normal.

Cortisol reactivity, an index of hypothalamic-pituitary-adrenal function, may be another mechanism by which psychosocial stress is associated with future hypertension.[22] In a prospective sub-study of the Whitehall II cohort, with 3 years follow-up of an occupational cohort in previously healthy patients, investigators reported 15.9% of the patient sample developed hypertension in response to laboratory-induced mental stressors and found an association between cortisol stress reactivity and incident hypertension.[22]

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. Primary or essential hypertension accounts for 90-95% of adult cases, and a small percentage of patients (2-10%) have a secondary cause. Hypertensive emergencies are most often precipitated by inadequate medication or poor compliance.

Environmental and genetic/epigenetic causes

Hypertension develops secondary to environmental factors, as well as multiple genes, whose inheritance appears to be complex.[14, 23] Furthermore, obesity, diabetes, and heart disease also have genetic components and contribute to hypertension. Epidemiologic studies using twin data and data from Framingham Heart Study families reveal that BP has a substantial heritable component, ranging from 33-57%.[24, 25, 26]

In an attempt to elucidate the genetic components of hypertension, multiple genome wide association studies (GWAS) have been conducted, revealing multiple gene loci in known pathways of hypertension as well as some novel genes with no known link to hypertension as of yet.[27] Further research into these novel genes, some of which are immune-related, will likely increase the understanding of hypertension's pathophysiology, allowing for increased risk stratification and individualized treatment.

Epigenetic phenomena, such as DNA methylation and histone modification, have also been implicated in the pathogenesis of hypertension. For example, a high-salt diet appears to unmask nephron development caused by methylation. Maternal water deprivation and protein restriction during pregnancy increase renin-angiotensin expression in the fetus. Mental stress induces a DNA methylase, which enhances autonomic responsiveness. The pattern of serine protease inhibitor gene methylation predicts preeclampsia in pregnant women.[28]

Despite these genetic findings, targeted genetic therapy seems to have little impact on hypertension. In the general population, not only does it appear that individual and joint genetic mutations have very small effects on BP levels, but it has not been shown that any of these genetic abnormalities are responsible for any applicable percentage of cases of hypertension in the general population.[29]

Secondary causes of hypertension related to single genes are very rare. They include Liddle syndrome, glucocorticoid-remediable hyperaldosteronism, 11 beta-hydroxylase and 17 alpha-hydroxylase deficiencies, the syndrome of apparent mineralocorticoid excess, and pseudohypoaldosteronism type II.[5]

Causes of secondary hypertension

Renal causes (2.5-6%) of hypertension 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 the seminal experiment in 1934 by Goldblatt et al,[30] 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 a renal cause (although the true prevalence of hyperaldosteronism is not clear).

Another common endocrine cause is oral contraceptive use. Activation of the renin-angiotensin-aldosterone system (RAAS) is the likely mechanism, because hepatic synthesis of angiotensinogen is induced by the estrogen component of oral contraceptives. Approximately 5% of women taking oral contraceptives may develop hypertension, which abates within 6 months after 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. It would be better to group oral contraceptives and steroids with drug-induced hypertension.

Exogenous administration of the other steroids used for therapeutic purposes also increases blood pressure (BP), especially in susceptible individuals, mainly by volume expansion. Nonsteroidal anti-inflammatory drugs (NSAIDs) may also have adverse effects on BP. 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 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

• Autonomic dysfunction

• Sleep apnea

• 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 (including licorice root) or ephedrine (and ephedra)

• Nicotine

Other causes include the following:

• Hyperthyroidism and hypothyroidism

• Hypercalcemia

• Hyperparathyroidism

• Acromegaly

• Obstructive sleep apnea

• Pregnancy-induced hypertension

Obstructive sleep apnea (OSA) is a common but frequently undiagnosed sleep-related breathing disorder defined as an average of at least 10 apneic and hypopenic episodes per sleep hour, which leads to excessive daytime sleepiness. Multiple studies have shown OSA to be an independent risk factor for the development of essential hypertension, even after adjusting for age, gender, and degree of obesity.

Approximately half of individuals with hypertension have OSA, and approximately half with OSA have hypertension. Ambulatory BP monitoring normally reveals a "dip" in BP of at least 10% during sleep. However, if a patient is a "nondipper," the chances that the patient has OSA is increased. Nondipping is thought to be caused by frequent apneic/hypopneic episodes that end with arousals associated with marked spikes in BP that last for several seconds. Apneic episodes are associated with striking increases in sympathetic nerve activity and enormous elevations of BP. Individuals with sleep apnea have increased cardiovascular mortality, in part likely related to the high incidence of hypertension.

Although treatment of sleep apnea with continuous airway positive pressure (CPAP) would logically seem to improve CV outcomes and hypertension, studies evaluating this mode of therapy have been disappointing. A 2016 review of several studies indicated that CPAP either had no effect or a modest BP-lowering effect.[31] Findings from the SAVE study showed no effect of CPAP therapy on BP above usual care.[32] It is likely that patients with sleep apnea have other etiologies of hypertension, including obesity, hyperaldosteronism, increased sympathetic drive, and activation of the renin/angiotensin system that contribute to their hypertension. Although CPAP remains an effective therapy for other aspects of sleep apnea, it should not be expected to normalize BP in the majority of patients.

Causes of hypertensive emergencies

The most common hypertensive emergency is a rapid unexplained rise in BP in patients with chronic essential hypertension. Most patients who develop hypertensive emergencies have a history of inadequate hypertensive treatment or an abrupt discontinuation of their medications.[33, 34]

Other causes of hypertensive emergencies include the use of recreational drugs, abrupt clonidine withdrawal, post pheochromocytoma removal, and systemic sclerosis, as well as 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,[35] 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 factors: CNS trauma or spinal cord disorders, such as Guillain-Barré syndrome

• Coarctation of the aorta

• Preeclampsia/eclampsia

• Postoperative hypertension

Hypertension is a worldwide epidemic; accordingly, its epidemiology has been well studied. Data from National Health and Nutrition Examination Survey (NHANES) spanning 2011-2014 in the United States found that in the population aged 20 years or older, an estimated 86 million adults had hypertension, with a prevalence of 34%.[4]  

2017 Data from the Centers for Disease Control and Prevention's (CDC) National Center for Health Statistics (NCHS) spanning 2015-2016 show a hypertension prevalence of 29.0% among those aged 18 and older (see the following image).[36]  The following image shows prevalence of hypertension among adults aged 18 and over, by sex and age: United States, 2015–2016.

 

There was an increasing trend of hypertension in adults between 1999-2000 and 2009-2010, and 2013-2014, with mild falls in 2011-2012 and 2015-2016 (see the image below).[36]  The image below shows the age-adjusted trends in hypertension and controlled hypertension among adults aged 18 and over: United States, 1999–2016.

Overall, hypertension affects US men and women nearly equally, affecting an estimated 40.8 million men and 44.9 million women.[4]

Globally, an estimated 26% of the world’s population (972 million people) has hypertension, and the prevalence is expected to increase to 29% by 2025, driven largely by increases in economically developing nations.[37] The high prevalence of hypertension exacts a tremendous public health burden. As a primary contributor to heart disease and stroke, the first and third leading causes of death worldwide, respectively, high blood pressure was the top modifiable risk factor for disability adjusted life-years lost worldwide in 2013.[38, 39]

Between 2006 and 2011, there was a 25% increase in the number of people visiting US emergency rooms for essential hypertension, according to an analysis of data from the Nationwide Emergency Department Sample in 2014.[40] The reason for the increase, however, remained uncertain. The rate of emergency department visits also increased significantly, according to the study, rising from 190.1 visits per 100,000 population in 2006 to 238.5 visits per 100,000 population in 2011. Over the same period, however, admission rates decreased, from 10.47% in 2006 to 8.85% in 2011.[40]

Emergency department visits for hypertension with complications and secondary hypertension also rose, from 71.2 per 100,000 population in 2006 to 84.7 per 100,000 population in 2011, while again, admission rates fell, dropping from 77.79% in 2006 to 68.75% in 2011. The in-hospital mortality rate for admitted patients dropped as well, from 1.95% in 2006 to 1.25% in 2011.[40]

Hypertension and sex- and age-related statistics

Until age 45 years, a higher percentage of men than women have hypertension; from age 45 to 64 years, the percentages are nearly equal between men and women. Beyond age 64 years, a higher percentage of women have hypertension than men.[41]  (See the image below.)

Hypertension in black adults

Globally, black adults have among the highest rates of hypertension, with an increasing prevalence. Although white adults also have an increasing incidence of high BP, they develop this condition later in life than black adults and have much lower average BPs. In fact, compared to hypertensive white persons, hypertensive black individuals have a 1.3-fold higher rate of nonfatal stroke, a 1.8-fold higher rate of fatal stroke, a 1.5-fold higher mortality rate due to heart disease, and a 4.2-fold higher rate of end-stage renal disease (ESRD).[41]

Table 2, below, summarizes age-adjusted prevalence estimates from the National Health Interview Survey (NHIS) and the NCHS according to racial/ethnic groups and diagnosed conditions in individuals 18 years of age and older.

Table 2. NHIS/NCHS Age-Adjusted Prevalence Estimates in Individuals Aged 18 Years and Older in 2015. (Open Table in a new window)

Most individuals diagnosed with hypertension will have increasing blood pressure (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, may be associated with a risk of atherosclerotic disease in 30% of people and organ damage in 50% of people within 8-10 years after onset. Patients with resistant hypertension are also at higher risk for poor outcomes, particularly those with certain comorbidities (eg, chronic kidney disease, ischemic heart disease).[42]  Patients with resistant hypertension who have lower BP appear to have a reduced risk for some cardiovascular events (eg, incident stroke, coronary heart disease, or heart failure).[42]

Death from ischemic heart disease or stroke increases 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.[5]

Hypertensive retinopathy was associated with an increased long-term risk of stroke, even in patients with well-controlled BP, in a report of 2907 adults with hypertension participating in the Atherosclerosis Risk in Communities (ARIC) study.[43, 44] Increasing severity of hypertensive retinopathy was associated with an increased risk of stroke; the stroke risk was 1.35 in the mild retinopathy group and 2.37 in the moderate/severe group.

In a meta-analysis of pooled data from 19 prospective cohort studies involving 762,393 patients, Huang et al reported that, after adjustment for multiple cardiovascular risk factors, prehypertension was associated with a 66% increased risk for stroke, compared with an optimal blood pressure (< 120/80 mm Hg).[45, 46] Patients in the high range of prehypertension (130-139/85-89 mm Hg) had a 95% increased risk of stroke, compared with a 44% increased risk for those in the low range of prehypertension (120-129/80-84 mm Hg).[45, 46]

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%.[47]

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 the highest BP was compared to the lowest BP.[48] Multiple Risk Factor Intervention Trial (MRFIT) data showed that the relative risk for coronary artery disease mortality was 2.3 to 6.9 times higher for persons with mild to severe hypertension than it was for persons with normal BP.[49] The relative risk for stroke ranged from 3.6 to 19.2. The population-attributable risk percentage for coronary artery disease varied from 2.3 to 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.[50]

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 the NHANES I and III showed a decrease in mortality over time in hypertensive adults, but the mortality gap between hypertensive and normotensive adults remained high.[51]

Clinical trials have demonstrated the following benefits with antihypertensive therapy[5] :

• Average 35-40% reduction in stroke incidence

• Average 20-25% reduction in myocardial infarction

• Average >50% reduction in heart failure

Moreover, it is estimated that 1 death is prevented per 11 patients treated for stage 1 hypertension and other cardiovascular risk factors when a sustained reduction of 12 mm Hg in systolic BP over 10 years is achieved.[5] However, for the same reduction is systolic BP reduction, it is estimated that 1 death is prevented per 9 patients treated when cardiovascular disease or end-organ damage is present.[5]

Hypertension is a lifelong disorder. For optimal control, a long-term commitment to lifestyle modifications and pharmacologic 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: an increase in body mass index (BMI) and waist circumference is associated with an increased risk of developing conditions with high cardiovascular risk, such as hypertension, diabetes mellitus, impaired fasting glucose, and left ventricular hypertrophy (LVH)[52]

• Appropriate amounts of aerobic physical activity

• Diets low in salt, total fat, and cholesterol

• Adequate dietary intake of potassium, calcium, and magnesium

• Limited alcohol consumption

• Avoidance of cigarette smoking

• Avoidance of the use of illicit drugs, such as cocaine

Following the documentation of hypertension, which is confirmed after an elevated blood pressure (BP) on at least three separate occasions (based on the average of 2 or more readings taken at each of ≥2 follow-up visits after initial screening), a detailed history should extract the following information:

• Extent of end-organ damage (eg, heart, brain, kidneys, eyes)

• 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. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) identifies the following as targets of end-organ damage[5] :

• Heart: left ventricular hypertrophy, angina/previous myocardial infarction, previous coronary revascularization, and heart failure

• Brain: stroke or transient ischemic attack, dementia

• Chronic kidney disease

• Peripheral arterial disease

• Retinopathy

The JNC 7 identifies the following as major cardiovascular risk factors[5] :

• Hypertension: component of metabolic syndrome

• Tobacco use, particularly cigarettes, including chewing tobacco

• Elevated LDL cholesterol (or total cholesterol ≥240 mg/dL) or low HDL cholesterol: component of metabolic syndrome

• Diabetes mellitus: component of metabolic syndrome

• Obesity (BMI ≥30 kg/m2): component of metabolic syndrome

• Age greater than 55 years for men or greater than 65 years for women: increased risk begins at the respective ages; the Adult Treatment Panel III used earlier age cut points to suggest the need for earlier action

• Estimated glomerular filtration rate less than 60 mL/min

• Microalbuminuria

• Family history of premature cardiovascular disease (men < 55 years; women < 65 years)

• Lack of exercise

Obtain a history of the patient’s use of over-the-counter medications; herbal medicines such as herbal tea containing licorice (the issue is products containing licorice root; large amount of licorice in the US is licorice candy, but black licorice and over-the-counter licorice root supplements are increasingly available); ephedrine/ephedra; current and previous unsuccessful antihypertensive medication trials; oral contraceptives; ethanol; and illicit drugs such as cocaine. The patient’s lifestyle factors should also be included, such as changes in weight, dietary intake of sodium and cholesterol, exercise level, and psychosocial stressors.[7]

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.

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.[5, 7] 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.[53] "Nondipping" is the loss of the usual physiologic nocturnal drop in blood pressure and is associated with an increased cardiovascular risk.

A study by Wong and Mitchell indicated that independent of other risk factors, the presence of certain signs of hypertensive retinopathy (eg, retinal hemorrhages, microaneurysms, cotton-wool spots) is associated with an increased cardiovascular risk (eg, stroke, stroke mortality).[54]  Consequently, perform a funduscopic eye evaluation to identify any signs of early or late, chronic or acute hypertensive retinopathy, such as arteriovenous nicking or vessel wall changes (eg, copper/silver wiring, hard exudates, flame-shaped hemorrhages, papilledema). Acute or chronic ocular changes can be the initial finding in asymptomatic patients that requires a primary care referral. Alternatively, 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. In addition, examine the neck for carotid bruits, distended veins, or enlarged thyroid gland.[5, 7] 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.

Blood pressure is a powerful determinant of risk for ischemic stroke and intracranial hemorrhage; in fact, 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 are associated with a significant incidence of strokes. The American Heart Association notes that individuals whose blood pressure level is lower than 120/80 mm Hg have about 50% the lifetime stroke risk of that of hypertensive individuals.

The main pathologic findings are in the heart, which shows an increase in mass caused principally by left ventricular hypertrophy. Histologically, the individual myocytes are enlarged and show nucleomegaly (“box car” nuclei) (see the image below). Hearts that are enlarged secondary to hypertension have an increased incidence of arrhythmia and death. 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.

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 (eg, neurologic, cardiovascular). 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,[55] as well as acute myocardial infarction. Hypertension is also one of several conditions that have been increasingly recognized as having an association with posterior reversible encephalopathy syndrome (PRES), a condition characterized by headache, altered mental status, visual disturbances, and seizures.[56]

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 black 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. Note that BNP is inversely proportional to the degree of a patient’s obesity.[57]

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, although various health data showed a decreasing trend between 1963 and 1988, followed by an upward trend. Hypertension is now commonly discovered in children, and the long-term health risks to these children 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 cases of secondary hypertension are attributed to renovascular disease.

Hypertension is the most common medical problem encountered during pregnancy, complicating 2-3% of pregnancies.[58]

A large, population-based study compared 26,651 pregnant women with hypertensive disorders to 213,397 pregnant women without hypertensive disorders to determine risk of end-stage renal disease and found that the incidence of chronic kidney disease was almost 11-fold higher in the hypertensive group.[59] This group also exhibited a 14-fold increased risk for end-stage renal disease. The risk was much greater for women with preeclampsia or eclampsia.[60]

The American College of Obstetricians and Gynecologists (ACOG) recommends that women with prior preeclampsia who have delivered preterm (< 37.5 weeks) or who have a history of recurrent preeclampsia undergo yearly assessment of blood pressure, lipid profile, plasma glucose, and body weight.[61]

Mineralocorticoid excess secondary to primary hyperaldosteronism is characterized by excessive production of aldosterone. Previously considered a rare cause of hypertension, PA is now recognized to be the most common cause of secondary hypertension. Renal sodium retention, kaliuresis, hypokalemia, and hypochloremic metabolic alkalosis are the common manifestations. It should be considered in patients who have an exaggerated hypokalemic response to a thiazide diuretic or who have hypokalemia unprovoked by a diuretic. These patients develop increased intravascular volume, resulting in hypertension. Hypokalemia, however, is present in less than half of patients with PA, and thus the ratio of plasma aldosterone to renin activity should be used for screening of suspected cases. 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.

The incidence of primary hyperaldosteronism was 1.5% in one study.[11] However, the true incidence of primary aldosteronism has been estimated to be as high as 5-15% and is often associated with metabolic syndrome.[62] Related to this, obesity is increasingly associated with PA and treatment with aldosterone receptor antagonists have proven effective in this population.

In general, the evaluation of hypertension primarily involves accurately measuring the patient’s blood pressure, performing a focused medical history and physical examination, and obtaining results of routine laboratory studies.[5, 6] A 12-lead electrocardiogram should also be obtained. These steps can help determine the following[5, 6, 7] :

• Presence of end-organ disease

• Possible causes of hypertension

• Cardiovascular risk factors

• Baseline values for judging biochemical effects of therapy

In an analysis of 4388 patients enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) study, a prediction model based on Framingham Heart Study criteria was better than prehypertension at identifying young adults who went on to develop new hypertension in the following 25 years. The c index for incident hypertension was 0.84 using the Framingham prediction model and 0.71 using prehypertension.[64, 65]

Criteria used in the CARDIA prediction model included age, sex, body mass index (BMI), smoking, systolic blood pressure (BP), and parental history of hypertension. Prehypertension was defined as systolic BP 120-139 mm Hg or diastolic BP 80-89 mm Hg.

Pulse wave velocity appears to have the potential to predict the progression of BP and development of hypertension in young adults (age 30-45 years).[66]

Initial workup

Initial laboratory tests may include urinalysis; fasting blood glucose or A1c; hematocrit; serum sodium, potassium, creatinine (estimated or measured glomerular filtration rate [GFR]), and calcium; and lipid profile following a 9- to 12-hour fast (total cholesterol, high-density lipoprotein [HDL] cholesterol, low-density lipoprotein [LDL] cholesterol, and triglycerides). An increase in cardiovascular risk is associated with a decreased GFR level and with albuminuria.[5]

Assessment of suspected secondary causes

Other studies may be obtained on the basis of clinical findings or in individuals with suspected secondary hypertension and/or evidence of target-organ disease, such as complete blood count (CBC), chest radiograph, uric acid, and urine microalbumin.[5] Table 2, below, summarizes the Seventh Report of the Joint National Committee of Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) screening tests for specific identifiable causes of hypertension.

Table 2. Identifiable Hypertension and Screening Tests (Open Table in a new window)

Microalbuminuria is an early indication of diabetic nephropathy and is also a marker for a higher risk of cardiovascular morbidity and mortality. 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.[12]

Measurement of the ratio of aldosterone to plasma renin activity (PRA) is performed to detect evidence of primary hyperaldosteronism. A ratio of more than 20-30 is suggestive of this condition. Most antihypertensive medications can falsely raise or lower this ratio; thus, an appropriate washout period is necessary to obtain an accurate aldosterone-renin ratio.

As mentioned above, less than half of patients with PA have hypokalemia. However, an underlying secondary cause of hyperaldosteronism should be strongly suspected in patients with unprovoked hypokalemia or who exhibit an exaggerated hypokalemic response to a thiazide. It is important to note that aldosterone levels can be falsely low in the presence of hypokalemia. Hypokalemia and metabolic alkalosis are relatively late manifestations of primary hyperaldosteronism. 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 measured. If the PRA is high, the likely cause is estrogen therapy, renovascular hypertension, malignant hypertension, or salt-wasting renal disease (or blockade of the renin-angiotensin system—the far more common reason). In the presence of low PRA, the serum aldosterone level can be measured (aldosterone and renin should be measured together; separate measurements will lead to inaccuracy). A low aldosterone level indicates licorice ingestion or other mineralocorticoid ingestion. A high aldosterone level indicates primary hyperaldosteronism. A computed tomography 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.

Evaluation of hypertensive emergencies

Electrolytes, blood urea nitrogen (BUN), and creatinine levels are used to identify renal impairment. A complete blood cell (CBC) count and smear help 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 a toxicology screen, pregnancy test, and endocrine testing.

If the patient’s history suggests renal artery stenosis and if a corrective procedure is considered, further noninvasive radiologic investigations (eg, computed tomographic angiography [CTA], magnetic resonance angiography [MRA]) or invasive renal angiography can be performed.[5, 6, 67] Concern over the risk of nephrogenic systemic fibrosis (NSF) 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.

For more information on NSF and contrast-induced nephropathy, see the US Food and Drug Administration (FDA) Web page Information on Gadolinium-Based Contrast Agents[68] and the American College of Radiology’s (ACR) Manual on Contrast Media (version 7).

Digital subtraction angiography

Digital subtraction angiography (DSA) with arterial injection of radiocontrast dye is the criterion standard for the evaluation of renal and pulmonary causes of hypertension, but this modality carries the risk of dye nephropathy and atheroemboli in patients with diabetes or chronic kidney disease. Captopril radionuclide scanning imaging technique does not give anatomic detail and is less often used, but this study can provide important information regarding the functionality of renal artery stenosis in the absence of advanced chronic kidney disease.

Echocardiography

The main indication for echocardiography is evaluation for end-organ damage in a patient with borderline-high blood pressure (BP). Therefore, the presence of left ventricular hypertrophy (LVH) despite normal or borderline-high BP measurements requires antihypertensive therapy. Echocardiography may detect left atrial dilatation, LVH, and diastolic or systolic left ventricular dysfunction more frequently than electrocardiography. In addition, a stress echocardiogram can provide prognostic information in patients with hypertension and coronary artery disease (CAD).[69]

Effective management and treatment of hypertension requires clinicians and patients to work together to balance pharmacologic and nonpharmacologic interventions and prevent target organ damage.[3]

The 2016 American Diabetes Association's (ADA's) standards of medical care in diabetes indicate that a majority of patients with diabetes mellitus have hypertension. In patients with type 1 diabetes, nephropathy is often the cause of hypertension, whereas in type 2 diabetes, hypertension is one of a group of related cardiometabolic factors.[70, 71]  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 artery disease.

Other studies have demonstrated that a reduction in blood pressure (BP) may result in improved renal function. Therefore, earlier detection of hypertensive nephrosclerosis (using means to detect microalbuminuria) and aggressive therapeutic interventions (particularly with angiotensin-converting enzyme inhibitor drugs [ACEIs]) may prevent progression to end-stage renal disease.[12]

NOTE: A group was empaneled to write the Eighth Joint National Committee (JNC 8) guideline, but this effort was discontinued by the National Heart, Lung, and Blood Institute (NHLBI). A paper was published in The Journal of the American Medical Association in 2014 that is generally referred to as "JNC 8" but officially, there are no JNC 8 guidelines sanctioned by the NHLBI, nor has JNC 8 been endorsed by the American Heart Association (AHA), American College of Cardiology (ACC), or many other organizations that endorsed JNC 7. 

2017 ACC/AHA guidelines

The 2017 ACC/AHA guidelines eliminate the classification of prehypertension and divides it into two levels[1, 2] : (1) elevated BP, with a systolic pressure (SBP) between 120 and 129 mm Hg and diastolic pressure (DBP) less than 80 mm Hg, and (2) stage 1 hypertension, with an SBP of 130 to 139 mm Hg or a DBP of 80 to 89 mm Hg.

In adults at increased risk of heart failure (HF), the optimal BP in those with hypertension should be less than 130/80 mm Hg.

Adults with HFrEF (HF with reduced ejection fraction) and hypertension should be prescribed GDMT (guideline-directed management and therapy) titrated to attain a BP of less than 130/80 mm Hg.

Nondihydropyridine calcium channel blockers (CCBs) are not recommended in the treatment of hypertension in adults with HFrEF.

Adults with hypertension and chronic kidney disease (CKD) should be treated to a BP goal of less than 130/80 mm Hg.

After kidney transplantation, it is reasonable to treat patients with hypertension to a BP goal of less than 130/80 mm Hg. After kidney transplantation, it is reasonable to treat patients with hypertension with a calcium antagonist on the basis of improved glomerular filtration rate (GFR) and kidney survival.

Immediate lowering of SBP to lower than 140 mm Hg in adults with spontaneous intracerebral hemorrhage (ICH) who present within 6 hours of the acute event and have an SBP between 150 mm Hg and 220 mm Hg is not of benefit to reduce death or severe disability and can be potentially harmful.

Adults with acute ischemic stroke and elevated BP who are eligible for treatment with intravenous (IV) tissue plasminogen activator (tPA) should have their BP slowly lowered to below 185/110 mm Hg before thrombolytic therapy is initiated.

In adults with an acute ischemic stroke, BP should be less than 185/110 mm Hg before administration of IV tPA and should be maintained below 180/105 mm Hg for at least the first 24 hours after initiating drug therapy.

For adults who experience a stroke or transient ischemic attack (TIA), treatment with a thiazide diuretic, ACEI, or angiotensin receptor blocker (ARB), or combination treatment consisting of a thiazide diuretic plus ACEI, is useful.

In adults with an untreated SBP greater than 130 mm Hg but less than 160 mm Hg or a DBP greater than 80 mm Hg but less than 100 mm Hg, it is reasonable to screen for the presence of white coat hypertension by using either daytime ABPM (ambulatory BP monitoring) or HBPM (home BPM) before diagnosis of hypertension.

In adults with untreated office BPs that are consistently between 120 mm Hg and 129 mm Hg for SBP or between 75 mm Hg and 79 mm Hg for DBP, screening for masked hypertension with home BPM (or ABPM) is reasonable.

In adults with hypertension, screening for primary aldosteronism is recommended in the presence of any of the following concurrent conditions: resistant hypertension, hypokalemia (spontaneous or substantial, if diuretic induced), incidentally discovered adrenal mass, family history of early-onset hypertension, or stroke at a young age (< 40 years).

Adult men and women with elevated BP or hypertension who currently consume alcohol should be advised to drink no more than two and one standard drinks per day, respectively.

Two or more antihypertensive medications are recommended to achieve a BP target of less than 130/80 mm Hg in most adults with hypertension, especially in black adults with hypertension.

Women with hypertension who become pregnant should not be treated with ACEIs, ARBs, or direct renin inhibitors.

Use of BP-lowering medications is recommended for secondary prevention of recurrent cardiovascular disease (CVD) events in patients with clinical CVD and an average SBP of 130 mm Hg or higher or an average DBP of 80 mm Hg or higher, and for primary prevention in adults with an estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk of 10% or higher and an average SBP of 130 mm Hg or higher or an average DBP of 80 mm Hg or higher.

Use of BP-lowering medication is recommended for primary prevention of CVD in adults with no history of CVD and with an estimated 10-year ASCVD risk below 10% and an SBP of 140 mm Hg or higher or a DBP of 90 mm Hg or higher.

Adults with an elevated BP or stage 1 hypertension who have an estimated 10-year ASCVD risk below 10% should be managed with nonpharmacologic therapy and have a repeat BP evaluation within 3 to 6 months.

Adults with stage 1 hypertension who have an estimated 10-year ASCVD risk of 10% or higher should be managed initially with a combination of nonpharmacologic and antihypertensive drug therapy and have a repeat BP evaluation in 1 month.

For adults with a very high average BP (eg, SBP ≥180 mm Hg or DBP ≥110 mm Hg), evaluation followed by prompt antihypertensive drug treatment is recommended.

Simultaneous use of an ACE, ARB, and/or renin inhibitor is potentially harmful and is not recommended to treat adults with hypertension.

2017 ACP/AAFP guidelines

The American College of Physicians (ACP) and the American Academy of Family Physicians (AAFP) released their guidelines regarding hypertension in adults aged 60 years, including the following[72] :

• Clinicians should initiate treatment in patients aged 60 years or older who have persistent SBP at or above 150 mm Hg to achieve a target of less than 150 mm Hg to reduce the risk for stroke, cardiac events, and death.
• If patients 60 years or older have a history of stroke or transient ischemic attack or have high cardiovascular risk, physicians should consider starting or increasing drug therapy to achieve an SBP of less than 140 mm Hg to reduce the risk for stroke and cardiac events.
• Consider initiating or intensifying pharmacologic treatment in some adults aged 60 years or older at high cardiovascular risk based on individualized assessment, to achieve a target SBP of less than 140 mm Hg to reduce the risk for stroke and cardiac events. Factors include comorbidity, medication burden, risk of adverse events, and cost. Generally, increased cardiovascular risk includes known cardiovascular disease, diabetes, or chronic kidney disease with a glomerular filtration rate of less than 45 mL/min/1.73 m ².

Lifestyle modifications

Lifestyle modifications are essential for the prevention of high BP, and these are generally the initial steps in managing hypertension. As the cardiovascular disease risk factors are assessed in individuals with hypertension, pay attention to the lifestyles that favorably affect 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 BP and a possibly significant (17%) reduction in future adverse cardiovascular events if at least one antihypertensive medication is taken at bedtime.

In a study that attempted to formulate a predictive model for the risk of prehypertension and hypertension, as well as an estimate of expected benefits from population-based lifestyle modification, investigators reported that the majority of risk factors have a larger role in prehypertension and stage 1 hypertension than in stage 2 hypertension. The investigators derived multistep composite risk scores by assessing significant risk factors in the progression from prehypertension to hypertension, as well as the regression of prehypertension to normal; they indicated that as the number of risk factors included in intervention programs increases, the size of the expected mean risk score decreases. In men, the 5-year predicted cumulative risk for stage 2 hypertension decreased from 23.6% (in the absence of an intervention program) to 14% (with 6-component intervention); the results were similar in women.

Cholesterol level targets

The top 10 key recommendations from the AHA, ACC, and multiple other medical societies for reducing the risk of ASCVD through cholesterol management are summarized below.[73, 74]

• Emphasize a heart-healthy lifestyle across the life course of all individuals.
• In patients with clinical ASCVD, reduce low-density lipoprotein cholesterol (LDL-C) levels with high-intensity statin therapy or the maximally tolerated statin therapy.
• In individuals with very high-risk ASCVD, use an LDL-C threshold of 70 mg/dL (1.8 mmol/L) to consider the addition of nonstatins to statin therapy.
• In patients with severe primary hypercholesterolemia (LDL-C level ≥190 mg/dL [≥4.9 mmol/L]), without calculating the 10-year ASCVD risk, begin high-intensity statin therapy.
• In patients 40 to 75 years of age with diabetes mellitus and an LDL-C level of ≥70 mg/dL: Start moderate-intensity statin therapy without calculating their 10-year ASCVD risk.
• In patients aged 40 to 75 years evaluated for primary ASCVD prevention: Have a clinician–patient risk discussion before starting statin therapy.
• Assess patient adherence and the percentage response to LDL-C–lowering medications and lifestyle changes with a repeat lipid measurement 4-12 weeks after initiation of statin therapy or dose adjustment; repeat every 3-12 months as needed.

In nondiabetic patients aged 40 to 75 years and with the following characteristics[73, 74] :

• LDL-C levels ≥70 mg/dL (≥1.8 mmol/L), at a 10-year ASCVD risk of ≥7.5%: Start a moderate-intensity statin if a discussion of treatment options favors statin therapy.

• A 10-year risk of 7.5-19.9% (intermediate risk): Risk-enhancing factors favor initiation of statin therapy.

• LDL-C levels ≥70-189 mg/dL (≥1.8-4.9 mmol/L), at a 10-year ASCVD risk of ≥7.5-19.9%: If a decision about statin therapy is uncertain, consider measuring coronary artery calcium (CAC) levels.

 

The American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) now recommend LDL goals of < 55 mg/dL, < 70 mg/dL, < 100 mg/dL, and < 130 mg/dL for individuals at extreme, very high, high/moderate, and low risk for cardiovascular events, respectively, as outlined below.[75]  

Extreme-risk patients: Goals: LDL < 55 mg/dL, non-HDL < 80 mg/dL, apolipoprotein B (apoB) < 70 mg/dL

• Progressive ASCVD, including unstable angina, in patients after achieving an LDL-C < 70 mg/dL

• Established clinical cardiovascular disease in patients with diabetes, chronic kidney disease (CKD) stages 3/4, or heterozygous familial hypercholesterolemia (HeFH)

• History of premature ASCVD (< 55 yr of age in men, < 65 in women)

Very-high-risk patients: Goals: LDL < 70 mg/dL, non-HDL < 80 mg/dL, apoB < 80 mg/dL

• Established or recent hospitalization for acute coronary syndrome; coronary, carotid, or peripheral vascular disease; 10-y risk >20%

• Diabetes or CKD stages 3/4 with one or more risk factors

• HeFH

High-risk patients: Goals: LDL < 100 mg/dL, non-HDL < 130 mg/dL, apoB < 90 mg/dL

• Two or more risk factors and 10-year risk 10-20%

• Diabetes or CKD stages 3/4 with no other risk factors

Moderate-risk patients: Goals: Same goals as high risk

• Two or more risk factors and 10-y risk < 10%

Low-risk patients: Goals: LDL < 130 mg/dL, non-HDL < 160 mg/dL, apoB not relevant

• 0 risk factors

Surgical intervention

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 and for patients with a unilateral solitary aldosterone-producing adenoma, because hypertension is cured by tumor resection. Of note, patients with benign adenomas may be able to be treated with spironolactone instead of surgery. In patients with fibromuscular renal artery disease, angioplasty has a 60-80% success rate for improvement or cure of hypertension. Another intervention that initially seemed to hold great promise for the treatment of resistant hypertension is renal artery denervation. However, more recent controlled studies have suggested little benefit on BP from percutaneous renal denervation therapy, and ongoing studies are testing this intervention using newer techniques.[76]

Consultations

Consultations with a nutritionist and exercise specialist are often helpful in changing lifestyle and initiating weight loss. Consultation with a hypertension specialist is indicated for management of secondary hypertension attributable to a specific cause.

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 BP by 2-8 mm Hg.[8, 77]

One randomized controlled trial published found that moderate dietary sodium reduction (about 2500 mg Na+ or 6 g NaCl per day) added to angiotensin-converting enzyme (ACE) inhibition was more effective than dual blockade (ACE inhibitor [ACEI] and angiotensin II receptor blocker [ARB]) in reducing both proteinuria and BP in nondiabetic patients with modest chronic kidney disease. Furthermore, a low-sodium diet added to dual therapy yielded additional reductions in both BP and proteinuria, emphasizing the beneficial effect of dietary salt reduction in the management of hypertensive patients with renal insufficiency.

The 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. 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.[71, 78]

Dietary potassium, calcium, and magnesium consumption have an inverse association with BP. Lower intake of these elements potentiates the effect of sodium on BP. Oral potassium supplementation may lower both systolic and diastolic BP.[79] Calcium and magnesium supplementation have elicited small reductions in BP.

In population studies, low levels of alcohol consumption have shown a favorable effect on BP, with reductions of 2-4 mm Hg. However, the consumption of 3 or more drinks per day is associated with elevation of BP. Daily 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.[71, 78]

Emerging evidence based on small randomized controlled trials suggests that dark chocolate may lower BP via improved vascular endothelial function and increased formation of nitric oxide. A meta-analysis of 13 randomized controlled trials that compared dark chocolate with placebo confirmed a significant mean SBP reduction of -3.2 mm Hg and DBP reduction of -2 mm Hg in hypertensive and prehypertensive subgroups.[80] However, several important questions needs to be answered before dark chocolate can be universally recommended as a lifestyle intervention.

Although many studies implicate a high fructose diet as a contributing factor to the metabolic syndrome and hypertension, a 2012 review of Cochrane database disputed this relationship.[81]

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 whose weight is 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.[5] These activities include brisk walking for 30 minutes a day, 5 days per week. More intense workouts of 20-30 minutes, 3-4 times a week, may also lower BP and have additional health benefits.[5]

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.[82] The trial showed that after 4 months, clinic-measured BP was reduced by 16.1/9.9 mm Hg in patients in the DASH-plus-weight management group; by 11.2/7.5 mm Hg in the DASH-alone group; and by 3.4/3.8 mm Hg 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.[82]

The 2016 and 2017 ADA diabetes standards support increasing physical activity. The recommendations emphasize that exercise is an important part of diabetes management in addition to reducing cardiovascular risk factors, contributing to weight loss, and improving overall well-being.[71, 83]  Moreover, patients with diabetes and severe hypertension (SBP ≥140 mm Hg or DBP ≥90 mm Hg) at diagnosis or afterward should receive drug therapy along with lifestyle modifications.[71, 83]

In 2018, the Physical Activity Guidelines Advisory Committee of the US Department of Health and Human Services (HHS) released their key recommendations, including the following[84, 85] :

• Regular physical activity minimizes excessive weight gain, helps maintain weight within a healthy range, improves bone health, and prevents obesity, even in children as young as 3-5 years.

• In pregnant women, physical activity helps reduce excessive weight gain in pregnancy and helps reduce the risk of developing gestational diabetes and postpartum depression.

• Regular physical activity has been shown to improve cognitive function and to reduce the risk of dementia; falls and fall-related injuries; and cancers of the breast, esophagus, colon, bladder, lung, endometrium, kidney, and stomach. It also helps retard the progression of osteoarthritis, type 2 diabetes, and hypertension.

• Children aged 3-5 years: Should be physically active throughout the day to enhance growth and development.

• Children aged 6-17 years: Sixty minutes or more of moderate-to-vigorous physical activity per day.

• Adults: At least 150-300 minutes per week of moderate-intensity aerobic physical activity, OR 75-150 minutes per week of vigorous-intensity aerobic physical activity, OR an equivalent combination of moderate- and vigorous-intensity aerobic activity; muscle-strengthening activities should be performed on two or more days per week.

• Older adults: Multicomponent physical activity to include balance training, aerobic activity, and muscle-strengthening activity.

• Pregnant and postpartum women: At least 150 minutes of moderate-intensity aerobic activity weekly.

• Adults with chronic conditions or disabilities who are able: Follow key guidelines and perform both aerobic and muscle-strengthening activities.

If lifestyle modifications are insufficient to achieve the goal blood pressure (BP), there are several drug options for the treatment and management of hypertension. Based on the Seventh Report of the Joint National Committee of Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) and the 2010 Institute for Clinical Systems Improvement (ICSI) guideline on the diagnosis and treatment of hypertension recommendations, thiazide diuretics were the preferred initial agents in the absence of compelling indications.[5]

However, the updated JNC 8 guidelines no longer recommend only thiazide-type diuretics as the initial therapy in most patients. According to the JNC 8 guidelines, angiotensin-converting enzyme inhibitors [ACEIs] /angiotensin receptor blockers [ARBs], calcium channel blockers [CCBs], and thiazide diuretics are equally efficacious in hypertensive non-black populations, whereas CCBs and thiazide diuretics are favored in black patients with hypertension.[10]

Compelling indications may include high-risk conditions that can be direct sequelae of hypertension (heart failure, ischemic heart disease, chronic kidney disease, recurrent stroke) or that are commonly associated with hypertension (diabetes, high coronary disease risk), as well as drug intolerability or contraindications.[5] In such compelling cases, another class of drugs should be initiated. An ACEI, ARB, and CCB are all acceptable alternative agents. Beta-blockers are no longer considered first-line therapy for hypertension, but these agents can be used in cases with compelling indications aside from hypertension, such as systolic heart failure. There are several opinions regarding which antihypertensive agents to use initially, because some patients may respond to a therapy that others may not.

The following are drug class recommendations for compelling indications based on various clinical trials[5] :

• Heart failure: Diuretic, beta-blocker, ACEI/ARB, aldosterone antagonist

• Following myocardial infarction: Beta-blocker, ACEI

• Diabetes: ACEI/ARB

• Chronic kidney disease: ACEI/ARB

Note that different stages of these diseases may alter their treatment management.

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 that older drugs (eg, diuretics, beta-blockers) and newer antihypertensive agents (eg, ACEIs, CCBs) have similar results.

In addition, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study concluded that there were no differences in primary coronary heart disease outcome or mortality for the thiazide-like diuretic chlorthalidone, the ACEI lisinopril, and the CCB amlodipine.[5] In a systematic review and meta-analysis, investigators also determined that in patients with essential hypertension without preexisting renal disease, no significant difference was found between Ras inhibitors and other antihypertensive agents in preventing renal dysfunction.

A post hoc analysis of data from the randomized ACCOMPLISH trial concluded that benazepril plus amlodipine (B+A) was more effective than benazepril plus hydrochlorothiazide (B+H) in reducing cardiovascular events in adults with high-risk stage 2 hypertension and coronary artery disease (CAD).[86, 87]

In this study, 5314 patients with CAD and 6192 without CAD were given B+A or B+H. Among patients with CAD, the incidence of cardiovascular events was 16% with B+H and 13% with B+A, a hazard reduction of 18% (P = 0.0016).[86, 87] The composite secondary endpoint of cardiovascular mortality, myocardial infarction, and stroke occurred in significantly fewer B+A patients than B+H patients (5.74% vs 8%; P = 0.033). All-cause mortality was 23% lower in the B+A arm (P = 0.042).

Single agent versus multiagent treatment approach

Over 50% of patients with hypertension will require more than one drug for blood pressure control.[7] In stage 1 hypertension, a single agent is generally sufficient to reduce BP, whereas in stage 2, a multidrug approach may be needed. Initiation of 2 antihypertensive agents, either as 2 separate prescriptions or as a fixed-dose combination, should also be considered when BP is more than 20 mm Hg above the systolic goal (or 10 mm Hg above the diastolic goal).[5]

Several situations demand the addition of a second drug, because 2 drugs may be used at lower doses to avoid the adverse effects that may occur with higher doses of a single agent. Diuretics generally potentiate the effects of other antihypertensive drugs by minimizing volume expansion. Specifically, the use of a thiazide diuretic in conjunction with a beta-blocker or an ACEI has an additive effect, controlling BP in up to 85% of patients.

The ALTITUDE trial was halted because it was shown that aliskiren can cause adverse events—nonfatal stroke, renal complications, hyperkalemia, and hypotension—when used in combination with an ACEI or an ARB in patients with type 2 diabetes and renal impairment who are at high risk of cardiovascular and renal events.

Hypertension is not only disproportionately high in diabetic individuals, but it also increases the risk of diabetes 2.5 times within 5 years in hypertensive patients.[5] In addition, hypertension and diabetes are both risk factors for cardiovascular disease, stroke, progression of renal disease, and diabetic retinopathy.[5]

For patients aged 18 years or older with diabetes, the 2013 Eighth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure ("JNC 8") recommends initiating treatment at systolic blood pressure (SBP) levels of 140 mm Hg or greater or at diastolic BP (DBP) levels of 90 mm Hg or greater, and then treat to a goal BP below 140/90 mm Hg.[88, 89]

The JNC 7 and the 2016 American Diabetes Association (ADA) standard of medical care recommended blood pressure control in diabetic individuals be controlled to 130/80 mm Hg or lower, primarily to prevent or lower the risk of progression from diabetic nephropathy to end-stage renal disease.[5, 71]

This notion is being challenged by data from the ACCORD trial, which showed that in patients with type 2 diabetes, targeting an SBP of less than 120 mm Hg compared with less than 140 mm Hg did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events.[90] A total of 4733 patients with type 2 diabetes were randomly assigned to intensive therapy or standard therapy, with a mean SBP of 119.3 mm Hg in the intensive group and 133.5 mm Hg in the standard group. No difference was observed in terms of primary outcome (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) and no difference was noted in annual rates of death from any cause.

However, annual rates of stroke, a prespecified secondary outcome, were significantly reduced in the intensive therapy group (0.32% vs 0.53%). Serious adverse events attributed to antihypertensive treatment was significantly greater in the intensive therapy group (3.3% vs 1.3%). Thus, other than a minor decrease in stroke rate, intensive BP control in diabetes did not improve outcome and was associated with a greater rate of serious adverse events.

In general, patients with diabetes type 1 or type 2 and hypertension have shown clinical improvement with diuretics, angiotensin-converting enzyme inhibitors (ACEIs), beta-blockers, angiotensin receptor blockers (ARBs), and calcium antagonists.[5] Most studies, however, have shown superiority of ACEIs or ARBs over calcium antagonists in diabetic patients. A notable exception is the ACCOMPLISH trial, which showed that, in patients at high risk for cardiovascular events, the combination of benazepril (an ACEI) and amlodipine (a CCB), was superior to the combination of benazepril plus hydrochlorothiazide (a thiazide diuretic).[91] About 60% of the patient cohort had diabetes.

Two or more antihypertensive drugs at maximal doses should be used to achieve optimal BP targets in patients with diabetes and hypertension.[71] Either an ACEI 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 BP goals, a thiazide diuretic is indicated for those patients with an estimated GFR of 30 mL/min/1.73 m2 or greater, and a loop diuretic is indicated for those with an estimated GFR of less than 30 mL/min/1.73 m2. Regardless of which antihypertensive drugs are used, kidney function and serum potassium levels should be monitored.[71]

In a subgroup analysis from the TRINITY study (TRIple therapy with olmesartan medoxomil, amlodipine, and hydrochlorothiazide in hyperteNsive patienTs studY), Chrysant et al reported that in patients with hypertension and diabetes, triple-combination drug therapy resulted in greater BP reductions and BP-goal achievement (< 130/80 mm Hg) than dual-combination drug therapy. The triple-combination regimen consisted of olmesartan medoxomil, 40 mg; amlodipine besilate, 10 mg; and hydrochlorothiazide, 25 mg.

Ruggenenti et al found that in patients with type 2 diabetes who have hypertension, combined manidipine and delapril therapy helped improve health in patients with cardiovascular disease, retinopathy, and neuropathy, as well as stabilized insulin sensitivity.[92] However, neither of these agents are available in the US.

A randomized, placebo-controlled study of 119 patients demonstrated that adding spironolactone to existing treatment in patients with resistant hypertension and diabetes mellitus significantly lowered blood pressure. Systolic and diastolic blood pressure were each significantly reduced in the spironolactone group and unchanged in the placebo group at 4 months.[93]

In a study that evaluated BP pattern changes during the development of hypertension in patients with or without diabetes mellitus using data from the Mexico City Diabetes Study (MCDS) and the Framingham Offspring Study (FOS), investigators found that although baseline diabetes mellitus was a significant predictor of incident hypertension, baseline hypertension was an independent predictor of incident diabetes mellitus. They indicated that development of hypertension and diabetes mellitus track each other over time; transition from normotension to hypertension was characterized by a sharp increase in BP values; and insulin resistance was not only a common feature of prediabetes and prehypertension, but it was also an antecedent of progression to the two respective disease states.[94]

2017 ADA guidelines

The ADA released updated guidelines in 2017, as follows[83] :

Blood pressure should be measured at every routine clinical care visit. Patients found to have an elevated blood pressure (≥140/90 mm Hg) should have blood pressure confirmed using multiple readings, including measurements on a separate day, to diagnose hypertension.

All hypertensive patients with diabetes should have home blood pressure monitored to identify white coat hypertension.

Orthostatic measurement of blood pressure should be performed during initial evaluation of hypertension and periodically at follow-up, or when symptoms of orthostatic hypotension are present, and regularly if orthostatic hypotension has been diagnosed.

Most patients with diabetes and hypertension should be treated to a systolic blood pressure goal of < 140 mm Hg and a diastolic blood pressure goal of < 90 mm Hg.

Lower systolic and diastolic blood pressure targets, such as < 130/80 mm Hg, may be appropriate for individuals at high risk of cardiovascular disease if they can be achieved without undue treatment burden.

For patients with systolic blood pressure >120 mm Hg or diastolic blood pressure >80 mm Hg, lifestyle intervention consists of weight loss if overweight or obese; a Dietary Approaches to Stop Hypertension (DASH)-style dietary pattern, including reduced sodium and increased potassium intake; increased fruit and vegetable consumption; moderation of alcohol intake; and increased physical activity.

Patients with confirmed office-based blood pressure ≥140/90 mm Hg should, in addition to lifestyle therapy, have timely titration of pharmacologic therapy to achieve blood pressure goals.

Patients with confirmed office-based blood pressure ≥160/100 mm Hg should, in addition to lifestyle therapy, have prompt initiation and timely titration of 2 drugs or a single-pill combination of drugs demonstrated to reduce cardiovascular events in patients with diabetes.

Treatment for hypertension should include drug classes demonstrated to reduce cardiovascular events in patients with diabetes: ACEIs, ARBs, thiazide-like diuretics, or dihydropyridine calcium channel blockers. Multiple-drug therapy is generally required to achieve blood pressure targets (but not a combination of ACEIs and ARBs).

An ACEI or ARB, at the maximum tolerated dose indicated for blood pressure treatment, is the recommended first-line treatment for hypertension in patients with diabetes and urine albumin-to-creatinine ratio ≥300 mg/g creatinine or 30–299 mg/g creatinine. If one class is not tolerated, the other should be substituted.

For patients treated with an ACEI, ARB, or diuretic, serum creatinine/estimated glomerular filtration rate and serum potassium levels should be monitored.

Pregnant women with diabetes and preexisting hypertension or mild gestational hypertension with systolic blood pressure < 160 mm Hg, diastolic blood pressure < 105 mm Hg, and no evidence of end-organ damage do not need to be treated with pharmacologic antihypertensive therapy.

In pregnant patients with diabetes and preexisting hypertension who are treated with antihypertensive therapy, systolic or diastolic blood pressure targets of 120–160/80–105 mm Hg are suggested in the interest of optimizing long-term maternal health and fetal growth.

Hypertensive emergencies are characterized by severe elevations in blood pressure (BP) (>180/120 mm Hg) associated with acute end-organ damage.[5] Examples include hypertensive encephalopathy, intracerebral hemorrhage, acute myocardial infarction, acute left ventricular failure with pulmonary edema, aortic dissection, unstable angina pectoris, eclampsia,[5] or posterior reversible encephalopathy syndrome (PRES) (a condition characterized by headache, altered mental status, visual disturbances, and seizures).[56] Patients with hypertensive emergencies should be monitored and managed in an intensive care unit.[33, 95]

The primary goal of the physician is to determine which patients with acute hypertension are exhibiting symptoms of end-organ damage and require immediate intravenous parenteral antihypertensive therapy. That is, the fundamental principle in determining the necessary emergent care of the hypertensive patient is the presence or absence of end-organ dysfunction.

Initial treatment goals are to reduce the mean arterial BP by no more than 25% within minutes to 1 hour. If the patient is stable, reduce the BP to 160/100-110 mm Hg within the next 2-6 hours.[5] Several parenteral and oral therapies can be used to treat hypertensive emergencies, such as nitroprusside sodium, hydralazine, nicardipine, fenoldopam, nitroglycerin, or enalaprilat. Other agents that may be used include labetalol, esmolol, and phentolamine.[5] Avoid using short-acting nifedipine in the initial treatment of this condition because of the risk of rapid, unpredictable hypotension and the possibility of precipitating ischemic events.[5] Once the patient’s condition is stabilized, the patient’s BP may be gradually reduced over the next 24-48 hours.

Exceptions to the above recommendation include the following[5] :

• Patients with an ischemic stroke (currently, no clear evidence exists for immediate antihypertensive treatment)

• Patients with aortic dissection (their systolic BP should be lowered to < 100 mm Hg, if tolerated)

• Patients in whom BP is lowered to allow thrombolytic therapy (eg, stroke patients)

Approximately 3-45% of adult patients presenting to an emergency department have at least one increased BP during their stay in the ED, but only a small percentage of patients will require emergency treatment. However, medical therapy and close follow-up are necessary in patients who present to the ED with acutely elevated BPs (systolic BP >200 mm Hg or diastolic BP >120 mm Hg) that remain significantly elevated until discharge.[96]

Guidelines recommendations

The 2017 American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommendations for hypertensive crises and emergencies include the following[1] :

• Admit adults with a hypertensive emergency to an ICU for continuous monitoring of BP and target organ damage, as well as for parenteral administration of an appropriate medication.
• For adults with a compelling condition (ie, aortic dissection, severe preeclampsia or eclampsia, or pheochromocytoma crisis), lower SBP to below 140 mm Hg during the first hour and to below 120 mm Hg in aortic dissection.
• For adults without a compelling condition, reduce the SBP to a maximum of 25% within the first hour; then, if the patient is clinically stable, lower the BP to 160/100 -110 mm Hg over the next 2-6 hours, and then cautiously to normal over the following 24-48 hours.

For further information, see the Medscape Drugs & Diseases article Hypertensive Emergencies in Emergency Medicine.

In patients who are pregnant, the goal of antihypertensive treatment is to minimize the risk of maternal cardiovascular or cerebrovascular events. Hypertensive disorders—categorized as chronic hypertension, preeclampsia, chronic hypertension with superimposed preeclampsia, gestational hypertension, and transient hypertension (see Table 3, below)— may contribute to maternal, fetal, or neonatal morbidity and mortality, particularly in the first trimester.[5]

Table 3. Hypertensive Disorders in Pregnancy (Open Table in a new window)

In normal pregnancy, women’s mean arterial pressure (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 BP 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.

Lifestyle modifications are generally sufficient for the management of pregnant women with stage 1 hypertension who are at low risk for cardiovascular complications during pregnancy.[4] Restrictions to lifestyle modifications may include aerobic exercise (theoretical increased preeclampsia risk from inadequate placental blood flow) and weight reduction, even in obese pregnant women. Reduction of sodium intake and avoidance of tobacco and alcohol use are similar to those for individuals with primary hypertension.[5]

Although the primary risk of chronic hypertension in pregnancy is development of superimposed preeclampsia, no evidence suggests that pharmacologic treatment of mild hypertension reduces the incidence of preeclampsia in this population.

Antihypertensive therapy should be started in pregnant women 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 of less than 160 mm Hg.

Women who have preexisting end-organ damage from chronic hypertension or who have previously required multidrug therapy for BP control should have a lower threshold for starting antihypertensive medication (ie, >139/89 mm Hg) and a lower target BP (< 140/90 mm Hg). The JNC 7 recommendations are to continue antihypertensive medication as needed to control BP and to reinstate antihypertensive therapy when the SBP is 150-160 mm Hg or the DBP is 100-110 mm Hg.

Selection of antihypertensive medication

Although reducing maternal risk is the goal of treating chronic hypertension in pregnancy, it is fetal safety that largely directs the choice of antihypertensive agent. Methyldopa is generally the preferred first-line agent because of its safety profile.[5] Other drugs that may be considered include labetalol, beta-blockers, and diuretics. Data are limited regarding the use of clonidine and calcium antagonists in pregnant women with chronic hypertension; however, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor (ARB) antagonists should be avoided because of the risk of fetal toxicity and death.[5]

For further information, see the Medscape Drugs & Diseases articles Hypertension and Pregnancy, Preeclampsia, and Eclampsia.

According to Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), pediatric hypertension is defined as high blood pressure (BP) that persists on repeated measurements, at the 95th percentile or higher for age, height, and sex.[5] More cases of chronic hypertension are seen in children who are obese, have inactive lifestyles, or have a family history of hypertension or cardiovascular disease.[5]

Guidelines recommendations

The 2017 American College of Cardiology/American Heart Association (ACC/AHA) guidelines updated their definitions of BP categories and stages.[97]

In children up to age 13 years, BP categories and stages are defined as follows:

• Normal BP: Below 90th percentile
• Elevated BP: From the 90th percentile or higher to less than the 95th percentile or 120/80 mm Hg to below the 95th percentile (whichever is lower) 
• Stage 1 hypertension: From the 95th percentile or higher to less than the 95th percentile plus 12 mm Hg, or 130/80 to 139/89 mm Hg (whichever is lower) 
• Stage 2 hypertension: The 95th percentile or higher plus 12 mm Hg, or 140/90 mm Hg or higher (whichever is lower)

In children aged 13 years or older, BP categories and stages are defined as follows:

• Normal BP: SBP Less than 120 mm Hg and DBP less than 80 mm Hg (ie, < 120/< 80 mm Hg)
• Elevated BP: 120/below 80 mm Hg to 129/below 89 mm Hg (ie, 120/< 80 to 129/< 80 mm Hg)
• Stage 1 hypertension: 130/80 to 139/89 mm Hg
• Stage 2 hypertension: At 140/90 mm Hg or higher (≥140/90 mm Hg)

The 2017 American Academy of Pediatrics (AAP) recommendations include the following[97] :

• Measure BP yearly in all children and adolescents aged 3 years and older.
• Evaluate BP in all children and adolescents aged 3 years and older at every healthcare visit if they are obese, are taking medications known to increase BP, have renal disease, or a history of aortic arch obstruction or coarctation, or diabetes.
• Trained clinicians in the office setting should make a hypertension diagnosis children or adolescents in the presence of auscultatory-confirmed BP readings at or over the 95th percentile for age and height at three separate visits.
• Perform ambulatory BP monitoring (ABPM) to confirm hypertension in children and adolescents with elevated BP measurements for 1 year or longer or with stage 1 hypertension over three clinic visits.
• Perform ABPM in children and adolescents with suspected white coat syndrome; the diagnosis is based on a mean systolic BP (SBP) and diastolic BP below the 95th percentile and an SBP and DBP load less than 25%.
• Children and adolescents aged 6 years and older do not need to undergo extensive evaluation for secondary causes of hypertension if there is a family history of hypertension, they are overweight/obese, and/or do not have a history or physical examination findings suggestive of a secondary cause of hypertension.
• In children and adolescents undergoing evaluation for high BP, obtain a perinatal history, appropriate nutritional history, physical activity history, psychosocial history, and family history, as well as perform a physical examination to identify findings suggestive of secondary causes of HTN.
• At the time when pharmacologic therapy for hypertension is being considered, perform echocardiography to evaluate for cardiac target organ damage (LV mass, geometry, and function).
• Hypertensive children and adolescents being evaluated for left ventricular hypertrophy (LVH) should not undergo electrocardiography.
• LVH should be defined as an LV mass greater than 51 g/m ² (males and females) for children and adolescents older than age 8 years and defined by an LV mass greater than 115 g/body surface area (BSA) (boys) or more than 95 g/BSA (girls).
• Screening Doppler renal ultrasonography may be used to assess for potential renal artery stenosis (RAS) in normal weight children and adolescents age 8 years and older with suspected renovascular hypertension
• Routine testing for microalbuminuria is not recommended for children and adolescents primary hypertension.
• Nonpharmacologic and pharmacologic treatment goals in children and adolescents diagnosed with hypertension should be a reduction in SBP and DBP to below the 90th percentile and less than 130/80 mm Hg in adolescents aged 13 years and older.
• Failure of lifestyle modifications in hypertensive children and adolescents (especially those with LVH on echocardiography, symptomatic hypertension, or stage 2 hypertension without a clearly modifiable factor) should prompt initiation of pharmacotherapy with an angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), long-acting calcium channel blocker (CCB), or thiazide diuretic.
• Evaluate children and adolescents with chronic kidney disease (CKD) for hypertension at each medical encounter. In the presence of both CKD and hypertension, treat to lower the 24-hour mean arterial pressure (MAP) below the 50th percentile by ABPM. Regardless of apparent BP control with office measures, assess BP by ABPM at least yearly to screen for masked hypertension in children and adolescents with both CKD and hypertension.
• Evaluate for proteinuria in children and adolescents with both CKD and hypertension. If all three conditions are present, treat with an ACEI or ARB.
• Evaluate children and adolescents with type 1 or 2 diabetes for hypertension at each medical encounter. Treat if the BP is at or over the 95th percentile or more than 130/80 mm Hg in adolescents aged 13 years and older.

Lifestyle interventions should be initiated in all hypertensive children. When lifestyle modifications are inadequate for BP control or are unsuccessful in patients with more elevated BP, pharmacologic therapy must be considered.[5]  In general, the selection of antihypertensive agents in children is similar to that in adults, but the doses are smaller and must be closely titrated. Extreme cautions are necessary with antihypertensive therapy in sexually active teenage girls and in those who are pregnant; ACEI and ARBs should not be used.

Continuous IV infusions are the most appropriate initial therapy in acutely ill infants with severe hypertension. The advantages of IV infusions are numerous; the most important advantage is 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, care must be taken to avoid too rapid a reduction in BP, so as to avoid cerebral ischemia and hemorrhage. Premature infants, in particular, are already at 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.

In a large study that evaluated the incidence of hypertension, associated risk factors, and the use of antihypertensive drugs in the neonatal intensive care unit (NICU) setting, the risk for hypertension was found to be greatest in neonates with a high severity of illness assessment, extracorporeal membrane oxygenation (ECMO), coexisting renal disorder, and renal failure.[98] Nearly 58% of infants received antihypertensive therapy, with a median duration of 10 days, and 45% received more than one agent. The most common antihypertensive drugs were vasodilators (64.2% of hypertensive neonates), followed by ACEIs (50.8%), calcium channel blockers (24%), and alpha- and beta-blockers (18.4%).[98]

For further information, see the Medscape Drugs & Diseases article Pediatric Hypertension.

2017 ACP/AAFP guidelines

The American College of Physicians (ACP) and American Academy of Family Physicians (AAFP) released updated guidelines on the pharmacologic treatment of hypertension in adults aged 60 years and older in January 2017.[72, 99]  A few of their recommendations are outlined below.

Clinicians should initiate treatment in patients aged 60 years or older who have persistent systolic blood pressure (SBP) at or above 150 mm Hg to achieve a target of below 150 mm Hg to reduce the risk for stroke, cardiac events, and death.

If patients 60 years or older have a history of stroke or transient ischemic attack or have a high cardiovascular risk, physicians should consider starting or increasing drug therapy to achieve an SBP of less than 140 mm Hg to reduce the risk for stroke and cardiac events.

Consider initiating or intensifying pharmacologic treatment in some adults aged 60 years or older at high cardiovascular risk based on an individualized assessment, to achieve a target SBP of below 140 mm Hg to reduce the risk of stroke or cardiac events. Factors include comorbidity, medication burden, risk of adverse events, and cost. Generally, an increased cardiovascular risk includes known cardiovascular disease, diabetes, or chronic kidney disease with a glomerular filtration rate (GFR) of less than 45 mL/min/1.73 m2.

2014 "JNC 8" guidelines

The Eighth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8) recommends for patients aged 60 years or older, initiate therapy in those who have SBP levels at 150 mm Hg or greater or whose diastolic BP levels are 90 mm Hg or greater and to treat to below those thresholds.[88, 89] These guideline recommendations are based on the results of several trials demonstrating a lack of benefit for a more stringent SBP goal than 140 mm Hg.[100, 101] However, more recently, this has been challenged by results of the Systolic Blood Pressure Intervention Trial (SPRINT) study, particularly a prespecified subgroup analysis in elderly patients older than 75 years who exhibited reduced overall mortality with an SBP target less than 120 mm Hg rather than 140 mm Hg.[102] Although the results of the SPRINT substudy are intriguing, more research will be necessary to determine the optimal BP targets in the elderly, particularly those with diabetes or prior stroke, who were excluded from the SPRINT trial.

The classic trials for treatment of isolated systolic hypertension in the elderly are the Systolic Hypertension in the Elderly Program (SHEP)[103] and the Systolic Hypertension in Europe (Syst-EUR)[104] studies. Systolic pressure continues to rise progressively throughout life, reaching the highest levels in later stages of life. By the age of 60 years, of those with hypertension, about two thirds have isolated systolic hypertension, and by the age of 75 years, nearly all hypertensive patients have systolic hypertension, of which three quarters of cases are isolated hypertension.[5] 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 plasma renin activity (PRA), blood pressure responds well to angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) therapy. Low doses of diuretics may also be effective. Thiazide-type diuretics may be particularly beneficial for patients aged 55 years or older with hypertension or CVD risk factors and for patients aged 60 years or older with isolated systolic hypertension.[7] The SHEP trial found that chlorthalidone stepped-care therapy for 4.5 years was associated with a longer life expectancy at 22-year follow-up in patients with isolated systolic hypertension.[103] The Syst-Eur trial used a study design and sample size similar to those of the SHEP trial, in which treatment with the CCB nitrendipine resulted in significant reduction in stroke and overall CVD events.[104]

Calcium antagonists are quite useful because of their strong antihypertensive effects. Often, combining 2 drugs at a lower dose may be preferable to using a single drug at a high dose, because of the potential for adverse effects with the higher dose. Beta-blockers may not be as effective as other first-line agents in patients aged 60 years and older, especially for stroke prevention, and should probably be used when other indications are present, such as heart failure, previous myocardial infarction, and angina.[7]

Elderly patients should also be encouraged to lose weight if necessary, be more physically active, reduce their salt intake, and avoid excessive alcohol intake.[5]

 

For black patients, relative to non-Hispanic white persons, hypertension is more common and more severe, develops earlier, results in more clinical sequelae, and is associated with other comorbidities (eg, cardiovascular risk factors).[5] As with all prehypertensive and hypertensive patients, weight and sodium reduction (eg, DASH diet) can be effective for BP control.

The Eighth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure ("JNC 8") recommends initiating therapy with a thiazide-type diuretic or calcium channel blocker (CCB) in black patients with hypertension.[88, 89] In addition, regardless of race or diabetes status, in patients 18 years or older with CKD, initial or add-on therapy should consist of an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) but not both (ie, do not use an ACEI and an ARB in the same patient).[88, 89]

Beta-blocker, ACEI, or ARB monotherapy in black patients may be less effective for BP reduction than in white patients.[5] In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), thiazide-type diuretics or CCBs were more effective than ACEIs in black patients. However, combination therapy with a diuretic and agents of the other drug classes eliminated the differences in BP reduction between racial groups.[5] In general, therapy is initiated at the lowest recommended dose of the selected agent; then, it is titrated upward, or another drug is added to reach the goal BP.[7]

In one study, Weinberger et al reported that the combination of aliskiren and amlodipine, a calcium channel blocker, was more effective than amlodipine alone in treating black patients with stage 2 hypertension and obesity or metabolic syndrome.[105] However, in December 2011, Novartis, the manufacturer of aliskiren, terminated the ALTITUDE study because of an increased incidence of adverse events (nonfatal stroke, renal complications, hyperkalemia, hypotension) when aliskiren was added to ACEI or ARB therapy. The study involved patients with type 2 diabetes and renal impairment at high risk for cardiovascular and renal events.

Hypertension, especially stage 2 hypertension, can affect the retina, choroid, and optic nerve, as well as increase intraocular pressure (IOP).[5] In hypertensive retinopathy, the most common finding is generalized or focal narrowing of the retinal arterioles; occlusion or leakage of the retinal vessels may occur with acute or advanced hypertension. Hypertensive choroidopathy most commonly manifests in young patients with acute elevated blood pressure (BP), such as that which occurs in eclampsia or pheochromocytoma.[5]

Treatment of ocular hypertension varies. Depending on the severity of the ocular hypertension, management may include observation or initiation of antihypertensive therapy. In general, pharmacologic treatment is initiated in patients who have an increased risk of developing glaucoma.

Blood pressure control may result in regression of signs of hypertensive retinopathy, but spontaneous resolution may also be possible.[54] Among the issues that still need to be clarified are the following:

• Whether antihypertensive agents with potential direct beneficial microvascular effects (eg, angiotensin-converting enzyme inhibitors [ACEIs]) would reduce the damage of retinopathy beyond the reduction caused by lowered blood pressure

• Whether the specific reduction of hypertensive retinopathy also leads to reduction in cardiovascular disease morbidity and mortality

• Whether established risk-reducing interventions in targeted persons with hypertensive retinopathy would lead to additional advantages, as compared to the use of strategies without regard to retinal findings

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 BP. 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.

For further information, see the Medscape Drugs & Diseases article Ocular Hypertension.

The goals of therapy for renovascular hypertension (RVHT) are maintenance of normal blood pressure (BP) and prevention of end-stage renal disease (ESRD). 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 another.

It is important to note that the presence of renal artery stenosis or fibromuscular dysplasias are not always associated with renovascular hypertension. In addition, the potential benefits of percutaneous interventions are not proven. A trial by Bianchi et al failed to show improvement in systolic blood pressure, serum creatinine, renal events, mortality, or vascular events in patients with renal artery stenosis who underwent percutaneous renal artery intervention.[12]

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. 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. 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.

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.

Angiotensin-converting enzyme inhibitors (ACEIs) are effective in patients with unilateral renal artery stenosis; however, ACEIs need to be avoided in patients with bilateral renal artery stenosis or stenosis of a solitary kidney. A diuretic can be combined with an ACEI. Because of their glomerular vasodilatory effect, calcium antagonists are effective in renal artery stenosis and do not compromise renal function.

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 (eg, accelerated hypertension, vasculitis, hepatitis B, and IV drug abuse) may also lead to hypertension.

For further information, see the Medscape Drugs & Diseases article Renovascular Hypertension.

Resistant hypertension is defined as uncontrolled blood pressure (BP) (previously ≥140/90 mm Hg; ≥130/90 mm Hg per the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines[1] ) despite treatment with antihypertensive agents of three or more different classes, of which one is a diuretic,[42, 106] or controlled BP on a four-drug regimen. Data suggest that the addition of low-dose spironolactone provides significant additive BP reduction in both black patients and white patients who have resistant hypertension, with or without primary hyperaldosteronism.[107] However, ambulatory BP is normal in more than one third of patients with resistant hypertension, stressing the importance of monitoring patients to achieve correct diagnosis and management.[108] Patients should also be monitored for medication nonadherence,[106] which has been reported to be as high as 66% in those with resistant hypertension.[109] At-risk patients should also be tested for occult obstructive sleep apnea.

2018 AHA updated guidelines

Three important points emphasized in the 2018 updated AHA guidelines on resistant hypertension include (1) routine queries about patients' sleep patterns, as poor sleep duration and quality can interfere with blood control (BP) control; (2) lifestyle modifications (eg, low-sodium diet, weight loss, exercise, ≥6 hours of uninterrupted sleep each night; and (3) considering a change in antihypertensive agents from hydrochlorothiazide to chlorthalidone or indapamide if an above-goal BP persists despite adherence to a three-drug regimen and an optimal lifestyle (if the BP remains elevated despite the drug change, consider adding spironolactone as a fourth agent. Be extra vigilant if the estimated glomerular filtrate rate [eGFR] is < 30 mL/min/1.73 m2).[42, 110]  Clinicians should also assess and ensure optimal medication adherence in patients with resistant hypertension.

If the patient's BP is still not at target despite the above steps, the AHA suggests the following steps on the basis of expert opinion, and emphasizes they should be tailored to the patient[42] :

1. Unless the patient's heart rate is below 70 bpm, add a beta-blocker such as metoprolol succinate or bisoprolol, or a combined alpha-beta-blocker such as labetalol or carvedilol. If a beta-blocker is contraindicated, a central alpha-agonist such as a clonidine patch weekly or guanfacine at bedtime may be considered; if these agents are not tolerated, once-daily diltiazem may be considered. If the patient's BP is still not at target, then:

2. Add hydralazine 25 mg three times daily and uptitrate to the maximum dose. Concomitant use of a beta-blocker and a diuretic is required. If a patient has congestive heart failure and reduced ejection fraction, administer hydralazine on a background of isosorbide mononitrate 30 mg daily (max: 90 mg daily). If the patient's BP is still not at target, then:

3. Substitute minoxidil 2.5 mg two to three times daily for hydralazine and uptitrate. Concomitant use of a beta-blocker and a loop diuretic is required. If the patient's BP is still not at target, then:

4. Consider referring the patient to a hypertension specialist and/or for clinical trials.

 

There was initial enthusiasm for catheter-based renal sympathetic denervation in the treatment of resistant hypertension based on several early studies that compared renal denervation to standard medical treatment. Originally published as a small, 45-patient proof-of-principle and safety study in 2009,[111] a follow-up nonrandomized study with 153 patients (Symplicity HTN-1) conducted in Australia, Europe, and the United States showed that this technique lowered BP for an extended period of up to 2 years in patients with resistant hypertension (defined here as a SBP >160 mm Hg and taking more than three antihypertensive drugs, including a diuretic).[112] Postprocedure office BPs were reduced by 20/10 mm Hg, 24/11 mm Hg, 25/11 mm Hg, 23/11 mm Hg, 26/14 mm Hg, and 32/14 mmHg at 1, 3, 6, 12, 18, and 24 months, respectively. The complication rate was 3% and consisted of three groin pseudoaneurysms and one renal artery dissection, all managed without further sequelae.

Subsequently, an open-label prospective, randomized study conducted in 24 centers in Europe, Australia, and New Zealand (Symplicity HTN-2) confirmed the safety and efficacy of this treatment in 106 patients randomized to renal denervation with previous treatment (n = 52) or to previous treatment alone (n = 54).[113] At 6 months, renal denervation resulted in a reduction in SBP of 10 mm Hg or more in 84% of patients, compared to 35% of controls. No serious procedure-related or device-related complications occurred.

Of note, these earlier studies were unblinded and did not include a sham procedure as a control. The first single-blind, randomized, sham-controlled trial of renal denervation therapy, SYMPLICITY HTN-3, failed to demonstrate a significant difference in office-based BP measurements after 6 months.[114] Although recruitment for ongoing studies of renal denervation in the United States were halted based on these results, a number of new studies that attempt to address shortcomings in SYMPLICITY HTN-3 by utilizing modifications such as bipolar electrode catheters and denervation of the main renal arteries along with distal branches and accessory arteries are recruiting patients.[76]

Additional experimental therapies for resistant hypertension include iliac artery-vein fistulas and baroreceptor activation treatment (BAT) by an implantable stimulator.[109, 115]

Causes of resistant hypertension

Causes of resistant hypertension include improper BP measurement, volume overload, drug-induced or other causes, and associated conditions such as obesity or excessive alcohol intake.

Improper BP measurement

Improper BP measurement may result in falsely high readings, such as when the wrong-sized cuff is used, when patients have heavily calcified or arteriosclerotic brachial arteries, or in cases of white-coat hypertension (observed in 20-30% of patients[63] ).

In one study, investigators determined that a true diagnosis of resistant hypertension with ambulatory BP monitoring (ABPM) is associated with a more severe degree of vascular dysfunction (versus white-coat resistant hypertension), as measured by hyperemia-induced forearm vasodilation (HIFV) and serum biomarkers.[116] However, there is no direct association between BP levels and other types of abnormalities in vascular function (eg, compliance).[116]

Falsely high readings due to white-coat hypertension may be avoided by having patients rest before the measurement, by having a nurse check the blood pressure, or by arranging to have the blood pressure monitored at home. Development of hypotensive symptoms with the patient on medication is an indication of this type of hypertension. White-coat hypertension can also be evaluated by the use of a 24-hour ambulatory monitor.

Inadequate treatment and patient nonadherence

Inadequate treatment is common in cases of resistant hypertension[5] ; in several published series, this has been described as the most common cause of resistant hypertension. Patients may not be on an effective drug or drug dose, or concomitant volume expansion may occur as a side effect of the drug.

Nonadherence with medical therapy[42, 117] 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 suggest better compliance with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) than with some of the other antihypertensive medications.[118]

Extracellular volume expansion

Extracellular volume expansion may contribute to the inability to lower systemic BP. The volume expansion may occur because of renal insufficiency or because of sodium retention due to treatment with vasodilators, a high-salt diet, or insufficient dosing of a diuretic. This condition can be treated with more aggressive diuretic therapy until clinical signs of extracellular volume depletion (eg, orthostatic hypotension) develop. The JNC 7 recommends a thiazide-type diuretic for the majority of hypertensive patients but notes that patients with a decreased GFR or who are in heart failure often require therapy with a loop diuretic.[5]

Vasoactive substances

Resistant hypertension may be encountered in patients who are ingesting vasoactive substances despite taking antihypertensive drugs regularly. Salt and alcohol are common examples; others include 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 parenchymal disease, renal artery stenosis, primary hyperaldosteronism, obstructive sleep apnea, pheochromocytoma/paraganglioma, Cushing syndrome, coarctation of the aorta).[42] Primary hyperaldosteronism is estimated to have a prevalence of 20% in this population.[119]

Obstructive sleep apnea is also associated with resistant hypertension, with 85% of patients with resistant hypertension having an elevated apnea/hypopnea index. A study by Pedrosa et al also found that two good predictors of sleep apnea in patients older than 50 years with resistant hypertension is a large neck circumference and snoring.[120]

However, treatment with CPAP may reduce BP in patients with resistant hypertension and sleep apnea. In the Spanish open-label, randomized HIPARCO trial, 98 patients with obstructive sleep apnea (OSA) and resistant hypertension who were treated with 12 weeks of continuous positive airway pressure (CPAP) had significantly improved 24-hour mean and diastolic blood pressure (BP) measurements, as compared to BP in 96 patients who did not receive CPAP therapy.[121, 122] Reductions in 24-hour mean and diastolic BP in the CPAP group were 3.1 mm Hg and 3.2 mm Hg, respectively, but there was no change in 24-hour systolic BP. However, a per-protocol analysis showed reductions in 24-hour mean BP (4.4 mm Hg) and diastolic BP (4.1 mm Hg) and a significant decrease in 24-hour systolic BP (4.9 mm Hg).[121, 122]

In addition, 35.9% of those on CPAP therapy showed improvements in their nocturnal BP pattern (ie, ≥10% decrease in average nighttime vs average daytime BP), as compared to 21.6% in the control group. There was also a significant correlation between duration of CPAP use and the reduction in BP levels.[121, 122]

Pseudohypertension in an overestimation of intra-arterial pressure by cuff blood pressure (BP) measurement. This may be observed in elderly individuals who have thickened, calcified arteries, as the cuff has relatively more difficulty compressing such arteries; much higher cuff pressure may be required to occlude a thickened brachial artery. The diastolic BP may also be overestimated.

Consider pseudohypertension in situations in which no organ damage occurs despite markedly high BP measurements, 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.

Following suspicion of pheochromocytoma (labile, elevated blood pressure [BP]; paroxysmal hypertension with headache palpitations, pallor, perspiration),[5] the presence of a tumor should be confirmed biochemically by measuring urine and plasma concentrations of catecholamine or their metabolites. Keep in mind that catecholamine testing is subject to an increased rate of false positives, which can be due to medication effects or measurement conditions. In most situations, computed tomography scanning or magnetic resonance imaging 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. Positron emission tomography (PET) scanning and octreotide scanning may also be used.

Surgical resection is the treatment of choice for pheochromocytoma, because hypertension is cured by tumor resection. In the preoperative phase, nonspecific alpha-adrenergic blockade is indicated with phenoxybenzamine, and following adequate alpha-adrenergic blockade, beta-adrenergic blockade is added if excess tachycardia is present. These patients are often volume contracted and require saline or sodium tablets. Catecholamine production 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.

For further information, see the Medscape Drugs & Diseases article Pheochromocytoma.

The prevalence of primary hyperaldosteronism increases with the severity of hypertension, being 2% in stage 1 and 20% in resistant hypertension.[119] Hypokalemia (an unprovoked or an exaggerated hypokalemic response to a thiazide) and metabolic alkalosis are important clues to the presence of primary hyperaldosteronism. However, these are relatively late manifestations; in a large subset of patients, the serum potassium concentration and bicarbonate are within the reference range, and additional screening testing is needed in patients with high index of suspicion for primary hyperaldosteronism.

Measurement of the ratio of plasma aldosterone to 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 (ie, urinary aldosterone excretion rate greater than 12-14 μg/24 hours, with urine sodium at least 200 mEq/24 hours). Saline suppression testing can also be used to confirm the diagnosis.

The appropriate therapy depends on the cause of excessive aldosterone production. A CT scan with dynamic protocol may help localize an adrenal mass, indicating adrenal adenoma, which may be a nonsecreting incidentaloma or a hypersecreting 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.

For further information, see the Medscape Drugs & Diseases article Hyperaldosteronism.

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

• Nurse or pharmacist 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. 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.[123] Cochrane recommendations include the recommendation that family practices and community-based clinics have an organized system of regular follow-up and review of their patients with hypertension. A randomized trial found that systolic BP decreased in individuals with poor BP control at baseline with use of home BP management consisting of nurse-administered behavioral management and nurse-administered and physician-administered medication management.[124]

Antihypertensive drug therapy should be implemented by means of a vigorous stepped care approach when patients do not reach target BP levels.

A comprehensive strategy for reduction of mortality and morbidity associated with hypertension must include prevention strategies, earlier detection, and adequate treatment. Ideally, a population strategy should be used 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, excessive sodium consumption, physical inactivity, and/or alcohol consumption. Even a small reduction in BP confers significant health benefits. A reduction of 2 mm Hg 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 diet rich in fruits and vegetables and low-fat meat, fish, and dairy products

Screening

Guidelines on screening for hypertension have been issued by the following organizations:

• United States Preventive Services Task Force (USPSTF)
• Joint National Committee (JNC)
• American College of Obstetricians and Gynecologists (ACOG)
• Department of Veterans Affairs (VA)/Department of Defense (DoD)
• European Society of Hypertension (ESH)/European Society of Cardiology (ESC)

The 2013 joint European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) guidelines recommend that ambulatory blood-pressure monitoring (ABPM) be incorporated into the assessment of cardiovascular risk factors and hypertension.[125, 126]

A comparison of the recommendations for blood pressure screening is provided in Table 4 below.

Table 4. Guidelines for Blood Pressure Screening in Adults (Open Table in a new window)

Hypertension Classification

In the United States, the most widely used classification of blood pressure for adults aged 18 years or older is from the 2003 Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), as follows[5] :

• Normal: Systolic lower than 120 mm Hg, diastolic lower than 80 mm Hg
• Prehypertension: Systolic 120-139 mm Hg, diastolic 80-89 mm Hg
• Stage 1: Systolic 140-159 mm Hg, diastolic 90-99 mm Hg
• Stage 2: Systolic 160 mm Hg or greater, diastolic 100 mm Hg or greater

However, the 2017, the American College of Cardiology/American Heart Association (ACC/AHA) updated their guidelines for the prevention, detection, evaluation, and management of high blood pressure in adults by eliminating the classification of prehypertension and dividing it into two levels[1, 2] :

• Elevated blood pressure with a systolic pressure between 120 and 129 mm Hg and diastolic pressure less than 80 mm Hg
• Stage 1 hypertension, with a systolic pressure of 130 to 139 mm Hg or a diastolic pressure of 80 to 89 mm Hg

The 2013 and 2018 ESH/ESC guidelines utilize the following classification system, which was first introduced in its 2002 guidelines[9, 126] :

• Optimal: Systolic lower than 120 mm Hg and diastolic lower than 80 mm Hg
• Normal: Systolic 120-129 mm Hg and/or diastolic 80-84 mm Hg
• High normal: Systolic 130-139 mm Hg and/or diastolic 85-89 mm Hg
• Grade 1: Systolic 140-159 mm Hg and/or diastolic 90-99 mm Hg
• Grade 2: Systolic 160-179 mm Hg or greater and/or diastolic 100-109 mm Hg
• Grade 3: Systolic 180 mm Hg or greater and/or diastolic 110 mm Hg or greater
• Isolated systolic hypertension: 140 mm Hg or greater and diastolic lower than 90 mm Hg

Both the classifications above are based on the average of two or more readings taken at each of two or more visits after initial screening.[5, 126]  

Target Blood Pressure

Target blood pressures have been provided in guidelines from the following organizations:

• Joint National Committee (JNC)
• European Society of Hypertension (ESH)/European Society of Cardiology (ESC)
• American Heart Association/American College of Cardiology/American Society of Hypertension (AHA/ACC/ASH)
• American Heart Association/American College of Cardiology (ACC)/Centers for Disease Control and Prevention (AHA/ACC/CDC)
• American Society of Hypertension/International Society of Hypertension (ASH/ISH)
• Department of Veterans Affairs (VA)/Department of Defense (DoD)
• American Diabetes Association (ADA)
• American College of Cardiology/American Heart Association (ACC/AHA)

A group was empaneled to write the Eighth Joint National Committee (JNC8) guideline, but this effort was discontinued by the National Heart, Lung, and Blood Institute (NHLBI). A paper was published in The Journal of the American Medical Association in 2014 that is generally referred to as 'JNC 8' but officially, there are no JNC 8 guidelines sanctioned by the NHLBI, nor has JNC 8 been endorsed by the AHA, ACC, or many other organizations that endorsed JNC7. 

A comparison of the target blood pressure recommendations for the guidelines issued by various organizations is provided in Table 5, below.

Table 5. Target Blood Pressure Recommendations (Open Table in a new window)

SPRINT Trial

It should be noted that, aside from the ADA guidelines, existing guideline recommendations on target BP goals were developed prior to the Systolic Blood Pressure Intervention Trial (SPRINT) study, an NIH sponsored trial that demonstrated a 25% decrease in cardiovascular events or death with targeting a systolic BP less than 120 mm Hg versus 140 mm Hg in patients at increased cardiovascular risk.[133] These intriguing results suggest a benefit from more-intensive BP targets than are recommended in existing guidelines. However, the generalizability of the SPRINT results remain unclear. Importantly, the SPRINT trial excluded patients with diabetes mellitus or prior cerebrovascular accident. These populations have been studied previously in the ACCORD and SPS3 trials, respectively, which failed to demonstrate significant benefits to stringent BP targets of below 120-130 mm Hg.[90, 134]

It is also important to recognize that the SPRINT trial utilized an automatic oscillometric office BP method without human participation, which typically yields a systolic BP that is 7-10 mm Hg lower than the standard office-based BP used in most studies.[109] This suggests that the lower systolic BP target in the SPRINT trial may be closer to more moderate targets in other studies, and that stringent systolic BP targeting of 120 mm Hg in standard clinical practice may increase the rate of adverse events such as hypotension, electrolyte abnormalities, and acute kidney injury.[133, 135]

A large meta-analysis of hypertension studies that tested systolic BP targets (including the SPRINT trial) demonstrated a reduction in cardiovascular outcomes and overall mortality with a systolic BP target below 130 mm Hg, although the magnitude of the benefit decreased with BP goals progressively below 150 mm Hg.[136] Future guidelines will likely incorporate the results of the SPRINT trial into target BP recommendations, which may result in lower target BPs, at least for patients with high cardiovascular risk but without diabetes or prior cerebrovascular accidents. 

Management

Many guidelines exist for the management of hypertension. Two of the most widely used recommendations are the 2003 Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)[5] and annually updated guidelines from the American Diabetes Association (ADA).[71]  

In 2013, both the JNC 8 and the updated joint guidelines from the European Society of Hypertension/European Society of Cardiology (ESH/ESC) were released. In 2014 and 2015, guidelines were issued by the following organizations:

• American Heart Association/American College of Cardiology/American Society of Hypertension (AHA/ACC/ASH) ^[130]
• American Society of Hypertension/International Society of Hypertension (ASH/ISH) ^[132]
• Department of Veterans Affairs/Department of Defense (VA/DoD) ^[129]

In 2017, the ACC/AHA as well as the American College of Physicians (ACP) and the American Academy of Family Physicians (AAFP) released guidelines for the prevention, detection, evaluation, and management of high blood pressure in adults[1]  and the elderly,[72] respectively.

​JNC 7

Key messages of the JNC 7 were as follows[5] :

• The goals of antihypertensive therapy is the reduction of cardiovascular and renal morbidity and mortality, with the focus on controlling the systolic BP, as most patients will achieve diastolic BP control when the systolic BP is achieved

• Prehypertension (systolic 120-139 mm Hg, diastolic 80-89 mm Hg) requires health-promoting lifestyle modifications to prevent the progressive rise in BP and cardiovascular disease

• In uncomplicated hypertension, a thiazide diuretic, either alone or combined with drugs from other classes, should be used for the pharmacologic 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

ADA 2016 Standard of Medical Care

In its 2016 Standards of Medical Care in Diabetes, the ADA makes the following recommendations for the control of high blood pressure [71] :

• Initiation of pharmacotherapy is recommended for all diabetic patients with confirmed office-based blood pressure >140/90 mm Hg
• Treat with a regimen that includes either an ACEI or an ARB; if one class is not tolerated, the other can be substituted
• Multiple-drug therapy (including a thiazide diuretic and ACEI/ARB, at maximal doses) is generally required to achieve blood pressure targets
• Serum creatinine/estimated glomerular filtration rate (eGFR) and serum potassium levels should be monitored in patients receiving ACEIs, ARBs, or diuretics

2017 ADA guidelines

The ADA released updated guidelines for patients with hypertension and diabetes in 2017, as follows[83] :

Blood pressure should be measured at every routine clinical care visit. Patients found to have an elevated blood pressure (≥140/90 mm Hg) should have blood pressure confirmed using multiple readings, including measurements on a separate day, to diagnose hypertension.

All hypertensive patients with diabetes should have home blood pressure monitored to identify white coat hypertension.

Orthostatic measurement of blood pressure should be performed during initial evaluation of hypertension and periodically at follow-up, or when symptoms of orthostatic hypotension are present, and regularly if orthostatic hypotension has been diagnosed.

Most patients with diabetes and hypertension should be treated to a systolic blood pressure goal of < 140 mm Hg and a diastolic blood pressure goal of < 90 mm Hg.

Lower systolic and diastolic blood pressure targets, such as < 130/80 mm Hg, may be appropriate for individuals at high risk of cardiovascular disease if they can be achieved without undue treatment burden.

For patients with systolic blood pressure >120 mm Hg or diastolic blood pressure >80 mm Hg, lifestyle intervention consists of weight loss if overweight or obese; a Dietary Approaches to Stop Hypertension (DASH)-style dietary pattern, including reduced sodium and increased potassium intake; increased fruit and vegetable consumption; moderation of alcohol intake; and increased physical activity.

Patients with confirmed office-based blood pressure ≥140/90 mm Hg should, in addition to lifestyle therapy, have timely titration of pharmacologic therapy to achieve blood pressure goals.

Patients with confirmed office-based blood pressure ≥160/100 mm Hg should, in addition to lifestyle therapy, have prompt initiation and timely titration of 2 drugs or a single-pill combination of drugs demonstrated to reduce cardiovascular events in patients with diabetes.

Treatment for hypertension should include drug classes demonstrated to reduce cardiovascular events in patients with diabetes: ACEIs, ARBs, thiazide-like diuretics, or dihydropyridine calcium channel blockers. Multiple-drug therapy is generally required to achieve blood pressure targets (but not a combination of ACEIs and ARBs).

An ACEI or ARB, at the maximum tolerated dose indicated for blood pressure treatment, is the recommended first-line treatment for hypertension in patients with diabetes and urine albumin-to-creatinine ratio ≥300 mg/g creatinine or 30–299 mg/g creatinine. If one class is not tolerated, the other should be substituted.

For patients treated with an ACEI, ARB, or diuretic, serum creatinine/estimated glomerular filtration rate and serum potassium levels should be monitored.

Pregnant women with diabetes and preexisting hypertension or mild gestational hypertension with systolic blood pressure < 160 mm Hg, diastolic blood pressure < 105 mm Hg, and no evidence of end-organ damage do not need to be treated with pharmacologic antihypertensive therapy.

In pregnant patients with diabetes and preexisting hypertension who are treated with antihypertensive therapy, systolic or diastolic blood pressure targets of 120–160/80–105 mm Hg are suggested in the interest of optimizing long-term maternal health and fetal growth.

2017 ACC/AHA guidelines

The 2017 ACC/AHA guidelines eliminate the classification of prehypertension and divides it into two levels[1, 2] : (1) elevated BP, with a systolic pressure (SBP) between 120 and 129 mm Hg and diastolic pressure (DBP) less than 80 mm Hg, and (2) stage 1 hypertension, with an SBP of 130 to 139 mm Hg or a DBP of 80 to 89 mm Hg.

In adults at increased risk of heart failure (HF), the optimal BP in those with hypertension should be less than 130/80 mm Hg.

Adults with HFrEF (HF with reduced ejection fraction) and hypertension should be prescribed GDMT (guideline-directed management and therapy) titrated to attain a BP of less than 130/80 mm Hg.

Nondihydropyridine calcium channel blockers (CCBs) are not recommended in the treatment of hypertension in adults with HFrEF.

Adults with hypertension and chronic kidney disease (CKD) should be treated to a BP goal of less than 130/80 mm Hg.

After kidney transplantation, it is reasonable to treat patients with hypertension to a BP goal of less than 130/80 mm Hg. After kidney transplantation, it is reasonable to treat patients with hypertension with a calcium antagonist on the basis of improved glomerular filtration rate (GFR) and kidney survival.

Immediate lowering of SBP to lower than 140 mm Hg in adults with spontaneous intracerebral hemorrhage (ICH) who present within 6 hours of the acute event and have an SBP between 150 mm Hg and 220 mm Hg is not of benefit to reduce death or severe disability and can be potentially harmful.

Adults with acute ischemic stroke and elevated BP who are eligible for treatment with intravenous (IV) tissue plasminogen activator (tPA) should have their BP slowly lowered to below 185/110 mm Hg before thrombolytic therapy is initiated.

In adults with an acute ischemic stroke, BP should be less than 185/110 mm Hg before administration of IV tPA and should be maintained below 180/105 mm Hg for at least the first 24 hours after initiating drug therapy.

For adults who experience a stroke or transient ischemic attack (TIA), treatment with a thiazide diuretic, ACEI, or angiotensin receptor blocker (ARB), or combination treatment consisting of a thiazide diuretic plus ACEI, is useful.

In adults with an untreated SBP greater than 130 mm Hg but less than 160 mm Hg or a DBP greater than 80 mm Hg but less than 100 mm Hg, it is reasonable to screen for the presence of white coat hypertension by using either daytime ABPM (ambulatory BP monitoring) or HBPM (home BPM) before diagnosis of hypertension.

In adults with untreated office BPs that are consistently between 120 mm Hg and 129 mm Hg for SBP or between 75 mm Hg and 79 mm Hg for DBP, screening for masked hypertension with home BPM (or ABPM) is reasonable.

In adults with hypertension, screening for primary aldosteronism is recommended in the presence of any of the following concurrent conditions: resistant hypertension, hypokalemia (spontaneous or substantial, if diuretic induced), incidentally discovered adrenal mass, family history of early-onset hypertension, or stroke at a young age (< 40 years).

Adult men and women with elevated BP or hypertension who currently consume alcohol should be advised to drink no more than two and one standard drinks per day, respectively.

Two or more antihypertensive medications are recommended to achieve a BP target of less than 130/80 mm Hg in most adults with hypertension, especially in black adults with hypertension.

Women with hypertension who become pregnant should not be treated with ACEIs, ARBs, or direct renin inhibitors.

Use of BP-lowering medications is recommended for secondary prevention of recurrent cardiovascular disease (CVD) events in patients with clinical CVD and an average SBP of 130 mm Hg or higher or an average DBP of 80 mm Hg or higher, and for primary prevention in adults with an estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk of 10% or higher and an average SBP of 130 mm Hg or higher or an average DBP of 80 mm Hg or higher.

Use of BP-lowering medication is recommended for primary prevention of CVD in adults with no history of CVD and with an estimated 10-year ASCVD risk below 10% and an SBP of 140 mm Hg or higher or a DBP of 90 mm Hg or higher.

Adults with an elevated BP or stage 1 hypertension who have an estimated 10-year ASCVD risk below 10% should be managed with nonpharmacologic therapy and have a repeat BP evaluation within 3 to 6 months.

Adults with stage 1 hypertension who have an estimated 10-year ASCVD risk of 10% or higher should be managed initially with a combination of nonpharmacologic and antihypertensive drug therapy and have a repeat BP evaluation in 1 month.

For adults with a very high average BP (eg, SBP ≥180 mm Hg or DBP ≥110 mm Hg), evaluation followed by prompt antihypertensive drug treatment is recommended.

Simultaneous use of an ACE, ARB, and/or renin inhibitor is potentially harmful and is not recommended to treat adults with hypertension.

2017 ACP/AAFP guidelines

The American College of Physicians (ACP) and the American Academy of Family Physicians (AAFP) released their guidelines regarding hypertension in adults aged 60 years, including the following[72] :

• Clinicians should initiate treatment in patients aged 60 years or older who have persistent SBP at or above 150 mm Hg to achieve a target of less than 150 mm Hg to reduce the risk for stroke, cardiac events, and death.
• If patients 60 years or older have a history of stroke or transient ischemic attack or have high cardiovascular risk, physicians should consider starting or increasing drug therapy to achieve an SBP of less than 140 mm Hg to reduce the risk for stroke and cardiac events.
• Consider initiating or intensifying pharmacologic treatment in some adults aged 60 years or older at high cardiovascular risk based on individualized assessment, to achieve a target SBP of less than 140 mm Hg to reduce the risk for stroke and cardiac events. Factors include comorbidity, medication burden, risk of adverse events, and cost. Generally, increased cardiovascular risk includes known cardiovascular disease, diabetes, or chronic kidney disease with a glomerular filtration rate of less than 45 mL/min/1.73 m ².

Collaborative AHA/ACC/CDC advisory recommendations

A science advisory on the treatment of hypertension, issued in November 2013 via a collaborative effort by the American Heart Association (AHA), the American College of Cardiology (ACC), and the Centers for Disease Control and Prevention (CDC), describes criteria for successful hypertension management algorithms and advocates the creation of algorithms that can be incorporated into a system-level approach to high BP, as well as modified to accommodate different practice settings and patient populations.[131, 137]

A joint AHA/ACC/CDC algorithm in the report includes the following recommendations[131, 137] :

• BP: Recommended goal of 139/89 mm Hg or less

• Stage 1 hypertension (systolic BP 140-159 mm Hg or diastolic BP 90-99 mm Hg): Can be treated with lifestyle modifications and, if needed, a thiazide diuretic

• Stage 2 hypertension (systolic BP >160 mm Hg or diastolic BP >100 mm Hg): Can be treated with a combination of a thiazide diuretic and an ACEI, an angiotensin receptor blocker, or a calcium channel blocker

• Patients who fail to achieve BP goals: Medication doses can be increased and/or a drug from a different class can be added to treatment

Joint ESH and ESC guidelines

In June 2013, the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) released new guidelines for the management of hypertension, recommending that all patients, except special populations such as patients with diabetes and the elderly, be treated to below 140 mm Hg systolic BP.[125, 126]  The guidelines advise that physicians should make decisions on treatment strategies based on the patient's overall level of cardiovascular risk.

Recommendations of the new ESH and ESC guidelines include[125, 126] :

• In patients younger than 80 years, the systolic BP target should be 140 to 150 mm Hg, but physicians can go lower than 140 mm Hg if the patient is fit and healthy; the same advice applies to octogenarians—however, the patient's mental capacity and physical heath should also be considered if targeting to less than 140 mm Hg

• Patients with diabetes should be treated to below 85 mm Hg diastolic BP

• Salt intake should be limited to approximately 5 to 6 g per day

• Body-mass index (BMI) should be reduced to 25 kg/m2 and waist circumferences should be reduced to less than 102 cm in men and less than 88 cm in women

• Ambulatory BP monitoring (ABPM) should be incorporated into the assessment of risk

• Effective combination therapies include thiazide diuretics with ARBs, calcium-channel antagonists, or ACEIs; or, calcium-channel antagonists with ARBs or ACEIs

• Dual renin-angiotensin system blockade (ie, ARBs, ACEIs, and direct renin inhibitors) is not recommended because of the risks of hyperkalemia, low BP, and kidney failure

American Society of Hypertension/International Society of Hypertension

Joint guidelines were issued in 2013 by the American Society of Hypertension and the International Society of Hypertension (ASH/ISH) with the intent of providing an international primer with general information, especially for communities and countries with low resources. On their website, the ASH cautions that “these guidelines should be considered more as ‘an expert opinion piece,’ given that they are not systematically evidence-based and were not developed using guideline development protocol stipulated by the Institute of Medicine (IOM).”[132]

Treatment recommendations are given for hypertensive patients with or without another major medical condition are provided in Table 6, below.[138]

Table 6. American Society of Hypertension/International Society of Hypertension Treatment Recommendations (Open Table in a new window)

Department of Veterans Affairs/Department of Defense

In 2014, the Department of Veteran’s Affairs/Department of Defense (VA/DoD) released an update of their 2004 guidelines for diagnosis and management of hypertension in primary care settings. Initiation of pharmacotherapy is recommended for all adults with either systolic BP ≥160 mm Hg or diastolic BP ≥90 mm Hg and for adults with a history of stroke, transient ischemic attack, or asymptomatic carotid artery disease and systolic BP ≥140 mm Hg.[129]

Treatment may also be considered for adults ages ≥60 years with systolic BP < 160 mm Hg. Combination therapy should be initiated for adults with systolic BP >20 mm Hg or diastolic BP >10 mm Hg above the target goal. Additional recommendations include the following[129] :

• Thiazide-type diuretic as first-line therapy either as monotherapy or in combination with other drugs
• Chlorthalidone or indapamide is preferred over hydrochlorothiazide
• For patients who cannot tolerate thiazide-type diuretics, or as supplementary therapies for patients who do not reach their hypertensive goals with thiazide-type diuretics, or for those starting on combination therapy: ACEIs or ARBs (but not both together); long-acting dihydropyridine calcium channel blockers
• For patients with chronic kidney disease, ACEIs or ARBs for improving kidney outcomes
• In African Americans, recommend against ACEIs or ARBs as monotherapy
• In African Americans with stage 1-3 chronic kidney disease, the combination of a thiazide-type diuretic (for cardiovascular protection) with either an ACEI or an ARB (for renal protection)

Lifestyle modifications

JNC 7 and AHA-ASA lifestyle modification recommendations

The Seventh Report of the Joint National Committee of Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommendations to lower blood pressure (BP) and decrease cardiovascular disease risk include the following, with greater results achieved when 2 or more lifestyle modifications are combined[5] :

• Weight loss helps to prevent hypertension (range of approximate systolic BP reduction [SBP], 5-20 mm Hg per 10 kg); recommendations include the DASH (Dietary Approaches to Stop Hypertension) diet (range of approximate SBP reduction, 8-14 mm Hg), which is rich in fruits and vegetables and encourages the use of fat-free or low-fat milk and milk products

• Limit alcohol intake to no more than 1 oz (30 mL) of ethanol per day for 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 oz (15 mL) of ethanol per day for women and people of lighter weight (range of approximate SBP reduction, 2-4 mm Hg)

• Reduce sodium intake to no more than 100 mmol/d (2.4 g sodium or 6 g sodium chloride; range of approximate SBP reduction, 2-8 mm Hg)[8]

• 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

• Engage in aerobic exercise at least 30 minutes daily for most days (range of approximate SBP reduction, 4-9 mm Hg)

The 2010 American Heart Association-American Stroke Association (AHA-ASA) guidelines for the primary prevention of stroke makes the following recommendations[139] :

• Hypertension: the AHA-ASA guidelines recommend regular blood pressure screening, lifestyle modification, and drug therapy; lower risk of stroke and cardiovascular events are seen when systolic blood pressure levels are lower than 140 mm Hg and diastolic blood pressure levels are less than 90 mm Hg

• In patients who have hypertension with diabetes or renal disease, the BP goal is lower than 130/80 mm Hg

• Diet and nutrition: a diet that is low in sodium and high in potassium is recommended to reduce BP; diets that promote the consumption of fruits, vegetables, and low-fat dairy products, such as the DASH-style diet, help lower BP and may lower the 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 or more of moderate intensity activity on a daily basis

• Obesity and body fat distribution: weight reduction in overweight and obese persons is recommended to reduce BP and the risk of stroke

Hypertensive Emergencies

In the 2013, the American College of Emergency Physicians (ACEP) released an update of its 2006 guidelines for hypertension in the emergency department (ED), which are focused on treating hypertensive urgency. The recommendations include the following[140] :

• In ED patients with asymptomatic markedly elevated blood pressure, routine screening for acute target organ injury (eg, serum creatinine, urinalysis, electrocardiogram [ECG]) is not required.
• In select patient populations (eg, those with poor follow-up), screening for an elevated serum creatinine level may identify kidney injury that affects disposition (eg, hospital admission)
• In patients with asymptomatic markedly elevated blood pressure, routine ED medical intervention is not required
• In select patient populations (eg, poor follow-up available), emergency physicians may treat markedly elevated blood pressure in the ED and/or initiate therapy for long-term control (Consensus recommendation)
• Patients with asymptomatic markedly elevated blood pressure should be referred for outpatient follow-up (Consensus recommendation)

The 2017 American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommendations for hypertensive crises and emergencies include the following[1] :

• Admit adults with a hypertensive emergency to an ICU for continuous monitoring of BP and target organ damage, as well as for parenteral administration of an appropriate medication.
• For adults with a compelling condition (ie, aortic dissection, severe preeclampsia or eclampsia, or pheochromocytoma crisis), lower SBP to below 140 mm Hg during the first hour and to below 120 mm Hg in aortic dissection.
• For adults without a compelling condition, reduce the SBP to a maximum of 25% within the first hour; then, if the patient is clinically stable, lower the BP to 160/100 -110 mm Hg over the next 2-6 hours, and then cautiously to normal over the following 24-48 hours.

Hypertension in Pregnancy

Hypertensive disorders during pregnancy are classified into the four following categories, as recommended by the 2000 National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy[141] :

• 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.

However, the JNC 7 categorizes hypertensive disorders during pregnancy as follows (see Table 7, below)[5] :

• Chronic hypertension
•  Preeclampsia
• Chronic hypertension with superimposed preeclampsia
• Gestational hypertension
• Transient hypertension

The 2013 American College of Obstetricians and Gynecologists (ACOG) uses a classification system similar to that of JNC 7.[142]

In 2014, the Society of Obstetricians and Gynecologists of Canada (SOGC) released revised guidelines that classify hypertension in pregnancy as follows[138] :

• Preexisting hypertension
• Gestational hypertension
• Preeclampsia
• Other hypertensive effects (transient hypertensive effect, white-coat hypertensive effect, masked hypertensive effect)

Table 7. JNC 7 Classification of Hypertensive Disorders in Pregnancy (Open Table in a new window)

Specific guidelines for the management of hypertension during pregnancy have been issued by the American College of Obstetricians and Gynecologists (ACOG), Society of Obstetricians and Gynecologists of Canada (SOGC). In addition, recommendations for managing hypertension in pregnancy are included in broader hypertension management guidelines from the following organizations:

• Joint National Committee (JNC)
• European Society of Hypertension (ESH)/European Society of Cardiology (ESC)
• American Diabetes Association (ADA)

JNC 7 recommends treating women with chronic (preexisting) hypertension and no evidence of end-organ damage whose blood pressure is 150-160 mm Hg systolic or 100-110 mm Hg diastolic[5]

The ESH/ESC guidelines recommend considering treatment for pregnant women with chronic hypertension and BP ≥150/95 mm Hg; or in those women with BP ≥140/90 mm Hg who have gestational hypertension, subclinical organ damage, or symptoms.[126]

The 2013 ACOG guidelines recommend that in pregnant women with chronic hypertension treated with antihypertensive medication, BP levels should be maintained between 120/80 mm Hg and 160/105 mm Hg.[142]

Although reducing maternal risk is the goal of treating chronic hypertension in pregnancy, fetal safety largely directs the choice of antihypertensive agent. Methyldopa is generally the preferred first-line agent because of its safety profile.[5, 126, 142] Other drugs that may be considered include labetalol, beta-blockers, and diuretics.[6] ACOG does not recommend the use of any of the following[142] :

• ACEIs
• ARBs
• Renin inhibitors
• Mineralocorticoid receptor antagonists

 

Severe hypertension

There is consensus across guidelines (JNC 7, ESH/ESC, ACOG, SOGC) for the need to acutely manage severe hypertension, defined as systolic BP ≥160 mm Hg or diastolic BP ≥110 mm Hg or both, with the goal of preventing maternal stroke and avoiding intrauterine growth restriction (IUGR).[5, 126, 138, 142]

In 2015, the American College of Obstetricians and Gynecologists Committee on Obstetric Practice issued updated guidelines regarding the emergency treatment of acute-onset severe hypertension during pregnancy, including the following[143] :

• Acute-onset, severe hypertension that is accurately measured using standard techniques and is persistent for 15 minutes or longer is considered a hypertensive emergency
• Intravenous (IV) labetalol and hydralazine have long been considered first-line medications for the management of acute-onset, severe hypertension in pregnant and post-partum women; available evidence suggests that oral nifedipine also may be considered as a first-line therapy
• Parenteral labetalol should be avoided in women with asthma, heart disease, or congestive heart failure
• When urgent treatment is needed before the establishment of IV access, the oral nifedipine algorithm can be initiated as IV access is being obtained, or a 200-mg dose of labetalol can be administered orally; the latter can be repeated in 30 minutes if appropriate improvement is not observed
• Magnesium sulfate is not recommended as an antihypertensive agent, but it remains the drug of choice for seizure prophylaxis in severe preeclampsia and for controlling seizures in eclampsia
• Sodium nitroprusside should be reserved for extreme emergencies and used for the shortest amount of time possible because of concerns about cyanide and thiocyanate toxicity in the mother and fetus or newborn, and increased intracranial pressure with potential worsening of cerebral edema in the mother
• Adoption of standardized, evidence-based clinical guidelines for managing patients with preeclampsia is needed; individuals and institutions should have mechanisms in place for prompt initiation of medication when a patient presents with a hypertensive emergency

Hypertension and diabetes in pregnancy

In pregnant patients with diabetes and chronic hypertension, the ADA 2016 Standards of Medical Care in Diabetes recommends blood pressure targets of 110–129/65–79 mm Hg in the interest of optimizing long-term maternal health and minimizing impairment of fetal growth. ACEIs and ARBs are contraindicated during pregnancy.[143]

The 2017 ADA position statement on diabetes and hypertension indicates no antihypertensive pharmacotherapy is necessary for pregnant women with diabetes and preexisting hypertension or mild gestational hypertension with an SBP below 160 mm Hg and a DBP below 105 mm Hg, and no evidence of end organ damage.[83] For pregnant women with diabetes and preexisting hypertension on antihypertensive therapy, suggested BP targets are an SBP of 120-160 mm Hg and a DBP target of 80-105 mm Hg.

Many therapeutic agents can be used for the pharmacologic management of hypertension. General recommendations established by the Eighth Report of the Prevention, Detection, Evaluation, and Treatment of the Joint National Committee on High Blood Pressure (JNC 8) and the American College of Cardiology/American Heart Association (ACC/AHA) guidelines for initial pharmacologic treatment of stage 1 hypertension include a thiazide-type diuretic, angiotensin-converting enzyme inhibitors (ACEIs), calcium channel blockers (CCBs), or angiotensin-receptor blockers (ARBs).[1, 10]  For Black patients, ACEIs and ARBs are less effective than thiazide diuretics and CCBs in lowering blood pressure and preventing stroke.[1, 10]  

There is inadequate evidence to support beta blockers as initial treatment unless the patient has specific cardiovascular comorbidities (eg, heart failure, ischemic heart disease).[1, 10]     

Class Summary

Thiazide diuretics are used as monotherapy, or they can be administered adjunctively with other antihypertensive agents. Thiazide diuretics inhibit reabsorption of sodium and chloride mostly in the distal tubules. Long-term use of these drugs may result in hyponatremia.[144]

They also increase potassium and bicarbonate excretion and decrease calcium excretion and uric acid retention. Thiazides do not affect normal blood pressure.

Keep in mind that all available loop and thiazide diuretic agents, except ethacrynic acid, possess a sulfonamide group, which has important clinical relevance to those individuals with allergies to sulfonamide agents.

Hydrochlorothiazide (Microzide)

Hydrochlorothiazide is approved for the management of hypertension, alone or in combination with other antihypertensive agents. Unlike potassium-sparing combination diuretic products, hydrochlorothiazide may be used in patients who cannot risk the development of hyperkalemia, including patients taking ACE inhibitors.

Hydrochlorothiazide is available as oral tablets or capsules in doses ranging from 12.5-50 mg. The usual dose is 12.5 mg given alone or in combination with other antihypertensives, with a maximum dose of 50 mg daily. Doses greater than 50 mg are associated with hypokalemia.

Chlorthalidone (Thalitone)

Chlorthalidone is indicated for the management of hypertension either alone or in combination with other antihypertensives. The initial dosage is 25 mg as a single daily dose. Dosage can be titrated to 50 mg if the clinical response is not adequate. If additional control is required, increase the dosage to 100 mg once daily, or a second antihypertensive drug may be added. Doses greater than 100 mg daily usually do not increase effectiveness. Increases in serum uric acid and hypokalemia are dose-related over the 25-100 mg/day range.

Metolazone (Zaroxolyn)

Metolazone is approved for the treatment of hypertension either alone (uncommon) or in combination with other antihypertensives. The initial dosage for hypertension is 2.5 to 5 mg given once daily. Metolazone does not decrease glomerular filtration rate or the renal plasma flow and may be a more effective option for patients with impaired renal function.

Indapamide

Indapamide is chemically not a thiazide, although its structure and function are very similar. The drug enhances the excretion of sodium, chloride, and water by inhibiting the transport of sodium ions across the renal tubule. The hypovolemic action of indapamide is believed to be responsible for the drug's beneficial cardiovascular effects. The half-life of indapamide is approximately 14 hours, so the drug can be taken just once daily. Adverse effects tend to be somewhat milder than with thiazides.

Class Summary

The potassium-sparing diuretics interfere with sodium reabsorption at the distal tubules (primarily in the collecting duct region of the nephron), decreasing potassium secretion. Potassium-sparing diuretics have a weak diuretic and antihypertensive effect when used alone.

Triamterene

Triamterene is used alone or with other medications (often a kaliuretic diuretic such as hydrochlorothiazide) to treat edema and high blood pressure. Because triamterene increases potassium levels, caution is required when combining triamterene with ACE inhibitors, angiotensin receptor blockers, aliskiren, and other drugs that increase potassium levels. Potassium level should be monitored at start of treatment, dose change, and during illness that affects renal function. The recommended dose is 100 mg twice daily (maximum dose is 300 mg/d).

Amiloride (Midamor)

Amiloride is a potassium-conserving (antikaliuretic) drug that, compared with thiazide diuretics, possesses weak natriuretic, diuretic, and antihypertensive activity. It is approved as adjunctive treatment with thiazide diuretics or other kaliuretic-diuretic agents for hypertension or congestive heart failure. It is unrelated chemically to other known antikaliuretic or diuretic agents. Amiloride has little additive diuretic or antihypertensive effect when added to a thiazide diuretic. Amiloride can be given at a dose of 5-10 mg daily in 1-2 divided doses for hypertension. Amiloride has a black box warning for hyperkalemia, which, if not corrected, is potentially fatal. This incidence is greater in patients with renal impairment or diabetes mellitus and in the elderly.

Class Summary

Loop diuretics act on the ascending limb of the loop of Henle, inhibiting the reabsorption of sodium and chloride. The loop diuretics are highly protein-bound and therefore enter the urine primarily by tubular secretion in the proximal tubule, rather than by glomerular filtration.

Loop diuretics are commonly used to control volume retention. Generally, thiazide diuretics are recommended for most patients with a diagnosis of hypertension; however, loop diuretics are more commonly prescribed for patients with decreased glomerular filtration rate or heart failure. Loop diuretics do not reduce blood pressure as effectively as thiazide diuretics when they are used as monotherapy, especially if they are dosed once daily.

Keep in mind that all available loop and thiazide diuretic agents, except ethacrynic acid, possess a sulfonamide group, which has important clinical relevance to those individuals with allergies to sulfonamide agents.

Furosemide (Lasix)

Furosemide is approved for the treatment of hypertension alone (uncommon) or in combination with other antihypertensive agents. Hypertensive patients who cannot be adequately controlled with thiazides will probably also not be adequately controlled with furosemide alone. The initial dosing recommendations for hypertension are usually 80 mg (divided into 40 mg twice a day). If clinical response is not sufficient, additional antihypertensives may be added. Patients should be monitored carefully because furosemide is a potent diuretic. If given in excessive amounts, it can cause profound diuresis with water and electrolyte depletion. Furosemide is available as an oral tablet and injection solution.

Torsemide (Demadex)

Torsemide can be used as monotherapy or in combination with other antihypertensive agents. The initial dose is 5 mg once daily. The dose can be titrated to 10 mg once daily. If adequate response is not seen, an additional antihypertensive agent may be needed. Torsemide is available as an oral tablet and injection solution.

Bumetanide

Bumetanide is FDA approved for the treatment of edema. It is also used off-label for the treatment of hypertension. The usual dosage range for bumetanide for hypertension is 0.5-2 mg/day given once or twice a day.[3]

Class Summary

Angiotensin converting enzyme inhibitors (ACEIs) are the treatment of choice in patients with hypertension, chronic kidney disease, and proteinuria. ACEIs reduce morbidity and mortality rates in patients with heart failure, patients with recent myocardial infarctions, and patients with proteinuric renal disease. ACEIs appear to act primarily through suppression of the renin-angiotensin-aldosterone system. ACEIs prevent the conversion of angiotensin I to angiotensin II and block the major pathway of bradykinin degradation by inhibiting ACE. Accumulation of bradykinin has been proposed as an etiologic mechanism for the side effects of cough and angioedema. ACEIs can cause injury or even death to a developing fetus. In pregnant patients, ACEIs should be discontinued as soon as possible.

It is important to note that the blood-pressure-lowering effects of ACEIs and thiazides are approximately additive, and there is also the potential for hyperkalemia when ACEIs are coadministered with potassium supplements or potassium-sparing diuretics. In addition, a study by Harel et al found an increased risk for hyperkalemia when aliskiren, a direct renin inhibitor, and ACEIs or angiotensin receptor blockers (ARBs) were used together.[145] Careful monitoring of serum potassium levels is warranted when these agents are used in combination.[145] Furthermore, in patients with hypertension plus type 2 diabetes and renal impairment who are at high risk of cardiovascular and renal events, there is an increased risk of nonfatal stroke, renal complications, hypokalemia, and hypotension when aliskiren is added to ACEI or ARB therapy.

Fosinopril

Fosinopril may be used alone or in combination with other antihypertensive agents. Initial dose is 5 mg daily up to a maximum of 40 mg daily. May be divided into twice daily dosing. Unlike most ACE inhibitors that are primarily excreted by the kidneys, fosinopril is eliminated by both renal and hepatic pathways, making it a safer choice in patients with renal failure and heart failure patients with impaired kidney function.

Captopril

Captopril is indicated for the treatment of hypertension. It can be used alone or in combination with other antihypertensive drugs, such as diuretics or beta-adrenergic-blocking agents. The initial dose is 25 mg given 2 to 3 times daily. If reduction of blood pressure is not achieved after 1 or 2 weeks, the dose can be titrated to 50 mg 2 or 3 times daily. If further blood reduction is required after addition of a diuretic, the dose of captopril may be increased to 100 mg 2 or 3 times daily and then, if necessary, to 150 mg 2 or 3 times daily (while continuing the diuretic).

Ramipril (Altace)

Ramipril is indicated for the treatment of hypertension alone or in combination with thiazide diuretics. The initial dosing recommendation for ramipril is 2.5 mg daily for patients who are not receiving a diuretic. Doses can range from 2.5-20 mg/day given once or twice a day.

Enalapril (Vasotec)

Enalapril is effective alone or in combination with other antihypertensive agents, especially thiazide-type diuretics. The initial dose of enalapril is 5 mg daily. Dosage can range from 10-40 mg/day administered as a single dose or in 2 divided doses.

Lisinopril (Prinivil, Zestril)

Lisinopril may be used as monotherapy or concomitantly with other classes of antihypertensive agents. The initial dose of lisinopril is 10 mg daily. The dosage can range from 20-40 mg/day as a single daily dose. Doses up to 80 mg/day have been used; however, they do not show a greater effect.

Quinapril (Accupril)

Quinapril may be used alone or in combination with thiazide diuretics. The initial dose is 10 to 20 mg daily for patients not on diuretics. If blood pressure is not controlled with quinapril monotherapy, adding a diuretic should be considered.

Class Summary

Generally, ACE inhibitors should remain the initial treatment of choice for hypertension. Angiotensin II receptor antagonists or angiotensin receptor blockers (ARBs) are used for patients who are unable to tolerate ACE inhibitors. ARBs competitively block binding of angiotensin-II to angiotensin type I (AT1) receptors, thereby reducing effects of angiotensin II–induced vasoconstriction, sodium retention, and aldosterone release; the breakdown of bradykinin should not be inhibited. If monotherapy with an ARB is not sufficient, adding a diuretic should be considered.

ARBs can cause injury or even death to a developing fetus. If a patient becomes pregnant, ARBs should be discontinued as soon as possible.

Note that a study by Harel et al found an increased risk for hyperkalemia when aliskiren and ARBs or ACE inhibitors were used together[145] ; therefore, careful monitoring of serum potassium levels is warranted when these agents are used in combination.[145] Furthermore, in patients with hypertension and type 2 diabetes and renal impairment who are at high risk of cardiovascular and renal events, there is an increased risk of nonfatal stroke, renal complications, hypokalemia, and hypotension when aliskiren is added to ACE inhibitor or ARB therapy.

Losartan (Cozaar)

Losartan may be used alone or in combination with other antihypertensive agents, including diuretics. The initial dose is 50 mg daily; however, in patients on diuretic therapy, the initial dose is 25 mg daily. A low-dose diuretic (eg, hydrochlorothiazide) may be added if blood pressure is not controlled. Losartan can be titrated up to 100 mg daily.

Valsartan (Diovan)

Valsartan is approved for the treatment of hypertension in adults and in children 6-16 years of age. It may be used alone or in combination with other antihypertensive agents. The initial dose is 80 or 160 mg once daily when used as monotherapy in patients who are not volume depleted. The valsartan dose may be increased (maximum 320 mg/day), or a diuretic may be added if additional blood pressure reduction is required. The addition of a diuretic has a greater effect than dose increases above 80 mg.

Olmesartan (Benicar)

Olmesartan is indicated for hypertension either alone or in combination with other antihypertensives. The initial dose is 20 mg daily when used as monotherapy. The dose may be titrated to 40 mg daily if greater effect is desired. Doses greater than 40 mg have not been shown to have greater effects. If monotherapy is not sufficient, adding a diuretic should be considered.

Eprosartan (Teveten)

Eprosartan may be used alone or in combination with other antihypertensives, such as diuretics and calcium channel blockers. The initial dose is 600 mg once daily when used as monotherapy in patients who are not volume depleted. The dose may be titrated if clinical response is not sufficient. The usual dosage range is 400-800 mg once or twice daily.

Azilsartan (Edarbi)

Azilsartan is indicated for hypertension, either alone or in combination with other antihypertensives. The usual dose is 80 mg once daily. Consider starting with an initial dose of 40 mg once daily in patients receiving high-dose diuretics.

Class Summary

Beta-blockers are generally not recommended as first-line agents for the treatment of hypertension; however, they are suitable alternatives when a compelling cardiac indication (eg, heart failure, myocardial infarction, diabetes) is present. Selective beta-blockers specifically block beta-1 receptors alone, although they can be nonselective at higher doses.

Caution should be used in administering these agents in the setting of asthma or severe chronic obstructive pulmonary disease (COPD), regardless of beta-selectivity profile. In addition, exacerbations of angina and, in some cases, myocardial infarction have been reported following abrupt discontinuance of beta-blocker therapy. The doses should be gradually reduced over at least a few weeks.

Atenolol (Tenormin)

Atenolol is approved for the management of hypertension used alone or concomitantly with other antihypertensive agents, particularly with a thiazide-type diuretic. The initial dose is 50 mg daily, alone or added to diuretic therapy. If adequate clinical effect is not seen, the dose can be titrated to 100 mg daily. Other studies suggest that atenolol lacks specific potential for stroke reduction.

Metoprolol (Lopressor, Toprol XL)

Metoprolol is approved for the management of hypertension alone or concomitantly with other antihypertensive agents. The initial dose for metoprolol immediate release is 100 mg daily in single or divided doses, with or without a diuretic (maximum 450 mg/day). Metoprolol extended-release formulation can be started at a dose of 25-100 mg daily in a single dose, with or without a diuretic (maximum 400 mg/day).

Propranolol (Inderal LA, InnoPran XL)

Propranolol is approved for the management of hypertension alone or concomitantly with other antihypertensive agents. The initial dose is 40 mg given twice daily, alone or added to diuretic therapy. Dose can be titrated based on a patient's clinical response. The maintenance dose can range from 120-240 mg/day (maximum 640 mg/day). Exacerbations of angina and, in some cases, myocardial infarction, following abrupt discontinuance of propranolol therapy have been reported. The propranolol dose should be gradually reduced over at least a few weeks.

Bisoprolol (Zebeta)

Bisoprolol is approved for the management of hypertension alone or in combination with other antihypertensive agents. This agent is a more specific beta-1 blocker than other beta-blockers. The initial dose is 5 mg once daily (reduce to 2.5 mg for patients with bronchospastic disease). The dosage can be titrated to 10 mg/day and then to 20 mg/day if necessary.

Timolol

Timolol is indicated for the treatment of hypertension. It is used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics. The initial dose is 10 mg given twice daily. The total daily dose can be titrated to a maximum of 30 mg administered in divided doses. Avoid abrupt cessation of therapy, because of the risk of exacerbation of ischemic heart disease.

Class Summary

Beta-blockers, such as labetalol and carvedilol, have peripheral vasodilatory effects that act via antagonism of the alpha-1 receptor in addition to beta-receptors.

Labetalol (Trandate)

Labetalol is indicated for the management of hypertension. Labetalol tablets may be used alone or in combination with other antihypertensive agents, especially thiazide and loop diuretics. The initial dose is 100 mg given twice daily. The dose may be titrated after 2-3 days in increments of 100 mg twice a day every 2-3 days (maximum 2400 mg/day).

Labetalol's actions at alpha-1 and beta-receptors lead to vasodilation and decreased total peripheral resistance, which results in decreased blood pressure without a substantial decrease in resting heart rate, cardiac output, or stroke volume.

Carvedilol (Coreg, Coreg CR)

Carvedilol is approved for the management of essential hypertension. It can be used as monotherapy or in combination with other antihypertensive agents, especially thiazide-type diuretics. The initial dose is 6.25 mg given twice daily. The dose can be titrated at intervals of 7-14 days to 12.5 mg twice daily, then to 25 mg twice daily as needed (maximum 50 mg/day).

Similar to labetalol, carvedilol antagonizes both alpha-1 and beta-receptors. Carvedilol lowers standing blood pressure more than supine blood pressure; orthostatic hypotension may occur.

Class Summary

Agents such as acebutolol and pindolol possess intrinsic sympathomimetic activity (ISA). These agents can be used alone or in combination with other antihypertensive agents, particularly with a thiazide-type diuretic.

Acebutolol (Sectral)

Acebutolol is a cardioselective, beta-adrenoreceptor-blocking agent, which possesses mild intrinsic sympathomimetic activity in its therapeutically effective dose range. Initial dose in uncomplicated, mild to moderate hypertension is 400 mg daily, or twice-daily dosing may be required for adequate 24-hour blood pressure control. Optimal response is usually achieved with dosages of 400 to 800 mg/day; however, some patients have been maintained on as little as 200 mg/day.

Pindolol

Pindolol is indicated in the management of hypertension and can be used alone or with other antihypertensive agents, particularly with a thiazide-type diuretic. The initial dose is 5 mg twice daily alone or in combination with other antihypertensive agents. An antihypertensive response usually occurs within the first week of treatment. Maximal response, however, may take as long as 2 weeks or even longer.

Class Summary

Vasodilators relax blood vessels to improve blood flow, thus decreasing blood pressure.

Hydralazine

Oral hydralazine is indicated for essential hypertension, alone or as an adjunct. Initial dose is 10 mg given 4 times daily for the first 2 to 4 days, then 25 mg 4 times a day for 1 week. Hydralazine IV or IM is indicated for severe essential hypertension when the drug cannot be given orally or when there is an urgent need to lower BP. Hydralazine may lower blood pressure by exerting a peripheral, vasodilating effect through a direct relaxation of vascular smooth muscle. Caution should be used when hydralazine is administered in patients with concomitant coronary artery disease.

Minoxidil

Minoxidil is indicated in severe hypertension that is symptomatic or associated with end-organ damage and is not manageable with maximum therapeutic doses of a diuretic plus 2 other antihypertensives. The initial dose is 5 mg/day as a single dose and can be titrated to 10, 20, and then 40 mg in single or divided doses as needed (maximum 100 mg/day). Minoxidil reduces elevated systolic and diastolic blood pressure by decreasing peripheral vascular resistance. The blood pressure response to minoxidil is dose-related and proportional to the extent of hypertension. Concomitant therapy with an antiadrenergic agent and loop diuretic is generally required.

Class Summary

Calcium channel blockers (CCBs) can be divided into dihydropyridines and nondihydropyridines. Dihydropyridines bind to L-type calcium channels in the vascular smooth muscle, which results in vasodilatation and a decrease in blood pressure. They are effective as monotherapy in black patients and elderly patients. Some examples of dihydropyridines include amlodipine, nifedipine, clevidipine, and felodipine. Non-dihydropyridines such as verapamil and diltiazem 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.[146]

Nifedipine (Adalat CC, Afeditab CR, Nifediac CC, Nifedical XL, Procardia XL)

Nifedipine extended-release is indicated for the treatment of hypertension alone or in combination with other antihypertensive agents. The usual dose for nifedipine is 30-60 mg once daily (maximum 90 mg/day); when used for hypertension, nifedipine can be administered to a maximum of 120 mg/day.

Clevidipine (Cleviprex)

Clevidipine butyrate is a dihydropyridine L-type CCB that is rapidly metabolized in blood and tissues and does not accumulate in the body. L-type calcium channels mediate the influx of calcium during depolarization in arterial smooth muscle. It is indicated for the reduction of BP when oral therapy is not feasible or is not desirable.

Amlodipine (Norvasc, Katerzia)

Amlodipine is a dihydropyridine CCB that has antianginal and antihypertensive effects. Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.

Felodipine (Plendil)

Felodipine is a dihydropyridine CCB that inhibits the influx of extracellular calcium across the myocardial and vascular smooth muscle cell membranes. These effects elicit an increased oxygen delivery to the myocardial tissue, a decreased total peripheral resistance, a decreased systemic blood pressure, and a decreased afterload.

Diltiazem (Cardizem CD, Cardizem LA, Cartia XT, Dilacor XR, Dilt-CD, Dilt-XR, Matzim LA, Taztia XT, Tiazac)

Diltiazem is a nondihydropyridine CCB that produces its antihypertensive effect primarily by relaxation of vascular smooth muscle and the resultant decrease in peripheral vascular resistance. The magnitude of blood pressure reduction is related to the degree of hypertension.

Verapamil (Calan, Calan SR, Covera-HS, Isoptin SR, Verelan, Verelan PM)

Verapamil is a nondihydropyridine that produces its antihypertensive effect by a combination of vascular and cardiac effects. It acts as a vasodilator with selectivity for the arterial portion of the peripheral vasculature. As a result, the systemic vascular resistance is reduced, usually without orthostatic hypotension or reflex tachycardia.

Class Summary

Aldosterone antagonists compete with aldosterone receptor sites, reducing blood pressure and sodium reabsorption.

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. Although this agent is more specific than spironolactone at the mineralocorticoid receptor, it is less potent. There have also been some minimal reports of gynecomastia.

Eplerenone is indicated for the treatment of hypertension. Eplerenone may be used alone or in combination with other antihypertensive agents.

Spironolactone

Spironolactone is usually used in combination with other drugs for patients who cannot be treated adequately with other agents or for whom other agents are considered inappropriate. The initial dose ranges from 50-100 mg daily in single or divided doses. Spironolactone can cause hyperkalemia; therefore, potassium supplementation should not be given concurrently. Other adverse effects include gynecomastia and impotence, which often mitigates the use of spironolactone in younger men.

Class Summary

Centrally acting alpha2-agonists stimulate presynaptic alpha2-adrenergic receptors in the brain stem, which reduces sympathetic nervous activity.

Methyldopa

Methyldopa stimulates central alpha-adrenergic receptors by a false transmitter, exerting a direct effect on peripheral sympathetic nerves. Decreases in blood pressure are greatest when the patient is standing but are also significant when the patient is supine. Postural hypotension has been reported in patients receiving methyldopa. Methyldopa is not associated with a rebound effect, as with clonidine.

Clonidine (Catapres)

Clonidine stimulates alpha2-adrenoreceptors in the brain stem, activating an inhibitory neuron, which in turn results in reduced sympathetic outflow. These effects result in a decrease in peripheral resistance, renal vascular resistance, blood pressure, and heart rate. Clonidine can be used alone or in combination with other antihypertensives. Clonidine is associated with a rebound effect, especially at higher doses or with more severe hypertension.

Guanfacine (Tenex)

Guanfacine is an orally active antihypertensive agent whose principal mechanism of action appears to be stimulation of central alpha-2 adrenergic receptors. By stimulating these receptors, guanfacine reduces sympathetic nerve impulses from the vasomotor center to the heart and blood vessels. This results in a decrease in peripheral vascular resistance and a reduction in heart rate. Guanfacine may be given alone or in combination with other antihypertensive agents, especially thiazide-type diuretics.

Class Summary

Renin inhibitors act within the renin-angiotensin system (RAS), a hormone system important in the regulation of blood pressure, electrolyte homeostasis, and vascular growth. Renin inhibitors have an additive effect when used with diuretics. Avoid the use of these agents in pregnancy.

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. This agent remains under investigation.

Keep in mind that aliskiren can cause adverse events when used in combination with ACE-inhibitor or angiotensin-receptor-blocker (ARB) therapy. In patients who have hypertension and type 2 diabetes and renal impairment and are at high risk of cardiovascular and renal events, there is an increased risk of nonfatal stroke, renal complications, hypokalemia, and hypotension when aliskiren is added to ACE inhibitor or ARB therapy. See the Novartis December 2011 press release, "Novartis announces termination of ALTITUDE study with Rasilez®/ Tekturna® in high-risk patients with diabetes and renal impairment."

Class Summary

Alpha-blockers are generally not recommended as initial monotherapy. They selectively block postsynaptic alpha1 -adrenergic receptors. They dilate arterioles and veins, thus lowering blood pressure. These drugs can be combined with any of the other antihypertensives in other drug classes. Common side effects seen in this drug class include dizziness, headache, and drowsiness, in addition to orthostatic and first-dose hypotension.

Prazosin (Minipress)

Prazosin is a competitive antagonist at postsynaptic alpha1-receptors. Prazosin causes peripheral vasodilation by selective, competitive inhibition of vascular postsynaptic alpha1-adrenergic receptors, thus reducing peripheral vascular resistance and blood pressure.

Terazosin

Terazosin causes peripheral vasodilation by selective, competitive inhibition of vascular postsynaptic alpha1-adrenergic receptors, thereby reducing peripheral vascular resistance and blood pressure. Terazosin reduces blood pressure in both the supine and the standing positions, with more dramatic effects on diastolic blood pressure.

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 a decrease in total peripheral resistance and blood pressure. The antihypertensive effect of doxazosin mesylate results from a decrease in systemic vascular resistance.

Class Summary

Reserpine is a peripherally acting adrenergic agent. It is indicated for mild hypertension and can be used as adjunctive therapy with other antihypertensive agents in more severe forms of hypertension.

Reserpine

Reserpine reduces blood pressure by depleting sympathetic biogenic amines. The result of reserpine's effects on biogenic amines is sympathetic dysfunction, with a subsequent decrease in peripheral vascular resistance and a lowering of blood pressure often associated with bradycardia. This agent is also associated with depression.

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 patients will require multiple medications to achieve their blood pressure targets and will benefit from drug combinations. Drug combination therapy may also help to improve patient compliance.

Drug combinations include—but are not limited to—the following:

- Amlodipine/benazepril (Lotrel)

- Amlodipine/olmesartan (Azor)

- Amlodipine/telmisartan (Twynsta)

- Amlodipine/valsartan (Exforge)

- Amlodipine/valsartan/hydrochlorothiazide (Exforge HCT)

- Amlodipine/aliskiren (Tekamlo)

- Amlodipine/aliskiren/hydrochlorothiazide (Amturnide)

- Olmesartan/amlodipine/hydrochlorothiazide (Tribenzor)

- Trandolapril/verapamil (Tarka)

- Benazepril/hydrochlorothiazide (Lotensin HCT)

- Captopril/hydrochlorothiazide (Capozide)

- Enalapril/hydrochlorothiazide (Vaseretic)

- Fosinopril/hydrochlorothiazide

- Lisinopril/hydrochlorothiazide (Prinzide, Zestoretic)

- Moexipril/hydrochlorothiazide (Uniretic)

- Quinapril/hydrochlorothiazide (Accuretic)

- Candesartan/hydrochlorothiazide (Atacand HCT)

- Eprosartan/hydrochlorothiazide (Teveten HCT)

- Irbesartan/hydrochlorothiazide (Avalide)

- Losartan/hydrochlorothiazide (Hyzaar)

- Olmesartan/hydrochlorothiazide (Benicar HCT)

- Telmisartan/hydrochlorothiazide (Micardis HCT)

- Valsartan/hydrochlorothiazide (Diovan HCT)

- Atenolol/chlorthalidone (Tenoretic)

- Bisoprolol/hydrochlorothiazide (Ziac)

- Metoprolol/hydrochlorothiazide (Lopressor HCT)

- Nadolol/bendroflumethiazide (Corzide)

- Propranolol/hydrochlorothiazide

- Aliskiren/hydrochlorothiazide (Tekturna HCT)

- Clonidine/chlorthalidone (Clorpres)

- Spironolactone/hydrochlorothiazide (Aldactazide)

- Triamterene/hydrochlorothiazide (Dyazide, Maxzide)

- Methyldopa/hydrochlorothiazide

- Amiloride/hydrochlorothiazide

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.

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.

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.

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.

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.

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.