Blood Pressure Classification

The classification of blood pressure, described in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) published in 2003,1 places patients into one of four categories (Table 70–1). Most notable is the designation of prehypertension, which combines what had previously been classified as normal and high-normal blood pressure. The basis for this reclassification was the recognition of the strong correlation between adverse outcomes and blood pressure levels, including levels previously considered normal. In addition, those with prehypertension were known to be at high risk to progress to hypertension. This new classification was aimed to identify individuals early in the progression of disease, at a time when lifestyle modifications could slow the progression or prevent the development of hypertension entirely.

Since the JNC 7 publication, other published guidelines have generally retained the categories of stage 3 hypertension (systolic ≥180 mm Hg or diastolic ≥110 mm Hg) and isolated systolic hypertension.2-7 Although the European Society of Hypertension and the European Society of Cardiology recognized the potential value of the prehypertensive category, they expressed concern that the lay public’s perception of the term would limit the adoption of this classification.2 In addition, they recommended thresholds for hypertension based on individual cardiovascular risk.

Blood Pressure Measurement

To apply the previously mentioned classifications in clinical practice, blood pressure must be recorded accurately. However, measurement of blood pressure, although one of the most important measurements in clinical medicine, is also one of the measurements with the greatest source of error. Blood pressure can be measured intra-arterially by insertion of a catheter into the lumen of an artery, but this method is impractical and is rarely used in clinical examination, except in intensive care units. The gold standard for clinical measurement of blood pressure is readings taken by a trained health care provider using a mercury sphygmomanometer. Aneroid and automated sphygmomanometers have increased in popularity over recent years. When used as a substitute for a mercury sphygmomanometer, a protocol for regular periodic calibration of the device should be in place.1,8 Regardless of the device used, it is important to appreciate that blood pressure is a variable hemodynamic phenomenon that is influenced by many factors. Therefore, the circumstances and procedures for blood pressure measurement must be standardized.

Blood pressure measurements can be taken in the clinic, at home, or by ambulatory blood pressure monitoring. To maintain its predictive value, blood pressure measurement should be standardized with trained observers following the established protocol. Tight clothing should be removed, the arm supported at heart level, and talking avoided during the measurement. Patients should be seated for at least 5 minutes in a chair (rather than on an examination table), with feet flat on the floor and in a quiet room before the measurement is made.9,10 Cuffs of the appropriate size should be used such that the bladder encircles at least 80% of the upper arm and has a width equal to at least 40% of arm circumference. Using too small a cuff will lead to overestimation of blood pressure. The distal margin of the cuff should be at least 3 cm proximal to the antecubital fossa. The cuff should be inflated to a pressure of approximately 30 mm Hg above the point where the palpable pulse disappears. The mercury column should be deflated at 2 to 3 mm per second. The onset of phase I of the Korotkoff sounds (tapping sounds corresponding to the appearance of a palpable pulse) corresponds to systolic pressure. The disappearance of sounds (phase V) corresponds to diastolic pressure. The fifth phase should be used except in situations in which the disappearance of sounds cannot reliably be determined because sounds are audible even after complete deflation of the cuff. This occurs commonly in pregnant women, for example, in which case the fourth phase (muffling of the sounds) may be used to define diastolic blood pressure. At least two measurements spaced 1 to 2 minutes apart should be taken. Blood pressure should be measured in both arms at the first visit to detect possible differences because of peripheral vascular disease; if present, the higher value should be used. Measurement of blood pressure in the standing position should be undertaken initially and periodically, especially in those who are at risk of postural hypotension.4,11,12 Atrial fibrillation can make the measurement of blood pressure particularly difficult due to marked beat-to-beat variability. Although improvements in technology have occurred, this is a particularly important consideration when using semiautomatic or automated devices.13 In such circumstances, multiple auscultatory readings are recommended.

Ambulatory Blood Pressure Measurement

Ambulatory blood pressure measurement, a noninvasive fully automated technique in which multiple blood pressure measurements are recorded over an extended period of time (typically 24 hours), has gained in credibility. Several prospective studies have documented that the average level of ambulatory blood pressure predicts risk of morbid events better than clinic blood pressure. Normal ambulatory blood pressure values for adults (nonpregnant) are <135/85 mm Hg while awake and <120/75 mm Hg during the night.1,8,11 The most common application of ambulatory blood pressure monitoring is to ascertain an individual’s usual level of blood pressure outside the clinic setting, and thereby identify individuals with white-coat hypertension in whom there is a large discrepancy between clinic and home measurements. In addition to mean absolute levels of ambulatory blood pressure, certain diurnal ambulatory blood pressure patterns may predict blood pressure–related complications. Nighttime (asleep) blood pressure is usually lower than daytime blood pressure; individuals with a nondipping pattern (<10% blood pressure reduction from night to day) appear to be at increased risk for blood pressure–related complications compared with those with a normal dipping pattern. Other evidence suggests that the nighttime blood pressure may be a better predictor of cardiovascular risk. Other applications of ambulatory blood pressure monitoring are in patients with apparently refractory hypertension but little target-organ damage, suspected autonomic neuropathy, apparent drug resistance, hypotensive symptoms with antihypertensive medications, and episodic hypertension. Ambulatory blood pressure monitoring will also detect the presence of masked hypertension, which is defined as a normal clinic blood pressure and a high ambulatory blood pressure and is the reverse of white-coat hypertension. Although the presence of masked hypertension is associated with increased cardiovascular risk, the therapeutic implications of this diagnosis remain uncertain at this time.14,15

Home Blood Pressure Monitoring

Home blood pressure monitoring is a useful adjunct in the management of hypertension and is a practical option to assess differences between office and out-of-office blood pressure by eliminating the white-coat effect. Proper use of a validated and accurate device for home blood pressure measurement and adequate training are important in enhancing the value of self-blood pressure measurement. Normal home blood pressure levels are readings <135/85 mm Hg.16,17 Home blood pressure monitoring also has been shown to improve compliance with antihypertensive medications and to be at least as good a predictor of cardiovascular risk as office-based blood pressure readings.

Impedance Cardiography

Impedance cardiography (ICG) is a potentially promising noninvasive method of hemodynamic monitoring to facilitate the achievement of blood pressure control. It can be performed in the provider’s office setting in approximately 5 to 10 minutes. Sensors are applied to the neck and thorax that measure beat-to-beat impedance changes of blood flow through the aortic arch, allowing several hemodynamic parameters to be calculated including stroke volume, cardiac output, and systemic vascular resistance. The validity and reproducibility of this noninvasive method of determining hemodynamic abnormalities have been demonstrated.18 ICG data have shown promise in the evaluation of hypertensive patients.19 Two prospective, although uncontrolled, studies have suggested that ICG-guided antihypertensive therapy may have utility in achieving blood pressure control in uncontrolled hypertensive patients.20-22 This method of hemodynamic monitoring may work in part by reinforcing the need for additional agents, especially diuretics.20

History and Physical Examination and Laboratory Evaluation

The three main goals of the initial evaluation of the hypertensive patient are to (1) assess the presence of target-organ damage related to hypertension, especially damage that might influence choice of therapy; (2) determine the presence of other cardiovascular risk factors and disease; and (3) evaluate for possible underlying secondary causes of hypertension. These goals are usually accomplished by a thorough medical history, physical examination, and appropriate laboratory investigations.11

History

The key issues that need to be addressed in the history include:

• Duration, age of onset, and previous levels of high blood pressure;
  
• Previous antihypertensive therapy and its impact on blood pressure and adverse effects;
  
• Symptoms suggestive of secondary causes of hypertension (see Secondary Causes of Hypertension);
  
• Use of medications that influence blood pressure such as oral contraceptives, licorice, carbenoxolone, nasal drops, cocaine, amphetamines, steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), erythropoietin, and cyclosporine;
  
• Lifestyle factors, such as dietary intake of fat and salt, alcohol use, smoking, physical activity, and weight gain since early adult life;
  
• History of symptoms of neurologic dysfunction, heart failure, coronary heart disease, or peripheral arterial target-organ damage; and
  
• Presence of other cardiovascular risk factors.

Physical Examination

In addition to blood pressure measurement, the physical examination should search for signs of secondary hypertension and for evidence of organ damage. During the physical examination, note should be made of blood pressure, features of Cushing syndrome, tuberous sclerosis or skin stigmata of neurofibromatosis (suggesting possible pheochromocytoma), palpation of enlarged kidneys (polycystic kidney), auscultation of abdominal bruits (renovascular hypertension) and precordial murmurs (aortic coarctation or aortic disease), and diminished and delayed femoral pulses (aortic coarctation or aortic disease); these features all suggest secondary hypertension. Other signs, such as carotid bruits; motor or sensory defects; funduscopic abnormalities; abnormal cardiac rhythms; ventricular gallop; pulmonary rales; dependent edema; and absence, reduction, or asymmetry of pulses and cold extremities, may suggest end-organ damage (Table 70–2).

Laboratory Tests

Routine investigations before initiation of therapy include urine for protein and blood, serum creatinine (estimated glomerular filtration rate [GFR]) and electrolytes, fasting blood glucose, fasting lipid profile, and electrocardiogram (ECG). Generally, it is not necessary to do more extensive tests unless blood pressure control is not achieved or there are clinical or laboratory clues of secondary hypertension. An echocardiogram may be helpful in evaluating cardiac function in patients with cardiac symptoms or findings. Additional workup is guided by the clinical presentation in an individual patient and the need to evaluate possible causes of secondary hypertension.

Risk Assessment

Increased cardiovascular risk across the whole range of blood pressure is well described.23,24 However, the coexistence of other risk factors results in a significant increase in cardiovascular disease risk associated with any blood pressure stratum. Those at highest absolute risk include people with multiple risk factors, those with diabetes who tend to demonstrate risk factor clustering, and those who have already suffered a cardiovascular event. Thus, during the evaluation, the key risk factors that need to be considered are age (>45 years for men, >55 years for women), family history of premature cardiovascular disease (age <55 in men, age <65 years in women), cigarette smoking, dyslipidemia, diabetes, obesity (body mass index >30 kg/m2), reduced GFR (<60 mL/min), and presence of albuminuria. Online tools, such as those developed from the Framingham Study, can be used to quantify risk of cardiovascular disease.24 Other risk factors have been proposed but remain to be confirmed (see Chap. 52, 53, 54, 55).

Secondary hypertension is said to be present when the hypertension results from a specific cause in contrast to the more common primary form (essential hypertension) in which no direct cause is known. The most common causes of secondary hypertension are renal artery stenosis, renal parenchymal disease, sleep apnea, primary aldosteronism, Cushing syndrome, and pheochromocytoma.25-29 Table 70–3 summarizes the clinical clues suggesting secondary hypertension.

Renal Artery Stenosis

Renovascular hypertension occurs in 1% to 2% of the overall hypertensive population, but the prevalence may be as high as 10% in patients with resistant hypertension and even higher in patients with accelerated or malignant hypertension. Clinical clues to renovascular disease include (1) onset of hypertension before age 30 years (especially without a family history) or recent onset of significant hypertension after age 55 years; (2) an abdominal bruit, particularly if it continues into diastole and is lateralized; (3) accelerated or resistant hypertension; (4) recurrent (flash) pulmonary edema; (5) renal failure of uncertain etiology, especially with a normal urinary sediment; (6) coexisting diffuse atherosclerotic vascular disease, especially in heavy smokers; and (7) acute renal failure precipitated by antihypertensive therapy, particularly angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs).30 Fibromuscular dysplasia can cause renovascular hypertension in younger patients, especially women between 15 and 50 years of age. However, atherosclerotic renal artery stenosis occurs in older persons, is bilateral in 35% to 50% of cases, and is associated with atherosclerosis of the coronary, carotid, and lower extremity vessels. Hypertension in this setting is often resistant to standard therapy.31

Numerous invasive and noninvasive tests are available to screen for renal artery stenosis in appropriate patients.32 Before starting any evaluation, it is important to remember that screening tests and angiography are unlikely to benefit patients who are judged not to be candidates for either surgery or angioplasty. In contrast, if fibromuscular dysplasia is suspected as the etiology of renal artery disease, it is best to proceed directly to renal angiography. The duplex ultrasonography test is noninvasive and safe in all age groups, and can be used in serial follow-up to assess patients with impaired renal function after revascularization. However, sensitivity and specificity of this measurement are operator dependent, and there can be significant false-negative or false-positive results as a consequence of the operator’s inexperience or the presence of obesity or bowel gas.33 The ACE-inhibitor renal scintiscan, in which administration of oral captopril decreases the GFR of the affected kidney using the tracer technetium 99–diethylenetriamine pentaacetic acid, is a highly sensitive and specific nuclear imaging test that can be used to identify critical renal artery stenosis. The test lacks anatomic information about the renal arteries, and its accuracy is reduced in patients with impaired renal function.34,35

Three-dimensional gadolinium magnetic resonance angiography has been established as a reliable technique for the detection and grading of renal artery stenosis. Using current software and digital subtraction techniques, the sensitivity and specificity of this test to diagnose renal artery stenosis exceeds 90%. Major disadvantages are related to costs; false-positive artifacts related to respiration, peristalsis, and tortuous vessels; and inability to identify nonostial stenosis or stenoses in accessory renal arteries.36 In addition, in patients with impaired renal function, administration of gadolinium has been associated with development of nephrogenic systemic fibrosis. Renal angiography remains the gold standard for diagnosis. It provides information about the site and severity of stenoses and appropriate revascularization strategies. The need for contrast and its related complications limits its usefulness in patients with impaired renal function. Spiral computed tomography with angiography combines high sensitivity and high specificity.

Treatment of renal artery stenosis is controversial. With the current armamentarium of antihypertensive drugs, satisfactory blood pressure control can be achieved, even in patients with renovascular hypertension. Invasive options to correct the stenosis include renal artery angioplasty with stent placement and surgical revascularization. Case series have reported that angioplasty can restore renal function37,38 and prevent recurrent heart failure.39 However, trials comparing medical therapy with angioplasty/stent placement have thus far failed to confirm the beneficial findings.40,41 A large trial evaluating whether stenting atherosclerotic renal artery stenosis reduces the incidence of cardiovascular and renal events is ongoing.42

A multidisciplinary approach, including the participation of a hypertension specialist, interventional radiology, and vascular surgery, is needed to review all options in a given patient. The central question is whether the benefits of renal revascularization on both blood pressure control and prevention of progressive renal injury outweigh the risks of the procedure. The use of various risk factors has been proposed to select patients who are likely to benefit from revascularization. Urinary protein excretion of at least 1 g/d; hyperuricemia; creatinine clearance of <40 mL/min; age <65 years; the presence of coronary artery disease (CAD), arterial occlusive disease of the legs, or cerebrovascular disease; and a resistance index of <80 in the segmental arteries of both kidneys, as measured by Doppler ultrasonography, are useful in identifying patients who are less likely to benefit.43,44

Sleep Apnea

Obstructive sleep apnea is a common medical condition characterized by abnormal collapse of the pharyngeal airway during sleep, causing repetitive arousals from sleep. It affects 4% of middle-aged men and 2% of middle-aged women.45,46 Obstructive sleep apnea may occur in up to 50% of patients with hypertension.47-53 The most common clinical presentation of obstructive sleep apnea is loud snoring, breathing pauses observed by the bed partner, and excessive daytime sleepiness. A formal sleep study usually is needed for diagnosis of obstructive sleep apnea and the determination of corrective interventions. There are several questionnaires that can be used in screening for this disorder.54,55 Although there is consensus that continuous positive airway pressure treatment can reduce nocturnal blood pressure in patients with obstructive sleep apnea, the effect on daytime blood pressure is less clear. Selected patients may be candidates for oral appliances, uvulopalatopharyngoplasty, or other surgical procedures. Sleep apnea is associated with elevated aldosterone levels, and aldosterone antagonists have been used to treat sleep apnea–related hypertension.56,57

Primary Aldosteronism

Screening for hyperaldosteronism should be considered for at least the following patients: hypertensive patients with spontaneous hypokalemia (K+ <3.5 mmol/L); hypertensive patients with marked diuretic-induced hypokalemia (K+ <3.0 mmol/L); patients with hypertension refractory to treatment with three or more drugs; and hypertensive patients found to have an incidental adrenal adenoma.58 Screening for hyperaldosteronism includes assessment of plasma aldosterone and plasma renin activity measured under standardized conditions (ie, the collection of morning samples taken from patients in a sitting position after resting at least 15 minutes). Antihypertensive drugs, with the exception of aldosterone antagonists, may be continued before initial testing. The screening test is considered positive if the plasma aldosterone/renin activity ratio is >25. The diagnosis of primary aldosteronism is established by demonstrating inappropriate autonomous hypersecretion of aldosterone after oral or intravenous saline loading.59,60

Primary aldosteronism may be caused by the presence of an adrenal adenoma or bilateral adrenal hyperplasia. Imaging with adrenal computed tomography scan or magnetic resonance imaging may help differentiate between the two conditions, although selective adrenal venous sampling may be needed. The treatment of confirmed unilateral aldosterone-producing adenoma is surgical removal of the affected adrenal gland, usually by laparoscopic adrenalectomy. Before pursuing the surgery, patients should be treated medically for 8 to 10 weeks to correct metabolic abnormalities and to control blood pressure. Medical treatment with aldosterone antagonists (spironolactone or eplerenone) should be considered for patients with adrenal hyperplasia, bilateral adenoma, or increased risk of perioperative complications. Amiloride is another alternative for the patient who is intolerant to spironolactone.60,61

Cushing Syndrome

Cushing syndrome results from excessive concentrations of circulating free glucocorticoids. Endogenous Cushing syndrome is more common in women; corticotropin-dependent causes account for approximately 80% to 85% of cases. Of these, 80% are caused by pituitary adenomas (Cushing disease), with the remaining 20% caused by ectopic corticotrophin syndrome (Cushing syndrome).62,63 Cortisol excess predisposes to hypertension by salt retention and glucose intolerance. The presence of facial plethora, rounded face, decreased libido, menstrual irregularity, hirsutism, depression and emotional liability, thin skin in the young, easy bruising, and proximal weakness are clinical clues for Cushing syndrome. The 24-hour urinary free cortisol (>90 mg/d; sensitivity = 100%; specificity = 98%) is a useful screening test for Cushing syndrome. The single-dose (1-mg) overnight dexamethasone suppression test is equally sensitive but is a little less specific than the 24-hour urinary cortisol. Treatment of Cushing syndrome is either medical or surgical. Metyrapone, ketoconazole, and mitotane can all be used to lower cortisol by directly inhibiting synthesis and secretion in the adrenal gland.64

Pheochromocytoma

Patients with paroxysmal and/or severe sustained hypertension who are refractory to the usual antihypertensive therapy should be evaluated for pheochromocytoma. The presence of headaches, palpitations, sweating, panic attacks, and pallor in a hypertensive patient are symptoms suggesting a possible pheochromocytoma. Triggering of hypertension by β-blockers, anesthesia, monoamine oxidase inhibitors, micturition, or changes in abdominal pressure should also raise the suspicions for pheochromocytoma. It may also be present in some other rare conditions such as patients with hypertension and multiple endocrine neoplasias (MEN-2A/2B), von Recklinghausen neurofibromatosis, or von Hippel-Lindau disease. A 24-hour urinary metanephrine (cutoff point of >3.70 nmol/d) is highly sensitive and specific when done carefully, but urine collection is inconvenient and may be incomplete. Plasma metanephrines (metanephrine >0.66 nmol/L or normetanephrine >0.30 nmol/L) are easy to obtain and may represent a good screening test for pheochromocytoma, especially if the patient is symptomatic or blood pressure is elevated at the time of collection. Because these tests have limited specificity (85%), a positive plasma metanephrine should be confirmed by the 24-hour urinary metanephrine-to-creatinine ratio (cutoff point of >0.354; specificity = 98%) before proceeding to anatomic localization of the tumor. Imaging studies commonly used to localize pheochromocytomas include computed tomography scan and meta-iodobenzylguanidine scintigraphy, the latter is particularly useful when an extra-abdominal focus is suspected. α-Blockers (eg, prazosin, doxazosin, phenoxybenzamine) should be used as first-line agents in suspected pheochromocytoma. Treatment of benign pheochromocytoma should be surgical resection. It is important not to use β-blockers alone because the unopposed α activity will worsen the vasoconstriction, resulting in a further increase in blood pressure. Thus, β-blockers should generally be withheld until surgery is performed, unless there are arrhythmias present and adequate α-blockade has been achieved. Perioperative care of the patient with pheochromocytoma requires administration of intravenous fluids to ensure adequate volume expansion to avoid shock after tumor removal and phentolamine hydrochloride as needed for severe hypertension. For patients with inoperable or metastatic malignant pheochromocytoma, blood pressure and adrenergic symptoms may be controlled with α-adrenergic blockade plus β-blockade and/or tyrosine hydroxylase inhibition with metyrosine.

Hypertension is the most important preventable cause of premature death,65 and treatment should focus on achieving the recommended blood pressure goal. The benefits of antihypertensive therapy for the prevention of cardiovascular and renal mortality and morbidity are well established.11 The best evidence demonstrating benefit comes from clinical outcome trials assessing the effect of drug treatment. However, there are recent data relating a reduction in clinical outcomes with lifestyle changes. For most patients, reduction to <140 mm Hg for the systolic blood pressure and <90 mm Hg for the diastolic blood pressure are the recommended goals of most guideline panels, with lower goals (<130/80 mm Hg) recommended in those with diabetes and chronic kidney disease (see Table 70–7 later in this chapter). Observational studies suggest benefit at lower blood pressures, which has been sufficient evidence to influence some guideline recommendations. However, these studies need to be confirmed by specific randomized outcome trials. A recent Cochrane meta-analysis found the evidence insufficient to recommend a blood pressure goal lower than 140/90 mm Hg.66

Lifestyle Modification

Recent controlled trials have confirmed that lifestyle changes can lower blood pressure.67,68 Clear verbal and written guidance on lifestyle measures should be provided for all hypertensive patients and those with prehypertension (see Table 70–1). Lifestyle interventions reduce the need for drug therapy, enhance the antihypertensive effects of drugs, and favorably influence overall cardiovascular disease risk.11 Conversely, failure to adopt these measures may attenuate the response to antihypertensive drugs.

Lifestyle changes for patients with high blood pressure include weight reduction, dietary changes (notably reduction of salt intake), moderation of alcohol intake, cessation of smoking, and aerobic exercise (Table 70–4). Weight loss of as little as 10 lb (4.5 kg) reduces blood pressure and/or prevents hypertension in a large proportion of overweight persons. A diet rich in fruits, vegetables, and low-fat dairy products with a reduced content of dietary cholesterol and saturated and total fat (Dietary Approaches to Stop Hypertension [DASH] eating plan) is helpful in lowering blood pressure.69 The DASH eating plan is also rich in potassium and calcium. Patients should be instructed in methods to reduce dietary salt to <6 g/d (<2.3 g/d sodium).70 Regular aerobic physical activity such as brisk walking at least 30 min/d most days of the week should become part of the hypertensive patient’s life. Alcohol intake should be limited to no more than 1 oz (30 mL) of ethanol, the equivalent of two drinks, per day in most men, and no more than 0.5 oz of ethanol (one drink) per day in women and lighter weight persons. For overall cardiovascular risk reduction, patients should be strongly counseled to stop smoking.

Pharmacology of Available Antihypertensives

There are nine classes of drugs available for the treatment of hypertension (Table 70–5).

Diuretics are a critical part of the antihypertensive armamentarium. They can be separated based on their mechanism of action.

Thiazide-Type Diuretics

Thiazide-type diuretics inhibit the Na-Cl cotransporter in the distal tubule to reduce extracellular volume and cardiac output. Diuresis is essential to their antihypertensive action, and their antihypertensive efficacy can be antagonized by high salt intake. Diuresis does not fully explain their long-term blood pressure reduction, and these drugs do cause some vasodilatation.71 Other proposed antihypertensive mechanisms of these agents include activation of Ca2+-activated K+ channels and alteration of vascular smooth muscle cytosolic pH by inhibiting vascular carbonic anhydrase. Hydrochlorothiazide and chlorthalidone are the most commonly prescribed agents of this class in the United States. Chlorthalidone has 1.5 to 2.0 times the potency of hydrochlorothiazide.72 Clinical outcome data with thiazide-type diuretics have used doses equivalent to 12.5 to 25 mg/d of chlorthalidone or 25 to 50 mg/d of hydrochlorothiazide and have shown similar benefit across the class of agents.73 In the recent Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial, hydrochlorothiazide at a dose half that used in previous clinical outcome studies (12.5-25 mg/d) was less effective in preventing cardiovascular events than amlodipine (5-10 mg/d) each combined with an ACE inhibitor.74 Indapamide at the recommended doses produces less hypokalemia; although at higher doses, it behaves similar to other thiazides. Thiazide diuretics were the primary agents used in the initial studies that demonstrated the benefit of blood pressure reduction in patients with hypertension. With the exception of metolazone and indapamide, most thiazide diuretics lose their antihypertensive effectiveness when the GFR declines to <30 to 40 mL/min. Most adverse effects of thiazide-type diuretics are related to fluid and electrolyte abnormalities. Hypokalemia, hyponatremia, hypochloremia, hypomagnesemia, metabolic alkalosis, hypercalcemia, and hyperuricemia are among the adverse effects, and serum electrolyte levels should be monitored at regular intervals. Diuretics can also increase blood glucose and lipids (each ~5 mg/dL). The effect of anticoagulants, uricosuric medications, sulfonylureas, and insulin may be diminished by thiazides. Conversely, they can increase the effect of diazoxide, loop diuretics, digitals, lithium, NSAIDs, and bile acid sequestrants. The hyponatremia can be concerning, especially in the elderly.

Loop Diuretics

Loop diuretics inhibit Na-K-2Cl transport in the thick ascending limb of the loop of Henle and include furosemide, bumetanide, ethacrynic acid, and torsemide. Because of their short half-life, they are less effective than thiazide-type diuretics in lowering blood pressure in patients with normal renal function when prescribed once or twice daily. In those with estimated GFR <30 to 40 mL/min/1.73 m2, their use is essential to achieve blood pressure goals. They are also usually required for volume control in those requiring vasodilators, especially minoxidil. Most adverse reactions are related to electrolyte abnormalities (ie, extracellular volume depletion, hypokalemia, hyponatremia, hypochloremic alkalosis, hyperuricemia, and hyperglycemia). Increased Mg and Ca excretion may lead to hypomagnesemia and hypocalcemia. NSAIDs and probenecid blunt the effect of loop diuretics, and thiazide diuretics have synergic effects with loop diuretics.

Potassium-Sparing Diuretics

The potassium-sparing diuretics triamterene and amiloride inhibit the renal epithelial Na channels and cause small increases in NaCl excretion. They are relatively weak diuretics and are rarely used as a single agent in the treatment of hypertension or edema. They are useful in preventing diuretic-induced hypokalemia when prescribed with other diuretics or as an alternative in patients with primary aldosteronism. The most serious adverse effect of this class of diuretics is hyperkalemia. Use with NSAIDs, ACE inhibitors, ARBs, and β-blockers and in diabetic hypertensives with or without nephropathy increases the risk of this adverse effect.

Antagonists of Mineralocorticoid Receptors

These are another class of potassium-sparing diuretics. Mineralocorticoids bind to the mineralocorticoid receptor to cause salt and water retention and increase the excretion of potassium and H+. The two available mineralocorticoid antagonists are spironolactone and eplerenone. Mineralocorticoid antagonists, often in combination with thiazides or loop diuretics, are effective in treating hypertension. They are particularly useful in the treatment of primary aldosteronism. They have also been shown to be effective in resistant hypertension regardless of aldosterone level.60 The major adverse effects of these agents include hyperkalemia, hypertriglyceridemia, and antiandrogen effects like breast pain, gynecomastia, and sexual dysfunction in males. Eplerenone is more selective for the mineralocorticoid receptor than spironolactone and less likely to produce antiandrogenic effects.

Calcium Channel Blockers

Calcium channel blockers (CCBs) inhibit calcium entry into vasculature smooth muscle through the voltage-sensitive L-type Ca2+ channels, resulting in vasodilation of peripheral arteries. Two subclasses of CCBs, dihydropyridines (DHPs; eg, nifedipine) and non-DHPs (eg, verapamil and diltiazem) are available (see Table 70–5

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