a hormone released in response to angiotensin II that causes excretion of potassium and retention of water and sodium.
proteins of the renin-angiotensin-aldosterone system. Angiotensin I is produced by the actions of renin on angiotensinogen, and angiotensin II is produced by the actions of angiotensin-converting enzyme on angiotensin I.
an enzyme responsible for the production of angiotensin II.
receptors of the nervous system that detect changes in the stretching of arterial walls.
the force exerted on vessel walls by the blood within, reported in the units mm Hg (millimeters of mercury).
Cardioselective beta blockers
agents that act primarily on beta1 receptors and avoid the noncardiac issues associated with beta2 blockade in the respiratory and other body systems.
receptors of the nervous system that detect changes in levels of oxygen, carbon dioxide, or other chemicals.
the force of a heartbeat.
Diastolic blood pressure
the pressure of the blood against the vessel walls when the heart is at rest.
a state of persistently elevated blood pressure.
enlargement of a tissue or organ.
a sudden drop in blood pressure that occurs when a patient stands.
also known as essential hypertension, this form of hypertension does not have a single identifiable cause.
an increase in heart rate in response to sudden vasodilation.
an enzyme released by the kidney that initiates a cascade of events that lead to the production of angiotensin II and increases in blood pressure.
Renin-angiotensin-aldosterone system (RAAS)
a series of proteins and enzymes that help to regulate blood pressure and is a target of numerous antihypertensive agents.
a form of hypertension with an identifiable cause, such as a disease or medication.
a device used to measure blood pressure.
Systolic blood pressure
the force of the blood against the vessel walls during a heartbeat.
narrowing of the blood vessels as a result of contraction of the smooth muscles in the vessel walls.
After completing this chapter, you should be able to
Define the terms blood pressure and hypertension.
Describe the various mechanisms used by the body to regulate blood pressure.
List the blood pressure values associated with each blood pressure classification.
Identify the consequences of untreated hypertension.
Explain nonpharmacological strategies used to treat hypertension.
Describe the mechanism of action, typical dosing, and side effects of the commonly used antihypertensive agents.
State the brand and generic names and pharmacological classes of the most commonly used antihypertensive agents and combinations.
Hypertension, defined as a persistently high blood pressure, is one of the most common disorders affecting the cardiovascular system. It affects as many as 72 million Americans, nearly a quarter of the population.1 If left unchecked, the damage can affect nearly every organ system in the body, and lead to severe heart disease, the leading cause of death in the United States. What makes this disorder particularly dangerous is the utter lack of symptoms in the vast majority of cases. Earning it the nickname “The Silent Killer,” only the most severe high blood pressure provides patients with a hint of its presence, allowing for years of organ damage to take place before a patient is diagnosed. Even when caught early through blood pressure screening, it is often difficult to convince patients to take medications with obvious side effects to treat a disease they never knew was present. With proper treatment, however, hypertension can be brought under control and the risks of organ damage can be effectively reduced. In this chapter, the basics of blood pressure will be introduced, including its measurement and the body’s natural mechanisms of regulation, followed by a review of the causes of hypertension and its treatment.
Mr. Anderson, a 52-year-old male, went to his doctor’s office for a checkup. His blood pressure was measured at 153/98 mm Hg.
Pathophysiology of Hypertension
The Basics of Blood Pressure
Blood pressure is a term used to describe the force that blood exerts on the vessel walls around it. One component of this pressure comes from the force of each heartbeat. As the left ventricle contracts, blood is forced through the aortic valve and into the systemic vasculature, increasing the amount of pressure in the arteries. The other component of blood pressure is the friction of blood against the walls of the arteries, also known as systemic vascular resistance (SVR). This friction opposes blood flow, making it more difficult for the heart to circulate blood around the body.
Like many other body systems, blood pressure must be kept in a delicate balance, high enough to adequately supply the body with oxygen but not excessively high where it may lead to organ damage. Though the contraction of the heart and the SVR are its two main components, the body employs a number of other factors to influence blood pressure and keep it in a desirable range. One such mechanism comes from the nervous system, with the sympathetic autonomic nervous system (SANS) acting to increase blood pressure and the parasympathetic autonomic nervous system (PANS) working to reduce it. Special receptors called baroreceptors and chemoreceptors can detect changes in arterial stretching and concentrations of oxygen, respectively. They then send signals to the brain to either increase or decrease the blood pressure, accordingly.
Hormones also play a large role in regulating blood pressure and are often targets of antihypertensive medications. In response to signals from the SANS, the hormones epinephrine and norepinephrine, also known as catecholamines, are released from the adrenal glands. When these hormones interact with the heart, they cause an increase in contractility, raising blood pressure by raising cardiac output. In the vasculature, epinephrine and norepinephrine cause the blood vessels to constrict, increasing SVR.
If the kidneys sense a decline in blood pressure, they release a substance called renin. When renin interacts with angiotensinogen, angiotensin I is produced. This protein further interacts with angiotensin-converting enzyme to release an active protein called angiotensin II. Angiotensin II acts on the vasculature to cause a profound vasoconstriction, increasing blood pressure. In addition to its direct effects on blood vessels, angiotensin II signals for the release of a hormone called aldosterone. This hormone causes the kidneys to reabsorb extra water in exchange for potassium, increasing the total volume circulating in the bloodstream and further raising blood pressure. This regulatory mechanism is referred to as the renin-angiotensin-aldosterone system (RAAS) and is a target of many antihypertensive medications. See Figure 15-1 for a depiction of the RAAS. These and a number of other hormones all work together to help maintain an appropriate blood pressure.
Since blood pressure reflects two different forces, it must be measured with two different values: the systolic and diastolic blood pressures. Systolic blood pressure refers to the pressure in the arteries during a contraction of the heart, or systole. It is the larger of the two values as it includes both the pressure of the SVR and the added pressure of a heartbeat. Diastolic blood pressure is the term used to describe the pressure in the arteries when the heart is at rest, or diastole. It is mainly a measure of SVR, alone.
Clinicians screen for hypertension by measuring the blood pressure. This is done using a device, commonly called a blood pressure cuff, but professionally known as a sphygmomanometer, made up of an inflatable cuff and a pressure gauge that gives a blood pressure reading in mm Hg (Hg is the chemical symbol for mercury, the liquid metal long used in the hollow column of devices for measuring many kinds of pressure, including that of the atmosphere). The cuff is fitted snuggly around a patient’s upper arm and inflated to a pressure well above the expected blood pressure value, effectively stopping the flow of blood through the artery. Next, the pressure is slowly released from the cuff. When the pressure of the cuff is reduced to the point where the artery opens, blood will begin to flow through the artery once more, making a sound that can be heard using a stethoscope. The pressure reading on the cuff at the instant the sound is heard corresponds to the patient’s systolic blood pressure. To detect the diastolic pressure, the cuff is deflated until the sounds of the blood flow become very faint or disappear. The pressure on the gauge at this point corresponds to the patient’s diastolic blood pressure. A normal blood pressure is a systolic pressure less than 120 mm Hg and a diastolic pressure less than 80 mm Hg. These two values are usually documented as the systolic blood pressure over the diastolic pressure, such as 120/80 (Figure 15-2).
What was Mr. Anderson’s systolic blood pressure? What was his diastolic blood pressure?
When measuring blood pressure, clinicians must ask patients if they have recently smoked, drunk caffeinated beverages, or exercised as these activities may elevate blood pressure temporarily.
Classification and Causes of Hypertension
The American College of Cardiology and American Heart Association have released a classification scheme to help clinicians diagnose patients with hypertension.2Table 15-1 lists the blood pressure values and their corresponding diagnoses. Since blood pressure can be temporarily elevated, the average of two different blood pressures obtained at separate office visits is used to diagnose hypertension. Patients with Stage I hypertension are those with mild disease and are often treated with only one medication, as opposed to patients with stage II hypertension, who have moderate to severe disease and often require at least two agents for control.
At his previous office visit, Mr. Anderson’s blood pressure was 148/88. How would his blood pressure status be classified? How many agents will he likely be started on to bring his pressure under control?
The most common type of hypertension is known as primary (or essential) hypertension, occurring in more than 90% of all patients with hypertension. In these cases, the exact cause of the elevated blood pressure is difficult to identify since many different factors play a role in its development. One such factor is genetics. It has been shown that patients with hypertensive family members are at an increased risk of developing the condition. This is likely due to inheritable dysfunctions in one of the many regulatory systems such as the RAAS or adrenal hormones. A patient’s lifestyle also can have a large influence on the risk of developing high blood pressure. Diets high in sodium and limited physical activity have been shown to be important risk factors. Because of its varying causes, primary hypertension cannot be cured. The goal of therapy is control of the condition, reducing blood pressure to less than 140/90 mm Hg in higher-risk patients.
For the fewer than 10% of patients with secondary hypertension, the high blood pressure is caused by an underlying condition or medication. The list of possible secondary causes is long, but some of the most common culprits are kidney disease, cancers of the adrenal gland, hyperthyroidism, and sleep apnea. In addition to diseases, medications and supplements such as nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, nasal decongestants, and cocaine can also cause elevations in blood pressure. In many cases of secondary hypertension, a cure is possible if the underlying disease can be found and treated or the causative medication is stopped.
Mr. Anderson currently has no other health conditions and is not taking any medications. What type of hypertension does he likely have?
The stress of a doctor’s appointment is sometimes enough to increase a patient’s blood pressure temporarily. This is known as white coat hypertension. To verify that a patient has hypertension, clinicians may have patients check their own blood pressure at home for a comparison with in-office values.
Implications of Uncontrolled Hypertension
Because blood flow is a crucial requirement for the proper functioning of nearly every body system, hypertension has the potential to cause damage in many different areas of the body. The systems most at risk include the kidneys, brain, heart, vasculature, and eyes. The higher a patient’s blood pressure, the greater the risk of developing serious complications or death.
Perhaps the largest impact of hypertension can be seen in the cardiovascular system, where it is a major risk factor for the development of a heart attack or stroke. Elevated pressures accelerate the development of atherosclerotic plaques, accumulations of cholesterol and cellular debris that can block the flow of blood through a vessel. When these plaques rupture, small pieces can travel downstream and become lodged in smaller arterioles or capillaries, blocking blood flow. Without a supply of oxygen, the areas around the blockage begin to die. When these events happen in a coronary artery, the result is a heart attack, or myocardial infarction; if the ruptured plaque travels to the brain, the result is a stroke. Longstanding hypertension can also cause significant changes to the structure of the heart and blood vessels. After many years of pumping against high pressures, the heart can become enlarged, or hypertrophied, and the blood vessels can become less elastic (hardened). At their most severe, these changes can cause a patient to develop heart failure or arrhythmias. For a detailed discussion of heart disease, see Chapter 16.
As described in Chapter 14, the consequence of hypertension in the kidney is nephropathy. Under pressure, the small capillaries of the glomerulus become thickened and sclerosis, or scarring, reduces the nephron’s ability to filter blood. This condition can progress to renal failure, in which case the kidneys can no longer filter blood on their own. These patients require dialysis to remove cellular waste from the blood.
Mr. Anderson doesn’t have any symptoms and is concerned about the inconveniences involved in lowering his blood pressure. What types of health risks does Mr. Anderson face if his hypertension is not controlled?
Just as in the kidneys, it is the smallest blood vessels in the eyes that bear the brunt of the effects of elevated blood pressure. Though it usually requires extremely high pressures, the capillaries in the retina, the inner surface of the eye, can become damaged or even rupture. This condition, known as hypertensive retinopathy, causes swelling behind the eye and may lead to blindness.
Treatment of Hypertension
As the consequences of uncontrolled hypertension are numerous, the goal of treatment is to reduce the risk of developing hypertension-related complications and death. By keeping blood pressure less than 130/80 mm Hg, the chances of developing sclerosis and other vascular changes are reduced. To keep blood pressure below dangerous levels, clinicians rely on lifestyle changes and pharmacological treatments to decrease the chance of developing negative outcomes.
No treatment regimen for hypertension would be complete without paying attention to a patient’s lifestyle choices. Without making changes to lifestyle, controlling hypertension becomes difficult and often requires the addition of many drugs, each with its own side effects. To minimize the need for medications, clinicians focus on improving a number of important areas, including diet, exercise, weight, salt intake, and alcohol and tobacco exposure.
The types of foods a patient eats can have a direct impact on their overall hypertension control. By following a diet that is high in fruits, vegetables, whole grains, and fish and low in saturated fats, cholesterol, and salt, patients can lower their systolic blood pressure by 5–15 mm Hg. The Dietary Approaches to Stop Hypertension (DASH) diet is one example of a proper blood pressure–reducing diet. In addition to increasing fruits and vegetables while limiting saturated fats, the DASH diet recommends limiting sodium intake to less than 2.4 g daily.3 Excess salt in the diet causes the body to retain water. This extra volume in the blood vessels can increase blood pressure dramatically. To reach this goal, patients must be educated on the many hidden sources of sodium in the typical Western diet, such as processed foods and canned goods, in addition to table salt. Reducing sodium intake can often lower systolic blood pressure by an additional 2–8 mm Hg. Finally, the amount of alcohol a patient drinks can also negatively affect blood pressure. The DASH diet sets limits on daily alcohol ingestion to no more than two drinks for men and one drink for women.
An appropriate level of physical activity each day is important, not only for blood pressure control but for the overall health of all patients. Though most patients can safely include physical activity in their treatment regimens, patients who have signs of organ damage may need to consult their physician first. In general, experts recommend 30 minutes of aerobic exercise, such as brisk walking, jogging, bicycling, or swimming, most days of the week. If this goal is met, patients can expect an additional 4–9 mm Hg reduction in blood pressure.
In addition to any pharmacological treatments, list three lifestyle modifications that might improve Mr. Anderson’s blood pressure.
Though lifestyle modifications are often difficult to achieve, usually requiring intense follow-up and monitoring, those patients who manage to incorporate diet and exercise into their daily routines typically see significant weight loss. Even small reductions can have far-reaching effects, reducing the risk of developing a wide variety of medical conditions. Regarding hypertension, every 10 kg of weight that is lost equates to an estimated 5–20 mm Hg drop in blood pressure in patients who are overweight.
Diuretics, covered at length in Chapter 14, are a class of medications that cause water to be removed from the body. When extra volume is removed from the vasculature, blood pressure is reduced. Though there are a number of different types of diuretics, the classes most commonly used to treat hypertension are the thiazide, loop, and potassium-sparing diuretics. As a group, diuretics can cause electrolyte imbalances, as potassium, magnesium, and other electrolytes are lost along with extra water in the urine. To avoid the possibility of nocturia (the need to waken at night to urinate), they are usually dosed in the morning.
Mr. Anderson gets a prescription for hydrochlorothiazide 25 mg daily in addition to his lifestyle modifications. What lab tests may be ordered to check for side effects?
Thiazide and related diuretics are usually considered the first-line agents to treat hypertension in otherwise healthy patients. In addition to inhibiting the reabsorption of water at the distal convoluted tubule, thiazides have an additional antihypertensive effect: vasodilation. Because they relax the smooth muscle surrounding arteries and veins, thiazides are more effective than other diuretics at lowering blood pressure. Medications in this class are usually available in a generic form and are dosed once daily. Thiazide diuretics are generally well-tolerated antihypertensive medications. When being used for hypertension, lower doses of the thiazide diuretics are used, minimizing their potential to cause electrolyte disturbances. Thiazides may also cause hyperglycemia and increased uric acid levels, known as hyperuricemia—side effects not seen with other diuretics. These side effects could increase a patient’s risk of developing or worsening diabetes and gout.
For patients who develop kidney disease, the effectiveness of the thiazides can be drastically reduced and a switch to another medication is recommended if the glomerular filtration rate falls below 30 mL/min. Though they are not as effective at lowering blood pressure, loop diuretics retain much of their effectiveness when kidney function declines. Most are available generically. When used to control hypertension, bumetanide and furosemide require twice daily dosing, while torsemide and ethacrynic acid are dosed once daily. In addition to being useful for patients with kidney disease, loop diuretics play a large role in treating hypertension and edema in patients with congestive heart failure. Because of their increased potency, patients prescribed loop diuretics must be monitored closely for low electrolyte levels and orthostatic hypotension, a sudden drop in blood pressure upon rising from a lying or seated position to standing.
If renal function is very poor, metolazone, a thiazide-related diuretic, can be administered with a loop diuretic. When these agents are used together, they cause much more diuresis than either agent can cause alone.
The potassium-sparing diuretics allow the body to excrete sodium instead of potassium when causing a diuretic effect. If used alone, these medications are much less potent then other diuretics. They are most often ordered for an additive effect or to counteract the potassium loss seen with other diuretics. Spironolactone (Aldactone) and eplerenone (Inspra) are aldosterone antagonists, primarily used in patients with congestive heart failure. They lower blood pressure by blocking the ability of aldosterone to cause the body to retain water and sodium. Both are available in a generic form and are dosed once daily. Spironolactone’s unique side effect is gynecomastia, or a painful enlargement of the breasts in male patients. If it develops, patients can often be safely switched to eplerenone. The other potassium-sparing diuretics are available as individual ingredients or in combination with hydrochlorothiazide and include amiloride (Midamor, Moduretic) and triamterene (Dyrenium, Dyazide). Like thiazides, potassium-sparing diuretics should be avoided in patients with reduced kidney function and are typically dosed once daily. Table 14-4 (in Chapter 14) provides a summary of the available diuretics.
Calcium Channel Blockers
Calcium is an important cation necessary for vasoconstriction of blood vessels and quickening of the heart rate. In the arteries and veins, calcium must be transported from the extracellular fluid and into smooth muscle cells before vasoconstriction can occur. Using a similar transport mechanism, calcium must move into the autorhythmic cells of the sinoatrial node to raise the heart rate. These are important targets in the treatment of hypertension. The calcium channel blockers can inhibit the ability of cells to transport this important ion, causing vasodilation, slowing of the heart rate, and a drop in blood pressure. This class of medications can be divided into two subgroups: the dihydropyridines and the nondihydropyridines. Though they both inhibit calcium transport and lower blood pressure, these two subgroups are very different from one another. Dihydropyridines act primarily in the vasculature, causing vasodilation with very little effect on heart rate, whereas the nondihydropyridines inhibit calcium transport in the cardiac tissue, mainly decreasing heart rate and contractility.
The larger of the two subgroups is the dihypropyridines. Medications in this group include amlodipine (Norvasc), felodipine (Plendil), isradipine (DynaCirc), nicardipine (Cardene SR), and nifedipine (Adalat CC, Procardia XL). Nearly all of the agents in this subgroup are dosed once daily, with the exception of the immediate-release formulations of isradipine and nicardipine, which are dosed twice daily. As described above, the effect of dihydropyridines on the vasculature is far greater than their effect on the cardiac tissue. If the vasodilation is too great, the heart rate may suddenly increase in an attempt to maintain adequate blood pressure. This phenomenon is known as reflex tachycardia and is much less common in the longer-acting agents. Other common side effects of the dihydropyridines include orthostatic hypotension, dizziness, headache, and edema. Because these agents cause dilation of the coronary arteries, dihydropyridine calcium channel blockers are very effective in treating chest pain and increasing oxygen supply to the heart.
The nondihydropyridine subgroup contains only two agents: diltiazem (Cardizem CD, Cardizem LA, Tiazac) and verapamil (Calan, Covera, Verelan), though they are available in a number of different formulations. In general, they are dosed once to twice daily, depending on which formulation is chosen. Because they slow the heart rate and decrease its contractility, the nondihydropyridines have side-effect profiles very similar to beta blockers, including bradycardia, hypotension, congestive heart failure, and dizziness. Like other calcium channel blockers, they may also cause edema. Constipation is another frequently reported side effect with diltiazem and verapamil, but it is particularly common with verapamil therapy. The ability of these agents to slow the heart rate makes them very useful in the treatment of arrhythmias, such as atrial fibrillation.
Be careful when dispensing verapamil and diltiazem. There are many different formulations of these drugs that are not interchangeable because of different release mechanisms. For example, Cardizem CD and Tiazac, both extended-release diltiazem capsules, cannot be interchanged with one another or with some generic diltiazem ER capsules (see Medication Table 15-2.)
The nondihydropyridine calcium channel blockers are broken down by the liver. Patients are often warned to limit their intake of grapefruit juice if they are taking these agents, as it interferes with the liver enzymes and can cause an increase in verapamil and diltiazem concentrations.
Angiotensin-Converting Enzyme Inhibitors
One of the most widely used classes of antihypertensive agents is the angiotensin-converting enzyme (ACE) inhibitors. As described above, angiotensin-converting enzyme is responsible for the formation of angiotensin II, a protein that causes vasoconstriction and signals for the release of aldosterone. At the same time, ACE is responsible for the breakdown of a number of substances that cause vasodilation. The overall effect of its release is vasoconstriction, an increase in plasma volume, and, consequently, an increase in blood pressure. As their name implies, the ACE inhibitors bind to angiotensin-converting enzyme, blocking its ability to create angiotensin II. When it is inhibited, the balance between vasodilation and vasoconstriction is tipped in favor of vasodilation and blood pressure is reduced. The medications in this class, including benazepril (Lotensin), enalapril (Vasotec), lisinopril (Prinivil, Zestril), and ramipril (Altace), among others, are available as generics. Nearly every agent in the class is typically dosed once daily, with the exception of captopril, which is dosed 2–3 times/day. In certain populations, however, ACE inhibitors may require twice daily dosing to get a full 24-hour antihypertensive effect.
ACE inhibitors are contraindicated in pregnancy.
Like other blood pressure medications, ACE inhibitors are initiated at lower doses and slowly titrated toward an effective dose. This is done to avoid possible side effects. If doses are increased too suddenly, blood pressure may drop quickly, causing dizziness, orthostatic hypotension, or palpitations. Other ACE inhibitor–specific side effects also must be carefully monitored. Angioedema is a possibly life-threatening reaction that causes swelling of the lips, tongue, and throat that has been associated with ACE inhibitors. In most cases, stopping the ACE inhibitor causes a reversal of the symptoms, but, when severe, patients may need to be put on a ventilator to support their breathing. Fortunately, this side effect is rare, but if it does occur these patients should never be exposed to ACE inhibitors again. Another rare consequence of ACE inhibitor use is kidney failure, though it usually only presents in patients with preexisting kidney disease or on other medications that damage the kidney. Because inhibiting angiotensin-converting enzyme also inhibits the release of aldosterone, patients taking these medicines need to have their potassium levels monitored closely. Without aldosterone, the body can retain potassium, leading to dangerous arrhythmias if potassium levels increase significantly. Finally, one of the most common side effects of ACE inhibitor use is a dry cough. Over time, using an ACE inhibitor causes an accumulation of the substances that are normally broken down by the angiotensin-converting enzyme. It is theorized that some of these substances can cause a patient to develop a dry cough that is unrelated to any infectious or allergic origin. Though this is not a sign of any physiological illness, it can be a significant annoyance for patients. To reverse the effect, the ACE inhibitor can be discontinued and therapy switched to another class of antihypertensive agent. Though a number of side effects have been outlined here, it should be noted that these agents are generally well tolerated.
Combining ACE inhibitors with potassium-sparing diuretics or potassium supplements significantly increases the risk of hyperkalemia, especially in patients with poor kidney function.
The ACE inhibitors have been studied in a number of clinical trials and have been found to be very effective agents in controlling hypertension, especially in a number of populations at increased risk of developing serious complications. Because this class of blood pressure agents causes a dilation of the renal arteries, they can be used in patients with kidney disease or diabetes to delay the onset or progression to renal failure. In patients with heart failure or who have had a heart attack, ACE inhibitors have been shown to protect the heart from the damaging effects of angiotensin II and aldosterone, increasing survival and decreasing the risk of additional cardiovascular events. In patients who have had a stroke, the combination of an ACE inhibitor and a diuretic has been shown to significantly reduce the risk of having a second stroke. For these reasons, ACE inhibitors are considered a very close second-line agent in the treatment of hypertension behind the thiazide diuretics.
Angiotensin II Receptor Blockers
The angiotensin II receptor blockers (ARBs, but sometimes called AIIRAs) are a class of medications that are closely related to the ACE inhibitors. Instead of preventing the production of angiotensin II, the ARBs interact with the angiotensin II receptor, interfering with the ability of the protein to carry out its functions. Candesartan (Atacand), losartan (Cozaar), olmesartan (Benicar), valsartan (Diovan), and the other ARBs are typically dosed once daily, though they may require twice daily dosing in some cases for a full 24-hour effect. Nearly all ARBs are available as generics. Because their mechanism of action is similar to the ACE inhibitors, there is a great deal of overlap in side effects. Like the ACE inhibitors, the ARBs are started at lower doses and increased slowly to avoid the side effects associated with large drops in blood pressure, such as dizziness, hypotension, and palpitations. Patients taking ARBs must also have their potassium levels and kidney function monitored closely to screen for hyperkalemia and kidney failure. Unlike the ACE inhibitors, the ARBs do not cause a dry cough, as the angiotensin-converting enzyme is not being inhibited. In patients who develop angioedema after ACE inhibitor use, the ARBs may be used cautiously since cross-reactivity is rare. The ACE inhibitors and the ARBs also differ in that the ARBs are not quite as well studied. Though the ARBs have proven benefit in preventing kidney damage, they have not yet been shown to be as effective as the ACE inhibitors in patients with cardiovascular disease or stroke. Therefore, ARBs are generally reserved for use as an alternative in patients who develop side effects to ACE inhibitor therapy (see Medication Table 15-3).
Direct Renin Inhibitors
The newest class of antihypertensive agents is the direct renin inhibitors (DRIs). The mechanism of action of this class involves blocking the ability of renin to initiate the cascade of events that lead to angiotensin II production. Currently, the only agent in the class approved by the Food and Drug Administration is aliskiren (Tekturna). This is a generic medication that is dosed once daily. Though aliskiren acts much earlier in the RAAS, many of the side effects and cautions are similar to those for ACE inhibitors and ARBs. Hyperkalemia, decreases in renal function, and angioedema are all possible side effects of DRI therapy. Because aliskiren is a newer agent, its exact role in treating hypertension has not been established. Its antihypertensive effectiveness is comparable to ACE inhibitors and ARBs, but studies are still underway to characterize its effect on nephropathy, cardiovascular disease, and stroke.
If blood pressure falls, the systemic vasculature can respond to signals from the autonomic nervous system (ANS) to increase blood pressure levels. To accomplish this, epinephrine and norepinephrine are released so they can interact with alpha1 (α1) receptors on the vessel walls. When these receptors are activated, the smooth muscle surrounding the vasculature is constricted, raising SVR and blood pressure. In patients with hypertension, medications can be administered that interfere with this interaction between the ANS and blood vessels. The alpha1 antagonists, also known as alpha blockers, are a class of medicines that inhibit the ability of the catecholamines to activate alpha1 receptors. This causes a vasodilation and lowering of blood pressure. Agents in this class include doxazosin (Cardura), prazosin (Minipress), and terazosin (Hytrin). All of the medications in this class are available generically. Doxazosin and terazosin are typically dosed once daily, whereas prazosin is dosed 2–3 times daily. The most common side effects of alpha1 antagonist administration are dizziness, palpitations, and orthostatic hypotension, all due to rapid drops in blood pressure. These effects usually happen after the first dose or with a dose increase. To avoid these side effects, these medicines can be taken at bedtime. A number of studies have shown that this class of medications, though excellent at lowering blood pressure, does not lower the risk of cardiovascular events or death. For this reason, alpha blockers are only used as adjuncts for patients not at goal on other antihypertensives. (Alpha1 receptors are also located in the prostate, and administering alpha1 blockers causes a relaxation of the smooth muscles and relief of urinary symptoms for men with benign prostatic hyperplasia, discussed in Chapter 11).
In addition to alpha receptors in the periphery, the ANS can also activate beta receptors located throughout the body. Beta1 (β1) receptors are found in the heart and the kidney and, when stimulated, cause an increase in heart rate, contractility, and renin release. Beta2 (β2) receptors are located in many tissues and help regulate a wide variety of systems, such as bronchodilation in the lungs. The beta antagonists, also known as beta blockers, interfere with the interaction of the catecholamines with these beta receptors. When these receptors are inhibited, hypertension is reduced as the heart rate and force of contraction are diminished and the release of renin is blocked. These medications are started at lower doses and slowly increased or decreased (titrated) based on their effect. Clinicians must be careful, however, to avoid the side effects associated with too much beta1 or unwanted beta2 blockade, including dizziness, hypotension, sexual dysfunction, bronchospasm, and exercise intolerance. This class of antihypertensive medications is further divided into subgroups, which include cardioselective, nonselective, and mixed α- and β-blockers.
Patients should receive a warning not to stop taking beta blockers abruptly. When beta blockers are discontinued, the dose must be decreased gradually over time to reduce the likelihood of rebound hypertension and withdrawal side effects. In some patients, abrupt discontinuation can lead to chest pain, heart attack, or death.
At their typical doses, the cardioselective beta blockers act primarily on beta1 receptors and avoid the noncardiac issues associated with beta2 blockade. This feature makes them the preferred subgroup of beta blockers for treatment of hypertension. The cardioselective beta blockers include atenolol (Tenormin), bisoprolol (Zebeta), and metoprolol (Lopressor, Toprol XL). Atenolol, bisoprolol, and the extended-release form of metoprolol, the succinate salt, can be dosed once daily but the immediate-release form of metoprolol, the tartrate salt, is dosed twice a day. The most common side effects of these agents are bradycardia, hypotension, congestive heart failure, dizziness, and impotence. If higher doses are used, cardioselectivity can be lost, allowing these agents to block beta2 receptors along with the beta1 receptors, possibly worsening asthma or diabetes symptoms.
The nonselective beta blockers, such as nadolol (Corgard), propranolol (Inderal), and timolol (Blocadren), interact with both the beta1 and beta2 receptors, blocking the actions of epinephrine and norepinephrine. Nadolol, timolol, and the extended-release versions of propranolol are dosed once daily, and the immediate- release form of propranolol is dosed twice daily. Like the selective beta blockers, their antihypertensive effects come from reducing the rate and force of the heart’s contractions while inhibiting the release of renin from the kidneys. The main difference with these agents, the fact that they also block beta2 receptors, allows them to have additional uses and side effects. Blockade of the beta2 receptors in the lungs may decrease the ability of the bronchioles to dilate, putting asthmatic patients at higher risk of asthma attacks. While their unique side effects often limit their use in hypertension, the nonselective beta blockade is desirable in a number of other disease states, such as glaucoma, tremors, and migraine headaches.
For patients with asthma, nonselective beta blockers can both increase the risk of an asthma attack and also reduce the effectiveness of beta2 agonist medications, like albuterol, used to treat the attack.
Carvedilol (Coreg) and labetalol (Normodyne, Trandate) are classified as mixed alpha and beta antagonists. These medications block alpha1, beta1, and beta2 receptors, lowering blood pressure by causing vasodilation, slowing the heart rate and decreasing contractility. Both of these agents are dosed twice daily, with the exception of extended-release carvedilol, which is only dosed once daily. Though most side effects are similar to those described for the alpha and beta antagonists, the addition of the alpha antagonist to the beta blockade further increases the risk of orthostatic hypotension.
Central Alpha2 Agonists
While blocking alpha1 receptors in the vasculature is one way blood pressure can be reduced, the alpha2 receptors in the brain have a very different function. The receptors in the central nervous system cause a decrease in blood pressure when they are activated. They do this by increasing the activity of the PANS, the part of the nervous system that counteracts the SANS, lowering heart rate, contractility, and causing vasodilation. Clonidine (Catapres), guanfacine (Tenex), guanabenz (Wytensin), and methyldopa (Aldomet) are agents designed to activate alpha2 receptors in the brain to lower blood pressure. All of the medications in this class are available generically. The oral formulations of these medications are typically administered twice daily, though guanfacine may be dosed once daily. (Note: because of their central activity, guanfacine and clonidine are also used in the treatment of attention deficit hyperactivity disorder; see Chapter 7 for more information.)
In addition to the typical oral preparations, clonidine is also available as a once weekly transdermal patch. Started at 0.1 mg/24 hr, the patch’s dose can be increased every 1–2 weeks to a typical maximum of 0.3 mg/24 hr. It is recommended to apply new patches at bedtime to a hairless portion of the upper arm or chest, reducing the risk of the patch falling off. To minimize redness at the site of application, patients should rotate the location of the patch each week.
Patients with transdermal patches should be reminded that the used patch must be removed and discarded at the time each new one is applied.
When the alpha2 agonists are discontinued, the dose must be decreased slowly over time to reduce the risk of developing rebound hypertension. Though the alpha2 agonists are very effective blood pressure lowering agents, several important side effects limit their use. Because these agents are centrally acting, there is an increased risk of developing depression. Long-term use has also been shown to cause an increase in water and sodium retention. Their potent reduction of blood pressure also equates to much higher rates of orthostatic hypotension and dizziness than is seen with other blood pressure agents. If higher doses are necessary, alpha2 selectivity may be lost, leading to activation of peripheral alpha1 receptors and vasoconstriction. Though the side effects are numerous, there are specific situations where an alpha2 agonist may be a good choice.
Clonidine transdermal patches are supplied in different strengths that come in similar packaging, but may have up to a threefold difference in potency. It is very important that the patient receive the strength ordered by the physician.
The use of alpha2 agonists is discouraged in older adults due to high rates of anticholinergic side effects, including confusion, sedation, constipation, urine retention, and blurry vision.
LOOK-ALIKE/SOUND-ALIKE—Clonidine has been confused with the brand name antiseizure medication Klonopin.
Direct Arterial Vasodilators
The direct arterial vasodilators are a class of hypertension medications that cause a relaxation of the smooth muscles surrounding arteries. This can result in profound decreases in blood pressure. Medications in this class include hydralazine (Apresoline) and minoxidil (Loniten). Both agents are generic. Hydralazine is typically dosed 2–4 times each day, and minoxidil is dosed 1–2 times each day. Like the alpha2 agonists, these agents are very effective at reducing blood pressure, but side effects tend to limit their use. When the arteries are suddenly dilated, the baroreceptors detect a drop in blood pressure and attempt to maintain adequate profusion. Signals are sent from the ANS to increase heart rate and retain fluid to keep blood pressure high. Over time, the body’s compensation leads to a drastic decrease in the efficacy of the direct arterial vasodilators, a phenomenon known as tachyphylaxis or tolerance. To avoid this result, hydralazine and minoxidil are usually prescribed in conjunction with beta blockers and diuretics to blunt the body’s compensatory mechanisms. Each agent also has unique side effects. Hydralazine has been shown to cause a drug-induced lupus. This is a disorder in which the body’s immune system begins to attack itself, causing joint pain, fatigue, and possible damage to the heart and lungs. The incidence of this side effect increases as the dose of the drug is increased, and, if it occurs, hydralazine must be discontinued. Minoxidil use may lead to hypertrichosis, or unwanted hair growth of the face, chest, arms, and back. To stop this hair growth, the minoxidil must be discontinued (see Medication Table 15-4).
Minoxidil is a common ingredient in many topical hair growth products used to treat baldness. Oral minoxidil, however, is indicated only for hypertension.
LOOK-ALIKE/SOUND-ALIKE—Hydralazine is often confused with hydroxyzine, an antihistamine.
In addition to the single products discussed above, many antihypertensive medications are available in combination forms. The most common pairings include ACE inhibitors, angiotensin receptor blockers, direct renin inhibitors, or beta blockers in combination with thiazide diuretics; however, many different couplings exist. As most hypertensive patients require more than two agents to control the disease, incorporating multiple ingredients in a single tablet or capsule can significantly reduce the pill burden, giving patients greater convenience and potentially improving adherence. However, the practice of combining blood pressure medications can also have considerable drawbacks. Healthcare practitioners who choose to use these products sacrifice a great deal of flexibility in dose adjustments when only certain options exist as combinations. If a patient experiences side effects and requires a dose reduction of one ingredient, a suitable combination product may not exist. Also, many combination products are available as brand name agents, leading to higher costs when compared with generic alternatives (see Medication Table 15-5).
Choosing an Agent
As described above, the options available to treat hypertension are numerous. To help decide among the multitude of classes, clinicians consider individual patient issues, including severity of hypertension, cost and insurance coverage, tolerability, and concurrent disease states. For otherwise-healthy patients with stage I hypertension, current guidelines recommend the use of thiazide diuretics, ACE inhibitors, and dihydropyridine calcium channel blockers as first-line agents. These affordable, well-tolerated agents have proven mortality reduction, even when compared to newer antihypertensive therapies.2 For patients with stage II hypertension, it is recommended to start two medications. There may be other clinical scenarios that call for specific agents. For patients with congestive heart failure, a history of heart attacks, or coronary artery disease, beta blockers, ACE inhibitors, and aldosterone antagonists have added benefit. Calcium channel blockers work well for patients with chest pain and older adults. For patients with diabetes, ACE inhibitors and ARBs have been shown to decrease the risk of cardiovascular events and the progression of kidney disease. An individualized drug regimen can make it possible for therapeutic goals to be reached while limiting the potential for side effects.
Mr. Anderson is back in the physician’s office 1 year after starting hydrochlorothiazide. His blood pressure has averaged 165/99 at his last two visits. He has also been diagnosed with type 2 diabetes. What additional antihypertensive therapy might help him reach his blood pressure goals and also may have added benefit in his new medical condition?
If hypertension is not adequately controlled, some patients may develop a hypertensive crisis, or a blood pressure elevated to a point greater than 180/120 mm Hg. Overall, there are two main categories of hypertensive crises: hypertensive urgencies and emergencies. A hypertensive urgency is defined as a blood pressure higher than 180/120 mm Hg in a patient who has no signs of organ damage or failure. In these cases, fast-acting oral therapies, such as captopril, labetalol, or clonidine, can be used to slowly bring the blood pressure to safer values. In hypertensive emergencies, however, patients have both an elevated blood pressure and show signs of organ damage or failure, such as blurred vision, kidney failure, or confusion. Healthcare practitioners must act quickly to start intravenous (IV) therapies to protect the patient’s organs and prevent further damage.
A number of IV treatment options exist to counter the effects of a hypertensive crisis. One of the most commonly used IV agents is sodium nitroprusside (Nitropress). Dosed initially at 0.3–0.5 mcg/kg/min, this vasodilator is titrated upward to meet blood pressure reduction goals. For a full discussion of sodium nitroprusside, see Chapter 16. Clevidipine (Cleviprex), a fast-acting IV nondihydropyridine calcium channel blocker, is typically started at 1–2 mg/hr. The most rapid-acting beta blocker, esmolol (Brevibloc), is another common choice. Patients usually receive a loading dose followed by a weight-based continuous infusion. Finally, fenoldopam (Corlopam) is an agent with a unique mechanism of action, targeting dopamine receptors to cause vasodilation. Its starting dose is 0.1–0.3 mcg/kg/min. In addition to these agents, a number of the classes described in the sections above contain agents available in an IV formulation. Dosing guidelines for IV hydralazine, enalapril, nicardipine, nitroglycerin, and labetalol are included in the Medication Tables in this chapter. Though they may have varying mechanisms, all of the above agents have similar characteristics, a rapid onset of action and a short duration allowing for careful control of a patient’s blood pressure. For these same reasons, similar side effects must be monitored, including hypotension and reflex tachycardia.
Hypertension is a very common disease state in the United States. In most cases, the cause is difficult to identify but is likely made up of genetic and environmental factors. This silent killer can be present for many years before the signs of its presence are made known. If left unchecked, it causes damage across numerous body systems and increases the risk of serious complications and death. Fortunately, the risks associated with hypertension can be greatly reduced if caught early through blood pressure screenings and treated with appropriate therapy. To ensure blood pressure goals are met, every treatment regimen must include both pharmacological and nonpharmacological treatment. Patients must be educated on the benefits of physical activity and dietary changes, while clinicians evaluate each patient carefully to determine which agents will help decrease blood pressure, reduce the risk of complications, and avoid unwanted side effects.
2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018;71:e127–e248.
2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018;71:e127–e248.)| false