Cardiovascular

Introduction

Cardiovascular disease is the leading cause of death in the United States, for both men and women, according to the Division for Heart Disease and Stroke Prevention at the Centers for Disease Control (CDC). About 630,000 Americans die from heart dis-

ease each year—that is one in every four deaths. Each minute, more than one per- son in the United States dies from a heart disease–related event. Coronary artery disease (CAD) is the most common heart diseasein the United States: someone has a heart attack every 40 seconds. There are also 12 million yearly visits to physician’s offices and close to 4 million hospital discharges

for cardiovascular disease (Heron, 2014; Centers for Disease Control and Prevention, 2017). Treatment of cardiovascular disease and monitoring for therapeutic efficacy

and side effects of the cardiovascular drugs used requires a comprehensive knowledge of the pharmacology of these medications. Nurses play a vital role in direct patient care; therefore, knowledge of cardiovascu- lar medications, assessment of therapeutic and adverse effects, knowledge of drug ef- fects on the body, and patient education

are essential. It is the goal of this chapter to equip the nurse with not only a thorough understanding of the medication classes and mechanisms of action of the drugs used to treat these cardiac conditions, but more im- portantly, to provide the rationale for select- ing appropriate drug regimens and ensure optimal therapeutic outcomes.

The Cardiovascular System

In broad terms, the cardiovascular sys- tem can be defined as a complex interre- lated network composed of the heart and blood vessels (of the circulatory system). Cardiovascular pharmacology is the study of the mechanism of action of drugs used to treat pathologies of the heart, the circulatory sys- tem, and interrelated physiological systems which comprise the cardiovascular system.

It is presupposed the nurse has a working knowledge of the normal structure and function of the heart and vasculature (for review, the reader is referred to one of the many anatomy and physiology references and resources). Since cardiovascular disease is one of the leading causes of all deaths in the United States, it is important to distinguish that cardiovascular “disease” is actually a group of disorders that affect the heart, the blood vessels, or both (see FIGURE 6-1). For example, some disorders involve only the heart itself. Pathologies attributed to the heart include the following:

• Malfunctions of the heart’s electrical im- pulses that result in rhythmic disturbances (arrhythmias)

• Poorly functioning valves, which result in blood “leakage” between chambers be- cause of insufficient force to move blood forward

• Atrophy or hypertrophy of individ-

ual chambers, whether from congeni- tal causes or disease processes, which can prevent adequate blood movement through the heart

• Acute infections, electrolyte imbalances, and fluid buildup around the heart, con- ditions that may create a cardiovascular crisis if not promptly treated

In contrast, conditions that affect the circulatory component of the cardiovascular system (including the blood vessels that

feed the heart; see Figure 6-1B) include

such cardiac disorders as hypertension (high blood pressure, which itself can have a variety of causative factors), hyperlipidemia (high cholesterol and/or triglyceride

levels, which are generally lifestyle related but can also have genetic causes), and congestive heart failure (CHF). Nearly all of these various conditions are treated with medication, although in some situations

the medications are adjuncts to surgical and lifestyle interventions.

The number of medication classes used to treat cardiovascular disease is as varied as the number of disorders themselves. The focus of this chapter, therefore, is restricted to the medication classes used in the treatment and long-term management of the cardiovascular conditions most commonly seen in the gen- eral population: hypertension (HTN), angina,

hyperlipidemia, and congestive heart failure. The medications used to prevent thrombosis and stroke by reducing coagulation of blood are also discussed, as these agents are frequently used in conjunction with therapies to treat underlying diseases to prevent cardiovascular crises such as heart attacks (myocardial infarction [MI]) and strokes.

Treatment of High Blood Pressure

Blood pressure measures the amount of force that blood exerts upon blood vessel walls as it

flows throughout the body. The two measure- ments of pressure are systolic blood pres- sure, which measures the force of blood pressing against vessel walls while the heart is contracting during a beat, and diastolic blood pressure, which is the force exerted while the heart muscle is relaxed between beats. The systolic measure- ment is typically anywhere from 40 to

50 mm Hg higher than the diastolic value. When the force that pushes against blood

vessels (pressure) remains consistently higher than the vessel walls can tolerate, the blood vessel becomes damaged. Left untreated,

this could lead to serious cardiovascular pa- thologies such as heart attack, heart failure, and stroke.

Two significant factors that affect blood pressure are cardiac output (CO) and systemic vascular resistance (SVR),

as a function of heart rate (HR). This relationship is often shortened to the follow- ing formula:

CO = HR × SVR

Cardiac output is the amount of blood the heart is able to pump in one minute, and systemic vascular resistance is the re- sistance to blood flowing, present in the body from the vasculature, after the exit from the left ventricle (not including the pulmonary vasculature).

According to the preceding equation, an increase in HR or SVR will cause blood pres- sure to increase; conversely, a decrease in the HR or SVR will cause a subsequent decrease in blood pressure. It follows then, that a drug which decreases either the HR or the SVR would be a useful pharmacological agent to lower blood pressure.

According to the preceding equation, however, all physiological factors that

contribute to CO and SVR must be consid- ered. Key physiological factors that affect CO and SVR include fluid volume and va- soconstriction. Fluid volume, the volume of blood passing through the blood vessels, plays a significant role in the regulation of blood pressure. Specifically, the greater the amount (volume) of blood to be pumped, the greater the pressure will be on the ves- sel walls; the risk of damage to the ves-

sel walls is increased. This can be likened

to a garden hose (blood vessel) connected

to a faucet (heart). If the faucet suddenly pumped three times more water than the hose could handle, the hose would be sub- jected to a significantly higher pressure than it was made to tolerate, which greatly in- creases the risk of damaging the hose. As a result of increased fluid in the body (blood volume), the heart must also work harder to compensate for the greater volume. Exces- sive fluid, therefore, can be harmful to both the heart and the vessels.

Vasoconstriction, similarly, affects blood pressure: less blood volume can pass through a constricted vessel than a dilated ves-

sel; thus, there is an increased resistance to the passage of blood which can also dam- age blood vessels. Restriction of blood vessel walls, regardless of cause, impedes the flow of blood through that vessel, and causes the pressure inside the vessel walls to increase. Persistent blood vessel constriction is associated with the development of hypertension.

The autonomic nervous system (ANS), the kidneys, and the renin–angiotensin– aldosterone system (RAAS) are the key contributors in the control of blood pressure (TABLE 6-1). Hypertension may develop for any number of reasons, ranging from genetic fac- tors to lifestyle factors (e.g., tobacco use, lack of exercise, high-sodium or low-potassium diet) to simple aging. Hypertension also accompanies a variety of chronic conditions, such as diabetes mellitus, renal disease, and sleep apnea (Story, 2012). In many instances, hypertension is a self-perpetuating condition in which high blood pressure damages renal blood vessels, leading to decreased blood flow to the kidney, which in turn triggers increased renin secretion (FIGURE 6-2). Because one of

the responses to renin is vasoconstriction,

this response increases peripheral resistance even further, creating a damaging feedback loop (see FIGURE 6-3, which shows the feed- back loop). Thus, prevention of hypertension and early treatment when it is first diagnosed can help prevent the upward spiral of high blood pressure.

Uncontrolled hypertension carries an even greater risk of a wide range of dis- eases, including not only MI and coronary artery disease, but also stroke, kidney dis- ease, aortic aneurysm, and heart failure,

among others. Hypertension is therefore ad- dressed with any of a variety of antihyper- tensive medications, including drugs in the following categories: angiotensin-convert- ing-enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), direct renin inhibi- tors (DRIs), aldosterone antagonists (AAs), beta-blockers, alpha-1-blockers, and cal- cium-channel blockers (CCBs).

The classes of drugs used to lower blood pressure are named for their mechanism

of action. However, to understand why, forexample, blocking beta-receptors or inhibit- ing the conversion of angiotensin will reduce blood pressure, one must understand the contributions these processes make toward cardiovascular function.

Given the relationship of CO, SVR, and HR in the equation given earlier, there are three ways to lower blood pressure: (1) lower CO (generally by reducing fluid volume);

(2) reduce HR (generally by inhibiting signals that normally increase HR); or (3) decrease SVR (generally by expanding or dilating blood vessels). Most of the medications used in therapy for hypertension alter one or more of these

What Is High Blood Pressure?

JNC 7: “Older” Guidelines for Treatment of Hypertension

The seventh report of the Joint National Committee (JNC 7) has served as the gold standard guideline for antihypertensive phar- macotherapy since it was published in 2003. Specifically, the JNC 7 defined and delineated “normal,” “prehypertension,” and “hyper- tension” blood pressure values and set treat- ment goals for initiating pharmacotherapy intervention accordingly. Their recommended guidelines for pharmacotherapeutic treatment goal was a resting systolic blood pressure less than 120 mm Hg and a resting diastolic blood pressure less than 80 mm Hg. Prehyperten- sion was defined as a resting systolic valuein the range of 120–139 mm Hg and/or a diastolic value in the range of 80–89 mm Hg. Hypertension was defined as having an average blood pressure of 140/90 mm Hg or higher most of the time.

JNC 8: Updated Guidelines for Treatment of Hypertension

In 2014 panel members of the Eighth Joint National Committee published guidelines that do not recommend blood pressure guidelines numerically. In hypertensive persons younger than 60 years, there is not sufficient evidence to support a systolic goal; nor is there suffi- cient evidence to support a diastolic goal in those younger than 30 years. There panel therefore recommends a target blood pres- sure below 140/90 mm Hg for those groups (James et al., 2014).

The Renin–Angiotensin– Aldosterone System (RAAS)

The renin–angiotensin–aldosterone system

is a hormone system that regulates blood pressure and water (fluid) balance. The second mech- anism by which drugs act to lower blood pressure is to decrease angiotensin II levels, thereby suppressing its activity in the RAAS. As noted in FIGURE 6-4, hypertension is often a self-sustaining condition, as systemic vaso- constriction leads to increased renin produc- tion in the kidneys, which in turn raises the circulating level of angiotensin I. However, neither of these products is itself respon- sible for the vasoconstriction and increases

in blood pressure. Angiotensin II, which

is created by the conversion of angioten- sin I by angiotensin-converting enzyme (ACE), is the product that causes potent vasoconstriction and the release of aldoste- rone, which then increases the retention of sodium and consequently water. By limiting the availability of angiotensin II, vasoconstric- tion and aldosterone release are likewise lim- ited, and volume expansion is curtailed. This reduces both the SVR and CO, thus lowering blood pressure.The RAAS feedback regulation pathway presents multiple pharmacotherapy “targets,” which can be exploited to lower blood pres- sure blood pressure. Each of these strategies is examined in turn.

There are several ways to go about reducing the activity of angiotensin II. One route is to limit its presence in the system, either by (1) reducing the availability of renin, thereby limiting the amount of angiotensin I available for conversion (drugs with this mechanism of action are called direct renin inhibitors [DRIs]), or (2) preventing ACE from acting on angiotensin I to produce angiotensin II (a

class of medications called ACE inhibitors does exactly that). Another possibility is to focus instead on blocking the receptors where angiotensin II binds to cells, which is the mechanism of action of a class of drugs called angiotensin II receptor blockers (ARBs). Note that using any of these methods does not mean there will be no angiotensin II available—angiotensinogen and angiotensin I are both converted to angiotensin II by means other than renin and ACE interactions. However, the goal of the therapy is not to eliminate the effects of angiotensin II (that would be harmful, rather than helpful) but rather to reduce them.

Direct Renin Inhibitors

As with many classes of medication, the name of this drug class is representative of the drug’s mechanism of action. Direct re-

nin inhibitors bind to the renin molecule

and form a “renin-drug complex,” which effectively inhibits renin activity. Recall that renin is responsible for the conversion of angiotensinogen to produce angiotensin I; decreasing renin levels and thereby reduces the amount of angiotensin I (see Figure 6-4). As the amount of angiotensin I in the RAAS decreases, the amount of the angiotensin II end product decreases as well. As angiotensin II decreases, less vasoconstriction and volume expan- sion occur, causing blood pressure decrease as well. Because the increase in renin secretion that accompanies hypertension tends to continu- ally promote blood pressure increases (Farag, Maheshwari, Morgan, Sakr Esa, & Doyle, 2015), this drug class adds another option to the hypertension pharmacotherapy arsenal.

This class of antihypertensive medica- tions is new, and there is currently only one FDA-approved DRI available; aliskiren was approved for use as an antihypertensive agent in 2007. DRI therapy for hypertension can be used as monotherapy, in conjunction with di- uretics, or with other antihypertensive treat- ments, although combination therapy should be undertaken with caution. Initial research found aliskiren to be a safe and effective al- ternative to ACE inhibitors and ARBs for pri- mary hypertension (Farag, Maheshwari, Morgan, Sakr Esa, & Doyle, 2015), and subse- quent trials identified combined therapy with ACE inhibitors or ARBs plus aliskiren at low doses as having potential benefits for high-risk patients with type 2 diabetes (Riccioni, 2013).

Adverse Effects of Direct Renin Inhibitors

Patients taking DRIs are much less likely

to experience the side effect of dry cough and angioedema than those receiving ACE in- hibitors (Makani et al., 2012). Patients with renal insufficiency, diabetes, or who take a DRI in combination with an ACE in- hibitor or an ARB have an increased risk of

hyperkalemia. DRIs are contraindicated in pregnancy due to the increased risk of fetal complications and, therefore, are not used in pregnancy-induced hypertension.

Angiotensin-Converting-Enzyme Inhibitors (ACE Inhibitors)

As with the DRIs, the name of the angioten- sin-converting-enzyme (ACE) inhibitor cat- egory of drugs is a helpful reminder of their mechanism of action. By limiting the produc- tion of the enzyme responsible for converting angiotensin I to angiotensin II, the amount of angiotensin II in the body decreases, which

in turn lowers blood pressure. In addition to converting angiotensin I to angiotensin II, the angiotensin-converting-enzyme (ACE) breaks down bradykinin, an endogenous compound released in response to inflammation; brady- kinin directly causes vasodilation. The inhibi- tion of bradykinin breakdown decreases blood pressure by a different, yet significant, second- ary mechanism of action. Increasing vasodi- lation reduces systemic vascular resistance (SVR), which leads to lower blood pressure (see BP Formula box). Patients most likely to benefit from ACE inhibitor drug therapy in- clude those with hypertension, diabetic and nondiabetic nephropathy, coronary artery dis- ease, and heart failure, as well as patients who have had a myocardial infarction (TABLE 6-2).

Adverse Effects of ACE inhibitors

Because this class of medications has “dual mechanisms of drug action” (inhibiting an- giotensin-converting enzyme produces two distinct physiological effects), lowering angio- tensin II and increasing bradykinin, it follows that use of this class of medications would produce multiple adverse effects. Indeed, ad- verse effects of ACE inhibitors can be grouped into two categories: (1) effects that are likely caused by the reduction in angiotensin II formation (hypotension, renal failure, and hyperkalemia) and (2) effects related to in- creased “kinins” (cough, angioedema, and anaphylaxis reactions); each is discussed in further detail.

Adverse Effects Related to Decreased Angiotensin II Activity

Patients who begin an anti-hypertensive drug therapy regimen may experience adverse ef- fects resulting from a significant decrease in their blood pressure. These symptoms are most commonly referred to the first-dose ef- fect and include weakness, dizziness, and syn- cope, in addition to severe hypotension that may occur. Patients who have intravascular volume depletion (hypovolemia), as well as those who have high renin levels are at par- ticular risk. For these patients, ACE inhibitor therapy initiation should be preceded with precautionary measures. If hypovolemia is a result of concurrent diuretic drug therapy (di- uretics decrease blood volume; discussed later in this chapter), the diuretic therapy should

be discontinued for a period of three to five days before starting ACE inhibitor therapy to ensure that the hypovolemia has been re- solved. Additionally, caution must be used when treating patients with compromised renal activity. Patients taking an ACE inhibi- tor may experience a decrease in their glo- merular filtration rate (GFR) severe enough to warrant discontinuation of therapy (Yusuf et al., 2008). Patients with known renal dis- ease should be treated with an alternative antihypertensive drug class, if possible; if not, the patient’s renal function should be closely monitored while taking an ACE inhibitor. ACE inhibitors block aldosterone release (the last step in the RAAS feedback loop); aldo- sterone increases urinary potassium excre- tion. As aldosterone levels decrease, the blood example, blocking beta-receptors or inhibit- ing the conversion of angiotensin will reduce blood pressure, one must understand the contributions these processes make toward cardiovascular function.

Given the relationship of CO, SVR, and HR in the equation given earlier, there are three ways to lower blood pressure: (1) lower CO (generally by reducing fluid volume);

What Is High Blood Pressure?

JNC 7: “Older” Guidelines for Treatment of Hypertension

The seventh report of the Joint National Committee (JNC 7) has served as the gold standard guideline for antihypertensive phar- macotherapy since it was published in 2003. Specifically, the JNC 7 defined and delineated “normal,” “prehypertension,” and “hyper- tension” blood pressure values and set treat- ment goals for initiating pharmacotherapy intervention accordingly. Their recommended guidelines for pharmacotherapeutic treatment goal was a resting systolic blood pressure less than 120 mm Hg and a resting diastolic blood pressure less than 80 mm Hg. Prehyperten- sion was defined as a resting systolic value in the range of 120–139 mm Hg and/or a diastolic value in the range of 80–89 mm Hg. Hypertension was defined as having an average blood pressure of 140/90 mm Hg or higher most of the time.

JNC 8: Updated Guidelines for Treatment of Hypertension

The Renin–Angiotensin– Aldosterone System (RAAS)

The renin–angiotensin–aldosterone system

in blood pressure. Angiotensin II, which

The RAAS feedback regulation pathway presents multiple pharmacotherapy “targets,” which can be exploited to lower blood pres- sure blood pressure. Each of these strategies is examined in turn.

As with many classes of medication, the name of this drug class is representative of the drug’s mechanism of action. Direct re-

nin inhibitors bind to the renin molecule

Adverse Effects of Direct Renin Inhibitors

Patients taking DRIs are much less likely

hyperkalemia. DRIs are contraindicated in pregnancy due to the increased risk of fetal complications and, therefore, are not used in pregnancy-induced hypertension.

Angiotensin-Converting-Enzyme Inhibitors (ACE Inhibitors)

Adverse Effects of ACE inhibitors

be discontinued for a period of three to five days before starting ACE inhibitor therapy to ensure that the hypovolemia has been re- solved. Additionally, caution must be used when treating patients with compromised renal activity. Patients taking an ACE inhibi- tor may experience a decrease in their glo- merular filtration rate (GFR) severe enough to warrant discontinuation of therapy (Yusuf et al., 2008). Patients with known renal dis- ease should be treated with an alternative antihypertensive drug class, if possible; if not, the patient’s renal function should be closely monitored while taking an ACE inhibitor. ACE inhibitors block aldosterone release (the last step in the RAAS feedback loop); aldo- sterone increases urinary potassium excre- tion. As aldosterone levels decrease, the blood level of potassium increases. For patients with normal renal function, treatment with ACE inhibitors may not be a serious issue, as the amount of potassium in the body increases only minimally. However, ACE inhibitor ther- apy should be used with caution in patients with renal insufficiency, diabetes, receiving hemodialysis, and those taking other medica- tions that can cause elevated potassium levels (such as a potassium-sparing diuretic) as hy- perkalemia can occur.

Adverse Effects Due to Kinin Increase

A dry cough is the most frequent side effect associated with the use of ACE inhibitors. However, the literature is conflicting with respect to the number of patients that stop treatment of their ACE-inhibitor treatment due to cough. A study conducted by Sato and Fukuda in 2015 report that up to 20% of pa- tients receiving an ACE inhibitor developed

a dry, “hacking” cough. In this same study, the authors stated that although 5.1% of these patients discontinued treatment due to the cough, another 5% of patients reported that the cough either resolved naturally or completely disappeared as treatment with

the ACE inhibitor continued. Once a patient develops a cough, if an additional ACE inhibi- tor is restarted at a later time, the patient will generally develop the cough again. Patients can be switched to an ARB medication (discussed in the next section), which has a much lower incidence of associated cough. Once a patient develops a cough, if an ad- ditional ACE inhibitor is restarted at a later time, the patient will generally develop the cough again.

Angiotensin II Receptor Blockers (ARBs)

As shown in Figure 6-3, blockade of angiotensin II receptors represents yet another pharmaco- logical target along the RAAS feedback loop. Angiotensin II receptor antagonists (or ARBs; TABLE 6-3) compete with the endogenous li- gand (angiotensin II) for binding sites on the angiotensin II receptor. While the antagonist (ARB) is bound to the receptor, angiotensin

*All ARBs present a risk of fetal toxicity and, therefore, are contraindicated for the treatment of pregnancy-induced hypertension. Concomitant use in conjunction with aliskiren (a direct renin inhibitor) is contraindicated in many of these medications.

II cannot bind to its receptor, thus blocking the vasoconstriction and volume expansion caused by angiotensin II, leading to higher blood pressure. Patients who may benefit from ARB therapy include those with hyper- tension, diabetic and nondiabetic nephropa- thy, coronary artery disease, heart failure after developing MI, or scleroderma.

According to the JNC 8, when compar- ing ARBs to ACE inhibitors, the panel con- cluded that these two classes of drugs are comparable and thus interchangeable for the initial treatment of hypertension in patients who do not have heart failure (James et al., 2014). First, their side-effect profiles differ. Unlike ACE inhibitors, ARBs do not increase the levels of bradykinin; thus, patients tak- ing ARBs are much less likely to experience the side effects of dry cough and angioedema than those taking ACE inhibitors. However, hypotension is more common with ARBs than with ACE inhibitors. ARBs are contra- indicated in pregnancy due to the increased risk of fetal complications; they cannot be used in pregnancy-related hypertension (pre-eclampsia).

Aldosterone Antagonists (AAs)

The class of aldosterone-antagonist medica- tions completes the pharmacological classesof medications that target the RAAS feed- back loop. At present, two drugs are avail- able: eplerenone and spironolactone, both of which are competitive antagonists at the aldosterone receptor (these drugs are also potassium-sparing diuretics; and are discussed later in this chapter). AAs work slightly dif- ferently in altering the RAAS than the three previously discussed classes. Angiotensin II causes both potent vasoconstriction and the release of aldosterone. Aldosterone signals to the kidneys to conserve water and maintain fluid volume. In normotensive individuals, this usu- ally does not present a problem. For patients with hypertension, however, increasing fluid volume can indeed negatively impact blood pressure levels.

Recall CO and SVR were shown to be key factors in determining blood pressure. In pa- tients with hypertension, both SVR and CO are increased due in part to increased blood volume related to heightened levels of aldo- sterone attributable to increased renin se- cretion. Reducing aldosterone activity can interrupt that sequence by decreasing water conservation and reducing fluid volume. Be- cause AA are competitive antagonists at the aldosterone receptor, they prevent aldoste- rone from signaling the kidneys to conserve water, allowing any excess fluid to be excreted as urine (diuresis). Decreased levels of aldoste- rone also produce increased potassium retention, less sodium retention, less volume expan- sion, and lower blood pressure.

Adverse Effects of Aldosterone Antagonists

AAs block the aldosterone receptors, which decreases the sodium and water reabsorption and increases the potassium retention. Thus, hyperkalemia is a risk with these drugs.

Drug–Drug Interactions Within RAAS Feedback Loop

Of note: it should be clear that using more than one of these RAAS-focused medica- tions simultaneously carries a risk of over- treatment—each drug class acts upon a different site along the RAAS feedback loop (Figure 6-3). Therefore, medications

from different RAAS-drug classes should not be used together unless there is a proven medical benefit for doing so.

Drug–Drug Interactions Associated With AAs

Both AAs are also classified as potassium-sparing diuretics, so they should not be used in combination with other

drugs in this class—namely, amiloride and triamterene—for fear of synergistic over- treatment leading to hyperkalemia. Similarly, use of supplemental potassium, whether taken over the counter (OTC) or by prescrip- tion, should be avoided with AAs, due to the likelihood of hyperkalemia. Less obvious, perhaps, is the potential interaction between vasopressin receptor antagonists (“vaptan” drugs), which should not be used with AAs for the simple reason that blocking the activ- ity of vasopressin reduces the amount of cir- culating aldosterone; in conjunction with an AA, one would again expect synergism and overtreatment. Cyclosporine is contraindi- cated because it lowers serum aldosterone; similarly, mifepristone should not be taken within 14 days of AA usage due to its effects on mineralocorticoid receptors.

The Role of the Autonomic Nervous System in Blood Pressure Regulation

The autonomic nervous system (ANS) is the branch of the nervous system that regulates “involuntary” physiological processes, such as heart rate (FIGURE 6-5). The ANS is subdivided into the sympathetic nervous system (SNS) and parasympathetic system (PANS) (see Chapter 5). The ANS plays a significant role regulating cardiovascular function in addi- tion to modulating the physiological control of blood pressure. In simplest terms, if the body suddenly requires more oxygen to sup- port an activity or respond to danger, the ANS automatically signals the heart to beat faster and circulate blood more rapidly. Such sig- nals are mediated by the neurotransmitters norepinephrine and epinephrine (formerly known as noradrenaline and adrenaline, re- spectively). Most readers have experienced an “adrenaline rush” in response to danger, be

it real or imagined—the heart rate increases (i.e., the heart “pounds”), breathing quickens, skin flushes, and muscles tense. This physio- logical response, known as the fight-or-flight response, is the result of the brain signal-

ing (via the ANS) the adrenal glands to re- lease norepinephrine (NE) and epinephrine (EPI), which bind to specific receptors lo- cated on the heart, called beta-receptors (β-receptors). When beta adrenoceptors (beta-receptors) are stimulated, automatic- ity in the sinoatrial (SA) node increases; the velocity of conduction through the atrioven- tricular (AV) node increases as well. These effects lead to a higher heart rate (HR) as well as increased myocontractility, producing more forceful contractions of the heart muscle. Nor- epinephrine and epinephrine are the natural ligands (agonists) for beta-receptors in the ANS (see Chapter 5). NE directly “activates” β-receptors on the heart, causing an increase in heart rate, which in turn increases blood pressure on the vasculature. Even when the body is not “stressed,” norepinephrine circu- lates throughout the body. Because activation

of beta-receptors on the heart causes increased blood pressure levels, one would expect that

an antagonist (or other chemical substance bound to the receptor site) would prevent re- ceptor activation by blocking the endogenous ligand from binding to its receptor. Hence, one mechanism to reduce blood pressure

is to restrict, or block, norepinephrine (and epinephrine) from binding to beta-receptors on the heart (which results in reduced heart muscle contractility and lower CO). This class of medications is known as beta-blockers (as their name implies) (TABLE 6-4).

Beta-receptors innervate organs through- out the periphery (see FIGURE 6-6), not just the heart (Chapter 5). Because this class of drugs blocks endogenous ligand-binding and re- ceptor activation, it is critical to know pre- cisely where other b-receptors in the body are located. Specific beta-receptors (β1-receptors) are found not only in the heart, but also in the kidney. Blocking β1-receptors in the kid- ney inhibits the release of renin (recall that this reduces the activity of the RAAS), which further decreases blood pressure. β2-receptors have a less powerful effect on the heartwhen stimulated. Activation of β2-receptors causes arterioles in the heart, lungs, and skel- etal muscles to dilate; induces bronchial di- lation, relaxation of the uterus in women, glycogenolysis in liver and skeletal muscle, and enhanced contraction of skeletal muscle;

and promotes the movement of potassium into cells.

Therefore, following administration of either a β1-receptor agonist or antagonist drugs produces a myriad of physiological ef- fects, in addition to the desired therapeutic effect for which the medication was given (in this discussion, to lower blood pressure). It is of utmost importance that the nurse be able to predict and/or anticipate these additional physiological responses following the admin- istration of a β-blocker to a patient, due to antagonist blockade of beta-receptors at sites on different organs and tissues throughout the body.

Beta-blockers are further classified by their specific receptor-binding profile:

• Nonselective beta-blockers block both beta- one (β1) and beta-two (β2) receptors on tissues located throughout the body; not only those on the heart.

• Selective beta-blockers are selective about which beta-receptors they “block”; in other words, selective β-blockers bind to beta-receptors located on cardiac tissue (β1-blockers), but do not bind to beta-receptors located on all the other organs, throughout the body

• First-generation beta-blockers are nonselec- tive and block both β1- and β2-receptors throughout the body.

• Second-generation beta-blockers are cardiose- lective drugs that block only β1-receptors at normal dosages

• Third-generation beta-blockers are typically mixed α1-/β-blockers and are therefore nonselective.

As evidenced by the most recent JNC 8 Guidelines, the use of beta-blockers for hy- pertension, despite their wide use, is not ne- cessarily the best first-line treatment for this condition. These findings is corroborated by

a 2017 Cochrane Database of Systematic Re- view conducted by the Cochrane Hyperten- sion Group, which studied the overall efficacy of initiating treatment of hypertension with beta-blockers. The authors concluded that ini- tiating treatment of hypertension with beta- blockers leads to modest CVD reductions, little or no effects on mortality, and are infer- ior to those of other antihypertensive drugs (such as diuretics, calcium-channel block-

ers, and rennin–angiotensin–system inhibi- tors) (Wiysonge, Bradley, Volmink, Mayosi, & Opie, 2017). It has been concluded that beta- blockers are not as effective preventing the number of deaths, strokes and heart attacks, as drugs in other classes of medications (used to treat hypertension).

While beta-blockers are not necessarily the best choice to treat hypertension, these medi- cations are used to treat many other medical conditions. For example, long-term treatment of angina, coronary artery disease, heart fail- ure, and dysrhythmias, and those who have recently experienced a myocardial infarc-

tion (MI). Medications of this class can also

be used for the prevention of migraine head- aches and anxiety attacks. In patients who have hypertension along with one or more of these other conditions, beta-blockers can offer a “two-for-one” option to potentially address both conditions simultaneously. However, cli- nicians should keep in mind (and inform patients) that abrupt beta-blocker discontinu- ation can cause a hyperadrenergic state that places the patient at increased risk for sig- nificant cardiovascular event or even death.Gradual tapering of the beta-blocker will re- duce this risk (Prescriber’s Digital Reference [PDR], 2018).

Adverse Effects of Beta-Blockers

Blockade of β2-receptors (on the lung) in- hibits bronchodilation; for this reason, use

of β-blockers has generally been avoided in patients with asthma over concerns regarding bronchoconstriction. Numerous studies report patients who have bronchospastic disease (e.g., asthma, chronic obstructive pulmonary disease [COPD]) should avoid nonselective beta-block- ers, but can use cardioselective β1-blockers with supervision (Morales et al., 2014).

Likewise, patients with significant pe- ripheral artery disease (PAD) and Reyn-

aud phenomenon should not be prescribed non-selective beta-blockers, for much the same reason: blockade of β2-receptors will limit the arterioles’ ability to dilate. Patients with mild to moderate PAD did not show an exacerbation of symptoms with beta-blockers (Radack & Deck, 1991), but even so, patients with these diseases should take beta-blockers with caution.

Beta-blockade prevents the normal re- sponse of tachycardia to low blood sugar and masks one of the classic signs and symptoms of hypoglycemia. Thus, medications based on this mechanism of action should be used with caution in patients with diabetes, par- ticularly insulin-dependent type 2 or type 1 diabetes. Also, the body’s responses to hypo- glycemia are glycogenolysis and gluconeo- genesis, which are slowed with beta-blocker medications, especially if the beta-blocker

is noncardioselective.

Depression, fatigue, and sexual dysfunc- tion were commonly reported as side ef-

fects of beta-blockers in early clinical trials.

A review of 15 trials with more than 35,000 patients using such medications showed only a small increase in reports of fatigue or sexual dysfunction, however, and no difference in depressive symptoms (Ko et al., 2002). Beta- blockers have significant adverse effects when combined with certain common medications, as described in TABLE 6-5.

Blockade of ` -Receptors 1

As mentioned earlier, some beta-blockers

also block the α1-receptors and thereby promote vasodilation, which helps to de- crease SVR. However, certain medications block only the α1-receptors without affecting β-receptors; these are, for obvious reasons, referred to as selective `1-blockers. Drugs

in this class include terazosin, doxazosin, and prazosin. Alpha-blockers act on the postsynaptic α1-receptors. As antagonists, alpha-blockers bind to the ligand-binding site on alpha1-receptors and thereby block receptor activation, preventing NE from binding to the smooth muscle receptors. When such agents are used to treat hypertension, the effect of blocking constriction of the arterioles and veins has the most significant impact on low- ering blood pressure. Patients who may benefit from α1-antagonist therapy include those with hypertension and benign prostatic hypertrophy (BPH). These agents are also often the drugs of choice for hypertensive crisis caused by pheo- chromocytoma (an adrenal gland tumor that causes hypersecretion of catecholamines).

Adverse Effects of Alpha-Blockers

Patients who take alpha-blockers may experi- ence weakness, dizziness, and syncope caused by a significant decrease in their blood pressure and the loss of the reflex vasoconstriction upon standing, known as postural hypotension. The patient should be counseled not to sit or stand up from a lying position too quickly. In addi- tion, there can be a first-dose effect charac- terized by severe hypotension. Patients who have intravascular volume depletion (hypovo- lemia) are at particular risk. Reflex tachycardia

is seen most often with the use of nonselec- tive alpha-antagonists, in response to the hy- potension, as the body works to stabilize the blood pressure.

Nasal congestion due to the dilation of the nasal mucosal arterioles is caused by

the α1-blockers antagonizing those recep- tors. Alpha-blocking medications should

be used with caution in the elderly and those with cataract surgery, as blockade of alpha-receptors in the eyes can lead to pupil dilation and blurred vision.

Drug–Drug Interactions

Some medications may increase the risk

of hypotension and other adverse effects if used with α1-antagonists. These agents in- clude alfuzosin, dutasteride/tamsulosin, silodosin, tadalafil, and tamsulosin.

Calcium-Channel Blockers

The last major class of antihypertensive medications is not “antihypertensive.” Calcium-channel blockers (CCBs) are,

in truth, more of a broad-spectrum vascular smooth muscle relaxant, and this property can be exploited to provide a number of bene-

fits to the heart and the cardiovascular sys- tem as a whole. This utility arises because calcium plays a major role in the mechanism of vascular smooth muscles contraction; cal- cium channels, which span the cell membrane channels, regulate the amount of calcium that enters the cell. In the heart, calcium levels af- fect the force and rate of contractions. Calcium entry causes the heart to contract with more force

(positive inotrope). It also increases the HR by affecting the rate in the SA node, and, the velocity of the conduction in the AV node. Blocking calcium channels, therefore, helps lower CO by both reducing the force of contraction and decreasing the frequency of contractions.

In the arteries, calcium-channel blockers impede the smooth muscle of arterial walls from contracting (i.e., constricting), resulting in smooth-muscle relaxation and the arterial dilation. Blood pressure levels decrease by de- creasing SVR, while simultaneously increas- ing oxygen flow to the heart. In sum, CCBs act on all three of the factors related to blood pressure: CO, SVR, and HR.

The rationale that supports CCB use as an- tihypertensive agents make them (the CCBs) valuable agents for treatment of other car- diovascular pathologies (see TABLE 6-6). For ex- ample, they are used to treat chest pain and cardiac dysrhythmias. Three subclasses (based upon chemical structures) of CCBs—the dihy- dropyridines, phenylalkylamines, and benzo- thiazepines—are used to treat chest pain and hypertension. In addition, the phenylalkyl- amines and benzothiazepines may be given intravenously for atrial fibrillation, atrial flut- ter, and supraventricular tachycardia (SVT). The longer-acting CCBs are indicated for el- derly patients with isolated systolic hyper- tension and one of the following coexisting conditions: angina pectoris, Raynaud phe- nomenon, asthma, or COPD; they may also be given to elderly patients who have not re- sponded to other medications.

Adverse Effects of Calcium Channel Blockers

All CCBs carry a risk of hypotension, head- ache/weakness, and dizziness related to the vasodilatory effects necessary for lowering

of the blood pressure. Edema of ankles and feet (peripheral edema) also may occur and is likely related to a redistribution of fluids from the intravascular space into the interstitial spaces. Unfortunately, diuretics may not be useful in resolving this type of edema.

Some specific effects are associated with particular classes of CCBs. Dihydropyridinesmay cause reflex tachycardia due to arterial dilation, and large doses of short-acting nife- dipine may increase the mortality of patients immediately following an MI (Furberg, Psaty, & Meyer, 1995). Phenylalkylamines and benzo- thiazepines reduce arterial pressure without as much reflex tachycardia as the dihydro- pyridines, but because of how these drugs act on the arterioles and the heart, a patient who has bradycardia or AV block is at risk. Con- stipation is also a concern with this group

of medications, with verapamil being more likely to cause constipation than diltiazem.

CCBs are among the few medications with known interactions with nutrients— specifically, components of grapefruit juice (Sica, 2006). Certain flavonoid and nonflavo- noid components of grapefruit juice interfere with presystemic clearance of these drugs, which means that less of the drug is metabo- lized before it enters the circulation; in turn, the overall bioavailability increases. The ef- fects of this interaction are similar to what

might be seen if the patient took a higher dose of the medication than was prescribed; symptoms include hypotension, bradycar- dia, and peripheral edema. Patients should be warned not to drink grapefruit juice or eat grapefruit while taking these medications.

Diuretics

Recall earlier in this chapter it was said that another physiological mechanism which serves to lower blood pressure levels is to decrease total body fluid—or fluid volume. Diuretics, first discovered in 1957, are a class of medications used to reduce blood pres- sure by lowering the fluid volume in the circulatory system and are a mainstay in

the treatment of hypertension. They have been shown, in placebo-controlled clinical studies, to significantly reduce cardiovas- cular morbidity and mortality (Salvetti & Ghiadoni, 2006). Commonly referred to as water pills, diuretics (TABLE 6-7) cause the kid- neys to excrete sodium and water from thesystemic circulation, which in turn lowers the fluid volume.

Diuretics have been used when initiating the stepped-care pharmacological treatment approach of antihypertensive drug therapy. FIGURE 6-7 illustrates the rationale for the use of diuretics to treat high blood pressure and both short-term and long-term effects us-

ing the thiazide class of medications. Several classes of diuretics are available to treat hy- pertension; diuretics are categorized into dif- ferent drug classes based upon and the drugs’ mechanism of action: thiazide diuretics, po- tassium-sparing diuretics, and loop diuretics.

Diuretics in the thiazide subclass also relax the walls of blood vessels, thereby reducing both CO and SVR.

As a class, diuretic drugs are attractive be- cause they are well-tolerated and can be used in combination with other classes of antihy- pertensive medications. However, not all sub- types of diuretics behave in the same manner, so close attention should be paid to a drug’s subclass and mechanism of action. (Another subclass of diuretics, carbonic anhydrase inhib- itors, is not used for treating hypertension be- cause these agents’ effects are too weak; such drugs are used primarily to treat glaucoma.)Acetazolamide

• A carbonic anchydrase inhibitor that inhibits the reabsorption of HCO3– in the proximal convoluted tubule.

Glomerular filtrate

1. Proximal convoluted tubule

2. Descending limb

4. Distal convoluted tubule

3. Ascending limb

Thiazides

• Inhibit reabsorption of Na+ and Cl– in the distal convoluted tubule, resulting in retention of water in the tubule.

• Most commonly used diuretic for the treatment of hypertension.

Spironolactone, Amiloride, Triamterene

• Spironolatone, an aldosterone antagonist, inhibits the aldosterone- mediated reabsorption of Na+ and secretion of K+.

• Amiloride and triamterene block Na+ channels.

• These agents can prevent loss of K+ that occurs with thiazide or loop diuretics.

Collecting tubule and duct

• Weak diuretic properties.

Bumetanide, Furosemide, Torsemide, Ethacrynic acid

• The loop diuretics inhibit the NA+/K+/2Cl– cotransport in the ascending loop of Henle, resulting in retention of Na+Cl–, and water in the tubule.

• These drugs are the most efficacious of the diuretics.

FIGURE 6-7 Treatment of hypertension: Mechanism of action of diuretics.

Thiazide Diuretics

Thiazide diuretics (hydrochlorothiazide [HCTZ], chlorthalindone) are very commonly prescribed for several reasons. First, they have a long history of safe, successful use for hyper- tension. Second, they are relatively inexpen- sive. Third, they are easy to use and have fairly minimal side effects, which means patients are more likely to take them as prescribed. In ad- dition, these agents’ efficacy is quite good: thi- azide diuretics are just as effective in reducing cardiovascular events in patients with hyper- tension as beta-blockers and ACE inhibitors, and they are actually better than either of the other classes in reducing stroke (Roush, Kaur, & Ernst, 2014). Of note, thiazide diuretics have been particularly successful in treating African American patients, in whom they tend to be the first-line therapy (see JNC 8 Guidelines; James et al., 2014). However, thiazide diuret- ics promote potassium loss and are thought

to increase the risk of new-onset diabetes, es- pecially when combined with beta-blockers; thus, use of these drugs in patients who are

at high risk for developing diabetes should be undertaken with caution. In such cases, the drugs should be prescribed at the lowest active dose and possibly in combination with ARBs, a pairing that has been shown to reduce the adverse impact on glucose tolerance. There

is an association between glucose intolerance and hypokalemia, and some have suggested that treating hypokalemia might reverse insu- lin resistance or prevent diabetes (Sica, Carter, Cushman, & Hamm, 2011).

Loop Diuretics

Loop diuretics get their name from the loop

of Henle in the kidney, which is where this class of drugs produces their effects. They bind to a carrier protein in the thick ascending limb of the loop of Henle that transports so- dium, chloride, and potassium ions; by doing so, they prevent NaCl (salt) as well as water from being reabsorbed, lowering fluid volume (Wittner, Di Stefano, Wangemann, & Greger, 1991). The thick ascending limb of the loop

of Henle is where a large proportion of thebody’s sodium transport occurs, so loop diuret- ics can reduce water reabsorption substantially more than thiazide diuretics (which work in the distal tubules of the kidney). The nega- tive aspect of this capability is that it promotes potassium loss and, potentially, hypokalemia. Furosemide is perhaps the best-known drug in this class; it is much more often prescribed for congestive heart failure (CHF), an indica- tion discussed later in this chapter.

Potassium-Sparing Diuretics

Potassium-sparing diuretics, unlike thiazide and loop diuretics, do not act on sodium trans- port mechanisms, so they avoid the problems associated with potassium loss. Two drugs in this class, spironolactone and eplerenone, are AAs (described earlier in the RAAS dis- cussion) and produce a diuretic effect by that mechanism; the other two members of this class, amiloride and triamterene, act dir- ectly on sodium channels and likewise do not promote excretion of potassium. In patients for whom hyperkalemia is an issue, these medications will make the problem worse

and should not be used. However, because potassium-sparing diuretics have relatively weak effects on overall sodium balance, they are often used in combination with other classes of diuretics as a way of maximizing fluid volume reduction while avoiding ex- cessive potassium loss and hypokalemia. An important drug interaction occurs with con- comitant use of trimethoprim-sulfamethox- azole antibiotic therapy, which acts similarly on the distal tubules as a potassium-sparing diuretic (Weir et al., 2010).

Hypertensive Emergencies

To this point, the discussion has been focused on the treatment of chronic hypertension stemming from a variety of causes. There is an additional form of hypertension that occurs

in an acute form, known as a hypertensive emergency. Hypertensive emergencies are instances in which the patient has both severe hypertension and a risk of end-organ damage (e.g., myocardial infarction, unstable angina, acute left ventricular failure with pulmonary

edema, acute aortic dissection, encepha- lopathy, stroke and life-threatening bleeding [intracerebral hemorrhage and subarachnoid hemorrhage]) (Chobanian et al., 2003; Perez & Musini, 2008). Careful management of the process of lowering the blood pressure is es- sential due to the risk of the antihypertensive treatment causing severe hypotension, which can lead to complications such as MI and stroke. Both oral and intravenous (IV) medi- cations are available for these purposes, but the IV route is preferred for patients at risk of end-organ damage. IV medications for hyper- tensive emergencies include medications from the following categories: vasodilators, CCBs, peripheral dopamine-1 agonists, beta-block- ers, and alpha-adrenergic blockers.

The primary goal of intervention in a hy- pertensive crisis is to safely reduce blood pressure. The appropriate therapeutic ap- proach of each patient will depend on their clinical presentation. Patients with hyper- tensive emergencies are best treated in an in- tensive care unit with titratable, intravenous, hypotensive agents. Rapid-acting intrave- nous antihypertensive agents are available, in- cluding labetalol, esmolol, fenoldopam, nicardipine, and sodium nitroprusside. Newer agents, such as clevidipine and fenoldopam, may hold considerable ad- vantages to other available agents in

the management of hypertensive crises. Sodium nitroprusside is an extremely toxic drug and its use in the treatment of hyperten- sive emergencies should be avoided. Similarly, nifedipine, nitroglycerin, and hydralazine should not to be considered first-line therapies in the management of hypertensive crises be- cause these agents are associated with signifi- cant toxicities and/or adverse effects.

Organs at Risk of Damage During a Hypertensive Crisis

• Eyes: Bleeding or swelling

• Brain: Complications from elevated

intracranial pressure, stroke • Kidneys: Renal failure

• Heart: MI, CHF

CCBs that are used for hypertensive emer- gencies are in the dihydropyridine category and include clevidipine and nicardipine. Esmolol is a predominantly cardioselective beta-blocker, and labetalol is a combined beta-receptor and alpha-adrenergic blocker. For emergency management, these drugs

are given via the IV route. (See the previous sections for additional information on these drug categories.)

Vasodilators include nitroprusside, which dilates both arterioles and veins by re- leasing nitrous oxide (NO), which then ac- tivates smooth muscle guanylyl cyclase, to form cGMP. cGMP inhibits entry of calcium into cells, thereby causing smooth muscle relaxation, by virtue of the decreased cal- cium. Nitroprusside is a very effective drug for lowering blood pressure quickly. This ef- fect occurs in less than 2 minutes and lasts for only 1 to 10 minutes, necessitating that the medication be administered as a continu- ous IV drip to maintain its effectiveness. In the body, nitroprusside is metabolized into cyanide; consequently, the patient must be monitored for signs of developing cyanide poisoning. The risk for cyanide poisoning cor- relates to both the length of therapy and the dosage level of medication administered. Pa- tients should be monitored for signs of tox- icity such as changes in mentation, miosis, tinnitus, gastrointestinal (GI) distress, methe- moglobinemia, and metabolic acidosis. The patient should be on continual and accurate blood pressure monitoring to facilitate titra- tion of the medication and to prevent severe hypotension. Pregnant women should not re- ceive nitroprusside, as this drug may cross the placental barrier.

Another vasodilator is hydralazine, which works primarily on the vascular smooth muscles of the arteriolar vessels and has minimal impact on the venous vessels. This drug is considered safe and is widely used for the acute hypertensive treatment of pregnant women. However, its hypotensive episodes can be difficult to predict in com- parison to other agents. Hydralazine can,

for instance, cause reflex tachycardia in re- sponse to the decrease in the arterial pres- sure. A beta-blocker may be considered to address this symptom. Hydralazine may also produce an increase in volume because the lowered blood pressure can cause an in- crease in sodium and, subsequently, water re- tention. A diuretic (see the earlier discussion) may be considered to address this increase in volume. Other adverse effects associated with hydralazine include chest pain, paradoxi- cal hypertension, peripheral edema, anxiety, disorientation, further increase of intracranial pressure, GI disturbances, diaphoresis, lupus- like syndrome, and peripheral neuritis.

Peripheral dopamine-1 agonists are another class of medications that promote vasodilation and thereby relieve high blood pressure during an acute crisis. Fenoldopam, for example, activates the dopamine-1 re- ceptors on the arterioles, which causes the vessels to vasodilate. It is as effective as nitroprusside and has even more benefits for the kidney because it acts on receptors in renal, coronary, mesenteric, and peripheral vessels. Acting as an antagonist, fenoldopam causes the renal arteries to dilate, which im- proves blood supply; it also promotes so- dium and water loss. Like nitroprusside, this medication has a rapid onset (less than five minutes) and short duration (half-life

of five minutes). Adverse effects include re- flex tachycardia in response to the vasodi- lation and increased intraocular pressure; fenoldopam should not be administered, or should be given only with great caution, to patients with glaucoma.

Some high blood pressure medications, such as ACE inhibitors and the angioten-

sin II receptor blockers may harm a pregnant mother and developing fetus, so should not be used during pregnancy. Reserpine, an al- kaloid that acts via monoamine depletion, should only be used when no alternatives ex- ist, as it may also be harmful during preg- nancy (Morelli, 2016). All pregnant patients should be counseled on medication use per the Pregnancy and Lactation Labeling Rules.

Cardiac Agents

Coronary Artery Disease

Coronary artery disease (CAD) is a condi- tion that occurs when blood flow to the heart is restricted, or completely blocked, depriving cardiac muscle of oxygen. Coronary artery dis- ease most commonly results from the buildup of cholesterol and other fatty materials (ath- erosclerotic plaques) in the wall of a coronary artery, in a process known as atherosclerosis (FIGURE 6-8). (Note: Fatty-plaque buildup occurs in arteries throughout the body; not just the coronary arteries of the heart.)

Chest Pain/Angina

Angina pectoris, known more commonly as chest pain, is characterized by the sudden onset of a “crushing” feeling of pressure, burning, squeezing, or suffocating pain in the chest. Chronic chest pain, or angina, gen- erally occurs as a result of coronary artery disease (FIGURE 6-9). Pain from angina can also radiate to the arms, shoulders, neck, jaw,

and throat, often leaving the patient uncer- tain of its origin. The “experience” of angi- nal pain varies among patients; symptoms also manifest differently depending upon the

type of angina causing the chest pain. The three forms of angina discussed in this sec- tion are exertional, variant, and unstable an- gina (FIGURE 6-10).

Exertional Angina

Also called chronic stable angina, exertional angina usually has somewhat predictable triggers. Physical exertion, emotional stress, cold weather, or large meals are common examples of conditions that can trigger ex- ertional angina in patients with underlying coronary artery disease. Each of these triggers places an increased workload on the heart, which in turn increases the heart’s need for oxygen. The angina is the body’s signal that the heart is not receiving adequate oxygen. The treatment goal is to balance the heart’s oxygen needs with the available supply by decreasing the demand for oxygen.

Acute episodes of angina are usually treated with nitroglycerin, which, like ni- troprusside, increases tissue cGMP, and is typically placed sublingually for rapid ab- sorption but can also be administered orally or intravenously. Longer-term prevention and decrease of severity/number of angina attacks requires the use of any of several medications, primarily CCBs, beta-blockers, and ranolazine, a medication specific to an- gina pain.

Variant Angina

Also called Prinzmetal angina, variant angina is caused by vasospasm of the coronary arter- ies (which supply blood to the heart muscle). Exertion is not a trigger for variant angina. This is in direct contrast to stable angina (re- call from the above discussion: chest pain oc- curs in a predictable pattern during exertion or exercise). Prinzmetal angina occurs at rest, often without a predictable pattern. The pa- tient experiences pain as a result of coronary artery spasms, which decrease the amount

of oxygen delivered to the heart. Therefore, the treatment goal for this type of angina is to increase the blood flow and oxygen supply to the heart. Medications used in the treatment of variant angina include nitrates and CCBs. Beta-blockers and ranolazine are not used to treat variant angina.

Unstable Angina

Unstable angina carries a much higher risk of mortality than chronic stable angina or vasospasm-related angina and is considered a medical emergency. The treatment recom- mendations are as follows:

1. Oxygen: Recommended for patients with an arterial saturation of less than 90%, patients in respiratory distress, or those at high risk for hypoxemia (Anderson et al., 2007).

2. Nitroglycerin: Either oral or IV nitroglycerine for patients who have continued hyperten- sion or are in heart failure.

3. Morphine: IV morphine is recommended for pain relief and/or relief from anxiety. The morphine should be titrated while monitor- ing the patient.

4. Antiplatelet therapy: Unless there are seri- ous contraindications, patients should re- ceive antiplatelet therapy with aspirin and a P2Y12 receptor blocker (Anderson et al., 2007). Anticoagulants are discussed later in this chapter.

5. Anticoagulation: Anticoagulation therapy should be initiated to reduce the risk of MI or stroke.

Antianginal Agents

Most of the drugs used to treat angina are al- ready familiar from the previous discussion

of hypertension. Because the cause of angina is reduced oxygen to the heart, it stands to reason that drugs such as beta-blockers and CCBs, which cause vasodilation, can increase blood flow to the heart and thereby relieve the pain. Thus, there is no need to reiterate the activity of those drug classes here. However, two other drugs, ranolazine and (especially) nitroglycerin, have important roles in treat- ing this condition, so they are discussed in more depth.

Ranolazine

The mechanism of action for ranolazine is not completely understood, but it can reduce the amount of sodium and calcium in the myocardial cells. As described in the earlier section on CCBs, the function of calcium in cardiac and vascular smooth muscle is to pro- mote contraction and vasoconstriction; thus

reducing the calcium level in these cells helps to relax both the vessels feeding the heart (increasing blood flow) and the heart muscle itself (reducing oxygen demand).

Cardiac Agents 199 Best Practices

Use of phosphodies- terase type 5 inhibi- tors (medications for erectile dysfunction) is absolutely contra- indicated in patients taking nitroglycerin or other nitrate medications, as the interaction between the drugs may be life threatening.

Adverse effects of this medi-

cation include alterations in heart

function, specifically a dose-related

increase in the QT interval that

places the patient at an increased

risk for serious dysrhythmias,

including torsades de pointes.

Patients with severe renal impair-

ment may experience blood pres-

sure elevation and should monitor their blood pressure closely. Other side effects include constipation, dizziness, nausea, and headache.

A few medications are known to have significant interactions with renolazine. Drugs that prolong the QT interval should

not be combined with renolazine due to in- creased risk of developing torsades de pointes. CYP3A4 inhibitors can increase the serum lev- els of renolazine, because it is metabolized through that mechanism; patients taking this drug should be warned to avoid grapefruit and grapefruit juice.

Nitroglycerin

Nitroglycerin—or more correctly, glyceryl trinitrate—is a well-known therapy for chest pain. It works through a series of reactions that begin with the uptake of nitrates by the vas- cular smooth muscle to produce vasodilation, primarily in the veins but also in the arterioles. The obvious benefit of this response is an in- creased amount of blood remaining in the per- ipheral tissues, so that less blood returns to the heart. With this reduction in preload, the heart has a decreased demand for oxygen. Nitrates also lessen coronary artery spasm, thereby in- creasing the oxygen supply even more.

Nitroglycerin is typically (perhaps even stereotypically) administered sublingually as a spray or dissolving tablet; however, it may also be administered orally as a long-acting cap- sule, as a sustained-release patch, or, in un- stable angina, intravenously. The development of tolerance to the vasodilation effects of ni- trates is one concern for patients receiving ni- trate therapy. To minimize nitrate tolerance, the smallest effective dose should be utilized, and patients using sustained-release patches should allow for a consistent period of time each day that the patch is removed.

Nursing Considerations

Adverse effects associated with nitroglycerin include headache, which is caused by the direct vasodilation and can be treated with acetaminophen. Orthostatic hypotension may also result from the collecting or pooling of blood in the veins; patients should move from a lying or sitting position slowly to al- low time for accommodation of their blood pressure. Reflex tachycardia may occur in re- sponse to the vasodilation as well, decreasing the patient’s blood pressure.

Nitroglycerin’s drug interactions in- clude phosphodiesterase type 5 (PDE5) in- hibitors, a group of medications used for erectile dysfunction; these medications are absolutely contraindicated with nitrates. Con- comitant use of nitrates and PDE5 inhibi- tors can cause life-threatening hypotension. Care should be exercised with patients tak- ing nitrates and other medications that lower blood pressure to decrease the risk of severe hypotension.

Hyperlipidemia

Lipids are a class of molecules that include

a variety of substances: fatty acids, sterols (including cholesterol), certain fat-soluble vitamins (A, D, E, and K), and glycerides. The word lipid is often misconstrued as cholesterol, as lipids is the overall term most often blan- ketly associated with the “prevention of heart disease,” along with triglycerides.

Cholesterol has also gained a bad reputa- tion, yet the cholesterol molecule is required for key biochemical and physiological func- tions. For example, cholesterol is required for the synthesis of hormones (i.e., adrenal corti- costeroids, estrogen, progesterone, and testos- terone); it is essential for the synthesis of bile salts; and it literally makes up part of all cell

membranes. In short, human beings could not live without cholesterol. The body obtains some of its necessary cholesterol from dietary sources, but the remaining amount is synthe- sized in the liver. However, too much of any molecular compound can become harmful.

Although most people know about

two kinds of cholesterol (characterized in

the media as “good” cholesterol and “bad” cholesterol), there are actually six major classes of lipoproteins. Only three of these six have been directly associated with the development of coronary artery sclerosis: very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high- density lipoprotein (HDL). An increase

in LDL cholesterol—the type popularly identified as “bad” cholesterol—correlates with an increase in the risk of coronary heart disease (CHD). Conversely, an increase in HDL (“good”) cholesterol correlates with a decrease in the risk of CHD. Remembering which is which is simply a matter of understanding that the names equate with the levels needed for health: LDL is the

type of cholesterol which should be remain low, while HDL is the molecule that needs

to stay high, to avoid dyslipidemia. VLDL is the principal transporter for other lipids, including triglycerides; a high triglyceride level generally equates to a high VLDL

level and is a risk factor for heart disease. Because VLDL is not directly measured, it is not a target for medication in the same way that HDL and LDL are; however, the total amount of triglycerides is addressed with pharmacologic therapy due to its correlation with cardiovascular disease.

Cholesterol (and triglyceride) levels are best controlled via lifestyle alterations, in which high-fat foods are avoided and, in particular, cholesterol-bearing foods (meats, eggs, and dairy products) are limited. How- ever, lifestyle modifications are not always successful. Some patients simply are not able to manage the dietary changes needed, while others, due to genetic factors, continue to have elevated cholesterol levels even with dietary modifications. For these situations, a variety of medical options are available. The goal of therapy is to reduce cholesterol and triglyceride levels so as to reduce risk of plaque buildup and the potential for throm- bosis leading to MI or stroke. (Medical ther- apies specifically intended to prevent clot formation are discussed later in this chapter.)

Statin Drugs

Statin drugs (TABLE 6-8) are among the most widely prescribed medications for hyperlip- idemia for one reason: this group of drugs is currently the most effective class available in terms of its ability to lower cholesterol levels, due to their mechanism of action (MOA). The MOA is exactly the same for each member

of the statin class of medications. The cho- lesterol molecule is synthesized in the liver

by an enzyme called HMG-CoA reductase;

the statin drugs directly inhibit the action of this enzyme, HMG-CoA reductase, thus dir- ectly decreasing the synthesis of the choles- terol molecule. Lower cholesterol levels have been shown to slow the progression of CHD, and the complications of CHD. The enzyme, HMG-CoA reductase, is most active during the sleeping hours; thus, this class of medications is more effective when taken right before bed- time. These drugs are effective in decreasing the risk of CHD events in patients who have CHD as well as those who do not show evi- dence of CHD. Because the majority of choles- terol synthesis in the body occurs at night, it is recommended that the shorter half-life statins

be taken at bedtime so they can have the greatest effect in reducing choles- terol levels.

Adverse effects related to the use

of statins vary. For some patients,

muscle symptoms ranging from my-

algia to myositis to rhabdomyoly-

sis can begin to appear within weeks

to months of starting statin therapy.

Muscle injury is far less common

when patients are taking statin ther-

apy alone. There is also a risk of liver tox- icity; elevation in the serum transaminase levels develops in 0.5% to 2% of patients who have been taking statins for a year or longer. While there is risk for liver injury, progression to liver failure is extremely rare. Liver function tests are recommended be- fore the start of treatment and every 6 to 12 months. Some statin drugs may increase the risk of type 2 diabetes, particularly in women (Byrne & Wild, 2011), but recent studies sug- gest that this outcome occurs primarily in those patients who already have other risk factors for diabetes (Waters et al., 2013). Thus, a patient’s baseline diabetes risk should be assessed carefully before using statin drugs and weighed against the risk of cardio- vascular events (Nichols, 2013).

Statins are considered to be harmful to pregnant women and the developing fetus. They should not be taken by women who are pregnant or who plan to become pregnant.

Drug interactions of note include those with other lipid-reducing agents, which

can increase the severity and incidence of statin-associated adverse events. Statins may also interact with drugs that inhibit CYP3A4 as statins are metabolized via this pathway; thus inhibition of CYP3A4 can elevate serum statin levels.

Fibrates

Fibrate drugs (TABLE 6-9) are derived from fibric acid, which lowers lipid levels, at least in part, by activating peroxisome proliferator-acti- vated receptors (PPARS) (Staels et al., 1998). Activating these receptors promotes the breakdown of fatty acids. Fibrates can lower serum triglycerides by 35% to 50% and raise serum HDL by 5% to 20%—a substantial improvement in patients with significantly el- evated triglycerides.

Adverse effects of fibrate drugs include muscle toxicity, especially when taken con- comitantly with a statin. Patients taking fibrates have also been identified as experi- encing elevations in their serum creatinine levels. Dyspepsia and formation of gallstones have been identified as common side effects of this drug class, with clofibrate in particular marked as causing the latter problem.

Known drug interactions include exac- erbation of muscle toxicity when fibrates are taken with statins, especially those that are metabolized by the CYP3A4 pathway; caution should be used when taking fibrates alongside any CYP3A4-inhibiting drug, or any other agent that likewise relies on this metabolic mechanism. Fibrates interfere with warfarin metabolism and increase this medication’s cir- culating levels (Dixon & Williams, 2009), so patients on warfarin should have their Inter- national Normalized Ratio (INR) monitored while taking fibrate drugs. Fenofibrate in- creases the clearance of cyclosporine, and patients can experience a significant reduc- tion in their serum cyclosporine levels.

Niacin

Niacin, also known as vitamin B3 or nico- tinic acid, is an essential nutrient that offers benefits for patients with dyslipidemia. In the liver, niacin inhibits the production of VLDL, which helps to lower LDL levels. It also raises HDL levels by decreasing the lipid transfer

of cholesterol from HDL to VLDL and slows down HDL clearance. In this way, niacin both lowers LDL levels and causes a reduc- tion in plasma fibrinogen levels. It is effective in patients with elevated cholesterol levels and those who have elevated lipids and low HDL levels. Some studies have suggested that niacin may be useful in decreasing mortality when used with patients for secondary pre- vention of CHD.

Niacin (vitamin B3) is available as an OTC product in the same strength as the prescription medication, but it comes in several different forms: nicotinic acid, inositol hexanicotinate, and nicotinamide. Neither nicotinamide nor inositol hexanicotinate

has been shown to lower lipid levels; thus,

if patients are told to take niacin and wish

to purchase it on an OTC basis rather than obtaining it by prescription, it is imperative that they be instructed to read the label and purchase nicotinic acid—otherwise, they

will not get the benefit of the medication.

A helpful pointer to patients is to avoid brands that advertise themselves as “no-flush niacin,” because these are almost universally made with inositol hexanicotinate. Such products are able to make “no flush” claims precisely because they lack nicotinic acid, the very substance needed to lower cholesterol!

Flushing is the most common adverse effect of niacin, and it can last from a few minutes to several hours. Flushing is more prevalent with the crystalline preparation versus the controlled-release formulation. This side effect is a minor consideration, how- ever; of greater concern is the fact that niacin can elevate serum glucose levels, which can be particularly problematic for those patients with diabetes. Nicotinic acid can also cause hyperuricemia, so patients with a history of gout should not take nicotinic acid. Pruri- tus, paresthesias, and nausea are other poten- tial adverse effects. Also, in patients who are on vasodilators for unstable angina pectoris, nicotinic acid can cause further hypotension, which can exacerbate chest pain.

Bile Acid Sequestrants

Bile acids are by-products of cholesterol and are excreted in the feces, but often a substan- tial amount of these acids are reabsorbed in the intestines. By binding bile acids in the intestines, bile acid sequestrants inhibit the reabsorption of bile acids. This lowers the cholesterol in the liver, which in turn encour- ages LDL receptors to be created; their pro- liferation then leads to additional reduction in serum cholesterol. Examples of this drug class include cholestyramine, colestipol, and colesevelam.

Patients with mild to moderately elevated LDL cholesterol levels are best served with this group of cholesterol-lowering agents. For patients with significantly higher serum LDL

levels, bile acid sequestrants are more effective when taken concomitantly with statins or nicotinic acid.

GI disturbances are the most

common adverse effects with these

drugs, including nausea, bloat-

ing, and cramping. Of note in re-

gard to drug interactions are those

with digoxin and warfarin. Both of

these agents may bind to bile acid se- questrants in the gut, which can impair the absorption of these two drugs and result is less-than-therapeutic serum levels.

Congestive Heart Failure

CHF is a progressive disease in which the heart is unable to pump with sufficient force to

push blood through the blood vessels. When this happens, fluid backs up in the vessels and leaks into the tissues and organs, particularly the lungs, leading to the shortness of breath and “congestion” that characterize CHF. Heart failure usually develops in the ventricles and can occur on one side of the heart or the other, or both sides simultaneously.

CHF has been described in terms of four stages of increasing severity (TABLE 6-10). Symp- toms of heart failure include reduced CO, shortness of breath with or without exertion, pulmonary edema, peripheral edema, angina, and jugular vein distention caused by the heart’s decreased inotropic strength. Appropriate pharmacologic treatment is selected based on the patient’s stage of CHF and response to the medication. Controlling volume overload can help alleviate left ven- tricular dysfunction. To reduce ventricular wall stress, drugs that affect the RAAS, and those that target the sympathetic nervous sys- tem effects on the heart can be employed. Three main groups of drugs are considered first-line therapy for CHF: diuretics, ACE in- hibitors or ARBs, and beta-blockers (all of which were discussed in detail in the earlier section on hypertension). The reason for us- ing these medications should be clear: They reduce the workload of the heart and lower overall fluid volume, both of which are im- portant considerations in patients with CHF.

Additionally, angiotensin receptor antago- nists (AAs), inotropic agents (which include cardiac glycosides [digoxin]), and vasodilators can be considered if treatment with the three main categories of drugs is not adequate. AAs and vasodilators were discussed previously; thus inotropic agents will be considered here.

Inotropic Agents

Inotropic agents affect contractions of the heart muscle. Inotropes can be either positive or negative. Positive inotropes cause increased cardiac contraction force, increasing cardiac workload, but improve cardiac function. Neg- ative inotropes decrease cardiac contraction force, which decreases cardiac workload. Pos- itive inotropes, primarily cardiac glycosides, have found utility for the treatment of CHF.

Cardiac Glycosides

The class of drugs known as cardiac glycosides is represented by the commonly prescribed medication digoxin (derived from the fox- glove plant Digitalis), acts on the heart both as a positive inotrope (leading to increased force of contraction) and a negative chronotrope (leading to altered impulse conduction) in

the heart.

Each time the heart contracts, sodium

and calcium ions move into myocyte intra- cellular space. The calcium ions cause re- lease of stored calcium ions within the cell

to interact with the myocyte contractile pro- teins, leading to contraction. This intracellu- lar calcium is re-stored during repolarization and relaxation. Cardiac glycosides bind the ATPase responsible for sodium and potas- sium movement, resulting in a decrease in the amount of sodium that moves out of the cell, resulting in less calcium recycled out of the myocyte, and increasing the amount of usable calcium inside the myocyte. By in- creasing usable calcium, myocardial contrac- tility is improved. The increased force raises the CO and arterial pressure. When arterial pressure increases, the baroreceptor reflex decreases the sympathetic stimulation of the heart and blood vessels, allowing the heart to pump more efficiently and in a more or- ganized manner. This reduces the symptoms of CHF and can treat some cardiac dysrhyth- mias. Increases in extracellular potassium ion concentration interfere with cardiac gly- coside binding of the ATPase, inhibiting the effectiveness of cardiac glycosides (such

as digoxin).

Digoxin has a narrow therapeutic index,

which facilitates the potential for undertreat- ment or toxicity. Because of the significant potential for under- or overtreatment with this agent, digoxin is now considered a sec- ondary treatment for CHF, to be used only if primary treatment is not adequate. Because of its negative chronotropic action, digoxin can also be useful in the treatment of atrial fibrillation, atrial tachycardia, and supra- ventricular tachycardia. However, in pa- tients who are being treated with this drug for CHF, digoxin’s negative chronotropic ef- fects can severely decrease HR and impact cardiac rhythm.

Nursing Considerations

The patient’s pulse should be checked be- fore the administration of each dose, if not more often. A low potassium level places the patient at increased risk for digoxin toxic- ity, so caution should be used in patients who have chronic hypokalemia; extreme caution should be used in patients with par- tial AV block or renal failure. Conversely, hyperkalemia reduces the drug’s effective- ness in such a way that if used in conjunction with medications that promote potassium retention, digoxin may prove less effective or completely ineffective.

A number of key drug interactions with digoxin have been identified. Diuretics that can cause hypokalemia put the patient at in- creased risk for digoxin toxicity. ACE in- hibitors and ARBs, in contrast, can increase potassium levels and decrease the response

to digoxin. Quinidine, an antidysrhythmic drug, can elevate digoxin levels and increase the risk of toxicity. Patients on quinidine may need digoxin dosage adjustments. Also, the CCB verapamil can elevate digoxin levels and increase the risk of digoxin toxicity.

Vasodilators are discussed in other parts of this chapter, and so are not discussed here, other than to point out that arterial and ve- nous dilatation improves the hemodynamic status of patients, decreasing resistance to blood flow, and cardiac workload.

Vasopressin, also called antidiuretic hormone (ADH), is released by the pitu- itary gland, and induces increased water re- sorption by the kidneys. Elevated vasopressin concentrations may increase peripheral vas- cular resistance and pulmonary capillary wedge pressure via free water resorption in the kidneys, leading to worsening of con- gestive heart failure. There are three known vasopressin receptors: V1a, V1b, and V2. V1b receptors are located in the central nervous system, V1a receptors are found both cen- trally and peripherally, and V2 receptors per- ipherally. V1a are involved in blood pressure regulation, while V2 receptors affect renal function.

One goal for treatment of CHF is to in- crease fluid elimination, while minimizing electrolyte loss, particularly of sodium (lead- ing to hyponatremia). Vasopressin antago- nism, especially of V2 receptors, increases urine output without associated sodium loss. Thus, vasopressin antagonists are some- times employed as part of the strategy to combat CHF. Two approved vasopressin an- tagonists are tolvaptan and conivaptan.

The resulting sodium retention can lead to an anticipated adverse ef- fect of increased thirst. Hyperkale- mia (potassium) may also be seen in patients taking these medications. Though these drugs do decrease pa- tient body weight, and improve so- dium concentrations, their benefits for patients with CHF appear to be marginal (Nistor et al., 2015).

Best Practices

Pay close attention to the patient’s potas- sium levels when us- ing digoxin therapy, as too little potas- sium could lead to digoxin toxicity and too much could cause the drug to lose its effectiveness.

Prevention of Thrombosis and Stroke: Anticoagulant Therapy 205

Prevention of Thrombosis

and Stroke: Anticoagulant Therapy

Earlier, we discussed therapy to reduce cholesterol levels. The reason these thera- pies are so widely used is that the long-term consequences of uncontrolled hyperlipid- emia include two of the most dreaded acute cardiac dysfunctions—stroke and MI. Plaque buildup in the arteries promotes the forma- tion of blood clots, which can block blood vessels and lead to tissue death locally. Often, this condition occurs in the deep veins of the legs (deep vein thrombosis [DVT]), which can provide a warning to patients of the need to address a propensity toward clotting before such an event takes place in the brain, the lungs, or the heart, which may prove fatal.

Prevention of strokes/MI, DVT, or pulmo- nary thrombosis relies on several classes of medications. Among the best known are the anticoagulants; some of these agents, such as heparin, are given intravenously, while others are taken orally (e.g., warfarin).

Anticoagulants

Heparin

Heparin, also known as unfractionated hep- arin, binds to antithrombin III (AT-III, part of the body’s anticoagulant system). When this occurs, a sequence of associated responses increases the efficacy of the body’s anticoagu- lant system and decreases the blood’s ability to clot. Heparin is therefore used to treat individuals with the potential for or past hist- ory of experiencing harmful clots. Indications that increase the risk of clotting include acute coronary syndromes, percutaneous coronary interventions, venous thromboembolism, and maintenance of IV catheter patency. Unfrac- tionated heparin therapy is reserved for the inpatient setting. Heparin is not absorbed well from the gut. Therefore, administration of this drug is lim- ited to IV and subcutaneous injection; it is not given intramuscularly, to decrease the possi- bility of bruising. The subcutaneous injections should be given in the abdomen, rotating be- tween the left and right sides above the il-

iac crest. It is also important to make sure not to aspirate before depressing the plunger on the syringe. In addition, the site should not be rubbed after removing the needle from the abdomen.

As with all anticoagulants, excessive bleeding is a primary concern. Frequent com- plete blood counts (CBC) and activated par- tial thromboplastin times (aPTT or APTT) tests are required to monitor the impact of the heparin therapy. The complete blood count will provide hemoglobin, hematocrit, and platelet levels. The aPTT measures the efficacy of the contact activation pathway and the common coagulation pathways.

Heparin can cause two types of throm- bocytopenia. The first type, simply referred to as heparin-induced thrombocytope-

nia (HIT), is benign and is the most com- mon. Three factors that increase a patient’s risk of developing HIT are unfractionated heparin therapy versus use of low-molec- ular-weight heparin (LMWH), surgical ver- sus medical patient, and female versus malepatient (Coutre, 2012). The second type of thrombocytopenia associated with heparin use, immunological HIT, is less common but far more serious. This form of HIT is an im- munological reaction to heparin therapy in which the body’s platelets are attacked. The condition is usually reversible if the heparin is discontinued. However, serious side effects such as skin necrosis, pulmonary embolism, gangrene of the extremities, stroke, or MI can occur (Lexicomp, 2012). Two additional side effects associated with heparin use in- clude elevation of aminotransferase levels and hyperkalemia due to heparin-induced aldosterone suppression.

The antidote for an overdose of heparin is protamine sulfate. After administration, the protamine sulfate combines with heparin to form a stable complex (salt), which neutral- izes the anticoagulant activity of the drugs.

Heparin may be given simultaneously with other anticoagulant agents when tran- sitioning a patient to an outpatient regi- men. In such a case, it is important to keep in mind that the heparin is likely to enhance the anticoagulation effect on the body when given in combination with these other drugs. Examples of some of the drugs that interact with heparin include other anticoagulants, antiplatelets, aspirin, NSAIDs, certain herbs, nitroglycerin, thrombolytic agents, and vitamin E.

Low-Molecular-Weight Heparin

LMWHs are not interchangeable with un- fractionated heparins, and the two groups

of drugs have different pharmacologic properties. Two examples of LMWH are enoxaparin (1 mg = 100 units of anti-Xa activity; World Health Organization First International Low Molecular Weight Hepa- rin Reference Standard) and dalteparin

(1 mg = 70–120 units of anti-Xa activity; World Health Organization First Inter- national Low Molecular Weight Heparin Reference Standard). As their name sug- gests, LMWHs have smaller heparin mol- ecules than the unfractionated heparins. The mechanism of action for LMWH is to have a small effect on the aPTT and a strong anti- factor Xa ability.

LMWH drugs are becoming widely pre- scribed because they are much more pre- dictable than the unfractionated heparins, have longer half-lives, are just as effective, and do not require the blood test monitor- ing necessary when unfractionated heparin is administered. Also important is that these medications, with the appropriate patient education, can be successfully managed in an outpatient setting.

Some examples of the uses of LMWH enoxaparin include DVT prophylaxis and treatment, percutaneous coronary inter- vention, and treatment of pulmonary em- bolism, ST elevation MI (ST-segment elevation myocardial infarction [STEMI]), and unstable angina or non-ST elevation MI (non-ST-segment elevation myocardial in- farction [NSTEMI]). Enoxaparin should not be administered intramuscularly. Adminis- tration should be subcutaneous only to the left or right anterolateral or posterolateral abdominal wall. It is important not to expel the air bubble in the syringe before admin- istration, to prevent inaccurate dosing. As with unfractionated heparin, the site should not be rubbed after injection. The patient may experience a burning sensation upon subcutaneous injection at the entry site. A single IV dose may be given to patients expe- riencing STEMI.

Enoxaparin has not been approved for use with dialysis patients by the Food and Drug Administration (FDA). If the patient has chronic kidney disease, the dosage should be decreased and the anti-Xa levels checked fre- quently. Elderly patients may have increased sensitivity to LMWH, and these drugs are not recommended in patients with renal impair- ment and age older than 70 years.

Patients receiving enoxaprin are at risk for excessive bleeding (may be increased in women weighing less than 45 kg and men weighing less than 57 kg), HIT, thrombocy- topenia, and hyperkalemia. Morbidly obese patients (body mass index greater than

40 kg/m2) will likely need adjusting/correcting of the weight-based dosage, but there is no consensus on specific recommendations.

Examples of some of the drugs that in- teract with LMWH heparin include antico- agulant drugs, antiplatelet agents, aspirin, NSAIDs, certain herbs, thrombolytic agents, and vitamin E.

Oral Anticoagulants

While injectable anticoagulants are used

in critical situations, for patients in whom thrombosis is merely a risk, preventive use of oral anticoagulant drugs is commonly under- taken. The drugs most often used for this pur- pose are the vitamin K antagonist warfarin as well as a class of drugs called direct throm- bin inhibitors (DTIs).

Warfarin

Warfarin blocks the availability of vitamin K in the body. With less vitamin K available, the liver’s production of clotting factors declines. The decreased amount of clotting factors in- creases the amount of time it takes for the blood to form a clot, which can be beneficial in people at risk of thrombosis.

The most harmful adverse effect of warfarin therapy is excessive bleeding, which is also the reason that lab work is necessary for patients on therapy. Patients receiving warfarin require close monitoring of their prothrombin times (PTs) and INR. The PT is particularly dependent on the clotting factors affected by warfarin, while the INR is a stan- dardized value that is calculated from the PT results. The exact target range will be deter- mined by the healthcare provider. The dosage of the medication should be adjusted to meet this goal. A PT that is below the target will re- quire an increase in the dosage; a PT or INR that is above the target will require a decrease in the dosage and monitoring for bleeding. In addition, patients should seek medical evalua- tion following any serious fall or head injury.

Patients should also take precautions to minimize the risk of harm from bleeding such as using a soft-bristle toothbrush, pro- actively reducing their risk of falling in the environment, using an electric razor instead of a blade, and avoiding activities that in- volve or have the risk of intense traumatic physical contact.

Alcohol should be limited to no more than one to two servings occasionally. Chronic alcohol abuse affects the body’s abil- ity to handle warfarin and also increases the risk of falls (Hull, Garcia, & Vazquez, 2018). Drug–Drug Interactions

Many drugs interact with warfarin, both prescription and OTC (TABLE 6-11). Because of this, patients who are receiving warfarin therapy should contact their healthcare pro- vider before taking any new OTC medica- tions, prescription medications, or vitamin supplements. It is especially important that vitamin K supplements be avoided in patients taking warfarin, as vitamin K promotes clot- ting and counteracts the effects of the drug.

Dietary Guidelines

Significant dietary guidelines must be fol- lowed while a patient is taking a vitamin K antagonist. A consistent vitamin K dietary in- take is essential for maintaining a therapeutic warfarin level. Patients need significant di- etary and safety education on ways to main- tain a consistent vitamin K dietary intake and to prevent falls and traumatic injuries. Most patients, unless they are very conscien- tious about consuming a healthy diet, will not know which foods contain vitamin K, or they may understand the “dietary guidelines” portion of the therapeutic intervention to mean that they must avoid foods rich in this vitamin. That is not actually the case: What is needed is maintenance of consistency in eat- ing leafy green vegetables and other common food sources. This may be challenging in areas where access to such vegetables is limited due to climate; if the patient’s intake falls (or in- creases) due to seasonal availability of certain foods, it may adversely affect the therapeutic efficacy of the warfarin regimen. Regular PT and INR lab work should be performed and evaluated by a healthcare provider to ensure safe and therapeutic levels if the patient has difficulty maintaining dietary consistency.

Direct Thrombin Inhibitors

An alternative to warfarin is the

DTI dabigatran etexilate. Although there are other drugs in this class, dabigatran etexilate is the first DTI that can be given orally. The body converts

this prodrug into dabigatran, which binds directly to thrombin. The benefit of this drug over other, similar medications is that dabigatran can actually bind to clot-bound thrombin, which is an effect not even IV heparin can achieve. Blocking the effect

of thrombin decreases the probability of a dangerous clot developing. Another ben- efit is that there is no need for lab work monitoring with dabigatran etexilate, unlike that required with heparin and warfarin therapy.

Dabigatran etexilate has been used for the prevention and treatment of venous and arterial thromboembolic disorders. It has been used primarily to treat venous thromboembo- lism (VTE) after orthopedic surgery. In 2010 the FDA approved the drug for the preven- tion of stroke and blood clots for patients who experience chronic atrial fibrillation.

The most significant adverse effect associ- ated with this DTI is excessive bleeding. How- ever, preapproval studies of the medication showed comparable rates of serious bleeding in patients taking dabigatran etexilate and patients receiving warfarin. Patients with liver or renal impairment should either avoid this medication or use it with extreme cau- tion and medical oversight due to their in- creased risk of developing excessive bleeding. Other side effects include GI disturbances.

In December 2012 the FDA issued a warn- ing against the use of dabigatran etexilate in patients with mechanical prosthetic heart valves, as a RE-ALIGN study indicated that these individuals may be at increased risk

of experiencing stroke, MI, and mechanical

Prevention of Thrombosis and Stroke: Anticoagulant Therapy 209 valve thrombosis compared to patients taking

warfarin (“Pradaxa,” 2012). Drug–Drug Interactions

Drugs that cause P-glycoprotein to increase or decrease its pumping rate impact the amount of dabigatran etexilate that is available in the bloodstream. Such medica- tions include antacids, drugs that decrease gastric acid secretion, and rifampin. Medica- tions that reduce the drug’s metabolism and, therefore, increase its presence in the blood- stream include verapamil, amiodarone, dronedarone, ketaconazole, quinidine, clarithromycin, and clopidogrel (Bussey & Edith, 2012).

Other drugs that affect platelets, such

as NSAIDs and other antiplatelet agents, should be avoided when taking dabigatran etexilate. Concomitant use of dabigatran etexilate with anticoagulants also increases the risk of excessive bleeding.

Direct Factor Xa Inhibitors

Factor Xa activates conversion of prothrom- bin to thrombin in the coagulation pathway. The end result of this pathway is the devel- opment of a clot. The inhibition of factor

Xa decreases the probability of developing life-threatening clots or from current ones becoming larger. Two drugs, rivaroxaban and apixaban, are specific inhibitors of activated factor X; both have excellent oral bioavailability.

Factor Xa inhibitors have a fast onset of action and consistent pharmacokinetic and pharmacodynamic actions (Kubitza, Becka, & Voith, 2005). Rivaroxaban reaches peak plasma concentrations within 2.5 to 4 hours after taking the medication orally (Lawrence, 2014). Rivaroxaban was found to be equiv- alent to enoxaparin followed by vitamin K antagonist treatment in patients with DVT (Lawrence, 2014).

There is no coagulation monitoring lab work required, and no known dietary restric- tions with either rivaroxaban or apixaban. Both drugs have been approved for the treatment and/or prevention of clots in pa- tients with atrial fibrillation, after knee or hip replacement, in DVT, and with pulmonary embolism (PE). Rivaroxaban is approved in the United States for treatment and preven- tion of acute pulmonary embolism and DVT. Apixaban, meanwhile, is indicated for pre- vention of stroke and thromboembolism in patients with atrial fibrillation.

As with all anticoagulants, adverse effects with rivaroxaban and apixaban include an increased risk of excessive bleeding. Because there is no known antidote to these drugs, and given that dialysis is not likely to re-

duce their presence in serum, patients should be given careful dosing instructions to help avoid overdose. Similar to patients taking the other anticoagulant medications, patients on rivaroxaban should avoid other antithrombic agents, aspirin, NSAIDs, combined P-gp and CYP3A4 inhibitors, P2Y12 platelet inhibitors, and fibrinolytic therapy, all of which could further increase the risk of excessive bleeding.

Antiplatelet Agents

A variety of oral medications inhibit plate-

let function directly. These drugs include aspirin, which inhibits the enzyme cy- clooxygenase, reducing the production of thromboxane A2 (stimulator of platelet aggre- gation). Use of low-dose aspirin as a “blood thinner” to prevent clotting is widespread

as a result. However, there are alternatives. Thienopyridines (clopidigrel, pasugrel) inhibit ADP-dependent platelet aggregation; the PDE5 inhibitor dipyridamole impairs platelet function by inhibiting the activity of adenosine deaminase and phosphodiesterase (it may also cause some vasodilation).

Aspirin is the most commonly used an- tiplatelet medication and is used to prevent ischemic stroke and cardiovascular events, despite evidence that it is not always the best medication for the job. For example, the CAPRIE study showed that a compos- ite outcome of stroke, MI, or vascular death was significantly reduced with clopidogrel treatment versus aspirin use (Cucchiara &

Messe, 2018). However most of the bene-

fit was observed in patients with PAD (Cuc- chiara & Messe, 2018). The combination

of aspirin and dipyridamole for second- ary stroke prevention appears to be addi- tive, and aspirin-extended-release with dipyridamole is significantly more effec- tive than aspirin alone for stroke prevention (Cucchiara & Messe, 2018).

All antiplatelet medications carry a risk of excessive bleeding. Aspirin is known to in- crease the risk of GI distress and bleeding. These risks can be decreased with lower dos- ages or enteric coatings. Also, patients may experience aspirin toxicity, which, in addi- tion to increased bleeding risk, may present

as tinnitus or ringing of the ears. Patients who experience aspirin allergies should also avoid a cross-allergy to NSAIDs.

Clopidogrel is associated with a slightly lower occurrence of GI upset or bleeding than aspirin (Cucchiara & Messe, 2018). With dipyridamole, headache is the most fre- quently reported adverse effect.

Similar to patients taking the other an- ticoagulant medications, patients on anti- platelet medications should avoid the use of other antiplatelet medications, antithrom- bic agents, NSAIDs, and fibrinolytic ther- apy, all of which could further increase the risk of excessive bleeding. Patients on long- term anticoagulation therapy may also be re- ceiving antiplatelet therapy, but only under the close supervision and monitoring of a healthcare provider.

Antiarrhythmic Agents

Cardiac cells depolarize and repolarize about once per second. Multiple proteins, affected by ion concentration fluctuations, are responsible for maintenance of cardiac rhythms. Outside of the proximal electrophysiology, the heart

is affected by input from the sympathetic and parasympathetic systems. When improper rhythms (arrhythmias) occur, pharmacologic intervention is sometimes indicated.

Ions move through specific channels or transporters in response to changes in electrical stimulation and ion concentra- tion gradients. Important ions for cardiac conduction include sodium, potassium, and calcium. At rest, potassium is allowed in myocytes, while sodium is excluded. Depo- larization of myocyte membranes briefly al- lows sodium ions in and potassium ions out, propagating the conduction signal, then so- dium is once again excluded from cells, while potassium returns. Also involved in ion exchange is calcium. Improper ion trans- port can result in improper cardiac rhythm. For a more complex review of cardiac con- duction, signal transmission and muscle con- traction, the reader is referred to physiology textbooks.

An arrhythmia occurs when the normal sequence of impulse initiation and propaga- tion is disturbed. Arrhythmias include rapid heart rhythms (tachycardia), premature de- polarizations, flutters, fibrillations, and signal re-entry, and can involve the atria (atrial) or ventricles (ventricular).

Antiarrhythmic drugs are sometimes un- predictable in their effects on patients, in

part because arrhythmias often involve mul- tiple mechanisms, and in part because drugs can affect multiple targets. These drugs usu- ally act by one of three mechanisms: by alter- ing conduction velocity; by changing cardiac cell excitability via altering the length ofimpulse refractory time; by suppressing ab- normal automaticity. Drugs are utilized to alter ion (sodium, potassium, calcium) chan- nels and conduction velocity, or affect sym- pathetic or parasympathetic actions on the heart. Antiarrhythmics are usually classified as members of four or five groups, though members of groups sometimes can be classi- fied in more than one group. The four main groups include sodium-channel blockers, beta-blockers, potassium-channel blockers, and calcium-channel blockers. A fifth grouping includes drugs that act by a variety of mechanisms.

Group I Antiarrhythmics: Sodium-Channel Blockers

Blockade of fast sodium channels slows electrical conduction in the heart. Group I antiarrhythmics bind to fast sodium chan- nels (which are involved in the rapid depo- larization [phase 0] of fast-response cardiac action potentials). The result is a reduction of inward-moving sodium, but utilizing drug concentrations that do not affect resting membrane potential (FIGURE 6-11).

This reduces the action potential trans- mission velocity, which can counter tachycar- dias caused by mechanisms including signal re-entry. Sodium-channel blockers also can affect refractory period. Therefore, there arethree subclasses of sodium-channel blockers, categorized as groups IA (increase refractory period), IB (decrease refractory period), or IC (no effect on refractory period).

Examples of group IA drugs in-

clude quinidine, procainamide, and disopryamide, and can be useful for treating atrial fibrillation and flutter, and supraventricular and ventricular tachyar- rhythmias. Examples of group IB drugs in- clude lidocaine, tocainide, and mexilitine. Group IB drugs tend to be useful for the treatment of ventricular tachycardias. Exam- ples of Group IC drugs include flecainide, propafenone, and moricizine, and can be useful for treating supraventricular and ven- tricular tachyarrhythmias.

Group II Antiarrhythmics: Beta-Blockers

Beta-1 antagonists (beta-blockers) affect beta-1-receptors located in the heart, eyes, and kidneys. When utilized as antiarrhyth- mics, they act by inhibiting sympathetic stimulation, especially by epinephrine and norepinephrine, of cardiac impulses. Nor- mally, sympathetic nerves increase pacemaker currents, causing increased heart rate. Sym- pathetic stimulation of the heart can also be a cause of aberrant pacemaker activity from in- creasing conduction velocity. β1-blockers can reduce these effects by decreasing reactivity of pacemaker cells to adrenergic sympathetic

stimulation (FIGURE 6-12). Examples of beta- blockers (though not necessarily β1-selective) that can be useful antiarrhythmics include acebutolol, propranolol, and esmolol.

Group III Antiarrhythmics: Potassium-Channel Blockers

Most drugs in Group III have potassium- channel blocking activity, but may also affect other ion channels, and so are not necessarily purely targeting potassium transport. Blocking potassium channels causes delayed repolar- ization of myocardial cells, increasing the re- fractory between beats (FIGURE 6-13). They canbe useful for treatment of tachyarrhythmias caused by reentry signals. Examples of Group III drugs include amiodarone, dofetilide, dronedarone, bretylium, sotalol, ibutilide, and dofetilide.

Group IV Antiarrhythmics: Calcium-Channel Blockers

Group IV antiarrhythmics are calcium- channel blockers (CCBs), and, by inhibit- ing calcium from crossing cell membranes, decrease firing rate of aberrant sites in the heart, decrease conduction velocity at the AV node, and reduce heart rate. Action at the AV node is useful for treating supraven- tricular tachycardias caused by reentry im- pulses (FIGURE 6-14).

Calcium channel blockers are subdivided into two categories, dihydropyridines and non-dihydropyridines, the latter being use- ful for arrhythmias. Dihydropyridines are more vascular-selective, and so more useful for treating hypertension via calcium channel blockade. The non-dihydropyridine class in- cludes the drugs diltiazem and verapamil.

Group V Antiarrhythmics: Miscellaneous

Group V antiarrhythmics include drugs that act via a variety of mechanisms other than those recognized as Groups I–IV. Included

in this class are adenosine and digoxin. Adenosine binds adenosine type-1 receptors

Ca2+

Compartment

containing internal calcium stores

Calcium channel

on the heart, which opens potassium chan- nels, and blocks calcium channels. The result is hyperpolarization of cells, and decreased conduction velocity. Adenosine, which is very short-lived in the body, can be used for rapid treatment of SVTs. Digoxin, which was previously discussed, is useful for ar- rhythmias because it reduces heart rate, and can be useful for treating atrial fibrillation and flutter.