468 Unit 4 Pharmacology of the Central Nervous System
Understanding Chapter 27
Key Concepts Summary 27.8 Marijuana is the most frequently abused illicit
substance.
27.1 A wide variety of substances may be abused by
patients. 27.9 Hallucinogens and club drugs cause an altered
state of thought and perception.
27.2 Drugs with a potential for abuse are restricted by
the Controlled Substances Act and are categorized 27.10 Stimulants such as amphetamines and cocaine
into schedules. increase the activity of the central nervous system.
27.3 Addiction is an overwhelming compulsion to 27.11 Nicotine is a powerful and highly addictive
continue repeated drug use. cardiovascular and central nervous system
stimulant.
27.4 Physical and psychologic dependence lead to
continued drug-seeking behavior despite negative 27.12 Inhalant abuse occurs when patients breathe the
health and social consequences. fumes of vaporized substances.
27.5 A withdrawal syndrome is a set of characteristic 27.13 Anabolic steroids are abused for their ability to
symptoms that occurs when an abused substance increase muscle strength.
is discontinued.
27.14 The nurse has a pivotal role in recognizing and
27.6 Tolerance occurs when the body adapts to a treating substance abuse.
drug and larger doses are needed to produce a
therapeutic effect.
27.7 Central nervous system depressants, which
include sedatives, opioids, and alcohol, decrease
the activity of the central nervous system.
CASE STUDY: Making the Patient Connection
Remember the patient To support herself and her heroin addiction, Jamie has
“Jamie Wilkins” at the become a prostitute. She states that she usually drinks at
beginning of the chapter? least four to five beers before she walks the streets at night.
Now read the remainder of If she cannot score enough heroin, she will smoke crack or
the case study. Based on the take Valium just to “mellow out.” Jamie says that her drug
information presented abuse is only to calm her nerves and get her through the
within this chapter, respond night. In periods when she was not able to obtain drugs,
to the critical thinking ques- she states she felt sick with trembling and perfuse sweat-
tions that follow. ing. However, she is convinced that she can stop any time
she wishes.
Jamie Wilkins has come to the counseling clinic to get infor-
mation and advice about her pregnancy and drug use. She Jamie reports that she has not had a menstrual period
is a 19-year-old woman who has been living with her boy- in 2 months and her breasts are swollen and tender. She is
friend for the past 18 months. Since she moved in, she has certain she is pregnant, although she has not been tested,
been a daily user of heroin. and is confused about what to do. She is hopeful that her
unemployed boyfriend is the father but is not totally sure.
Jamie has a long history of substance abuse. When she She believes that if she stops working, he will abandon her,
was 14 years old, her stepfather sexually abused her on a and there will be no means to support herself or a baby.
regular basis. To cope with the guilt and shame, she began
using alcohol and marijuana. On her 16th birthday, Jamie Critical Thinking Questions
ran away from home and never returned. Since then she
has done anything and everything possible to survive, 1. How would you classify Jamie’s substance abuse:
including selling herself for sex. physical dependence or psychologic dependence, or
both? Explain.
2. Create a list of abused substances reported by Jamie. Chapter 27 Pharmacology of Substance Abuse 469
What symptoms of withdrawal would you expect
with each? intervention you should consider when speaking with
Jamie?
3. What effect will Jamie’s substance abuse have on her 5. Addiction depends on multiple variables such as drug,
unborn baby? Should Jamie stop using drugs while user, and environmental factors. Based on the case
pregnant? Why or why not? study, describe how each variable contributes to
Jamie’s substance abuse.
4. As the nurse, describe your approach in dealing
with this patient. What is one evidence-based Answers to Critical Thinking Questions are available on the
faculty resources site. Please consult with your instructor.
Additional Case Study money, he cannot buy any liquor and has not been
drinking.
A neighbor reports that patient Martin Thomas was
discovered wandering the halls in his apartment build- 1. Define delirium tremens. What is the treatment priority
ing in a confused state. The neighbor states that Martin for this condition?
called him by the wrong name even though they have
known each other for several years. Martin was agitated 2. Discuss how food or beverages can increase the excre-
about not being able to find the bus stop. In the tion rate of alcohol.
emergency department, Martin appears apprehensive,
diaphoretic, and trembling. His nose and cheeks are 3. Describe the effects of alcohol on the central ner-
red with spider veins, and his abdomen is noticeably vous system. Is alcohol a stimulant or a depressant?
distended. He tells you that up until 3 days ago, he con-
sumed alcohol daily. However, because he has no Answers to Additional Case Study questions are available on the
faculty resources site. Please consult with your instructor.
Chapter Review 3. A nurse is teaching a patient who will begin vareni-
cline (Chantix) for smoking cessation. Which of the
1. The patient returned from major surgery 3 hours following instructions will the nurse give the patient?
ago and requests medication for pain. In consider- (Select all that apply.)
ing the best action for this patient, the nurse
knows that: 1. Doses will be increased over a week’s period and
the drug used for up to 6 months.
1. Prescription drugs rarely cause addiction
when used according to accepted medical 2. Smoking may continue because the drug blocks the
protocol. harmful effects of nicotine.
2. All drugs should be withheld until the patient’s 3. The drug is not known to cause any adverse effects
past substance abuse history is evaluated. and has an excellent safety profile.
3. It is best to wait until the patient can no 4. Any unusual rashes, skin reactions, or facial edema
longer tolerate the pain to avoid addiction should be reported immediately.
problems.
5. Any unusual changes in behavior including
4. Patients often request analgesia when it is not depression, hostility, or thoughts of suicide should
really needed. be reported immediately.
2. Which of the following statements made by the 4. Which parameter is most critical when a nurse
patient recovering from a substance use disorder is assessing a patient with an overdose of
would indicate high potential for relapse? sedatives?
1. “I need the help of a support system to stop using.” 1. Cardiac stimulation
2. “After I stop using, I will no longer have a desire to 2. Respiratory suppression
use drugs.”
3. Hepatic dysfunction
3. “Whom I hang out with doesn’t make any
difference in whether or not I use drugs.” 4. Depression of consciousness
4. “Talking with other recovering addicts will help
me cope.”
470 Unit 4 Pharmacology of the Central Nervous System 6. While teaching the patient about disulfiram
(Antabuse), which of the following should the
5. A 22-year-old heroin addict is exhibiting nurse instruct the patient to avoid?
withdrawal symptoms. Which symptoms
of withdrawal does the nurse 1. Mouthwash, alcoholic beverages, and over-the-
expect? counter cold medications
1. Somnolence, lethargy, and fatigue 2. Dairy products such as milk, cream, and yogurt
2. Dry skin, rash, and itching 3. Foods high in iron such as green leafy vegetables
3. Paranoia, hallucinations, and delusions 4. Driving or operating machinery while taking this
4. Chills, runny nose, and muscle spasms
medication
See Answers to Chapter Review in Appendix A.
References SAMHSA-HRSA Center for Integrated Health Solutions.
(n.d.). SBIRT: Screening, brief intervention, and referral to
American Psychiatric Association. (2013). Diagnostic and treatment. Retrieved from http://www.integration.
statistical manual of mental disorders (5th ed.). samhsa.gov/clinical-practice/SBIRT
Washington, DC: Author.
Substance Abuse and Mental Health Services
Center for Behavioral Health Statistics and Quality. (2015). Administration. (2014). Results from the 2013 National
Behavioral health trends in the United States: Results from Survey on Drug Use and Health: Summary of national
the 2014 National Survey on Drug Use and Health (HHS findings (NSDUH Series H-48, HHS Publication No.
Publication No. [SMA] 15-4927, NSDUH Series H-50). [SMA] 14-4863). Retrieved from http://www.
Retrieved from https://www.samhsa.gov/data/sites/ samhsa.gov/data/sites/default/files/
default/files/NSDUH-FRR1-2014/NSDUH-FRR1-2014. NSDUHresultsPDFWHTML2013/Web/
htm NSDUHresults2013.pdf
National Institute on Drug Abuse. (2016). Monitoring the U.S. Food and Drug Administration. (2017). FDA facts:
future survey: High school and youth trends. Retrieved Abuse-deterrent opioid medications. Retrieved from
from http://www.drugabuse.gov/publications/ https://www.fda.gov/NewsEvents/Newsroom/
drugfacts/high-school-youth-trends FactSheets/ucm514939.htm
National Institute on Drug Abuse for Teens. (2017).
Inhalants: How Many Teens Use Inhalants? Retrieved
from https://teens.drugabuse.gov/drug-facts/
inhalants
Selected Bibliography Kantor, E. D., Rehm, C. D., Haas, J. S., Chan, A. T., &
Giovannucci, E. L. (2015). Trends in prescription drug
Antoniou, T., & Juurlink, D. N. (2014). Dextromethorphan use among adults in the United States from 1999–2012.
abuse. Canadian Medical Association Journal, 186(16), JAMA, 314, 1818–1830. doi:10.1001/jama.2015.13766
E631. doi:10.1503/cmaj.131676
Klein, J. W. (2016). Pharmacotherapy for substance use
Aubin, H. J., Luquiens, A., & Berlin, I. (2014). disorders. Medical Clinics of North America, 100, 891–910.
Pharmacotherapy for smoking cessation: doi:10.1016/j.mcna.2016.03.011
Pharmacological principles and clinical practice. British
Journal of Clinical Pharmacology, 77, 324–336. Lee, J., Kresina, T. F., Campopiano, M., Lubran, R., &
doi:10.1111/bcp.12116 Clark, H. W. (2015). Use of pharmacotherapies in the
treatment of alcohol use disorders and opioid
Courtney, K. E., & Ray, L. A. (2014). Methamphetamine: dependence in primary care. BioMed Research
An update on epidemiology, pharmacology, clinical International, Article ID 137020, 11 pages.
phenomenology, and treatment literature. Drug and doi:10.1155/2015/137020
Alcohol Dependence, 143, 11–21. doi:10.1016/j.
drugalcdep.2014.08.003 Marshall, K., Gowing, L., Ali, R., & Le Foll, B. (2014).
Pharmacotherapies for cannabis dependence. Cochrane
Gordon, A. J., & Jenkins, J. A. (2015). The time is now: The Database of Systematic Reviews, 12, Art. No. CD008940.
role of pharmacotherapies in expanding treatment for doi:10.1002/14651858.CD008940.pub2
opioid use disorder. Substance Abuse, 36, 127–128. doi:10
.1080/08897077.2015.1033884
Nelson, M. E., Bryant, S. M., & Aks, S. E. (2014). Emerging Chapter 27 Pharmacology of Substance Abuse 471
drugs of abuse. Emergency Medicine Clinics of North
America, 32, 1–28. doi:10.1016/j.emc.2013.09.001. Weaver, M. F., Hopper, J. A., & Gunderson, E. W. (2015).
Designer drugs 2015: Assessment and management.
Soghoian, S. (2016). Disulfiram toxicity. Retrieved from Addiction Science & Clinical Practice, 10, 8. doi:10.1186/
http://emedicine.medscape.com/ s13722-015-0024-7
article/814525-overview
Zindel, L. R., & Kranzler, H. R. (2014). Pharmacotherapy
Storck, M., Black, L., & Liddell, M. (2016). Inhalant abuse of alcohol use disorders: Seventy-five years of progress.
and dextromethorphan. Child and Adolescent Psychiatric Journal of Studies on Alcohol and Drugs (Suppl.17), 79–88.
Clinics of North America, 25, 497–508. doi:10.1016/j. doi:10.15288/jsads.2014.s17.79
chc.2016.03.007
Swift, R. M., & Aston, E. R. (2015). Pharmacotherapy for
alcohol use disorder: Current and emerging therapies.
Harvard Review of Psychiatry, 23, 122. doi:10.1097/
HRP.0000000000000079
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Unit 5
Pharmacology of the
Cardiovascular System
CHAPTER 28 Review of the Cardiovascular System / 474
CHAPTER 29 Pharmacotherapy of Hyperlipidemia / 488
CHAPTER 30 Pharmacotherapy with Calcium Channel Blockers / 510
CHAPTER 31 Drugs Affecting the Renin-Angiotensin-Aldosterone System / 523
CHAPTER 32 Diuretic Therapy and the Pharmacotherapy of Chronic Kidney
Disease / 539
CHAPTER 33 Pharmacotherapy of Fluid Imbalance, Electrolyte, and Acid–Base
Disorders / 561
CHAPTER 34 Pharmacotherapy of Hypertension / 582
CHAPTER 35 Pharmacotherapy of Angina Pectoris and Myocardial Infarction / 602
CHAPTER 36 Pharmacotherapy of Heart Failure / 622
CHAPTER 37 Pharmacotherapy of Dysrhythmias / 641
CHAPTER 38 Pharmacotherapy of Coagulation Disorders / 661
CHAPTER 39 Pharmacotherapy of Hematopoietic Disorders / 691
473
Chapter 28
Review of the Cardiovascular
System
Chapter Outline Learning Outcomes
cc Structure and Function of the Cardiovascular After reading this chapter, the student should be able to:
System
1. Describe the major structures of the cardiovascular
cc Functions and Properties of Blood system.
Components of Blood
Hemostasis 2. Identify the components of blood and their
functions.
cc Cardiac Structure and Function
Cardiac Muscle 3. Construct a flowchart diagramming the primary
Coronary Arteries steps of hemostasis.
Cardiac Conduction System
Cardiac Output 4. Describe the structure of the heart and the function
of the myocardium.
cc Hemodynamics and Blood Pressure
Hemodynamic Factors Affecting Blood Pressure 5. Describe the role of the coronary arteries in
Neural Regulation of Blood Pressure supplying the myocardium with oxygen.
Hormonal Influences on Blood Pressure
6. Illustrate the flow of electrical impulses through the
normal heart.
7. Explain the major factors affecting cardiac output.
8. Explain the effects of cardiac output, peripheral
resistance, and blood volume on hemodynamics.
9. Discuss how the vasomotor center, baroreceptors,
chemoreceptors, and hormones regulate blood
pressure.
474
Chapter 28 Review of the Cardiovascular System 475
Key Terms ectopic foci, 481 preload, 482
erythropoietin, 475 prothrombin, 478
afterload, 482 extrinsic pathway, 477 renin-angiotensin-aldosterone
antidiuretic hormone (ADH), 485 fibrin, 478
atrial natriuretic fibrinogen, 478 system (RAAS), 485
hemopoiesis, 476 sinus rhythm, 479
peptide (ANP), 485 hemostasis, 477 stroke volume, 482
atrial reflex, 485 intrinsic pathway, 477 thrombin, 478
automaticity, 479 myocardium, 479 thrombopoietin, 476
baroreceptors, 485 peripheral resistance, 483 vasomotor center, 485
cardiac output (CO), 481 venous return, 482
chemoreceptors, 485
coagulation, 477
contractility, 482
It is likely that the nurse will administer more cardiovascu- • Regulation of blood pressure
lar drugs than any other class of medications. Why is this • Regulation of acid–base balance
the case? First, healthcare providers have discovered the • Regulation of fluid balance
huge benefits of keeping blood pressure and blood lipid • Regulation of body temperature
values within normal limits and how to prevent heart • Protection against invasion by microbes.
attacks and strokes. Second, the heart and vessels weaken
over time and, as the average lifespan of the population The cardiovascular system can function only with the
increases, more pharmacotherapy will be needed to treat cooperation of other body systems. For example, the role of
the chronic cardiovascular diseases of older adults. the autonomic nervous system in controlling heart rate and
blood vessel diameter is presented in Chapter 12. The kid-
A comprehensive knowledge of cardiovascular anat- neys are intimately involved in assisting the cardiovascular
omy and physiology is essential to understanding cardio- system with fluid and acid–base balance, as discussed in
vascular pharmacology, which encompasses the next Chapter 33. The respiratory system must bring oxygen to
11 chapters of this text. The purpose of this chapter is to the blood and remove carbon dioxide from it. The student
offer a brief review of the components of the structure and should view the cardiovascular system as an important
function of the cardiovascular system that will be impor- part of the body’s ability to maintain overall homeostasis.
tant to understand for pharmacotherapy. For more compre-
hensive treatments of these topics, the student should refer Functions and Properties of Blood
to an anatomy and physiology textbook.
28.2 Blood consists of formed elements
Structure and Function and plasma.
of the Cardiovascular System
Blood is a liquid connective tissue that consists of formed
28.1 The cardiovascular system consists of the elements suspended in plasma. The solid, formed elements
blood, heart, and blood vessels. of the blood are the erythrocytes, leukocytes, and platelets.
When combined, the formed elements comprise about 45%
The three major components of the cardiovascular system of the composition of blood.
are the blood, heart, and blood vessels, as shown in
Figure 28.1. These three components work as an integrated The most numerous blood cells are erythrocytes, which
whole to transport the essential oxygen, nutrients, and comprise 99.9% of the formed elements. Carrying the iron-
other substances that keep the body in homeostasis. Dis- containing protein hemoglobin, the erythrocytes are
ruption of this flow for even brief periods can have serious, responsible for transporting oxygen to the tissues and car-
if not lethal, consequences. The functions of the cardiovas- bon dioxide from the tissues to the lungs. A single erythro-
cular system are diverse and include the following: cyte can carry as many as 1 billion molecules of oxygen.
Erythrocyte homeostasis is controlled by erythropoietin, a
• Transport of nutrients and wastes hormone secreted by the kidney in response to low oxygen
• Pumping of blood levels in the blood. Once secreted, erythropoietin stimu-
lates the body’s production of erythrocytes. Insufficient
476 Unit 5 Pharmacology of the Cardiovascular System
AIR (OXYGEN) injury. Abnormally low numbers of plate-
Right Right Trachea Left lets, or thrombocytopenia, can result in seri-
pulmonary lung Bronchi lung ous delays in blood clotting. Platelet
artery homeostasis is controlled by the hormone
Left thrombopoietin, which promotes the for-
pulmonary mation of additional platelets. The role of
artery
Aorta platelets and thrombopoietin in blood coag-
Alveoli Alveoli ulation is a major topic in Chapter 38, which
discusses the pharmacotherapy of blood
coagulation.
The production and maturation of
LUNG LUNG blood cells, called hemopoiesis or hemato-
CAPILLARIES
CAPILLARIES poiesis, occurs in red bone marrow. It is here
that primitive stem cells of the blood become
Right Heart Left committed to forming erythrocytes, leuko-
pulmonary (blood) pulmonary cytes, or platelets. This process occurs con-
vein vein tinuously throughout the lifespan and is
subject to various homeostatic controls as
well as certain drugs and physical agents.
Veins Arteries For example, ionizing radiation and a large
number of drugs have the potential to
adversely affect bone marrow and cause
myelosuppression. Myelosuppression is a
very serious adverse effect that reduces the
Venules Arterioles number of erythrocytes, leukocytes, and
BODY thrombocytes, leaving patients susceptible
CAPILLARIES to anemia, infection, and bleeding. Many
drugs used to treat cancer and those given to
= Blood low in oxygen and high in reduce the possibility of transplant rejection
carbon dioxide (deoxygenated). can produce profound myelosuppression as
= Blood high in oxygen and low in a dose-limiting adverse effect.
carbon dioxide (oxygenated). Plasma is the fluid portion of blood that
Figure 28.1 The cardiovascular system. consists of water, proteins, electrolytes, lipo-
proteins, carbohydrates, and other regula-
numbers of erythrocytes or structural defects such as sickle tory substances. The primary proteins in plasma are
shapes lead to anemia, which is a common indication for albumins (54%), globulins (38%), and fibrinogen (7%).
pharmacotherapy (see Chapter 39). Albumin is the primary regulator of blood osmotic pres-
Although small in number, leukocytes serve an essen- sure (also called oncotic pressure), which determines the
tial role in the body’s defense against infection. Unlike movement of fluids among the vascular, interstitial, and
erythrocytes, which are all structurally identical, there are cellular compartments or spaces. Globulins, also known as
several types of leukocytes, each serving a different func- immunoglobulins or antibodies, are important in protect-
tion. For example, neutrophils are the most common leuko- ing the body from foreign agents such as bacteria or viruses.
cyte and they respond to bacterial infections through Fibrinogen is a critical protein in the coagulation of blood.
phagocytosis of the microbes. The second most common The liver synthesizes over 90% of the plasma proteins;
leukocyte, the lymphocyte, is the key cell in the immune therefore, patients with serious hepatic impairment will
response that responds by secreting antibodies (B lympho- have deficiencies in coagulation and in maintaining body
cytes) or secreting cytokines (T lymphocytes) that rid the defenses.
body of the microbe. A review of body defenses and the Serum is a term closely related to plasma. Serum con-
immune system is presented in Chapter 40. tains all the components of plasma, except clotting factors
The final formed elements of the blood are thrombo- such as fibrinogen have been removed. Serum is often used
cytes or platelets, which are actually fragments of larger for blood typing and for determining blood levels of sub-
cells called megakaryocytes. Platelets stick to the walls of stances such as cholesterol, glucose, and hormones.
damaged blood vessels to begin the process of blood coag- Fluid balance in the body is achieved by maintaining
ulation, which prevents excessive bleeding from sites of the proper amount of plasma in the blood. Too little water
Chapter 28 Review of the Cardiovascular System 477
in plasma results in dehydration, whereas too much causes Hemostasis is an essential mechanism that the body uses to
edema and hypertension (HTN). Various organs help to prevent excessive bleeding following injury. Medications can
maintain normal fluid balance, including the kidneys, gas- be used to modify several of these steps, either to speed up
trointestinal (GI) tract, and skin. The pharmacotherapy of or delay the clotting process (see Chapter 38).
fluid and electrolyte imbalances is an important topic in
pharmacology and is discussed in Chapter 33. Injury to a blood vessel triggers the clotting process. The
vessel spasms, causing constriction, which slows blood flow
CONNECTION Checkpoint 28.1 to the injured area. Platelets have an affinity for the damaged
vessel: They become sticky and adhere to each other and to
From what you learned in Chapter 3, what role does plasma protein the injured area. The clumping of platelets, or aggregation, is
play in the distribution of drugs? Answers to Connection Check- facilitated by adenosine diphosphate (ADP), the enzyme
point questions are available on the faculty resources site. Please thrombin, and thromboxane A2. Platelet receptor sites and
consult with your instructor. von Willebrand’s factor make adhesion possible. The aggre-
gated platelets disintegrate to initiate a platelet binding cas-
PharmFACT cade. Blood flow is further slowed, thus allowing the process
of coagulation, which is the formation of an insoluble clot, to
To maintain homeostasis, the body must make 3 million occur. The basic steps of hemostasis are shown in Figure 28.2.
erythrocytes every second. Red blood cells are so numerous
that they comprise approximately one third of all cells in the When collagen is exposed at the site of vessel injury,
body (Martini, Nath, & Bartholomew, 2015). the damaged cells initiate the coagulation cascade. Coagu-
lation itself occurs when fibrin threads create a meshwork
28.3 Hemostasis is a complex process involving that fortifies the blood constituents so that clots can
multiple steps and a large number of enzymes develop. During the cascade, various plasma proteins that
and factors. are circulating in an inactive state are converted to their
active forms. Two separate pathways, along with numer-
The process of hemostasis is complex, involving at least 13 ous biochemical processes, lead to coagulation. The intrin-
different clotting factors that contribute to the slowdown sic pathway is activated in response to injury and takes
and ultimate stoppage of blood flow. Hemostasis occurs in a several minutes to complete. The extrinsic pathway is acti-
series of sequential steps, sometimes referred to as a cascade. vated when blood leaks out of a vessel and enters tissue
spaces. The extrinsic pathway is less complex and is
Vessel injury Ruptured epithelium
Vessel spasm Spasm
Platelets
Platelets adhere
to injury site and
aggregate to
form plug
Formation of Fibrin
insoluble fibrin
strands and
coagulation
Figure 28.2 The basic steps in hemostasis.
478 Unit 5 Pharmacology of the Cardiovascular System
INTRINSIC PATHWAY EXTRINSIC PATHWAY
Collagen or other Damage exposes
XII activators tissue factor (III)
Active XII VII
XI Ca2+ Tissue factor +
Active XI (III) and
+ active VII positive feedback
IX
Ca2+
Active IX
VIII
Ca2+
X phospholipids (PL)
Active X
COMMON PATHWAY Prothrombin
positive feedback
Thrombin Ca2+,
V, PL
Fibrinogen
XIII Fibrin
Active XIII Ca2+
Cross-linked fibrin
Figure 28.3 The coagulation cascade. Both the intrinsic pathway and extrinsic pathway lead to a common
pathway and eventually a dense fibrin clot.
From Human Physiology: An Integrated Approach, 5th ed., by D. U. Silverthorn, 2010. Reprinted and electronically reproduced
by permission of Pearson Education, Inc., Upper Saddle River, New Jersey.
completed within seconds. The two pathways share some the blood in an inactive form. Vitamin K, which is made by
common steps and the outcome is the same—the formation bacteria residing in the large intestine, is required for the
of the fibrin clot. The steps in each pathway are shown in liver to make four of the clotting factors. Because of the cru-
Figure 28.3. cial importance of the liver in creating these clotting fac-
tors, patients with serious hepatic impairment often have
Near the end of the common pathway, a chemical abnormal coagulation.
called prothrombin activator (see Active X in Figure 28.3) is
formed. The prothrombin activator converts the clotting Cardiac Structure and Function
factor prothrombin to an enzyme called thrombin. Throm-
bin then converts fibrinogen, a plasma protein, to long 28.4 The heart is responsible for pumping blood
strands of fibrin. The fibrin strands provide a framework throughout the circulatory system.
to anchor the clot. Thus two of the factors essential to
clotting, thrombin and fibrin, are only formed after injury The heart is the hardest working organ in the body, pump-
to the vessels. The fibrin strands form an insoluble web ing blood from before birth to the last minute of life. With
over the injured area to stop blood loss. Normal blood clot- the continuous workload, it is not surprising that this
ting occurs in about 6 minutes. organ eventually weakens and that heart disease is the
leading cause of death in the United States. The heart is a
It is important to note that several clotting factors, frequent target for pharmacotherapy.
including thromboplastin and fibrinogen, are proteins
made by the liver that are constantly circulating through
Chapter 28 Review of the Cardiovascular System 479
The heart may be thought of as a thick, specialized The coronary arteries are important targets for phar-
muscle. The muscular layer, called the myocardium, is the macotherapy. Chapter 29 explains how reducing lipid lev-
thickest of the heart layers and is responsible for the physi- els in the blood can decrease the risk of atherosclerosis of
cal pumping action of the heart. The thickness of the myo- the coronary arteries (and other arteries). Chapter 35 dis-
cardium is greatest in the left ventricle because this chamber cusses how drugs can be used to reduce angina pain and
performs the greatest amount of work. Cardiac muscle con- decrease the risk of mortality following a heart attack.
tains extensive branching networks of cellular structures Chapter 36 introduces drugs that reduce the cardiac work-
that connect cardiac muscle cells to each other, allowing the load in patients with heart failure so that the heart does not
entire myocardium to contract as a coordinated whole. require as much oxygen from the coronary arteries.
Should myocardial cells (myocytes) die, the body is 28.6 The cardiac conduction system keeps
unable to replace them because cardiac muscle cells do not the heart beating in a synchronized manner.
undergo mitosis. If a large area of cardiac muscle becomes
deprived of oxygen and undergoes necrosis, the myocytes For the heart to function properly, the atria must contract
are replaced by fibrotic scar tissue and heart function simultaneously, sending their blood into the ventricles.
becomes impaired. The different regions of the heart may Following atrial contraction, the right and left ventricles
not contract in a coordinated manner because conduction then must contract simultaneously. Lack of synchroniza-
of the electrical potential may skip over areas of necrosis on tion of the atria and ventricles or of the right and left sides
the myocardium. This can result in heart failure or dys- of the heart may have profound consequences. Proper tim-
rhythmias, which are frequent indications for pharmaco- ing of chamber contractions is made possible by the car-
therapy (see Chapters 36 and 37). diac conduction system, a branching network of
specialized cardiac muscle cells that sends a synchronized,
The heart has four chambers that receive blood prior to electrical signal across the myocardium. These electrical
being pumped, as illustrated in Figure 28.4b. These cham- impulses, or action potentials, carry the signal for the car-
bers differ in size, depending on their function. The left ven- diac muscle cells to contract and must be coordinated pre-
tricle is the largest and most powerful chamber, because it cisely for the chambers to beat in a synchronized manner.
must hold and pump enough blood to all body tissues. Dur- The cardiac conduction system is illustrated in Figure 28.5.
ing heart failure, the size of the left ventricle and the thick-
ness of the myocardial layer in this chamber can increase in Control of the cardiac conduction system begins in a
size, a condition known as left ventricular hypertrophy. small area of tissue in the wall of the right atrium known as
the sinoatrial (SA) node or cardiac pacemaker. Cells in the
PharmFACT SA node have the property of automaticity, the ability to
spontaneously generate action potentials without an out-
The heart pumps about 8000 liters of blood every day, which side signal from the nervous system. The SA node gener-
is enough to fill forty 55-gallon drums or 8800 quart-size ates a new action potential approximately 75 times per
containers (Martini, Nath, & Bartholomew, 2015). minute under resting conditions. This is referred to as the
normal sinus rhythm. The SA node is greatly influenced by
28.5 The coronary arteries bring essential the activity of the sympathetic and parasympathetic divi-
nutrients to the myocardium. sions of the autonomic nervous system.
Working continuously around the clock, the heart requires Upon leaving the SA node, the action potential travels
a bountiful supply of oxygen and other nutrients. These quickly across both atria and through internodal pathways
are provided by the right and left coronary arteries and to the atrioventricular (AV) node. Myocytes in the AV node
their branches, as shown in Figure 28.4a. The coronary also have the property of automaticity, although less so
arteries have the ability to rapidly adapt to the heart’s than the SA node. Should the SA node malfunction, the AV
needs for oxygen. For example, during exercise the heart node has the ability to spontaneously generate action
rate and strength of contraction markedly increase, and potentials and continue the heart’s contraction at a rate of
healthy coronary arteries quickly dilate to provide oxygen 40 to 60 beats/min. Compared to other areas in the heart,
to meet this increased workload on the myocardium. impulse conduction through the AV node is slow. This
allows the atria sufficient time to completely contract and
The coronary arteries are subject to atherosclerosis, a empty their blood before the ventricles receive their signal
buildup of fatty plaque, which narrows the lumen and to contract. If the ventricles should contract prematurely,
restricts the blood supply reaching myocytes. If allowed to the AV valves will close and the atria will be prevented
progress, the narrowing results in chest pain, a condition from completely emptying their contents.
known as angina pectoris. The first sign of angina is pain
upon exercise or exertion, since this is when the workload As the action potential leaves the AV node, it travels
on the heart is increased. Continued narrowing increases rapidly to the AV bundle or bundle of His. The pathway
the risk of a myocardial infarction. between the AV node and the bundle of His is the only
480 Unit 5 Pharmacology of the Cardiovascular System Left common carotid artery
Left subclavian artery
Brachiocephalic Arch of aorta
artery
Left pulmonary
Superior vena cava artery
Right atrium Left atrium
Right coronary Great cardiac
artery vein
Coronary sulcus Left coronary
Right ventricle artery
Anterior cardiac
veins Left ventricle
(a) Apex
Superior vena cava Aorta
Right pulmonary artery Left pulmonary artery
Pulmonary trunk Left atrium
Right atrium Left pulmonary veins
Right pulmonary veins Pulmonary semilunar valve
Aortic semilunar valve
Fossa ovalis Bicuspid (mitral) valve
Left ventricle
Tricuspid valve Papillary muscle
Chordae tendineae
Right ventricle Interventricular septum
Trabeculae carneae
Inferior vena cava Myocardium
Visceral pericardium
(b)
Figure 28.4 The heart: (a) coronary arteries and veins; (b) chambers and valves.
Superior Chapter 28 Review of the Cardiovascular System 481
vena cava
1 Sinoatrial node Aorta
Right atrium
(pacemaker)
2 Internodal Left atrium
Purkinje
pathway fibers
3 Atrioventricular
Interventricular
node septum
4 Atrioventricular
bundle (bundle of His)
Bundle branches
5 Purkinje fibers
1. The sinoatrial (SA) node fires a stimulus across the walls of both
left and right atria causing them to contract.
2. The stimulus arrives at the atrioventricular (AV) node.
3. The stimulus is directed to follow the AV bundle (bundle of His).
4. The stimulus now travels through the apex of the heart through
the bundle branches.
5. The Purkinje fibers distribute the stimulus across both ventricles
causing ventricular contraction.
Figure 28.5 The cardiac conduction system.
electrical connection between the atria and the ventricles. It is important to understand that the underlying pur-
The impulse is conducted down the right and left bundle pose of the cardiac conduction system is to keep the heart
branches to the Purkinje fibers, which rapidly carry the beating in a regular, synchronized manner so that cardiac
action potential to all regions of the ventricles almost simul- output can be maintained. Dysrhythmias that profoundly
taneously. Should the SA and AV nodes become nonfunc- affect cardiac output have the potential to produce serious,
tional, cells in the AV bundle and Purkinje fibers can if not mortal, consequences. These types of dysrhythmias
continue to generate myocardial contractions at a rate of require pharmacologic intervention, as discussed in
about 30 beats/min. Chapter 37.
Although action potentials normally begin at the SA 28.7 Cardiac output is determined by stroke
node and spread across the myocardium in a coordinated volume and heart rate.
manner, other regions of the heart may also initiate beats.
These ectopic foci, or ectopic pacemakers, may send waves To understand how medications act on the heart and to
of depolarization across the myocardium that compete predict the consequences of pharmacotherapy, it is essen-
with those from the normal conduction pathway. The tim- tial to have a comprehensive knowledge of normal cardiac
ing and synchronization of atrial and ventricular contrac- physiology. This includes a thorough understanding of
tions may be affected. Although healthy hearts occasionally factors that determine the amount of blood pumped by the
experience an extra beat without incident, ectopic foci in heart and the forces acting on the chambers.
diseased hearts have the potential to cause dysrhythmias,
or disorders of cardiac rhythm. The events associated with The amount of blood pumped by each ventricle per
the cardiac conduction system are recorded on an electro- minute is the cardiac output (CO). The CO is essentially a
cardiogram (ECG). measure of how effectively the heart is performing as a
482 Unit 5 Pharmacology of the Cardiovascular System
pump. The average CO is 5 L/min. CO can be calculated by force? Although several factors affect preload, the most
multiplying stroke volume by the heart rate: important is venous return: the volume of blood returning
to the heart from the veins. Giving a drug that constricts
CO = stroke volume (mL/beat) × heart rate (beats/min) veins will increase venous return to the heart, as will sim-
ply increasing the total amount of blood in the vascular
Stroke volume: Stroke volume is the amount of blood system (increased blood volume). Drugs or other mecha-
pumped by a ventricle in a single contraction. What types nisms that constrict veins or increase blood volume will
of factors might cause a ventricle to eject more blood dur- therefore increase stroke volume and CO. Conversely,
ing a contraction? To understand these factors, a simple drugs that dilate veins or reduce blood volume will lower
comparison to a rubber band is useful. If you stretch a CO.
small rubber band 2 inches, it will snap back with a certain
force. Stretching the band 4 inches will cause it to snap Factors that increase cardiac contractility are called
back with greater force. The force of the snap will continue positive inotropic drugs. Examples of positive inotropic
to increase up to a certain limit, after which the rubber drugs include epinephrine, norepinephrine, thyroid hor-
band has been stretched as far as possible and has reached mone, and dopamine. Factors that decrease cardiac con-
maximum force (or it breaks!). tractility are called negative inotropic drugs. Examples
include quinidine and beta-adrenergic antagonists such as
Cardiac muscle fibers are analogous to rubber bands. If propranolol.
you fill the chambers with more blood, the fibers will have
more stretch and will “snap back” with greater force. This A second primary factor affecting stroke volume is
is known as Starling’s law of the heart: The strength (force) afterload. In order for the left ventricle to pump blood out
of contraction, or contractility, is proportional to the mus- of the heart, it must overcome a substantial “back pres-
cle fiber length (stretch). The contractility determines the sure” in the aorta. Afterload is the systolic pressure in the
amount of blood ejected per beat, or the stroke volume. The aorta that must be overcome for blood to be ejected from
degree to which the ventricles are filled with blood and the the left ventricle. As afterload increases, the heart pumps
myocardial fibers are stretched just prior to contraction is less blood, and stroke volume (and thus CO) decreases.
called preload. Up to a physiologic limit, drugs that The most common cause of increased afterload is an
increase preload and contractility will increase the CO. In increase in systemic blood pressure, or HTN. HTN creates
addition to preload, the force of contraction can be increased an increased workload on the heart, which explains why
by activation of beta1-adrenergic receptors in the auto- patients with chronic HTN are more likely to experience
nomic nervous system. heart failure. Antihypertensive drugs create less afterload,
increase stroke volume, and result in less workload for the
What causes the chambers to fill up with more blood, heart. Preload and afterload are illustrated in Figure 28.6.
become stretched (more preload), and contract with greater
(a) Preload (b) Afterload
Figure 28.6 (a) Preload is the degree to which the ventricles are filled with blood and the
myocardial fibers are stretched just prior to contraction. (b) Afterload is the systolic pressure in the
aorta that must be overcome for blood to be ejected from the left ventricle.
Chapter 28 Review of the Cardiovascular System 483
Heart rate: Heart rate is the second primary factor deter- Figure 28.7. The following simple formula should be mem-
mining CO. Heart rate is generally controlled by the auto- orized (as well as understood) because it will help in pre-
nomic nervous system, which makes the minute-by-minute dicting the actions and adverse effects of many classes of
adjustments demanded by the circulatory system. Both cardiovascular medications:
sympathetic and parasympathetic fibers are found in the
SA node, and heart rate is determined by which fibers are Blood pressure = CO × peripheral resistance
firing at a greater rate at any given moment. Circulating
hormones such as epinephrine and thyroid hormone also CO is determined by heart rate and stroke volume as
affect heart rate. In theory, drugs that increase heart rate discussed in Section 28.7. From the preceding equation, it is
will increase CO, although compensatory mechanisms easy to see that as CO increases, blood pressure also
may prevent this effect (see Section 28.8). In addition, a increases. This is important to pharmacology because med-
very rapid heart rate may not give the chambers sufficient ications that change the CO, stroke volume, or heart rate
time to completely fill, thus reducing CO. have the potential to influence a patient’s blood pressure.
CONNECTION Checkpoint 28.2 As blood speeds through the vascular system, it exerts
force against the walls of the vessels. Although the lining of
From what you learned in Chapter 12, predict what effect the fol- the blood vessel is extremely smooth, friction reduces the
lowing would have on heart rate: sympathomimetics, parasympa- velocity of the blood. Further friction is encountered as the
thomimetics, adrenergic agonists, and anticholinergics. Answers stream of fast-moving blood narrows to enter smaller ves-
to Connection Checkpoint questions are available on the faculty sels, divides into two channels (arteries), or encounters
resources site. Please consult with your instructor. fatty deposits on the vessel walls (plaque). Blood flow may
exhibit turbulence, a chaotic, tumbling motion that greatly
Hemodynamics and Blood increases friction. The friction that blood encounters in the
Pressure arteries is called peripheral resistance. Arteries have
smooth muscle in their walls, which controls the total
28.8 The primary factors responsible for peripheral resistance. For example, if the smooth muscle
blood pressure are cardiac output, peripheral constricts, the inside diameter or lumen of the arteries will
resistance, and blood volume. become smaller and create more resistance and higher
blood pressure. A large number of medications affect vas-
The homeostatic regulation of blood pressure is a key topic cular smooth muscle. Some of these drugs cause vessels to
in pharmacology because HTN is so prevalent in the popu- constrict, thus raising blood pressure, whereas others relax
lation. Regulation of blood pressure is complex with many smooth muscle, thereby opening the lumen and lowering
diverse factors, both local and systemic, interacting to blood pressure.
maintain adequate blood flow to the tissues. The three pri-
mary factors that regulate arterial blood pressure—CO, An additional factor responsible for blood pressure is
peripheral resistance, and blood volume—are shown in the total amount of blood in the vascular system, or blood
volume. Although the average person maintains a relatively
constant blood volume of approximately 5 L, this can be
Blood pressure
is determined by
Blood volume Peripheral resistance Cardiac output
determined by determined by determined by
Fluid retention Blood Diameter of arterioles Heart rate Stroke volume
• Dehydration viscosity • Sympathetic • Autonomic • Preload
• Aldosterone • Contractility
• ADH nervous system nervous • Afterload
• Angiotensin II system
Figure 28.7 The primary factors affecting blood pressure.
484 Unit 5 Pharmacology of the Cardiovascular System
changed by endogenous regulatory factors, certain disease 28.9 Neural regulation of blood pressure includes
states, and pharmacotherapy. More fluid in the vascular baroreceptor and chemoreceptor reflexes.
system increases venous pressure and venous return to the
heart, thus increasing CO and arterial blood pressure. Drugs It is critical for the body to maintain a normal range of
are frequently used to adjust blood volume. For example, blood pressure and for it to be able to safely and rapidly
infusion of intravenous (IV) fluids quickly increases blood change pressure as it proceeds through daily activities
volume and raises blood pressure. This is used to advantage such as sleep and exercise. Hypotension can cause dizzi-
when treating hypotension due to shock. On the other hand, ness and lack of adequate urine formation, whereas
diuretics cause fluid loss through urination, thus decreasing extreme HTN can cause vessels to rupture, resulting in
blood volume and lowering blood pressure. ischemia of critical organs. Figure 28.8 illustrates how the
body maintains homeostasis during periods of blood pres-
PharmFACT sure change.
It is estimated that all the blood vessels in an adult stretch The central and autonomic nervous systems are
through about 60,000 miles of internal body landscape intimately involved in regulating blood pressure. On a
(Marieb & Hoehn, 2016). minute-to-minute basis, blood pressure is regulated by a
cluster of neurons in the medulla oblongata called the
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Figure 28.8 Cardiovascular and renal control of blood pressure.
Chapter 28 Review of the Cardiovascular System 485
vasomotor center. Sensory receptors in the aorta and the the respiratory system can remove excess carbon dioxide
internal carotid artery provide the vasomotor center with (which returns pH to normal levels) and add more oxy-
vital information on conditions in the vascular system. gen to the blood.
Baroreceptors have the ability to sense pressure within
large vessels, whereas chemoreceptors recognize levels of CONNECTION Checkpoint 28.3
oxygen, carbon dioxide, and the acidity or pH in the
blood. The vasomotor center reacts to information from Many autonomic drugs dilate or constrict blood vessels. From what
baroreceptors and chemoreceptors by raising or lowering you learned in Chapter 12, which class of autonomic drugs is most
blood pressure accordingly. Nerve fibers travel from the commonly prescribed for HTN? Answers to Connection Checkpoint
vasomotor center to the arteries, where the smooth mus- questions are available on the faculty resources site. Please consult
cle is directed to either constrict (raise blood pressure) or with your instructor.
relax (lower blood pressure). As discussed in Chapter 16,
sympathetic outflow from the vasomotor center stimu- 28.10 Hormones may have profound effects
lates alpha1-adrenergic receptors on arterioles, causing on blood pressure.
vasoconstriction. Alpha2-adrenergic agonists can also
decrease blood pressure by their central effects on the Several hormones affect blood pressure, and certain classes
vasomotor center. of medications are given to either enhance or block the
actions of these hormones. For example, injection of the
The baroreceptor reflex is an important mechanism catecholamines epinephrine or norepinephrine will imme-
used by the body for making rapid adjustments to blood diately raise blood pressure, which is essential for patients
pressure. If pressure in the vascular system increases, the experiencing shock.
baroreceptors in the aortic arch and carotid sinus trigger
reflexes that constrict the arterioles and veins and acceler- Antidiuretic hormone (ADH) is a hormone released
ate the heart rate. Together, these actions return blood pres- by the posterior pituitary gland when blood pressure falls
sure to normal levels within seconds. or when the osmotic pressure of the blood increases. ADH,
also known as vasopressin, is a potent peripheral vasocon-
Drugs that raise or lower blood pressure can trigger strictor that quickly increases blood pressure. The hormone
the baroreceptor reflex. For example, antihypertensives also acts on the kidneys to conserve water and increase
administered by the IV route cause an immediate reduction blood volume, thereby causing blood pressure to increase.
in blood pressure that is recognized by the baroreceptors. The pharmacotherapy of ADH and related hormones is
The baroreceptors respond by attempting to return blood discussed in Chapter 65.
pressure back to the original levels. The resulting acceler-
ated heart rate, or reflex tachycardia, may cause the patient The renin-angiotensin-aldosterone system (RAAS) is
to experience palpitations. The baroreceptors are not able particularly important in the drug therapy of HTN. As
to offer a continuous or sustained reduction in blood pres- blood pressure falls, the enzyme renin is released by the
sure. Continued administration of an antihypertensive kidneys. Through a two-step pathway, angiotensin II is
drug will “overcome” the reflex. In addition, with aging or formed, which subsequently increases CO and constricts
certain disease states such as diabetes, the baroreceptor arterioles to return blood pressure to original levels. Angio-
response may be diminished. tensin II also promotes the release of aldosterone from the
adrenal gland, which causes sodium and water retention.
Another example of the baroreceptor reflex occurs Drugs that block the RAAS are key drugs in the treatment
when baroreceptors in the right atrium are triggered. These of HTN and heart failure.
receptors recognize excess stretching of the right atrium,
such as might occur when large amounts of IV fluids are Atrial natriuretic peptide (ANP) is a hormone that is
administered. The atrial reflex causes the heart rate and secreted by specialized cells in the right atrium when large
CO to increase until the backlog of venous blood (or IV increases in blood volume produce excessive stretch on the
fluid) is distributed throughout the body. atrial wall. ANP has multiple effects, all of which attempt
to return blood pressure to original levels. Sodium ion
The chemoreceptor reflex can also significantly transport in the kidney is affected, resulting in enhanced
affect blood pressure. Sensors in the carotid sinus and sodium and water excretion. The release of ADH and aldo-
near the aortic arch recognize levels of oxygen and car- sterone is suppressed by ANP. In addition, ANP reduces
bon dioxide and the acidity (pH) in the blood. Triggering sympathetic outflow from the central nervous system,
these chemoreceptors activates the sympathetic nervous resulting in dilation of peripheral arteries. A summary of
system and causes heart rate and CO to increase. The the various nervous and hormone factors influencing blood
purpose of this reflex is to circulate blood faster so that pressure is shown in Figure 28.9.
486 Unit 5 Pharmacology of the Cardiovascular System
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9CVGT CPF 5GETGVKQP QH
UQFKWO TGVGPVKQP PQTGRKPGRJTKPG
CPF GRKPGRJTKPG
Figure 28.9 Endocrine and nervous control of blood pressure.
*QOGQUVCUKU
$NQQF RTGUUWTG
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Understanding Chapter 28
Key Concepts Summary 28.4 The heart is responsible for pumping blood
throughout the circulatory system.
28.1 The cardiovascular system consists of the blood,
heart, and blood vessels. 28.5 The coronary arteries bring essential nutrients to
the myocardium.
28.2 Blood consists of formed elements and plasma.
28.6 The cardiac conduction system keeps the heart
28.3 Hemostasis is a complex process involving beating in a synchronized manner.
multiple steps and a large number of enzymes
and factors.
28.7 Cardiac output is determined by stroke volume Chapter 28 Review of the Cardiovascular System 487
and heart rate.
28.9 Neural regulation of blood pressure includes
28.8 The primary factors responsible for blood baroreceptor and chemoreceptor reflexes.
pressure are cardiac output, peripheral resistance,
and blood volume. 28.10 Hormones may have profound effects on blood
pressure.
References Martini, F. H., Nath, J. L., & Bartholomew, E. F. (2015).
Fundamentals of human anatomy and physiology (10th ed.).
Marieb, E. N., & Hoehn, K. N. (2016). Human anatomy and San Francisco, CA: Benjamin Cummings.
physiology (10th ed.). Hoboken, NJ: Pearson.
Selected Bibliography Silverthorn, D. U. (2016). Human physiology: An integrated
approach (7th ed.). Hoboken, NJ: Pearson.
D’Amico, D., & Barbarito, C. (2016). Health and physical
assessment in nursing (3rd ed.). Hoboken, NJ: Pearson.
Krogh, D. (2014). Biology: A guide to the natural world,
technology update (5th ed.). San Francisco, CA: Benjamin
Cummings.
“My mother had it and my
grandmother had it too. Now,
I’m told that I have it. My
doctor says my cholesterol level is
too high.”
Patient “Belinda Cummings”
Chapter 29
Pharmacotherapy of Hyperlipidemia
Chapter Outline Learning Outcomes
cc Types of Lipids and Lipoproteins After reading this chapter, the student should be able to:
cc Measurement and Control of Serum Lipids
cc Drugs for Dyslipidemias 1. Summarize the link between high blood cholesterol,
low-density lipoprotein levels, and atherosclerosis.
HMG-CoA Reductase Inhibitors
PROTOTYPE Atorvastatin (Lipitor), p. 496 2. Explain the different types of lipids and how they
Bile Acid Sequestrants are transported through the body.
PROTOTYPE Cholestyramine (Questran), p. 500
Niacin 3. Illustrate how lipids are transported through the
Fibric Acid Drugs blood.
PROTOTYPE Gemfibrozil (Lopid), p. 502
Miscellaneous Drugs for Dyslipidemias 4. Compare and contrast the clinical importance of the
different types of lipoproteins.
5. Give examples of how cholesterol and low-density
lipoprotein levels can be controlled with
nonpharmacologic means.
6. Categorize antihyperlipidemic drugs based on their
classification and mechanism of action.
7. Explain the nurse’s role in the safe administration of
drugs for lipid disorders.
8. For each of the classes shown in the chapter outline,
identify the prototype and representative drugs and
explain the mechanism(s) of drug action, primary
indications, contraindications, significant drug
interactions, pregnancy category, and important
adverse effects.
9. Apply the nursing process to care for patients
receiving pharmacotherapy for lipid disorders.
488
Chapter 29 Pharmacotherapy of Hyperlipidemia 489
Key Terms hyperlipidemia, 491 rhabdomyolysis, 496
hypertriglyceridemia, 491 steroids, 489
apoprotein, 489 lipoproteins, 489 sterol nucleus, 489
atherosclerosis, 489 low-density lipoprotein triglycerides, 489
dyslipidemia, 491 very low-density lipoprotein
high-density lipoprotein (LDL), 489
phospholipids, 489 (VLDL), 490
(HDL), 489 reverse cholesterol transport, 491
HMG-CoA reductase, 494
hypercholesterolemia, 491
Research during the 1970s and 1980s brought about a nutri- body, cholesterol is a vital component of plasma mem-
tional revolution as new knowledge about lipids and their branes and serves as a building block for essential bio-
relationships to obesity and cardiovascular disease allowed chemicals, including vitamin D, bile acids, cortisol,
people to make more intelligent lifestyle choices. Since then estrogen, and testosterone. Although clearly essential for
advances in the diagnosis of lipid disorders have helped to life, the body needs only minute amounts of cholesterol
identify those people at greatest risk for cardiovascular dis- because the liver is able to synthesize adequate amounts
ease and those most likely to benefit from pharmacologic from other chemicals. It is not necessary, nor desirable, to
intervention. As a result of this knowledge and from provide excess cholesterol in the diet. The dietary sources
advancements in pharmacology, the incidence of death due of cholesterol are obtained solely from animal products;
to most cardiovascular diseases has been declining, humans do not absorb the sterols produced by plants.
although they remain the leading cause of death in the
United States. 29.2 Lipoproteins are important predictors
of cardiovascular disease.
Types of Lipids and Lipoproteins
Because lipid molecules are not soluble in plasma, they
29.1 Lipids are classified as triglycerides, must be specially packaged for transport through the
phospholipids, or sterols. blood. To accomplish this, the body forms complexes
called lipoproteins, which consist of various amounts of
Three types of lipids are important to human physiology, cholesterol, triglycerides, and phospholipids bound to car-
as illustrated in Figure 29.1. The most common types are rier proteins. The protein component is called an apopro-
triglycerides or neutral fats, which consist of three fatty tein (apo- means “separated from” or “derived from”).
acids attached to a chemical backbone of glycerol. Triglyc- There are six primary classes (and numerous subclasses) of
erides are the major storage form of fat in the body and the apolipoproteins, each serving different roles in transport-
only type of lipid that serves as an important energy ing lipoproteins. The six classes are named apo A, apo B,
source. They account for 90% of the total lipids in the body. apo C, apo D, apo E, and apo H.
A second class, the phospholipids, is formed when a Lipoproteins are classified according to their composi-
phosphorous group replaces one of the fatty acids in a tri- tion, size, and weight or density, which come primarily
glyceride. This type of lipid comprises the majority of the from the amount of apoprotein present in the complex.
lipid bilayer that forms plasma membranes. Phospholipids Each type varies in lipid and apoprotein makeup and
also form spherical sacs called liposomes, which have been serves a different function in transporting lipids from the
used to develop unique drug delivery systems. Once sites of synthesis and absorption to the sites of utilization.
enclosed in a liposome, drugs such as amphotericin B and For example, high-density lipoprotein (HDL) contains the
doxorubicin are able to overcome certain obstacles to most apoprotein, up to 50% by weight. The highest amount
absorption and distribution. of cholesterol is carried by low-density lipoprotein (LDL).
Figure 29.2 illustrates the three basic lipoproteins and their
The third class of lipids, the steroids, is a diverse group compositions.
of substances having a common sterol nucleus or ring
structure. Cholesterol is the most widely known of the ste- To understand the pharmacotherapy of lipid disor-
roids, and its role in promoting atherosclerosis has been ders, it is important to know the functions of the major
clearly demonstrated. Atherosclerosis is the presence of lipoproteins and their roles in transporting cholesterol.
plaque—a fatty, fibrous material within the walls of the LDL transports cholesterol from the liver to the tissues and
arteries. Unlike the triglycerides that provide fuel for the organs, where it is used to build plasma membranes or to
490 Unit 5 Pharmacology of the Cardiovascular System
*1 GVE
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1
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Figure 29.1 Chemical structure of lipids.
synthesize other steroids. Once in the tissues it can also be to seventy percent of the cholesterol circulating in the blood
stored for later use. Storage of cholesterol in the lining of is found in LDL.
blood vessels, however, is not desirable because it contrib-
utes to plaque buildup. LDL is often called “bad” choles- Very low-density lipoprotein (VLDL) is the primary
terol because this lipoprotein contributes significantly to carrier of triglycerides in the blood. VLDL accounts for
plaque deposits and coronary artery disease (CAD). Sixty virtually all triglycerides being transported from the liver
to storage in adipose tissue. Through a series of steps,
(a) High-density Chapter 29 Pharmacotherapy of Hyperlipidemia 491
lipoprotein
45–50%
(b) Low-density 20%
lipoprotein 30%
5%
25%
45%
20%
10%
(c) Very low-density 5–10% Triglyceride
lipoprotein Phospholipid
10–15% Protein
15–20% Cholesterol
55–65%
Figure 29.2 Composition of lipoproteins: (a) HDL; (b) LDL; (c) VLDL.
VLDL is reduced in size to become LDL. Lowering LDL hypercholesterolemia, is the type of hyperlipidemia most
levels in the blood has been shown to decrease the inci- familiar to the public. Some patients exhibit an increase in
dence of CAD. triglyceride levels known as hypertriglyceridemia.
HDL is manufactured in the liver and small intestine Patients with lipid disorders are asymptomatic and
and assists in the transport of excess cholesterol away from often do not seek medical intervention until cardiovascular
the body tissues and back to the liver for metabolism in a disease has progressed to the point of producing chest pain
process known as reverse cholesterol transport. The cho- or hypertension. It is estimated that almost 32% of the adult
lesterol component of the HDL is then broken down to population in the United States has elevated cholesterol
unite with bile, which is subsequently excreted in the feces. levels and that only half of these people are being treated
Excretion via bile is the only route the body uses to remove for hyperlipidemia (Centers for Disease Control and Pre-
cholesterol. Because HDL transports cholesterol for vention, 2015). Because of the cost and the lack of symp-
destruction and removes it from the body, it is considered toms for lipid disorders, nurses may face challenges
“good” cholesterol. Patients with insufficient amounts of persuading patients of the value of antihyperlipidemic
HDL are at risk for atherosclerosis, even if their total cho- drug therapy. The long-term benefits of drug therapy and
lesterol levels are normal. the long-term consequences of hyperlipidemia and cardio-
vascular disease warrant consistent education on the
Several terms are used to describe lipid disorders. importance of drug therapy and lifestyle changes.
Dyslipidemia is a general term that refers to abnormal
amounts of lipids in the body. The most common type of Hyperlipidemia may be inherited or acquired. Cer-
dyslipidemia is hyperlipidemia meaning elevated levels of tainly, diets high in saturated fats and lack of exercise con-
lipids in the blood. The term hyperlipidemia, however, does tribute greatly to the development of hyperlipidemia and
not specify which lipid is elevated (cholesterol, triglycer- resulting cardiovascular diseases. However, genetics deter-
ide, or phospholipid). Elevated blood cholesterol, or mines one’s ability to metabolize lipids and contributes to
492 Unit 5 Pharmacology of the Cardiovascular System
high lipid levels in substantial numbers of patients. Some Table 29.1 Standard Laboratory Lipid Profiles
genetic dyslipidemias can be so severe as to cause CAD
and death due to myocardial infarction (MI) in patients as Laboratory Value Standard
young as 1 or 2 years (Mose, 2016). For most patients, dys- Type of Lipid (mg/dL)
lipidemias are the result of a combination of genetic and
environmental (lifestyle) factors. Total cholesterol Less than 200 Desirable
Measurement and Control 200–239 Borderline high risk
of Serum Lipids
240 or higher High risk
29.3 Blood lipid profiles are important
diagnostic tools in guiding the therapy of Low-density Less than 100 Optimal
dyslipidemias. lipoproteins 100–129 Near or above optimal
(LDLs) 130–159 Borderline high risk
Although high levels of cholesterol in the blood are
associated with cardiovascular disease, it is not enough 160–189 High risk
to simply measure total cholesterol in the blood. Because
some cholesterol is being transported for destruction, a 190 or higher Very high risk
more accurate profile is obtained by measuring the LDL
and HDL. The goal is to maximize the cholesterol car- High-density Less than 40 (men) or 50 Low risk
ried by high-density lipoproteins (HDL-C) and mini- lipoproteins (women) Desirable
mize the cholesterol carried by low-density lipoproteins (HDLs)
(LDL-C). This is sometimes stated as a ratio of LDL to Greater than 60
HDL. If the ratio is greater than 5 (five times more LDL
than HDL), the male patient is considered at risk for car- Serum Less than 150 Normal
diovascular disease. The normal ratio in women is triglycerides 150–199 Borderline high risk
slightly lower at 4.5.
200–499 High risk
Scientists have further divided LDL into subclasses of
lipoproteins. For example, one variety found in LDL, called 500 or higher Very high risk
lipoprotein (a), has been strongly associated with plaque for-
mation and heart disease. It is likely that further research From “Executive Summary of the Third Report of the National Cholesterol Education
will find other varieties with the expectation that drugs Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood
will be designed to be more selective toward the “bad” Cholesterol in Adults (Adult Treatment Panel III), Expert Panel on Detection, Evaluation,
lipoproteins. Table 29.1 gives the desirable, borderline, and and Treatment of High Blood Cholesterol in Adults,” 2001, JAMA, 285, 2486–2497.
high laboratory values for each of the major lipids and lipo-
proteins. These values change periodically as additional laboratory number, but is now established for the follow-
research becomes available on the association between ing treatment categories:
heart disease and lipid levels.
1. Patients with atherosclerotic CVD
Establishing treatment guidelines for dyslipidemia 2. Patients with diabetes, ages 40 to 75 years with LDL-C
has been challenging because the condition has no symp-
toms and the progression to cardiovascular disease may levels between 70 and 189 mg/dL
take decades. Until 2013, treatment guidelines focused on 3. Patients without CVD but who have LDL-C levels of
determining levels of LDL and HDL that could prevent
the development of cardiovascular disease (CVD). Essen- 190 mg/dL or higher
tially, if a patient exhibited laboratory values shown to be 4. Patients ages 40 through 75 years without CVD or dia-
at high risk (see Table 29.1), pharmacotherapy was initi-
ated and continued until these values returned to the betes but who have LDL-C levels 70 through 189 mg/dL
normal range. and 7.5% or greater 10-year risk of atherosclerotic CVD.
Major revisions were made to these guidelines by the Based on the results of hundreds of clinical trials over
American College of Cardiology (ACC) and the American many years, the ACC/AHA guidelines specifically recom-
Heart Association (AHA) in 2013 (Psaty & Weiss, 2014). mend statins as first-line therapy for all categories (see
The 2013 ACC/AHA guidelines no longer stress specific Section 29.5). Follow-up measures of LDL are recom-
target goals for LDL levels. The question of who should be mended to determine adherence to the drug regimen.
treated for high cholesterol levels is no longer based on a
The fourth category of the ACC/AHA guidelines, which
bases pharmacotherapy on a 7.5% or greater risk of athero-
sclerotic CVD, has been controversial. The calculation of risk
gives heavy emphasis to age, which suggests that most of the
population over age 60 should be on statin medications. Later
research suggested this guideline has been effective at pre-
venting CVD in this population (Greenland & Lauer, 2015).
Blood lipid profiles are used to classify the different pat-
terns of hyperlipidemias observed in clinical practice. These
patterns are shown in Table 29.2. The specific type of dyslipid-
emia exhibited by patients is considered when planning ther-
apy. For example, Type I requires dietary restrictions and does
not respond well to pharmacotherapy. Whereas the remain-
ing types respond to the statins, the hypertriglyceridemias
may respond better to therapy with fibric acid drugs (fibrates).
Chapter 29 Pharmacotherapy of Hyperlipidemia 493
Table 29.2 Types of Dyslipidemias
Name Laboratory Findings Features
Type I Triglycerides increased 3 times Rare condition, usually occurring in
Exogenous hyperlipidemia Chylomicrons increased childhood
LDL and cholesterol increased Common condition, may occur at any age
Type IIa
Familial hypercholesterolemia LDL, VLDL, cholesterol, and triglycerides increased May occur at any age but more commonly in
adults
Type IIb Chylomicrons, VLDL, cholesterol, and triglycerides
Combined familial hyperlipidemia increased Uncommon condition, occurs most
Carbohydrate-induced hypertriglyceridemia VLDL and triglycerides increased frequently in middle-aged adults
Cholesterol normal or elevated Most common dyslipidemia, occurs in
Type III Glucose intolerance middle-aged adults; associated with obesity,
Familial dysbetalipoproteinemia Hyperuricemia excessive alcohol intake, tobacco use, and
LDL, VLDL, cholesterol, and chylomicrons increased other lifestyle factors
Type IV Triglycerides increased 3 times Uncommon type, may begin in childhood
Endogenous hyperlipidemia Glucose intolerance and manifest in adults
Carbohydrate-induced hypertriglyceridemia Hyperuricemia
Type V
Mixed hyperlipidemia
Carbohydrate- and fat-induced hypertriglyceridemia
29.4 Lipid levels can often be controlled Saturated fats are the building blocks that the liver uses for
through therapeutic lifestyle changes. making cholesterol. The 2013 ACC/AHA guidelines call
for a reduction of saturated fat in the diet to 5% to 6% of
Therapeutic lifestyle changes (TLCs) should always be total calories. In addition, levels of trans fatty acids from
included in any plan for treating or preventing cardiovas- meat and dairy products should be reduced.
cular disease. Many patients with borderline high-risk lab-
oratory values can control their dyslipidemia entirely CONNECTIONS: Lifespan
through nonpharmacologic means. Considerations
Even in patients with high risk for whom drug therapy Pediatric Dyslipidemias
is indicated, using TLCs is important for reducing choles- and Lipid-Lowering Drugs
terol levels. All drugs for hyperlipidemia have adverse
effects, and implementing TLCs may allow for a reduction Many people consider dyslipidemia to be a condition that
in drug dosages. Following are the most important lipid- occurs with advancing age. Dyslipidemias are also a concern
reduction lifestyle interventions: for some pediatric patients, and multiple research studies
have demonstrated that the early stages of atherosclerosis
• Monitor blood lipid levels regularly, as recommended begin in childhood. With the increasing childhood obesity epi-
by the healthcare provider. demic, there is concern that dyslipidemias, CVD, and meta-
bolic syndrome will occur at younger and younger ages. Risk
• Maintain weight at an optimal level. factors for dyslipidemias in children are similar to those in
• Implement a medically supervised exercise plan. adults and include overweight or obesity, family history of dys-
• Reduce dietary saturated fats and cholesterol. lipidemias or premature CVD, hypertension, smoking or pas-
• Increase soluble fiber in the diet, as found in oat bran, sive smoke exposure, and known genetic lipid disorders. The
2011 National Heart, Lung, and Blood Institute Integrated
apples, beans, grapefruit, and broccoli. Guidelines for Cardiovascular Health and Risk Reduction in
• Eliminate tobacco use. Children and Adolescents recommended targeted screening
of lipid levels for children ages 2 and older with a positive or
The single most important lifestyle factor contributing unknown family history of dyslipidemia-related CVD or other
to dyslipidemia is a high amount of saturated fat in the major risk factor and universal screening in those ages 9 to
diet. Nutritionists recommend that the intake of dietary fat 11 years and again between 17 and 21 years. Additionally,
be limited to less than 30% of the total caloric intake and they recommended pharmacologic treatment with statins for
that cholesterol intake be reduced as much as possible. It is children with LDL levels above 190 mg/dL, or above 160 mg/dL
interesting to note that restriction of dietary cholesterol with the presence of two or more cardiovascular risk factors
alone will not result in a significant reduction in blood cho- before age 50 (Expert Panel on Integrated Guidelines for
lesterol levels. In fact, cutting back on cholesterol consump- Cardiovascular Health and Risk Reduction in Children and
tion may actually increase the amount of circulating Adolescents, 2011).
cholesterol. How is this possible? The liver reacts to a low-
cholesterol diet by making more cholesterol and by inhibit-
ing its excretion whenever saturated fats are present.
494 Unit 5 Pharmacology of the Cardiovascular System
Acetyl CoA HMG-CoA
HMG-CoA
reductase
To gallbladder
HO Cholesterol
CH3 OH CH2OH Bile salts
CO HO CO Excretion
OH
O OO Cortisol
Progesterone Testosterone
CH2OH OH
HO OHCC O
O HO Estradiol
Aldosterone
Figure 29.3 Cholesterol biosynthesis and excretion.
Nutritionists also recommend increased dietary intake production in human cells in the laboratory. This class of
of plant sterols as a means to reduce blood cholesterol levels. drugs, known as the statins, has revolutionized the treat-
Plant sterols, also called phytosterols or stanols, are lipids ment of lipid disorders. Statins can produce a dramatic
used by plants to construct their cell membranes. The struc- reduction in LDL cholesterol levels, lower triglyceride and
ture of plant sterols is very similar to that of cholesterol. VLDL levels, and raise the level of “good” HDL choles-
When ingested, however, the plant sterols compete with terol. High-intensity statin therapy is able to lower LDL
cholesterol for absorption in the digestive tract. When the levels by more than 50% and reduce the incidence of seri-
body absorbs the plant sterols, cholesterol is excreted from ous cardiovascular-related adverse events by 25% to 30%.
the body, less cholesterol is delivered to the liver, and serum This means that about one in every three or four heart
LDL (the “bad” cholesterol) levels fall. Rich, natural sources attacks, strokes, or blood clots can be prevented with
of plant sterols include wheat, corn, rye, oats, and rice, as appropriate statin therapy.
well as nuts and olive oil. In recent years, plant sterols have
been added to commercial products such as margarines, Cholesterol is manufactured in the liver by a series of
salad dressings, certain cereals, and some fruit juices. more than 25 metabolic steps, beginning with acetyl CoA, a
two-carbon unit that is produced from the breakdown of
Drugs for Dyslipidemias fatty acids (Figure 29.3). Of the many enzymes involved in
this complex pathway, HMG-CoA reductase (3-hydroxy-
29.5 The statins are the most effective drugs 3-methylglutaryl coenzyme A reductase) serves as the pri-
for reducing blood lipid levels. mary regulatory enzyme for the biosynthesis of cholesterol.
Under normal conditions, this enzyme is regulated through
In the late 1970s substances were isolated from various negative feedback. High levels of LDL cholesterol in the
species of fungi that were found to inhibit cholesterol blood will shut down production of HMG-CoA reductase,
thus turning off the cholesterol synthesis pathway.
Chapter 29 Pharmacotherapy of Hyperlipidemia 495
Pharmacotherapy Illustrated 29.1
Mechanisms of Action of Lipid-Lowering Drugs
Lipoprotein LDL Tissues Statins
lipase HDL Interfere with HMG-CoA
VLDL reductase, the critical
(for excretion) enzyme in the biosynthesis
of cholesterol
Niacin Cholesterol HMG-CoA
Decreases both VLDL
and LDL levels
Bile acids
Dietary
lipids
Fibric acid drugs Ezetimibe
Increase fatty acid breakdown Blocks the absorption
and eliminate triglyceride-rich of cholesterol from the
particles small intestine
Bile acid binding drugs Absorbed
Increase the excretion of lipids
cholesterol in the stool by
binding bile acids
Bile acid and drug
(excretion in feces)
Pharmacotherapy Illustrated 29.1 shows some of the steps Statins clearly slow the progression of CVD and reduce
in the biosynthesis of cholesterol and the importance of mortality in patients with a history of cardiovascular dis-
HMG-CoA reductase. ease. This type of therapy is called secondary prevention,
because the patient is already at risk for increased mortal-
The statins act by inhibiting HMG-CoA reductase, ity. Primary prevention is the administration of statins to
resulting in less cholesterol biosynthesis. As the liver makes patients with no history of CVD. The evidence for a reduc-
less cholesterol, it responds by making more LDL receptors tion in cardiovascular adverse events with statin therapy is
on the surface of liver cells. The greater number of LDL clear. In 2016, the U.S. Preventive Services Task Force (USP-
receptors on liver cells removes additional LDL from the STF) reviewed the evidence on the benefits and harms of
blood. Blood levels of both LDL and cholesterol are screening for and treatment of dyslipidemia in adults
reduced. The reduction in adverse cardiovascular events 21 years and older; the benefits and harms of statin use in
from the statins is especially high in those patients who reducing CVD events and mortality in adults without a his-
have diabetes as a comorbid condition with hyperlipid- tory of CVD; whether the benefits of statin use vary by sub-
emia. The drop in lipid levels is not permanent, however, group, clinical characteristics, or dosage; and the benefits
so patients must continue these drugs for the remainder of of various treatment strategies in adults 40 years and older
their lives or until their hyperlipidemia can be controlled without a history of CVD.
through dietary or lifestyle changes.
496 Unit 5 Pharmacology of the Cardiovascular System
The latest recommendations to initiate use of low- to and certain immunosuppressants should be avoided dur-
moderate-dose statins in adults ages 40 to 75 years without ing statin therapy, because these interfere with statin
a history of CVD depend on an estimate of the patient’s metabolism and increase the risk of severe myopathy. Lev-
10-year risk and the presence of major risk factors. These els of creatine kinase (CK), an enzyme released during
factors (exclusive of LDL levels) include the following. muscle injury, should be obtained if myopathy is suspected.
If CK levels become elevated during therapy, the drug
• Cigarette smoking should be immediately discontinued. Statins may be dis-
• Hypertension continued if muscle weakness persists even without CK
• Low HDL-C elevation. Nurses should urge all patients who develop
• Family history of premature heart disease in a first- unexplained muscle or joint pain during statin therapy to
immediately report this to the prescriber.
degree relative
• Age (men: 45 years or older; women: 55 years or older). Statins are pregnancy category X drugs because terato-
genic effects have been reported in laboratory animals
People who have none or one risk factor and a calcu- exposed to these drugs. Statins should not be used in
lated 10-year CVD risk of less than 10% should receive low- patients who may become pregnant, are pregnant, or who
to moderate-dose statins only when LDL-C levels reach are breastfeeding.
190 mg/dL or higher. At the other extreme, people with two
or more risk factors and a 10-year CVD risk of greater than Because cholesterol biosynthesis in the liver is higher
20% should receive drug therapy at a much lower LDL-C at night, statins with short half-lives such as lovastatin
level of 100 mg/dL. The current evidence is insufficient to should be administered in the evening. The other statins
assess the benefits of initiating statin use in adults 76 years have longer half-lives and are effective regardless of the
and older (U.S. Preventive Services Task Force, 2016). time of day they are taken.
Currently, seven statins are available for treating vari- Much research is ongoing to determine the other
ous types of dyslipidemias, and these are listed in Table 29.3. therapeutic effects of the drugs in the statin class. For
Although differences among the statins exist, their actions example, statins block the vasoconstrictive effect of the
and adverse effects are similar. Lovastatin, pravastatin, and A-beta protein, a significant chemical associated with
simvastatin are natural substances derived from fungi and Alzheimer’s disease. Cholesterol and A-beta protein had
have a different chemical structure than the synthetic very similar effects on blood vessels, both causing vaso-
statins. There are also differences in potency among the constriction. Preliminary research suggests that the
drugs. For example, the maximum daily dose for pitavas- statins may protect against dementia by inhibiting this
tatin is only 4 mg, whereas the dose is 80 mg for atorvas- protein, thus slowing dementia caused by blood vessel
tatin. The half-lives of the statins vary from 20 hours constriction. Research also suggests that the statins may
(rosuvastatin) to less than an hour (fluvastatin). Whereas have the ability to lower the incidence of colorectal can-
pravastatin is eliminated by the renal route, the other cer. The mechanism of this effect is unknown. Several
statins are metabolized by hepatic CYP450 enzymes. In attempts have been made to move low doses of certain
patients with renal disease, dosage adjustment is required statins to over-the-counter (OTC) status; however, the
for lovastatin, pravastatin, simvastatin, and rosuvastatin U.S. Food and Drug Administration (FDA) has not
but not for fluvastatin or atorvastatin. Research evidence approved these applications.
for cardiovascular adverse event prevention is greatest for
atorvastatin and rosuvastatin. However, in clinical practice PROTOTYPE DRUG Atorvastatin (Lipitor)
the choice of statin is often guided by the experience of the
prescriber and the response of each individual patient. Classification Therapeutic: Antihyperlipidemic
Pharmacologic: HMG-CoA reductase
All the statins are given orally (PO) and are tolerated
well by most patients. Adverse effects are rarely severe inhibitor, statin
enough to cause discontinuation of therapy. Minor adverse
effects include headache, abdominal cramping, diarrhea, Therapeutic Effects and Uses: Approved in 1996,
muscle or joint pain, and heartburn. atorvastatin was initially approved to treat hypercholester-
olemia. Following several years of use, it became evident
Severe myopathy and rhabdomyolysis are rare, but that the drug also prevents adverse cardiovascular events
serious, adverse effects of the statins. Rhabdomyolysis is a in high-risk patients. After 2 to 4 weeks of therapy, atorvas-
breakdown of muscle fibers usually due to muscle trauma tatin lowers LDL and VLDL cholesterol as well as triglyc-
or ischemia. The mechanism by which statins cause this erides. It appears to lower LDL cholesterol levels greater
disorder is unknown. During rhabdomyolysis, the contents than most other statins—as much as 60%. Atorvastatin
of muscle cells spill into the systemic circulation, causing may also be prescribed for the treatment of familial hyper-
potentially fatal acute renal failure. Macrolide antibiotics cholesterolemia. All patients receiving this drug should
such as erythromycin, azole antifungals, fibric acid drugs, be placed on a cholesterol-lowering diet, because this will
Chapter 29 Pharmacotherapy of Hyperlipidemia 497
Table 29.3 Drugs for Dyslipidemias
Drug Route and Adult Dose Adverse Effects
HMG-CoA Reductase Inhibitors (Maximum Dose Where Indicated)
atorvastatin (Lipitor)
fluvastatin (Lescol) PO: 10–20 mg once daily (max: 80 mg/day) Headache, dyspepsia, abdominal cramping, myalgia, back
lovastatin (Altoprev, Mevacor) pain, rash, pruritus
PO: 20 mg daily (max: 80 mg/day)
pitavastatin (Livalo) Rhabdomyolysis, severe myositis, elevated hepatic enzymes
pravastatin (Pravachol) PO (immediate release): 10–80 mg once daily
rosuvastatin (Crestor) (max: 80 mg/day)
simvastatin (Zocor) PO (extended release): 20–60 mg/day
Bile Acid Sequestrants
cholestyramine (Questran) PO: 1–4 mg daily (max: 4 mg/day)
colesevelam (Welchol)
colestipol (Colestid) PO: 10–40 mg daily (max: 80 mg/day)
Fibric Acid Drugs PO: 5–40 mg daily (max: 40 mg/day)
fenofibrate (Lofibra, TriCor, others)
PO: 5–40 mg daily (max: 80 mg/day)
fenofibric acid (Fibricor, Trilipix)
PO: 4–8 g bid–qid (max: 32 g/day) Constipation, nausea, vomiting, abdominal pain, bloating,
gemfibrozil (Lopid) dyspepsia
Other Drugs for Dyslipidemia PO: 1.875 g bid (max: 3.75 g/day)
alirocumab (Praluent) Gastrointestinal (GI) tract obstruction, vitamin deficiencies
PO: 5–20 g/day in divided doses (30 g/day granules due to poor absorption
or 16 g/day tablets)
PO: Initial dosing 50–160 mg/day depending on trade Myalgia, flulike symptoms, nausea, vomiting, increased
name serum transaminase and creatinine levels
PO (Fibricor: regular release): 35–105 mg once daily Rhabdomyolysis, cholelithiasis, pancreatitis
PO (Trilipix: delayed release): 45–135 mg once daily
PO: 600 mg bid (max: 1500 mg/day)
Subcutaneous: 75–150 mg q2wk Nasopharyngitis, injection-site reactions, influenza
evolocumab (Repatha) Subcutaneous: 140 mg q2wk or 420 mg once Serious hypersensitivity reactions
monthly Nasopharyngitis, injection-site reactions, influenza, back pain
ezetimibe and simvastatin (Vytorin) PO: 10 mg/10 mg or 10 mg/20 mg every evening Serious hypersensitivity reactions
(max: 10 mg/80 mg) Arthralgia, fatigue, abdominal pain, diarrhea
ezetimibe (Zetia) PO: 10 mg daily (max: 10 mg/day) Anaphylaxis, rhabdomyolysis
Nasopharyngitis, myalgia, upper respiratory tract infection,
arthralgia, diarrhea
icosapent (Vascepa) PO: 4 g/day Anaphylaxis, rhabdomyolysis
Arthralgia
lomitapide (Juxtapid) PO: 5–60 mg once daily Hypersensitivity
Abdominal pain, diarrhea, nausea, vomiting, dyspepsia,
reduced absorption of fat-soluble vitamins and fatty acids
mipomersen (Kynamro) Subcutaneous: 200 mg once weekly Fetal toxicity, hepatotoxicity
Injection-site reactions, flulike symptoms, nausea, headache,
niacin (Niaspan) Hyperlipidemia: PO: 250 mg regular release and elevations in serum transaminases
omega-3-acid ethyl esters (Lovaza) or 500 mg extended release daily (max: 6 g/day Flushing, nausea, pruritus, headache, bloating, diarrhea
regular release or 1–2 g/day extended release) Dysrhythmias
PO: 4 g/day Belching, dyspepsia, fishy taste
Hypersensitivity
Note: Italics indicate common adverse effects. Underline indicates serious adverse effects.
enhance the drug’s therapeutic effects. The primary goal in the time of day it is taken. Because atorvastatin is not
atorvastatin therapy is to reduce the risk of MI and stroke. excreted by the kidneys, no adjustment in dosage is nec-
essary in patients with chronic kidney disease (CKD).
To decrease gastrointestinal (GI) discomfort, atorvas- Extensive metabolism to active metabolites gives atorv-
tatin may be administered with food. It produces the astatin a long duration of action.
same degree of LDL cholesterol reduction regardless of
498 Unit 5 Pharmacology of the Cardiovascular System
Mechanism of Action: Atorvastatin acts by inhibit- when atorvastatin is administered concurrently with fibric
ing HMG-CoA reductase, the primary regulatory enzyme acid drugs or niacin. Atorvastatin may increase serum
in cholesterol biosynthesis. As the liver makes less choles- transaminases and CK levels. Herbal/Food: Grapefruit
terol, it responds by making more LDL receptors, remov- juice inhibits the metabolism of statins, allowing them to
ing LDL cholesterol from the blood. Blood levels of both reach high serum levels. Because HMG-CoA reductase in-
LDL and cholesterol are reduced. hibitors decrease the synthesis of Coenzyme Q10 (CoQ10),
patients may benefit from CoQ10 supplements. Red rice
Pharmacokinetics: yeast should not be taken with statins because it increases
their toxicity.
Route(s) PO
Pregnancy: Category X.
Absorption Rapidly absorbed but only 30%
Treatment of Overdose: No specific therapy is avail-
reaches the circulation; food able; patients are treated symptomatically.
reduces absorption Nursing Responsibilities: Key nursing implica-
tions for patients receiving atorvastatin are included in the
Distribution Widely distributed; crosses the Nursing Practice Application for Patients Receiving Phar-
macotherapy for Hyperlipidemia.
placenta and is secreted in breast
Drugs Similar to Atorvastatin (Lipitor)
milk; 98% bound to plasma
Other statins include fluvastatin, lovastatin, pitavastatin,
proteins pravastatin, rosuvastatin, and simvastatin.
Primary metabolism Hepatic; extensively metabolized Fluvastatin (Lescol): Approved in 1993, fluvastatin is a
synthetic statin that has the shortest half-life of all the
to active metabolites drugs in this class. Because the kidneys excrete less than
5% of a PO dose, dosage adjustment for patients with CKD
Primary excretion Biliary is not necessary. Fewer drug interactions are expected with
fluvastatin because it is not metabolized through the
Onset of action 2 weeks for lipid-lowering effect; hepatic CYP450 system. It is approved for hypercholester-
olemia and several other types of dyslipidemia. In 2003,
peak plasma level: 1–2 h the indications were expanded to include prevention of
major cardiac events such as cardiac death and nonfatal
Duration of action Half-life: 14 h (20–30 h for active MI. An extended release formulation, called Lescol-XL, is
available. The drug may be administered without regard
metabolites) to meals. Fluvastatin is well tolerated and its adverse
effects are similar to those of atorvastatin. It is contraindi-
Adverse Effects: Most patients tolerate atorvastatin cated in patients with severe hepatic impairment and in
well and only 2% or fewer discontinue the drug due to patients who are pregnant. Fluvastatin is a pregnancy
adverse effects. Common adverse effects include head- category X drug.
ache, intestinal cramping, diarrhea, and constipation. The
most serious adverse effect is rhabdomyolysis. Therapy is Lovastatin (Altoprev, Mevacor): Approved in 1987, lovas-
generally discontinued in patients reporting unexplained tatin, a natural substance derived from fungi, was the
muscle pain, weakness, fever, or fatigue due to the poten- first HMG-CoA reductase inhibitor marketed. Lovastatin
tial for rhabdomyolysis. is a prodrug with no intrinsic activity of its own, but the
liver converts it to several active metabolites. This drug
Contraindications/Precautions: Patients with he- may achieve a 20% to 40% reduction in LDL cholesterol.
patic impairment should be monitored carefully, because Lovastatin is more effective if administered in the evening
the liver extensively metabolizes atorvastatin and the and should be taken on an empty stomach to maximize
drug has been associated with a small risk of liver failure. absorption. Although only 10% of this drug is excreted by
Liver enzyme tests may become elevated during therapy, the kidneys, dosage adjustment for patients with CKD is
although this does not necessarily indicate liver damage. recommended. Lovastatin was originally approved for
Because atorvastatin is pregnancy category X, pregnancy hypercholesterolemia; however, its indications have
testing should be conducted prior to treatment in women been expanded to include slowing the progression of
of childbearing years, and these patients should be advised CVD and prevention of MI and stroke. An extended
to take precautions to prevent pregnancy during therapy.
Atorvastatin is contraindicated during lactation because
the drug is secreted in breast milk.
Drug Interactions: Because atorvastatin is a substrate
for hepatic CYP3A4, it has the potential to interact with
many other drugs. For example, it may increase digoxin
levels by 20% as well as increase levels of norethindrone
and ethinyl estradiol (oral contraceptives). Erythromycin
may increase atorvastatin levels by as much as 40%. Risk
of rhabdomyolysis increases with concurrent administra-
tion of atorvastatin with macrolide antibiotics, cyclospo-
rine, and azole antifungals. The risk of myopathy increases
Chapter 29 Pharmacotherapy of Hyperlipidemia 499
release form is available (Altoprev). Adverse effects are the simvastatin is an inactive prodrug that is changed to active
same as those of other drugs in this class. It is contraindi- metabolites by the liver. The drug can lower LDL choles-
cated in patients with severe hepatic impairment and in terol levels by as much as 47%. Although the kidneys
patients who are pregnant. Lovastatin is a pregnancy cate- excrete only 13% of the drug, dosage adjustment for
gory X drug. patients with significant CKD is recommended. The drug
may be taken with or without food but should be adminis-
Pitavastatin (Livalo): Approved in 2009, pitavastatin is tered in the evening for maximum effectiveness. It is
one of the newest drugs in the statin class. It is indicated approved for hypercholesterolemia, hypertriglyceridemia,
for patients with primary hyperlipidemia and mixed dys- slowing the progression of coronary atherosclerosis, and
lipidemia as an adjunctive therapy to diet to reduce ele- prevention of MI and stroke. Adverse effects are the same
vated total cholesterol, LDL, apolipoprotein B, and as those of other drugs in this class. Simvastatin is contra-
triglycerides, and to increase HDL. It may be administered indicated in patients with hepatic impairment and in those
with or without food and without regard to the time of who are pregnant. This is a pregnancy category X drug.
day. It has similar effectiveness and adverse effects as other
statins. Because it is only minimally metabolized by CONNECTION Checkpoint 29.1
CYP450 enzymes, it may exhibit fewer drug–drug interac-
tions than some of the other statins. However, like other Several of the statins are prodrugs. From what you learned in Chap-
drugs in this class, hepatic enzymes should be evaluated ter 4, what type of dosage adjustment should be made if these
regularly and there is a small risk of myopathy. This drug statin prodrugs are prescribed for a patient with hepatic cirrhosis?
is pregnancy category X and patients should be advised If a dosage adjustment is not made, what types of adverse effects
not to breastfeed during pitavastatin therapy. might you observe? Answers to Connection Checkpoint questions
are available on the faculty resources site. Please consult with your
Pravastatin (Pravachol): Like lovastatin, pravastatin is a instructor.
natural substance derived from fungi. Twenty percent of
the drug is excreted by the kidneys, and dosage adjust- PharmFACT
ment for patients with CKD is recommended. Like fluv-
astatin, it is not metabolized through the hepatic CYP450 The American Academy of Pediatrics recommends that all
system; thus fewer drug interactions are expected. The children undergo cholesterol screening once between the
drug may be taken without regard to meals and is slightly ages of 9 and 11 years and again from ages 17 to 21 years.
more effective if administered in the evening. Approved The Centers for Disease Control and Prevention compiled
in 1991, pravastatin is approved for primary hypercholes- and reviewed the results from the National Health and
terolemia, slowing the progression of coronary athero- Nutrition Examination Survey for 1999–2006 and found that
sclerosis and the prevention of MI and stroke. Unlabeled the prevalence of abnormal lipid levels among children ages
uses include other types of dyslipidemias. Pravigard PAC 12 to 19 years was 20.3%. This percent varied by body mass
is a copackage that contains separate aspirin and pravas- index with 14.2% of normal weight children, 22.3% of
tatin tablets in various dosage strengths. Adverse effects overweight children, and 42.9% of children with obesity
are the same as those of other drugs in this class. It is having had at least one abnormal lipid laboratory level
contraindicated in patients with hepatic impairment and (Schuman, 2013).
in those who are pregnant. Pravastatin is a pregnancy
category X drug. 29.6 Bile acid sequestrants may be combined
with statins to reduce LDL cholesterol levels.
Rosuvastatin (Crestor): Approved in 2003, rosuvastatin is
a second-generation statin that contains a sulfur group. Bile acids contain a high concentration of cholesterol and
This drug is the most potent, has the longest half-life in its are secreted by the liver to emulsify fats in the small intes-
class (20 hours), and is capable of lowering LDL choles- tine. After performing their digestive function, bile acids
terol by as much as 65%. Rosuvastatin is not a prodrug and are reabsorbed in the ileum and sent back to the liver to
it undergoes minimal hepatic metabolism. This drug may again become part of bile. This mechanism is known as
be administered with or without food and without regard enterohepatic circulation. In effect, the cholesterol in bile
to time of day. It is approved for hypercholesterolemia, acids is recycled, with only small amounts leaving the
hypertriglyceridemia, and for slowing the progression of body in the feces.
coronary atherosclerosis. Adverse effects are the same as
those of other drugs in this class. Rosuvastatin is a preg- Prior to the discovery of the statins, the primary means
nancy category X drug. of lowering blood cholesterol was through the use of bile
acid sequestrants or resins. The bile acid sequestrants bind
Simvastatin (Zocor): Approved in 1991, simvastatin is a to bile acids, forming a large complex that cannot be reab-
natural substance derived from fungi. Like lovastatin, sorbed from the small intestine. The enterohepatic circula-
tion of cholesterol is interrupted and the bound bile acids
500 Unit 5 Pharmacology of the Cardiovascular System
and cholesterol are eliminated in the feces. The liver PROTOTYPE DRUG Cholestyramine (Questran)
responds to the loss of cholesterol by making more LDL
receptors, which removes LDL cholesterol from the blood Classification Therapeutic: Antihyperlipidemic
in a mechanism similar to that of the statins. Pharmacologic: Bile acid sequestrant
The bile acid resins are capable of producing a 20% Therapeutic Effects and Uses: Approved in 1966,
drop in LDL cholesterol, which is generally less response cholestyramine is indicated for the reduction of elevated
than can be obtained from the statins. They are no longer serum cholesterol in patients with primary hypercholester-
considered first-line drugs for dyslipidemia, although they olemia (elevated LDL) who do not respond adequately to
are sometimes combined with statins for patients who have dietary modifications alone. Cholestyramine monotherapy
contraindications or intolerance to statins. slows the progression and increases the rate of regression
of coronary atherosclerosis. A secondary indication is to
The bile acid sequestrants tend to cause more frequent relieve pruritus associated with partial biliary obstruction.
adverse effects than statins. Because they are not absorbed It is available as a powder that is mixed with fluid before
into the systemic circulation, adverse effects are limited to being taken once or twice daily. The drug should be mixed
the GI tract, causing symptoms such as abdominal pain, with 60 to 180 mL of water, noncarbonated beverages,
bloating, diarrhea, steatorrhea, and constipation. In addi- highly liquid soups, or pulpy fruits (applesauce, crushed
tion to binding bile acids, these agents can bind drugs such pineapple) to prevent esophageal irritation. The patient
as digoxin and warfarin and increase the potential for should swallow the medication immediately after stirring.
drug–drug interactions. Bile acid sequestrants also inter- If taken with too small a fluid volume or if not completely
fere with the absorption of vitamins and minerals, and swallowed, the drug can swell in the throat or esophagus
nutritional deficiencies may occur with extended use. to cause an obstruction.
Other medications and vitamins should be taken at least
1 hour before or 4 hours after taking a bile acid sequestrant It may take 30 days or longer for cholestyramine to
to avoid drug interactions. produce its maximum effect. To avoid interference with
absorption, cholestyramine should not be taken at the same
Bile acid sequestrants may cause a transient increase in time as vitamins or other medications. An off-label indica-
triglyceride levels. This effect is particularly prominent and tion for cholestyramine is diarrhea caused by Clostridium
often sustained in patients with preexisting hypertriglyc- difficile, although antibiotics are the drugs of first choice.
eridemia. Because of this, the bile acid sequestrants are
generally not prescribed for patients with elevated triglyc- Mechanism of Action: Cholestyramine binds to
erides. Doses for the bile acid sequestrants are listed in bile acids, forming an insoluble complex containing
Table 29.3.
CONNECTIONS: Complementary and Alternative Therapies
Coenzyme Q10
Description Evidence
Coenzyme Q10 (CoQ10) is a lipid-soluble vitamin-like substance As with most dietary supplements, controlled research studies
found in most animal cells. It is an essential component in the with CoQ10 are often lacking and give conflicting results. Sup-
cell’s mitochondria for producing adenosine triphosphate (ATP) plementation with CoQ10 may be important to patients taking
energy. Because the heart requires high levels of ATP, a suffi- the HMG-CoA reductase inhibitors (statins) because these drugs
cient level of CoQ10 is especially important to that organ. significantly lower blood levels of CoQ10. Coenzyme Q10 and
cholesterol share the same metabolic pathways. Inhibition of the
History and Claims enzyme HMG-CoA reductase by statins decreases CoQ10 lev-
els. Many of the adverse effects of statins, including muscle
The applications of CoQ10 to treating disease are relatively weakness and rhabdomyolysis, may be due to the decrease in
recent, with the agent being claimed to be an antioxidant and CoQ10 levels; supplementation with CoQ10 may improve myop-
having benefited patients with heart failure in the mid-1960s. athy symptoms.
Subsequent reports have claimed that CoQ10 may be beneficial
in angina pectoris, dysrhythmias, periodontal disease, immune Foods richest in this substance are pork, sardines,
disorders, neurologic disease, obesity, diabetes mellitus, and beef heart, salmon, broccoli, spinach, and nuts. Older
cancers. adults appear to have an increased need for CoQ10.
Although CoQ10 can be synthesized by the body, many
Standardization amino acids and other substances are required for this
synthesis; thus patients with nutritional deficiencies may need
The dose of CoQ10 varies widely. Typical doses range from 100 supplementation.
to 200 mg/day.
Chapter 29 Pharmacotherapy of Hyperlipidemia 501
cholesterol that is excreted in the feces. Cholestyramine Pregnancy: Category B.
lowers LDL cholesterol levels by increasing LDL receptors
on hepatocytes. Treatment of Overdose: No specific therapy is avail-
able; patients are treated symptomatically.
Pharmacokinetics:
Nursing Responsibilities: Key nursing implications
Route(s) PO for patients receiving cholestyramine are included in the
Nursing Practice Application for Patients Receiving Phar-
Absorption Not absorbed macotherapy for Hyperlipidemia.
Distribution Not distributed; acts locally in Drugs Similar to Cholestyramine (Questran)
the alimentary canal Other bile acid sequestrants include colesevelam and
colestipol.
Primary metabolism Not metabolized
Colesevelam (Welchol): Approved in 2000, colesevelam
Primary excretion Feces is a bile acid-binding drug that is claimed to have more
bile acid-binding capacity than the older resins. The
Onset of action 1–2 days drug has the capacity to reduce LDL cholesterol by as
much as 20%. It may be administered as monotherapy
Duration of action 2–4 weeks or concurrently with statins to achieve greater efficacy.
At least 2 weeks of therapy may be necessary before
Adverse Effects: Cholestyramine is not absorbed or maximum therapeutic response is achieved. In 2008,
metabolized once it enters the intestine; thus it does not colesevelam was approved as an adjunct to diet, exer-
produce systemic adverse effects. Common GI-related cise, and antidiabetic drugs to improve glycemic control
adverse effects include constipation, bloating, belching, in patients with type 2 diabetes. It is not approved for
and nausea. Serious adverse effects include obstruc- patients with type 1 diabetes. The most common adverse
tion of the GI tract, hyperchloremic acidosis, and mal- reactions with colesevelam are constipation, dyspepsia,
absorption syndrome. Chronic use may cause increased and nausea. Colesevelam can interfere with the absorp-
bleeding due to hypoprothrombinemia associated with tion of other medications and should be administered
vitamin K deficiency. 4 hours after other PO drugs. Like cholestyramine, cole-
sevelam can increase serum triglyceride levels and is
Contraindications/Precautions: Cholestyramine contraindicated in patients with triglyceride levels
should be used cautiously in patients with GI disorders greater than 500 mg/dL. The large tablets can cause
such as peptic ulcer disease, hemorrhoids, inflammatory dysphagia or esophageal obstruction; thus this drug
bowel diseases, or chronic constipation, because bile should be used with caution in patients with swallow-
acid sequestrants may worsen or aggravate these con- ing disorders. An oral suspension, dissolved in 4 to
ditions. This drug should not be used in patients with 8 ounces of water, is available for patients who have dif-
complete biliary obstruction. Bile acid resins should be ficulty swallowing the tablets. This drug is pregnancy
used with caution in patients with hypertriglyceridemia category B.
because they may increase serum triglyceride concen-
trations. They are absolutely contraindicated if serum Colestipol (Colestid): Approved in 1977, colestipol acts
triglycerides rise above 400 mg/dL. Although chole- by the same mechanism as cholestyramine, has the same
styramine use is safe during pregnancy because it is not effectiveness in lowering LDL cholesterol, and exhibits
absorbed, precautions must be taken to ensure that this the same adverse effects. Other drugs should be admin-
drug is not interfering with vitamin absorption, espe- istered at least 1 hour before or 4 to 6 hours after a dose
cially folic acid. of colestipol to prevent interference with absorption.
Maximum therapeutic effects may take as long as a
Drug Interactions: Cholestyramine can bind to month to appear. Because the drug can increase serum
other drugs and interfere with their absorption, causing triglycerides, it should not be administered to patients
reduced effects. This interaction has been reported for with hypertriglyceridemia. Colestipol is rarely used as
digoxin, penicillins, iron supplements, thyroid hormone, monotherapy. In addition to its use in treating elevated
and thiazide diuretics, although it has the potential to HDL cholesterol, colestipol may be used off-label to
occur with any drug administered PO. Cholestyramine treat digoxin overdose, diarrhea, and pruritus associ-
may indirectly increase the effects of warfarin by bind- ated with biliary obstruction. This drug is pregnancy
ing to vitamin K, decreasing its absorption and lowering category B.
the levels of vitamin K in the body. The absorption of ral-
oxifene can be reduced as much as 60% if coadministered
with cholestyramine. To reduce the possibility of absorp-
tion interference, cholestyramine should be administered
1 hour before or 4 hours after other PO medications.
Herbal/Food: Cholestyramine may block the absorption
of iron and fat-soluble vitamins in food.
502 Unit 5 Pharmacology of the Cardiovascular System
PharmFACT Because supplemental niacin is available without a
prescription, patients should be instructed not to attempt
Familial hypercholesterolemia affects 1 in 200 people and is a self-medication with this drug. One form of niacin that is
genetic disease that predisposes people to premature CVD available OTC as a vitamin supplement, called nicotin-
(Gidding, 2016). amide, has no lipid-lowering effects. If niacin is to be used
to lower cholesterol, it should be done under medical
29.7 Niacin can reduce triglycerides and LDL supervision.
cholesterol levels, but adverse effects limit its
usefulness. 29.8 Fibric acid drugs lower triglyceride levels
but have little effect on LDL cholesterol.
Niacin, also called nicotinic acid, is a B-complex vitamin
(B3). Its ability to lower lipid levels, however, is unrelated Three fibric acid drugs are sometimes used for patients
to its role as a vitamin because much higher doses are with high triglyceride levels: fenofibrate (Lofibra, Tri-
needed to produce its antihyperlipidemic effects. For low- Cor, others), fenofibric acid (Fibricor, Trilipix), and gem-
ering cholesterol, the usual dose is 2 to 3 g/day. When fibrozil (Lopid). They are preferred drugs for treating
taken as a vitamin, the dose is only 25 mg/day. severe hypertriglyceridemia (Types IV and V hyperlip-
idemia), although they have little effect on LDL choles-
The primary action of niacin (Niaspan) is to decrease terol. Fibric acid drugs activate the enzyme lipoprotein
the production of VLDL, which lowers serum triglycer- lipase, which increases the breakdown and elimination
ide levels. Because LDL is synthesized from VLDL, the of triglyceride-rich particles from the plasma. The FDA
patient also experiences a reduction in LDL cholesterol does not recommend combining a fibric acid drug with
levels. Niacin also has the desirable effect of increasing a statin because it has not been shown to have cardio-
HDL levels, although this effect does not appear to be vascular benefits. Doses for the fibric acid drugs are
significant in reducing mortality from cardiovascular listed in Table 29.3.
disease. As with other lipid-lowering drugs, maximum
therapeutic effects may take a month or longer to The most common adverse effects of the fibrates relate
achieve. to the GI system: dyspepsia, diarrhea, abdominal pain,
nausea, and vomiting. Taking these medications with
Although effective at reducing LDL cholesterol by meals usually diminishes GI distress. Drugs in this class are
20%, niacin produces more adverse effects than the statins. generally not used in patients with hepatic impairment or
Intense flushing and hot flashes occur in almost every gallbladder disease.
patient. Taking one aspirin tablet 30 minutes prior to niacin
administration can reduce uncomfortable flushing in many PROTOTYPE DRUG Gemfibrozil (Lopid)
patients. In addition, a variety of uncomfortable GI effects
such as nausea, excess gas, and diarrhea are commonly Classification Therapeutic: Antihyperlipidemic
reported. Paresthesias, such as tingling in the extremities, Pharmacologic: Fibric acid drug (fibrate)
may also occur.
Therapeutic Effects and Uses: Approved in 1981,
More serious adverse effects such as hepatotoxicity gemfibrozil lowers serum triglycerides and LDL cho-
and gout are possible but uncommon. Patients with ele- lesterol. It is most effective in patients who present with
vated liver enzymes or a history of liver disease should use hypertriglyceridemia and VLDL. Effects of gemfibrozil
an alternate drug to lower lipids. In patients predisposed to include up to a 50% reduction in VLDL with an increase
gout, niacin may increase uric acid levels and precipitate in HDL. It is less effective than the statins at lowering
acute gout. LDL; thus it is not used as monotherapy. It is considered
a second-line therapy that is used when statins are ineffec-
Niacin is not usually prescribed for patients with dia- tive or not well tolerated.
betes mellitus because the drug can raise fasting glucose
levels. When beginning therapy, patients with diabetes Mechanism of Action: The exact mechanism of
should monitor their blood glucose levels more frequently action of gemfibrozil is unknown. The drug inhibits the
until the effect of niacin is determined. breakdown of stored fat, or lipolysis, in adipose tissue.
By inhibiting the uptake of free fatty acids by the liver,
Because of the high incidence of adverse effects, niacin hepatic production of triglycerides is decreased. The
is most often used in low doses in combination with a bile drug may also increase the excretion of cholesterol in
acid sequestrant; the beneficial effects of these drugs are the feces.
additive. Niacin was formerly combined with statins; how-
ever, the FDA determined that the combination did not
offer any reduction in cardiovascular mortality over simply
using a statin as monotherapy.
Chapter 29 Pharmacotherapy of Hyperlipidemia 503
Pharmacokinetics: Nursing Practice Application for Patients Receiving Phar-
macotherapy for Hyperlipidemia.
Route(s) PO
Drugs Similar to Gemfibrozil (Lopid)
Absorption Well absorbed
Drugs similar to gemfibrozil include fenofibrate and feno-
Distribution Unknown; distribution across fibric acid.
the placenta or secretion in Fenofibrate (Lofibra, TriCor, Others) and fenofibric acid
(Fibricor, Trilipix): Once absorbed, fenofibrate is quickly
breast milk is unknown; 99% converted to fenofibric acid, its active metabolite. Thus the
actions and adverse effects of the two drugs are the same.
bound to plasma protein Fenofibrate is indicated as supplemental therapy to diet to
reduce elevated LDL, total cholesterol, triglycerides, and apo
Primary metabolism Hepatic; undergoes B and to increase HDL in patients with primary hypercholes-
terolemia, hypertriglyceridemia, and mixed dyslipidemia.
enterohepatic recirculation Approved in 1993, fenofibrate may reduce serum triglycer-
ides by as much as 30%. One advantage of the fenofibrate
Primary excretion Primarily renal, 6% in feces formulations over gemfibrozil is that they may be taken once
daily rather than twice a day. The different formulations of
Onset of action 1–2 h fenofibrate and fenofibric acid vary in strength, bioavailabil-
ity, and whether the drug should be administered with a
Duration of action Half-life: 1.5 h meal. These forms are not interchangeable. One of the forms,
Trilipix, is approved for concurrent therapy with statins. The
Adverse Effects: The most common adverse effects of most frequent adverse effects are GI related, such as nausea,
gemfibrozil are GI related, such as abdominal cramping, vomiting, dyspepsia, constipation, flatulence, and abdomi-
diarrhea, nausea, and dyspepsia. Nervous system effects nal pain. Liver function tests should be performed periodi-
include headache, dizziness, peripheral neuropathy, and cally to monitor for elevated serum transaminases.
diminished libido. Serious adverse effects include choleli- Myopathy and rhabdomyolysis have been reported, and the
thiasis, anemia, and eosinophilia. risks for these adverse effects are increased when coadminis-
tered with a statin. Rash and photosensitivity are other
Contraindications/Precautions: Gemfibrozil may adverse effects. These drugs are pregnancy category C.
worsen or cause biliary disease; thus it is contraindicated
in patients with preexisting gallbladder disease or serious CONNECTION Checkpoint 29.2
liver impairment. Because it is excreted by the kidneys, the
drug should be used cautiously in patients with CKD From what you learned in Chapter 10, what changes in physiology
occur with aging that may require decreased starting dosages for
Drug Interactions: Although antihyperlipidemic antihyperlipidemic drugs? Answers to Connection Checkpoint ques-
drugs from different classes are sometimes combined to tions are available on the faculty resources site. Please consult with
produce an enhanced effect, the use of gemfibrozil with your instructor.
statins increases the risk of myositis and rhabdomyolysis.
CK levels should be regularly monitored during combined Miscellaneous Drugs
therapy and the combination immediately discontinued if for Dyslipidemias
myopathy is suspected. In most cases the risk of rhabdo-
myolysis, which may be fatal, outweighs the potential ben- 29.9 Newer strategies have been developed
efits of combined statin and gemfibrozil therapy. to treat dyslipidemias.
Concurrent use of gemfibrozil with PO anticoagulants The large numbers of people with elevated lipid values
may increase the risk of bleeding because the fibrate dis- has encouraged the pharmaceutical industry to investigate
places warfarin from its plasma protein binding sites. If a new drugs for controlling LDL cholesterol and triglycer-
patient is taking warfarin, dosages should be lowered. ides. The search for new and improved antilipidemics has
More frequent monitoring of prothrombin time (PT) and resulted in several new drugs for this condition.
international normalized ratio (INR) is necessary until sta-
bilization occurs. Ezetimibe (Zetia): Ezetimibe (Zetia) is the only drug in a
class called the cholesterol absorption inhibitors. Choles-
Gemfibrozil may enhance the hypoglycemic effects of terol is absorbed from the intestinal lumen by cells in the
antidiabetic drugs. Serum glucose levels must be carefully
monitored because the dosage of the antidiabetic drug
may require adjustment. Herbal/Food: No significant
interactions.
Pregnancy: Category C.
Treatment of Overdose: No specific therapy is avail-
able; patients are treated symptomatically.
Nursing Responsibilities: Key nursing implica-
tions for patients receiving gemfibrozil are included in the
504 Unit 5 Pharmacology of the Cardiovascular System
jejunum of the small intestine. Ezetimibe blocks this lomitapide (Juxtapid) and mipomersen (Kynamro), act by
absorption by as much as 50%, causing less cholesterol to very different and unique mechanisms. Therapy is very
enter the blood. Unlike the statins, the drug does not costly and will likely limit their widespread use.
inhibit cholesterol biosynthesis in the liver or increase the
excretion of bile acid. Ezetimibe is considered a first-line The primary protein that composes particles of LDL is
drug for patients who cannot tolerate statins. apo B. When assembling the lipoprotein, lipid molecules
are transported and loaded onto the apo B. Upon comple-
When given as monotherapy, ezetimibe produces a tion, the lipoprotein is assembled and leaves the intestine
modest reduction in LDL of about 20%. Adding a statin to or liver as chylomicrons or VLDL, which eventually raises
the therapeutic regimen reduces LDL by an additional 15% blood LDL levels. Lomitapide and mipomersen interfere
to 20%. The drug produces a slight drop in serum triglycer- with different aspects of this genesis of lipoprotein.
ides. Ezetimibe is available as a single tablet with a once-
daily dosing regimen. Vytorin is a fixed-dose combination Lomitapide is classified as a microsomal triglyceride
tablet containing ezetimibe and simvastatin, and Liptruzet transfer protein (MTP) inhibitor. Inhibition of MTP inter-
combines ezetimibe with atorvastatin. feres with the transfer of lipids to apo B, thus lowering
plasma levels of LDL. The drug is given PO and is indi-
Nasopharyngitis, myalgia, upper respiratory tract cated only for HoFH. GI adverse effects such as diarrhea,
infection, arthralgia, and diarrhea are the most common nausea, vomiting, dyspepsia, and abdominal pain occur in
adverse effects of ezetimibe, although these rarely require almost all patients. Drug interactions may be serious with
discontinuation of therapy. Because bile acid sequestrants medications that inhibit hepatic CYP3A4, including keto-
inhibit the absorption of ezetimibe, these drugs should not conazole, clarithromycin, lopinavir/ritonavir, or telithro-
be taken together. In addition, ezetimibe and statins should mycin. These drugs will markedly increase levels of
not be given concurrently to patients with serious hepatic lomitapide. Lomitapide is contraindicated during preg-
impairment or with elevated serum transaminase levels. nancy (category X).
Ezetimibe is pregnancy category C.
Mipomersen is classified as an inhibitor of apo B
Omega-3 fatty acids: Nutritionists have long reported the synthesis. The message for making apo B leaves the DNA
benefits of eating fish rich in omega-3 fatty acids such as as a strip of messenger RNA (mRNA). Mipomersen is a
tuna, salmon, and halibut. The two principal omega-3 fatty huge molecule that has mRNA complementary to apo B
acids are eicosapentaenoic acid (EPA) and docosahexae- (called an antisense message). The antisense message
noic acid (DHA). Vegetarian sources of omega-3 fatty acids binds to the apo B strip of RNA, preventing the synthesis
include flaxseed oil, soybeans, walnuts, and pumpkin of the apo B protein. Mipomersen is given as once-
seeds. weekly subcutaneous injection. The drug is pregnancy
category B.
The role of omega-3 fatty acids in preventing cardio-
vascular disease is well established. When taken as dietary Mipomersen and lomitapide carry identical black box
supplements, the omega-3 fatty acids are usually marketed warnings that the drugs can cause elevations in transami-
as fish oil. Fish oil supplementation has been shown to nases and may increase hepatic fat (hepatic steatosis). The
decrease mortality due to MI and stroke. A typical dose of drugs are contraindicated in patients with active hepatic
omega-3 fatty acids in fish oil capsules is 180 mg of EPA disease, and alanine transaminases (ALT) and aspartate
and 120 mg of DHA. aminotransferase (AST) must be measured prior to and
during therapy. The drugs are only available in restricted
Two prescription formulations of omega-3 fatty acids use programs that require prescribers and pharmacists to
are available: omega-3-acid ethyl esters (Lovaza) and icosa- be certified through special training.
pent (Vascepa). Both drugs are approved as an adjunct to
diet in the treatment of severe hypertriglyceridemia. PCSK9 inhibitors: A new strategy to manage increased
Adverse effects are minor and include belching, fishy taste, cholesterol levels is to inhibit PCSK9 (proprotein conver-
and arthralgia. The drugs should be used with caution in tase subtilisin kexin type 9), a protein that degrades recep-
patients who are allergic to seafood, especially shellfish. tors for LDL-C in the liver. Binding of the drug to PCSK9
increases the number of receptors available to clear LDL-C,
Drugs for familial hypercholesterolemia: Two drugs were thus lowering the level of LDL-C in the blood. Alirocumab
approved in 2013 for a very narrow indication: as an (Praluent) and evolocumab (Repatha), both approved in
adjunct to lowering LDL in patients with homozygous 2015, are monoclonal antibodies given by the subcutane-
familial hypercholesterolemia (HoFH). HoFH is a genetic ous route that inhibit PCSK9. They are indicated for
disorder in which the body has such high levels of choles- patients with heterozygous familial hypercholesterolemia
terol and LDL that cardiovascular disease begins in child- (HeFH) or HoFH who need more lowering of LDL-C than
hood and results in death by the mid-30s. Many of these can be attained with other therapies. The two PCSK9
patients have a diminished response to therapy with inhibitors are much more expensive than statins.
statins and other antihyperlipidemics. The two new drugs,
Chapter 29 Pharmacotherapy of Hyperlipidemia 505
CONNECTIONS: NURSING PRACTICE APPLICATION
Patients Receiving Pharmacotherapy for Hyperlipidemia
Assessment
Baseline assessment prior to administration:
• Obtain a complete health history including cardiovascular, musculoskeletal (preexisting conditions that might result in muscle or joint pain), GI (peptic
ulcer disease, hemorrhoids, inflammatory bowel disease, chronic constipation, gallbladder disease, dysphagia or esophageal strictures), and the pos-
sibility of pregnancy. Obtain a drug history including allergies, current prescription and OTC drugs, herbal preparations, and alcohol use. Be alert to
possible drug interactions.
• Evaluate appropriate laboratory findings, especially liver function studies, lipid profiles, and CK.
• Assess the patient’s ability to receive and understand instructions. Include family and caregivers as needed.
Assessment throughout administration:
• Assess for desired therapeutic effects (e.g., lowered total cholesterol and LDL levels, increased HDL levels).
• Continue periodic monitoring of lipid profiles, liver function studies, CK, and uric acid levels.
• Assess for adverse effects: musculoskeletal discomfort, nausea, vomiting, abdominal cramping, or diarrhea. Immediately report any severe musculo-
skeletal pain, unexplained muscle tenderness accompanied by fever, inability to perform activities of daily living (ADLs) due to musculoskeletal weak-
ness or pain, unexplained numbness or tingling of extremities, yellowing of the sclera or skin, severe constipation, straining with passing of stools, or
tarry stools.
Implementation
Interventions and (Rationales) Patient-Centered Care
Ensuring therapeutic effects: • Teach the patient to take the drug following appropriate guidelines (see
• Follow appropriate administration guidelines. (Many of the lipid-lowering Patient self-administration of drug therapy section below).
drugs have specific administration requirements. For best results, they • Encourage the patient and family to adopt a healthy lifestyle of low-fat
should be taken at night when cholesterol biosynthesis is at its highest.) food choices, increased exercise, decreased alcohol consumption, and
smoking cessation.
• Encourage appropriate lifestyle changes: lowered fat intake, increased
exercise, limited alcohol intake, and smoking cessation. Provide for • Encourage increased intake of foods rich in omega-3 and Coenzyme
dietitian consultation as needed. (Healthy lifestyle changes will support Q10: fish such as salmon and sardines, nuts, extra-virgin olive and
and minimize the need for drug therapy.) canola oils, beef, chicken, and pork. Supplementation may be needed;
instruct the patient to seek the advice of a healthcare provider before
Minimizing adverse effects: taking supplements.
• Continue to monitor periodic liver function tests and CK levels.
• Instruct the patient on the need to return periodically for laboratory
(Abnormal liver function tests or increased CK levels may indicate drug- work.
induced adverse hepatic effects or myopathy and should be reported.
Lifespan: Monitor the older adult frequently because age-related
physiologic changes may affect the drug’s metabolism or excretion.
Diverse Patients: Because statins metabolize through the CYP450
system pathways, monitor ethnically diverse patients to ensure optimal
therapeutic effects and to minimize adverse effects.)
• Continue to assess for drug-related symptoms, which may Teach the patient the importance of reporting signs or symptoms related to
indicate that adverse effects are occurring. (Lipid-lowering drugs adverse drug effects as follows:
often adversely affect the liver but may also cause drug-specific
adverse effects.) • Statins: Report unusual or unexplained muscle tenderness, increas-
ing muscle pain, numbness or tingling of extremities, or effects that
• Assess for the possibility of increased adverse effects when a com- hinder normal ADLs. Lifespan: The drug should not be taken during
bination of lipid-lowering drugs is used. (Lipid-lowering drugs may pregnancy, if pregnancy is suspected, or while breastfeeding.
be combined for better effects, but this increases the risk of adverse
effects.) • Bile acid resins: Report severe nausea, heartburn, constipation, or strain-
ing with passing stools. Any tarry stools or yellowing of the sclera or skin
should also be reported. Lifespan: The older adult may have an increased
risk of bleeding due to drug-related changes with vitamin K synthesis.
• Niacin: Report flank, joint, or stomach pain, or yellowing of the sclera
or skin.
• Fibric acid drugs: Report unusual bleeding or bruising, right upper
quadrant pain, muscle cramping, or changes in the color of the stool.
Patients with diabetes on PO medications may need a change in their
dosage and should monitor their glucose more frequently in early
therapy. Lifespan: Monitor the older adult for dizziness and assist with
ambulation to prevent falls. Diverse Patients: Research has indicated
that Hispanics and Native Americans may have a greater risk for devel-
opment of gallbladder disease than other ethnic groups.
• Instruct patients taking a combination of lipid-lowering drugs to be alert
to symptoms related to adverse effects of both drugs, as above.
• If long-term therapy is used, ensure adequate intake of fat-soluble vita- • Instruct the patient, family, or caregiver about foods high in folic acid
mins (A, D, E, K) and folic acid in the diet or consider supplementation.
(Lipid-lowering drugs may cause depletion or diminished absorption of and fat-soluble vitamins, and about the need to consult with the
these nutrients.)
healthcare provider about the need for vitamin and folic acid supple-
mentation while on long-term therapy. (continued )
506 Unit 5 Pharmacology of the Cardiovascular System
CONNECTIONS: NURSING PRACTICE APPLICATION (continued)
Implementation
Interventions and (Rationales) Patient-Centered Care
Patient understanding of drug therapy: • The patient, family, or caregiver should be able to state the reason for
• Use opportunities during administration of medications and during the drug, appropriate dose and scheduling, what adverse effects to
observe for and when to report them, and the anticipated length of
assessments to discuss the rationale for drug therapy, desired thera- medication therapy.
peutic outcomes, commonly observed adverse effects, parameters
for when to call the healthcare provider, and any necessary monitoring
or precautions. (Using time during nursing care helps to optimize and
reinforce key teaching areas.)
Patient self-administration of drug therapy: • The patient, family, or caregiver is able to discuss appropriate dosing
• When administering the medication, instruct the patient, family, or and administration needs.
caregiver in proper self-administration of the drug, e.g., during the • The patient takes the drug following appropriate guidelines:
evening meal. (Utilizing time during nurse administration of these drugs • Statins: Most are taken with the evening meal; avoid grapefruit and grape-
helps to reinforce teaching.)
fruit juice, which could inhibit the drug’s metabolism, leading to toxic levels.
• Bile acid resins: Take before meals with plenty of fluids, mixing
powders or granules thoroughly with liquid. Take other medications 1 h
before or 4 h after the bile acid resin is taken.
• Niacin: Take with cold water to decrease the sensation of flushing
associated with the drug. Take one adult-strength (325-mg) aspirin 30
min before the niacin dose.
• Fibric acid drugs: Take with a meal.
Understanding Chapter 29
Key Concepts Summary 29.6 Bile acid sequestrants may be combined with
statins to reduce LDL cholesterol levels.
29.1 Lipids are classified as triglycerides, phospholipids,
or sterols. 29.7 Niacin can reduce triglycerides and LDL cholesterol
levels, but adverse effects limit its usefulness.
29.2 Lipoproteins are important predictors of
cardiovascular disease. 29.8 Fibric acid drugs lower triglyceride levels but have
little effect on LDL cholesterol.
29.3 Blood lipid profiles are important diagnostic tools
in guiding the therapy of dyslipidemias. 29.9 Newer strategies have been developed to treat
dyslipidemias.
29.4 Lipid levels can often be controlled through
therapeutic lifestyle changes.
29.5 The statins are the most effective drugs for reducing
blood lipid levels.
CASE STUDY: Making the Patient Connection
Remember the patient checked at her church’s health fair where she was told that it
“Belinda Cummings” at the exceeded the normal value. As directed, she made an appoint-
beginning of the chapter? ment and saw her healthcare provider for a checkup.
Now read the remainder of
the case study. Based on the During the office visit, the nurse collects Belinda’s
information presented within social and health history. Belinda’s vital signs are within
this chapter, respond to the normal limits, except her blood pressure is elevated
critical thinking questions (142/90 mmHg). She is also slightly overweight and has
that follow. been on a low-carbohydrate diet for 1 week. Her favorite
foods are potato chips and all dairy products, especially
Belinda Cummings is a 39-year-old African American woman cheese. She admits to smoking less than a pack of cigarettes
who feels fine. However, she recently had her cholesterol level per day and occasionally drinks a glass of wine with din-
ner. Belinda is divorced and has one teenage son.
Chapter 29 Pharmacotherapy of Hyperlipidemia 507
A series of laboratory tests is completed during the Belinda is instructed to return to the office in 1 month for a
visit. Belinda’s physical examination is normal, and there follow-up visit.
are no ECG abnormalities. The blood tests are unremark-
able with the exception of the lipid profile. Critical Thinking Questions
Total Cholesterol Patient Value Normal Range 1. How would you respond to Belinda when she asks
Triglycerides 240 mg/dL Less than 200 you, “Is high cholesterol due to heredity or what I
HDL Cholesterol 199 mg/dL Less than 150 eat?”
LDL Cholesterol 30 mg/dL Greater than 60
Cholesterol-to- 184 Less than 100 2. What health teaching should you provide the patient
HDL Ratio 6.6 Less than 4.5 about ways to reduce high blood lipid levels?
The patient is placed on a standard cholesterol-lower- 3. Create a list of potential adverse effects that this
ing diet and prescribed atorvastatin (Lipitor) 10 mg daily. patient should be taught to watch for related to the
medication.
Answers to Critical Thinking Questions are available on the
faculty resources site. Please consult with your instructor.
Additional Case Study 2. What adverse effects related to Questran should David
watch for?
David Hamilton has been taking cholestyramine (Questran)
for elevated blood lipid levels for 2 years. He presents 3. If David’s triglyceride levels increase or remain
today in your clinic for a routine follow-up visit that will consistently high, what drug group(s) might be
include a lipid profile test. He states that he has been some- prescribed?
what consistent with his cholesterol-lowering diet and
attempting to get “a little more” exercise. You are the nurse Answers to Additional Case Study questions are available on
caring for David. the faculty resources site. Please consult with your instructor.
1. Outline key concepts related to health promotion
activities that you would want to be sure David
understands.
Chapter Review 3. The provider orders colestipol (Colestid) in combina-
tion with atorvastatin (Lipitor) for a patient with ele-
1. The patient taking atorvastatin (Lipitor) reports weak- vated low-density lipoprotein levels. The nurse
ness and fatigue, pain in the shoulders, and aching collaborates with the prescriber about which data
joints. The nurse initially assesses the patient for related to the patient?
which condition?
1. Past history of peptic ulcer disease
1. Rhabdomyolysis 2. Recent myocardial infarction
2. Renal failure 3. Laboratory value for serum sodium of 136 mEq/L
3. Rheumatoid arthritis 4. Allergies to foods high in tyramine
4. Hepatic insufficiency
4. Which assessment findings discovered by the nurse
2. A patient is receiving cholestyramine (Questran) for would be an expected adverse effect associated with
elevated low-density lipoprotein levels. Which niacin therapy? (Select all that apply.)
adverse effect should the nurse include in the care
plan to monitor the patient? 1. Fever and chills
2. Intense flushing and hot flashes
1. Orange-colored urine 3. Tingling of the fingers and toes
2. Abdominal pain 4. Dry mucous membranes
3. Sore throat and fever 5. Hypoglycemia
4. Decreased capillary refill
508 Unit 5 Pharmacology of the Cardiovascular System 6. The nurse is caring for a patient receiving gemfibrozil
(Lopid) for hyperlipidemia. The nurse would validate
5. The community health nurse visits a patient who has the order with the prescriber if the patient reported a
been prescribed lovastatin (Mevacor). Which state- history of which of the following? (Select all that
ment, if made by the patient, indicates that further apply.)
teaching is necessary concerning this drug therapy?
1. Gallbladder disease
1. “I should try to maintain my body weight at an 2. Angina
optimal level.” 3. Hypertension
4. Diabetes
2. “Most patients with lipid disorders don’t have any 5. Chronic kidney disease
symptoms.”
See Answers to Chapter Review in Appendix A.
3. “The best time for me to take this medication is
before I go to bed.”
4. “I will take my drug with beverages that contain
grapefruit juice.”
References Greenland, P., & Lauer, M. S. (2015). Cholesterol lowering
in 2015: Still answering questions about how and in
Centers for Disease Control and Prevention. (2015). High whom. JAMA, 314(2), 127–128. doi:10.1001/
cholesterol facts. Retrieved from http://www.cdc.gov/ jama.2015.7434
cholesterol/facts.htm
Mose, J. (2016). Familial hypercholesterolemia. Retrieved
Expert Panel on Detection, Evaluation, and Treatment of from http://emedicine.medscape.com/
High Blood Cholesterol in Adults. (2001). Executive article/121298-overview
summary of the third report of the National Cholesterol
Education Program (NCEP) Expert Panel on Detection, Psaty, B. M., & Weiss, N. S. (2014). 2013 ACC/AHA
Evaluation, and Treatment of High Blood Cholesterol guideline on the treatment of blood cholesterol: A fresh
in Adults (Adult Treatment Panel III). JAMA, 285, interpretation of old evidence. JAMA, 311, 461–462.
2486–2497. doi:10.1001/jama.285.19.2486 doi:10.1001/jama.2013.284203
Expert Panel on Integrated Guidelines for Cardiovascular Schuman, A. J. (2013). Making a difference: Point-of-care
Health and Risk Reduction in Children and screening for hyperlipidemia. Contemporary Pediatrics,
Adolescents; National Heart, Lung, and Blood Institute. 30(4), 38.
(2011). Expert Panel on Integrated Guidelines for
Cardiovascular Health and Risk Reduction in Children U.S. Preventive Services Task Force. (2016). Statin use for
and Adolescents: Summary report. Pediatrics, the primary prevention of cardiovascular disease in
128(Suppl. 5), S213–256. doi:10.1542/peds.2009-2107C adults: US Preventive Services Task Force
recommendation statement. JAMA, 316(19), 1997–2007.
Gidding, S. S. (2016). Familial hypercholesterolemia: Now doi:10.1001/jama.2016.15450
part of cardiovascular disease genetic epidemiology
research. Journal of the American College of Cardiology, 67,
2590–2592. doi:10.1016/j.jacc.2016.03.567
Selected Bibliography Gulum, A. H., & Hume, A. L. (2015). Statins: An update on
clinical issues and selected adverse effects. The Journal
American Heart Association. (2013). Statistical fact sheet: for Nurse Practitioners, 11(3), 287–294. doi:10.1016/j.
Youth & cardiovascular diseases—statistics. Retrieved nurpra.2014.09.004
from https://www.heart.org/idc/groups/heart-
public/@wcm/@sop/@smd/documents/ Pang, J., Chan, D. C., & Watts, G. F. (2014). Critical review
downloadable/ucm_319577.pdf of non-statin treatments for dyslipoproteinemia. Expert
Review of Cardiovascular Therapy, 12, 359–371. doi:10.158
Besseling, J., Kindt, I., Hof, M., Kastelein, J. J., Hutten, B. 6/14779072.2014.888312
A., & Hovingh, G. K. (2014). Severe heterozygous
familial hypercholesterolemia and risk for Patel, B. (2014). Pharmacology of statins: A brief overview.
cardiovascular disease: A study of a cohort of 14,000 Nurse Prescribing, 12, 451. doi:10.12968/
mutation carriers. Atherosclerosis, 233, 219–223. npre.2014.12.9.451
doi:10.1016/j.atherosclerosis.2013.12.020
Chapter 29 Pharmacotherapy of Hyperlipidemia 509
Ross, J. L. (2016). Statins in the management of pediatric Smith, R. J., & Hiatt, W. R. (2013). Two new drugs for
dyslipidemia. Journal of Pediatric Nursing, 31(6), homozygous familial hypercholesterolemia: Managing
723–735. doi:10.1016/j.pedn.2016.07.004 benefits and risks in a rare disorder. JAMA Internal
Medicine, 173, 1491–1492. doi:10.1001/
Rubenfire, M., & Lloyd-Jones, D. M. (2016). Expert jamainternmed.2013.6624
consensus on role of non-statin therapies for LDL-C lowering
for management of ASCVD risk. Retrieved from http:// Taylor, F., Huffman, M. D., Macedo, A. F., Moore, T. H.,
www.acc.org/latest-in-cardiology/ten-points-to- Burke, M., Davey Smith, G., … Ebrahim, S. (2013).
remember/2016/03/30/11/58/2016-acc-expert- Statins for the primary prevention of cardiovascular
consensus-decision-pathway-on-the-role-of-nonstatin disease. Cochrane Database of Systematic Reviews, 1, Art.
No. CD004816. doi:10.1002/14651858.CD004816.pub5
Sercombe, L., Veerati, T., Moheimani, F., Wu, S. Y., Sood,
A. K., & Hua, S. (2015). Advances and challenges of
liposome assisted drug delivery. Frontiers in
Pharmacology, 6, 286. doi:10.3389/fphar.2015.00286
“My friends all take diuretics for their
hypertension, but my provider is giving
me something called a ‘calcium channel
blocker.’ Would someone please tell me
what calcium has to do with high blood
pressure?”
Patient “Angela Rivera”
Chapter 30
Pharmacotherapy with Calcium
Channel Blockers
Chapter Outline Learning Outcomes
cc Physiologic Role of Calcium Channels in Muscle After reading this chapter, the student should be able to:
Contraction
1. Describe the role of calcium ions in the contraction
cc Types of Calcium Channels of smooth and cardiac muscle.
cc Consequences of Calcium Channel Blockade
cc Classification of Calcium Channel Blockers 2. Explain why the actions of the beta1-adrenergic
antagonists are similar to those of the calcium
Dihydropyridines channel blockers.
PROTOTYPE Nifedipine (Adalat CC,
Procardia XL), p. 515 3. Describe how calcium channel blockers interact with
Nondihydropyridines the L-type calcium channel.
PROTOTYPE Verapamil (Calan, Isoptin,
Verelan), p. 517 4. Identify the physiologic effects of calcium channel
blockers on arterial smooth muscle and cardiac
muscle.
5. Explain the classification of calcium channel blockers.
6. Compare and contrast the actions of
dihydropyridine versus nondihydropyridine
calcium channel blockers.
7. For each of the classes shown in the chapter outline,
identify the prototype and representative drugs and
explain the mechanism(s) of drug action, primary
indications, contraindications, significant drug
interactions, pregnancy category, and important
adverse effects.
8. Apply the nursing process to care for patients
receiving pharmacotherapy with calcium channel
blockers.
510
Chapter 30 Pharmacotherapy with Calcium Channel Blockers 511
Key Terms negative chronotropic effect, 513 sarcolemma, 511
negative inotropic effect, 513 sarcoplasmic reticula, 511
calcium channel, 511
dihydropyridines, 514
Since the approval of the first calcium channel blocker Recall from Chapter 15 that activation of beta1-adrenergic
(CCB) 30 years ago, this class of drugs has become one of receptors in cardiac muscle increases heart rate and con-
the most widely prescribed in cardiovascular medicine. tractility. This is because, in myocardial cells, the signal for
One reason for their widespread use is that these drugs opening calcium channels is linked to activation of the
treat two chronic diseases that affect millions of people:
hypertension (HTN) and coronary artery disease (CAD). Action potential
Their success is also related to their effectiveness and a
favorable safety profile. Ca2+ Ca2+
Closed Ca2+ channel
CCBs are also known as calcium channel antagonists. (a)
These drugs do not physically block calcium channels; Sarcolemma
therefore, antagonist is a more accurate term than blocker.
Because both terms are used interchangeably in clinical Open Ca2+ channels
practice, they are used as synonyms throughout this text.
Physiologic Role of Calcium Ca2+ Sarcoplasmic
Channels in Muscle Contraction reticulum
30.1 Calcium channels facilitate contraction Relaxed Actin and
in cardiac and smooth muscles. myosin
Ca2+ filaments
Recall from muscle physiology that the signal for contraction (b)
is an action potential traveling across the muscle plasma Ca2+
membrane, or sarcolemma. The action potential causes a Ca2+
depolarization that opens voltage-gated channels in the sar-
colemma, allowing ions to enter and leave the muscle cell. In Contracted
skeletal muscle, as in nervous tissue, the primary ion chan-
nels facilitate Na+ and K+ movement. In cardiac and smooth Figure 30.1 Calcium channels and muscle contraction:
muscle, a third type of voltage-gated channel, the calcium (a) Calcium channels open as the action potential travels along the
channel, is of particular importance to cardiovascular physi- sarcolemma. (b) Large amounts of calcium are released from storage
ology and pharmacotherapy. Contraction of these muscle in the sarcoplasmic reticula, causing actin and myosin filaments to
types requires the movement of calcium ions (Ca2+). slide and muscle contraction to occur.
Under resting conditions, the concentration of free
Ca2+ in the cytoplasm of a muscle cell is very low. Depolar-
ization of the sarcolemma, however, changes the amount of
free Ca2+ in two ways. First, calcium channels in the sarco-
lemma open, allowing extracellular calcium to rush into
the cell. Secondly, depolarization releases large amounts of
calcium ions stored in cellular structures called sarcoplas-
mic reticula. This huge increase in cytoplasmic Ca2+
removes the inhibition of actin and myosin filaments by the
proteins calmodulin (smooth muscle) or troponin C (car-
diac muscle) through a cascade of complex reactions. Actin
and myosin are then free to slide, and muscle contraction
occurs. This process is illustrated in Figure 30.1.
Muscle contraction is terminated when the amount of
free cytoplasmic Ca2+ is reduced, by either pumping to the
outside of the cell or by returning the Ca2+ to storage in the
sarcoplasmic reticulum.
512 Unit 5 Pharmacology of the Cardiovascular System
sympathetic nervous system. In effect, calcium channels ions travel. An intracellular portion serves as a second mes-
open when the sympathetic nervous system supplies the senger capable of initiating a cascade of events that signal
action potential, depolarizing the sarcolemma. This has the cell to perform specific functions.
important implications to pharmacology. Blocking cardiac
beta1 receptors with adrenergic antagonists will prevent The L-type calcium channel is regulated by voltage
the opening of calcium channels. Thus the cardiac effects changes across the sarcolemma. When an action potential
of beta1-adrenergic blockers, and their pharmacothera- depolarizes the membrane, the channel opens, allowing
peutic indications and adverse effects, are similar to those Ca2+ to rush in. The L-type channels are relatively slow,
of CCBs. which allows for a sustained flow of Ca2+ into the cell.
When a CCB medication is present, the channel changes
CONNECTION Checkpoint 30.1 shape. Although the drug does not physically block the
opening, the change in shape of the channel is enough to
From what you learned in Chapters 15 and 16, what type of drug– prevent Ca2+ from entering the muscle cell. The L-type cal-
drug interaction would you expect between a CCB and (a) a cium channel is illustrated in Figure 30.2.
beta-adrenergic antagonist such as propranolol (Inderal) and (b) a
sympathomimetic such as epinephrine? Answers to Connection L-type calcium channels are widespread in the cardio-
Checkpoint questions are available on the faculty resources site. Please vascular system, and these channels bind all current CCBs.
consult with your instructor. L-type calcium channels are also present in other tissues,
particularly in neurons and endocrine and sensory cells.
Types of Calcium Channels This leads to other potential uses of these drugs, a topic
discussed later in this chapter.
30.2 The calcium channel consists of multiple
subunits and is present in many tissues. T-type calcium channels are present in vascular smooth
muscle as well as the sinoatrial (SA) node where they are
Research has discovered different types of calcium ion involved in pacemaker functions of the heart. Like the
channels, which are named by the letters L, T, and N. L-type channels, they are also located in other tissues,
D ifferences in the structures and locations of the channels including the central nervous system (CNS). At this time,
are important to drug action. the only medication that acts by blocking T-type channels
is ethosuximide (Zarontin), which is used to treat absence
Pharmacologically, the most important calcium chan- seizures. Other potential indications for T-type CCBs
nels are the L type, because they are the ones that bind include pain, obesity, insomnia, and anxiety.
CCBs. L-type calcium channels are found on the sarco-
lemma of cardiac and smooth muscles. The channel spans N-type calcium channels are found throughout the
across the membrane and consists of three main parts. An nervous system. Their primary role appears to be to control
extracellular portion serves as a receptor to bind CCBs. A neurotransmitter release at synapses. They also are
central portion serves as a pore through which calcium involved in the transmission of pain impulses in the spinal
cord. At this time ziconotide is the only approved N-type
CCB. When delivered intrathecally, ziconotide blocks
(a) (b)
Drug Drug
receptor
Ca2+ channel open Ca2+ channel closed
Muscle contraction Muscle relaxation
= Calcium ion
Figure 30.2 L-type calcium channel: (a) Calcium channel opens when an
action potential passes across the sarcolemma. Calcium enters the cell and
muscle contraction occurs. (b) Calcium channel antagonist binds to the receptor,
changing its shape; channel closes and muscle relaxation occurs.
Chapter 30 Pharmacotherapy with Calcium Channel Blockers 513
CONNECTIONS: Community- is beneficial for patients with myocardial ischemia. Veins
Oriented Practice and cardiac preload are not affected by drugs in this class.
Calcium Channel Blockers and Effects Effects on the myocardium: Most CCBs reduce the
on Minerals force of myocardial contraction. This negative inotropic
effect occurs because these drugs reduce the inward move-
Patients may be concerned about taking calcium supplements ment of Ca2+ during the plateau phase of the action poten-
for osteoporosis prevention while taking CCBs. Calcium and tial. This delayed entry of Ca2+ prevents the release of Ca2+
magnesium supplements may actually help maintain a normal from its storage depots in the sarcoplasmic reticulum,
blood pressure or a lower high blood pressure, and as long as resulting in fewer actin–myosin cross bridges and a dimin-
normal doses are taken, do not appear to affect the antihyper- ished force of contraction.
tensive effects of CCBs. More recent research suggests that
CCBs may affect the body’s mineral content (Suliburska, For verapamil and diltiazem, the negative inotropic
Bogdanski, Szulinska, & Pupek-Musialik, 2014). CCBs, along effect is clearly apparent at therapeutic doses. The remain-
with other antihypertensive drugs such as beta blockers and der of the CCBs will only exhibit this effect at higher doses
angiotensin-converting enzyme (ACE) inhibitors, were found to or in overdose situations.
decrease serum zinc levels. Because depletion of some min-
erals such as zinc may have long-term effects on glucose and Effects on cardiac conduction: In general, CCBs exhibit
lipid metabolism, adequate mineral intake through diet or sup- a negative chronotropic effect: the property of slowing the
plementation should be considered when a patient is taking speed of electrical conduction across the myocardium.
CCBs or other antihypertensives. Under normal conditions, the SA node automatically gen-
erates an action potential because of an inward movement
N-type channels in the spinal cord to ease severe, chronic of Ca2+ through calcium channels. Blocking calcium entry
pain. Although the drug has limited applications, in the causes the SA node to generate fewer action potentials,
future other medications may be developed that target the thus decreasing automaticity and slowing heart rate. Simi-
neuronal N-type calcium channels to achieve pain relief. larly, some of the CCBs block calcium channels in the atrio-
ventricular (AV) node, reducing conduction velocity
Consequences of Calcium through this region of the heart and further slowing the
Channel Blockade spread of the action potential across the myocardium.
Because of these actions on the cardiac conduction system,
30.3 Blocking calcium channels has significant the CCBs are sometimes used to correct certain rhythm
physiologic effects on the heart and vascular abnormalities of the heart (see Chapter 37).
smooth muscle.
Not all CCBs affect cardiac conduction to the same
The therapeutic applications of CCBs are the result of degree. Verapamil and diltiazem exhibit this effect at thera-
actions of the drugs on vascular smooth muscle, cardiac peutic doses, whereas the remainder of the CCBs exhibit a
muscle, and the conduction system in the heart. Some negative chronotropic effect only at high doses, or not at all.
CCBs have greater actions on the heart, whereas others
have more effect on arteriolar smooth muscle. None of the CONNECTION Checkpoint 30.2
CCBs affects serum calcium levels.
From what you learned in Chapter 28, define afterload. If a drug
Effects on vascular smooth muscle: The influx of cal- increases afterload, what effect would this likely have on cardiac
cium ions into smooth muscle cells is essential for contrac- output? Answers to Connection Checkpoint questions are available on
tion. Because the degree of contraction of arterioles the faculty resources site. Please consult with your instructor.
controls peripheral resistance, the blockade of calcium
channels has significant physiologic effects on blood pres- Classification of Calcium
sure. All CCBs dilate peripheral arterioles, causing sys- Channel Blockers
temic blood pressure to decrease. Afterload is reduced,
resulting in lower myocardial oxygen demand and less 30.4 Calcium channel blockers are classified by
workload for the heart. This is particularly important for their chemical structures as dihydropyridines or
patients with angina, who will experience less chest pain nondihydropyridines.
due to the decrease in cardiac workload (see Chapter 35).
Despite the fact that all CCBs affect L-type calcium chan-
Another important group of vessels affected by CCBs nels, there are differences in actions and adverse effects
are the coronary arteries. Dilation of the coronary arteries among the specific drugs. This is because the drugs inter-
by the CCBs brings more blood to the myocardium, which act with different subunits of the calcium channel. This
gives rise to a classification of calcium channel antagonists
based on their chemical structures.
514 Unit 5 Pharmacology of the Cardiovascular System
The dihydropyridines are the largest class of CCBs. 30.5 The dihydropyridines are selective for
They include amlodipine (Norvasc), clevidipine (Cleviprex), vascular smooth muscle and are used to treat
felodipine (Plendil), isradipine, nicardipine (Cardene), nife- hypertension and angina pectoris.
dipine (Adalat CC, Procardia XL), nimodipine, and nisoldip-
ine (Nisocor). The dihydropyridines bind reversibly to All dihydropyridines have similar actions and adverse
closed-type (inactivated) calcium channels, changing the effects. All except clevidipine are well absorbed after oral
channels’ structure and making them unresponsive to depo- (PO) administration, and most are highly protein bound,
larization. Because closed-type channels are found in greater excreted by the liver, and undergo extensive first-pass
numbers in vascular smooth muscle than in cardiac muscle, metabolism. Because of this, dosage adjustments are nec-
dihydropyridines are primarily used for their vasodilation essary in patients with significant hepatic impairment.
effect on arterial smooth muscle.
Drugs in this class are highly selective for calcium
The remaining CCBs are chemically dissimilar to the channels located in vascular smooth muscle. At high doses,
dihydropyridines and bind to different subunits of the however, the dihydropyridines lose their selectivity and
L-type calcium channel. Although they are chemically dif- also affect calcium channels in the heart. All dihydropyri-
ferent from each other, diltiazem (Cardizem, Dilacor, Taztia dines are equivalent in effectiveness for treating HTN and
XT, Tiazac, others) and verapamil (Calan, Isoptin, Verelan) angina. Some are available in extended release formula-
have quite similar pharmacologic properties and may be tions that allow for once-daily dosing. Doses for the dihy-
grouped together as nondihydropyridines. These drugs dropyridines are listed in Table 30.2.
bind to open-type calcium channels, causing them to revert
to their inactivated or closed state. These drugs also delay The dihydropyridines are well tolerated in most patients.
reactivation of the calcium channel, thus slowing Common adverse effects include flushed skin, headache, diz-
repolarization of the muscle cell membrane. This effect is ziness, hypotension, peripheral edema, lightheadedness,
particularly noticeable in cardiac muscle, where the nondi- nausea, and diarrhea, although these are usually not severe
hydropyridines slow the speed of myocardial conduction. enough to discontinue therapy. The vasodilation caused by
Like the dihydropyridines, the nondihydropyridines have the blockade of calcium channels in vascular smooth muscle
a vasodilation effect on vascular smooth muscle. Indica- may cause reflex tachycardia. This is generally transient and
tions for the various CCBs that have been approved by the clinically important only in patients with preexisting myo-
U.S. Food and Drug Administration (FDA) are shown in cardial ischemia or dysrhythmias. If a CCB must be used for
Table 30.1. these patients, extended release formulations are selected
because they produce a more gradual change in blood pres-
sure with less reflex tachycardia.
Table 30.1 FDA-Approved Indications for Calcium Channel Blockers
Chronic Stable Vasospastic Unstable Subarachnoid
Angina Dysrhythmias Hemorrhage
Drug Hypertension Angina Angina
X X
Dihydropyridines X XX XX
amlodipine (Norvasc) X
clevidipine (Cleviprex) X X X
felodipine (Plendil) X XX
isradipine X
nicardipine (Cardene) X XX
nicardipine (Cardene SR) X XX
nifedipine (Adalat, Procardia XL) X
nimodipine X XX
nisoldipine (Sular)
Nondihydropyridines X
diltiazem (Cardizem, Dilacor) X
diltiazem extended release
(Cartia XT, Dilt-CD) X
diltiazem extended release (Cardizem
LA, Dilacor XR, Taztia XT, Tiazac)
diltiazem injection (Cardizem)
verapamil (Calan, Verelan)
verapamil injection (Isoptin)
Chapter 30 Pharmacotherapy with Calcium Channel Blockers 515
Table 30.2 Calcium Channel Blockers
Drug Route and Adult Dose (Maximum Dose Where Indicated) Adverse Effects
Dihydropyridines PO: 5–10 mg once daily (max: 10 mg/day) Flushed skin, hypotension, headache,
amlodipine (Norvasc) IV: 1–2 mg/h initial dose, gradually increased until goal blood dizziness, peripheral edema,
clevidipine (Cleviprex) pressure is reached (max: 16 mg/h) lightheadedness, nausea, diarrhea,
PO: 2.5–10 mg once daily (max: 10 mg/day) constipation
felodipine (Plendil) PO (controlled release): 5 mg once daily (max: 20 mg/day)
isradipine PO: 20–40 mg tid or 30–60 mg bid (Cardene SR) (max: 120 mg/day) Hepatotoxicity, MI, HF, confusion, mood
nicardipine (Cardene, Cardene SR) PO (extended release): 30–60 mg once daily (max: 120 mg/day) changes, gingival hyperplasia
nifedipine (Adalat CC, Procardia XL) PO: 60 mg qid for 21 consecutive days
nimodipine PO (extended release): 17–34 mg once daily (max: 34 mg/day)
nisoldipine (Sular)
Nondihydropyridines PO: 30 mg qid (max: 480 mg/day)
diltiazem (Cardizem, Dilacor, Taztia XT, Extended release: 120–240 mg once daily
others) PO: 80–160 mg tid (max: 480 mg/day)
verapamil (Calan, Isoptin, Verelan) PO (Verelan, Calan SR): 120–480 mg once daily
Note: Italics indicate common adverse effects. Underline indicates serious adverse effects.
PROTOTYPE DRUG Nifedipine (Adalat CC, Distribution Widely distributed; secreted in
Procardia XL) breast milk; 92–98% bound to
Primary metabolism plasma protein
Classification Therapeutic: Antihypertensive Primary excretion
Pharmacologic: Calcium channel Onset of action Hepatic; extensive first-pass
metabolism
blocker, dihydropyridine type Duration of action
Renal (80%) with small amounts
Therapeutic Effects and Uses: Approved in 1981, in feces (15%)
nifedipine is a CCB with several indications. For HTN it
may be given alone or in combination with drugs from 30–60 min (immediate release
other antihypertensive classes. Its ability to dilate the coro- capsules); 6 h (extended release
nary arteries makes it an important drug in the treatment tablet)
of chronic stable or variant angina (see Chapter 35). When
used as an antianginal, a beta-adrenergic blocker may be 4–8 h (24 h for extended release);
administered concurrently to prevent reflex tachycardia. half-life: 2–5 h
Nifedipine may be used off-label to treat hypertensive
emergency, persistent hiccups, or premature labor contrac- Adverse Effects: Nifedipine is well tolerated and seri-
tions, or to prevent migraines. ous adverse effects are not common. Most adverse effects
such as hypotension, dizziness, headache, and flushing
Nifedipine is usually prescribed as extended release are related to the vasodilation action of the drug. The most
tablets because this allows for once-daily dosing. At high common cardiovascular-related adverse effect is periph-
doses, the immediate release form of nifedipine should be eral edema, which occurs more frequently with nifedipine
used with great caution because its use has been associated than with other CCBs. Other severe, though rare, adverse
with an increased risk for myocardial infarction (MI). effects include hepatotoxicity, MI, heart failure (HF), severe
hypotension, and confusion.
Mechanism of Action: Nifedipine acts by selectively Contraindications/Precautions: The only contrain-
blocking calcium channels in vascular smooth muscle, dication is hypersensitivity to nifedipine or other dihydro-
including those in the coronary arteries, causing a de- pyridines. Caution must be observed when using nifedipine
crease in the amount of intracellular calcium available for in patients with bradycardia or HF because this drug has
muscle contraction. This results in a fall in blood pressure negative inotropic effects that can worsen these conditions.
and a diminished myocardial oxygen demand due to the The immediate release form is contraindicated in patients
reduced afterload. Nifedipine has no effect on myocardial with acute MI or cardiogenic shock. Because nifedipine
conduction except at toxic doses. causes blood pressure to fall, it should be used cautiously in
patients with preexisting hypotension. Any signs of worsen-
Pharmacokinetics: PO ing pulmonary edema call for discontinuation of the drug.
Route(s) Well absorbed (90%) Patients with significant hepatic impairment are at risk for
Absorption drug accumulation and toxicity. Older adults are at much
516 Unit 5 Pharmacology of the Cardiovascular System
greater risk of nifedipine toxicity and experience a higher hydrochlorothiazide (Tribenzor), benazepril (Lotrel), and
overall mortality when treated with this drug. telmisartan (Twynsta). This drug is pregnancy category C.
Drug Interactions: Nifedipine is a substrate for hepatic Clevidipine (Cleviprex): Approved in 2008, clevidipine is
CYP3A4 and may interact with drugs that induce or inhibit an injectable emulsion that is approved for the treatment of
this enzyme. When given concurrently with nifedipine, HTN when rapid control of blood pressure is desirable. The
other antihypertensive drugs have additive effects on blood dose is doubled every 90 seconds until the blood pressure
pressure. These additive hypotensive effects are used to approaches the goal, then the infusion is slowed, with dose
advantage in the pharmacotherapy of HTN (see C hapter 34). adjustments every 5 to 10 minutes. Blood pressure falls
Concurrent use of nifedipine with a beta-a drenergic blocker within minutes and must be monitored continuously dur-
increases the risk of HF due to additive negative inotropic ing the infusion. With such rapid titration, hypotension and
and chronotropic effects. Nifedipine may increase the serum reflex tachycardia may occur. The most common adverse
levels of digoxin by as much as 45%, leading to bradycardia effects are nausea, vomiting, and headache. Patients with
and digoxin toxicity. Alcohol potentiates the vasodilation HF must be monitored carefully because clevidipine may
action of nifedipine and could lead to syncope caused by a worsen this condition. This drug is pregnancy category C.
rapid drop in blood pressure. Herbal/Food: Grapefruit juice
may enhance the absorption of nifedipine. Melatonin may Felodipine (Plendil): Approved in 1991, felodipine is a
reduce the effectiveness of nifedipine by increasing blood dihydropyridine that has greater selectivity for vascular
pressure and heart rate. St. John’s wort can induce CYP3A4 smooth muscle than nifedipine and is approved only for
and increase the metabolism of nifedipine and reduce the the pharmacotherapy of HTN. It exerts no significant
plasma level of this drug. effects on the heart. Its elimination half-life of 11 to 16 hours
allows for once-daily dosing. Typical adverse effects are
Pregnancy: Category C. facial flushing, headache, peripheral edema, and reflex
tachycardia. Lexxel is a fixed-dose combination of felodip-
Treatment of Overdose: Overdosage may result in ine with enalapril. This drug is pregnancy category C.
pronounced hypotension, which is treated with rapid-
acting vasopressors such as dopamine or dobutamine. Cal- Isradipine: Approved in 1990, isradipine is the most potent
cium infusions may also be indicated. of the dihydropyridines and is approved for the pharmaco-
therapy of HTN, either alone or in combination with a thia-
Nursing Responsibilities: Key nursing implications zide diuretic. Chronic stable angina is an off-label indication
for patients receiving nifedipine are included in the Nurs- for the drug. The physiologic actions of isradipine are selec-
ing Practice Application for Patients Receiving Pharmaco- tive to arterioles, and the drug has no appreciable effect on
therapy with Calcium Channel Blockers. the heart. Reflex tachycardia is usually not significant. A
sustained release form is available for once-daily dosing.
Drugs Similar to Nifedipine (Adalat CC, Optimal response may require 2 to 4 weeks of therapy.
Procardia XL) Headache, facial flushing, and dizziness are the most com-
mon adverse effects. This drug is pregnancy category C.
Other dihydropyridines include amlodipine, clevidipine,
felodipine, isradipine, nicardipine, nimodipine, and Nicardipine (Cardene, Cardene SR): Approved in 1988,
nisoldipine. nicardipine is indicated for the pharmacotherapy of chronic
stable angina and HTN. Beta-adrenergic blockers or sublin-
Amlodipine (Norvasc): Amlodipine is indicated for the gual nitrates may be administered concurrently to reduce
treatment of HTN, chronic stable angina, and Prinzmetal’s the possibility of reflex tachycardia in patients with angina
variant angina. Approved in 1992, amlodipine has the lon- pectoris. A sustained release form (Cardene SR) allows for
gest half-life (35 hours) of the dihydropyridines, which once-daily dosing, and an intravenous (IV) form (Cardene
allows for once-daily dosing. Like other dihydropyridines, IV) is available for initiation of therapy in patients with
amlodipine affects mainly arteriolar smooth muscle, includ- severe HTN. An off-label use of nicardipine is for migraines.
ing that in the coronary arteries, and has no significant effect The actions, contraindications, and adverse effects are simi-
on cardiac conduction. The drug is well tolerated, with lar to those of nifedipine. Peripheral edema, dizziness,
headache, dizziness, and dose-dependent peripheral edema headache, and facial flushing are the most common adverse
being frequent adverse effects. Reflex tachycardia rarely effects. This drug is pregnancy category C.
occurs because the drug has a very gradual onset. In
the treatment of HTN, several weeks may be required to Nimodipine: Approved in 1988, nimodipine is an oral
achieve optimal outcomes. Amlodipine is used in many CCB with one very specific indication: to reduce the inci-
fixed-dose combination products with valsartan (Exforge), dence and severity of ischemic deficits in patients with
valsartan and hydrochlorothiazide (Exforge HCT), ator subarachnoid hemorrhage from ruptured intracranial
vastatin (Caduet), aliskiren (Amturnide, Tekamlo), berry aneurysms. The drug prevents vasospasm of the
perindopril (Prestalia), olmesartan (Azor), olmesartan and injured vessel and reduces the severity of the resulting
Chapter 30 Pharmacotherapy with Calcium Channel Blockers 517
neurologic deficit. Nimodipine appears to have a greater adverse effects. For example, slowing the heart rate can
smooth muscle relaxation effect on cerebral arteries than diminish cardiac output in patients with moderate or severe
arteries in other areas of the body. The most frequent HF and worsen this condition. Slowing impulse conduction
adverse effects are hypotension, edema, and headache. may cause partial or complete heart block in patients with
This drug carries a black box warning that it should never bradycardia or second-degree or third-degree AV block. Con-
be given by the parenteral route because life-threatening current treatment with a beta-adrenergic agonist may be nec-
adverse events have occurred when administered by this essary to counteract these adverse cardiac effects.
route. This drug is pregnancy category C.
Other adverse effects from the nondihydropyridines
PharmFACT include constipation, flushed skin, headache, dizziness,
edema of the ankles and feet, and lightheadedness. Gingival
It is estimated that 10% to 20% of patients taking calcium hyperplasia is an uncommon adverse effect that occurs with
channel antagonists will develop gingival hyperplasia. This long-term therapy and usually reverses after the drugs are
condition can be successfully managed by professional discontinued. Most patients tolerate the nondihydropyri-
dental care and oral antiseptic rinses such as chlorhexidine dine CCBs well and experience few serious adverse effects.
(Peridex) (Mejia, 2016).
PROTOTYPE DRUG Verapamil (Calan, Isoptin,
Nisoldipine (Sular): Approved in 1995, nisoldipine is Verelan)
selective for vascular smooth muscle and has no significant
effect on the myocardium. It is approved only for HTN but Classification Therapeutic: Antihypertensive, antiangi-
may be used off-label for angina. The extended release nal, antidysrhythmic
form, Sular, allows for once-daily dosing. Peripheral edema
and headache are relatively common in patients taking this Pharmacologic: Calcium channel
drug. Reflex tachycardia may cause angina pain in patients blocker; phenylalkylamine type
with myocardial ischemia. Like other CCBs, it should be
used with caution in patients with hypotension, peripheral Therapeutic Effects and Uses: Verapamil was the
edema, or HF. This drug is pregnancy category C. first CCB approved by the FDA in 1981. The drug is a class IV
antidysrhythmic (see Chapter 37) because it slows myocar-
30.6 The nondihydropyridines act on both dial conduction velocity, especially through the AV node,
vascular smooth muscle and the myocardium. and stabilizes certain types of abnormal heart rhythms. In
the vasculature, calcium channel blockade causes vasodila-
The nondihydropyridine group of CCBs consists of two tion of arterioles, which lowers blood pressure and reduces
drugs, verapamil (Calan, Isoptin, Verelan) and diltiazem cardiac workload. Verapamil also dilates the coronary
(Cardizem, Dilacor, Taztia XT, Tiazac, others). Although
the two drugs are chemically dissimilar, they share com- CONNECTIONS: Lifespan
mon physiologic actions, adverse effects, and indications. Considerations
Like the dihydropyridines, drugs in this class block Calcium Channel Blockers and Dementia
L-type calcium channels in vascular smooth muscle, caus-
ing vasodilation. As expected from this physiologic action, Dementia, particularly when associated with Alzheimer’s disease,
the nondihydropyridines are used in the pharmacotherapy is a devastating degenerative illness affecting over 5 million peo-
of HTN and angina. Thus the dihydropyridines and nondi- ple (Alzheimer’s Association, 2016). Although drug therapy can
hydropyridines share these two indications. Doses for the ease symptoms, there are no known cures at this time. Drugs
nondihydropyridines are listed in Table 30.2. such as cholinesterase inhibitors and N-methyl-D-aspartate
(NMDA) antagonist drugs may be used to delay symptoms, but
It is important to note that verapamil and diltiazem do not alter the disease’s progression (see Chapter 21). Past
have actions on the heart that the dihydropyridines do not studies have indicated that antihypertensive drugs may give
possess. These drugs block calcium channels in the myo- some protection against the progression of symptoms from mild
cardium, causing a negative inotropic effect. In addition, cognitive impairment to dementia. Although the use of CCBs has
the nondihydropyridines decrease the speed of myocardial not been definitively proven to exert this positive effect, the evi-
conduction, resulting in a slower heart rate. dence is growing (Lovell et al., 2015; Peters, Booth, & Peters,
2015). In a postmortem longitudinal study, Lovell et al. (2015)
These cardiac effects of the nondihydropyridines may be found that CCBs, but not other antihypertensive drugs, seemed
viewed as therapeutic or adverse, depending on the patient to significantly alter dementia progression and effects on the pro-
and the reasons for administering the drugs. For example, by duction of amyloid were noted. The authors caution that further
slowing conduction across the heart, verapamil and diltia- clinical trials are needed to demonstrate effects and determine
zem can suppress abnormal cardiac rhythms. They are indi- the mechanism of action. However, for the older adult with HTN
cated for specific types of dysrhythmias, such as atrial flutter at higher risk for dementia, CCBs may become a drug group of
or fibrillation (see Chapter 37). In certain patients, however, choice if such positive effects can be determined.
slowing the speed of conduction may result in serious
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