Pharmacology of the Cardiovascular System - Topic 1 Finals PDF

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 / 52...

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 2. Identify the components of blood and their Hemostasis functions. cc Cardiac Structure and Function 3. Construct a flowchart diagramming the primary Cardiac Muscle steps of hemostasis. Coronary Arteries 4. Describe the structure of the heart and the function of the myocardium. Cardiac Conduction System 5. Describe the role of the coronary arteries in Cardiac Output supplying the myocardium with oxygen. cc Hemodynamics and Blood Pressure 6. Illustrate the flow of electrical impulses through the Hemodynamic Factors Affecting Blood Pressure normal heart. Neural Regulation of Blood Pressure 7. Explain the major factors affecting cardiac output. Hormonal Influences on Blood Pressure 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 afterload, 482 ectopic foci, 481 preload, 482 antidiuretic hormone (ADH), 485 erythropoietin, 475 prothrombin, 478 atrial natriuretic extrinsic pathway, 477 renin-angiotensin-aldosterone peptide (ANP), 485 fibrin, 478 system (RAAS), 485 atrial reflex, 485 fibrinogen, 478 sinus rhythm, 479 automaticity, 479 hemopoiesis, 476 stroke volume, 482 baroreceptors, 485 hemostasis, 477 thrombin, 478 cardiac output (CO), 481 intrinsic pathway, 477 thrombopoietin, 476 chemoreceptors, 485 myocardium, 479 vasomotor center, 485 coagulation, 477 peripheral resistance, 483 venous return, 482 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 The cardiovascular system can function only with the over time and, as the average lifespan of the population cooperation of other body systems. For example, the role of increases, more pharmacotherapy will be needed to treat the autonomic nervous system in controlling heart rate and the chronic cardiovascular diseases of older adults. 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 to an anatomy and physiology textbook. Functions and Properties of Blood 28.2 Blood consists of formed elements and plasma. Structure and Function Blood is a liquid connective tissue that consists of formed of the Cardiovascular System elements suspended in plasma. The solid, formed elements 28.1 The cardiovascular system consists of the of the blood are the erythrocytes, leukocytes, and platelets. blood, heart, and blood vessels. When combined, the formed elements comprise about 45% of the composition of blood. The three major components of the cardiovascular system The most numerous blood cells are erythrocytes, which are the blood, heart, and blood vessels, as shown in comprise 99.9% of the formed elements. Carrying the iron- Figure 28.1. These three components work as an integrated containing protein hemoglobin, the erythrocytes are whole to transport the essential oxygen, nutrients, and responsible for transporting oxygen to the tissues and car- other substances that keep the body in homeostasis. Dis- bon dioxide from the tissues to the lungs. A single erythro- ruption of this flow for even brief periods can have serious, cyte can carry as many as 1 billion molecules of oxygen. if not lethal, consequences. The functions of the cardiovas- Erythrocyte homeostasis is controlled by erythropoietin, a cular system are diverse and include the following: hormone secreted by the kidney in response to low oxygen Transport of nutrients and wastes levels in the blood. Once secreted, erythropoietin stimu- Pumping of blood 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 Left lets, or thrombocytopenia, can result in seri- Trachea lung lung ous delays in blood clotting. Platelet Right Left pulmonary homeostasis is controlled by the hormone pulmonary artery artery thrombopoietin, which promotes the for- Bronchi mation of additional platelets. The role of 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 committed to forming erythrocytes, leuko- pulmonary Left vein pulmonary cytes, or platelets. This process occurs con- Heart vein tinuously throughout the lifespan and is (blood) 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 Injury to a blood vessel triggers the clotting process. The pharmacology and is discussed in Chapter 33. vessel spasms, causing constriction, which slows blood flow to the injured area. Platelets have an affinity for the damaged CONNECTION Checkpoint 28.1 vessel: They become sticky and adhere to each other and to the injured area. The clumping of platelets, or aggregation, is From what you learned in Chapter 3, what role does plasma protein 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- cade. Blood flow is further slowed, thus allowing the process PharmFACT 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 When collagen is exposed at the site of vessel injury, that they comprise approximately one third of all cells in the the damaged cells initiate the coagulation cascade. Coagu- body (Martini, Nath, & Bartholomew, 2015). lation itself occurs when fibrin threads create a meshwork that fortifies the blood constituents so that clots can develop. During the cascade, various plasma proteins that 28.3 Hemostasis is a complex process involving are circulating in an inactive state are converted to their multiple steps and a large number of enzymes active forms. Two separate pathways, along with numer- and factors. ous biochemical processes, lead to coagulation. The intrin- The process of hemostasis is complex, involving at least 13 sic pathway is activated in response to injury and takes different clotting factors that contribute to the slowdown several minutes to complete. The extrinsic pathway is acti- and ultimate stoppage of blood flow. Hemostasis occurs in a vated when blood leaks out of a vessel and enters tissue series of sequential steps, sometimes referred to as a cascade. 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 Fibrin Formation of 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 activators tissue factor (III) XII Active XII VII XI Ca2+ + Active XI Tissue factor + (III) and IX active VII Ca2+ positive feedback Active IX VIII Ca2+ X phospholipids (PL) Active X COMMON PATHWAY Prothrombin Ca2+, positive feedback V, PL Thrombin 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- Near the end of the common pathway, a chemical tors, patients with serious hepatic impairment often have called prothrombin activator (see Active X in Figure 28.3) is abnormal coagulation. formed. The prothrombin activator converts the clotting factor prothrombin to an enzyme called thrombin. Throm- bin then converts fibrinogen, a plasma protein, to long Cardiac Structure and Function strands of fibrin. The fibrin strands provide a framework to anchor the clot. Thus two of the factors essential to 28.4 The heart is responsible for pumping blood clotting, thrombin and fibrin, are only formed after injury throughout the circulatory system. to the vessels. The fibrin strands form an insoluble web The heart is the hardest working organ in the body, pump- over the injured area to stop blood loss. Normal blood clot- ing blood from before birth to the last minute of life. With ting occurs in about 6 minutes. the continuous workload, it is not surprising that this It is important to note that several clotting factors, organ eventually weakens and that heart disease is the including thromboplastin and fibrinogen, are proteins leading cause of death in the United States. The heart is a made by the liver that are constantly circulating through frequent target for pharmacotherapy.  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 unable to replace them because cardiac muscle cells do not 28.6 The cardiac conduction system keeps undergo mitosis. If a large area of cardiac muscle becomes the heart beating in a synchronized manner. 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 The heart has four chambers that receive blood prior to specialized cardiac muscle cells that sends a synchronized, being pumped, as illustrated in Figure 28.4b. These cham- electrical signal across the myocardium. These electrical bers differ in size, depending on their function. The left ven- impulses, or action potentials, carry the signal for the car- tricle is the largest and most powerful chamber, because it diac muscle cells to contract and must be coordinated pre- must hold and pump enough blood to all body tissues. Dur- cisely for the chambers to beat in a synchronized manner. ing heart failure, the size of the left ventricle and the thick- The cardiac conduction system is illustrated in Figure 28.5. 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 The coronary arteries are subject to atherosclerosis, a allows the atria sufficient time to completely contract and buildup of fatty plaque, which narrows the lumen and empty their blood before the ventricles receive their signal restricts the blood supply reaching myocytes. If allowed to to contract. If the ventricles should contract prematurely, progress, the narrowing results in chest pain, a condition the AV valves will close and the atria will be prevented known as angina pectoris. The first sign of angina is pain from completely emptying their contents. 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 Brachiocephalic Left subclavian artery artery Arch of aorta Superior vena cava Left pulmonary artery Right atrium Left atrium Right coronary Great cardiac artery vein Coronary sulcus Left coronary artery Right ventricle Anterior cardiac Left ventricle veins Apex (a) 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 Bicuspid (mitral) valve Fossa ovalis Left ventricle Tricuspid valve Papillary muscle Chordae tendineae Interventricular septum Right ventricle Trabeculae carneae Myocardium Inferior vena cava Visceral pericardium (b) Figure 28.4 The heart: (a) coronary arteries and veins; (b) chambers and valves.  Chapter 28 Review of the Cardiovascular System 481 Aorta Right atrium Superior vena cava 1 Sinoatrial node (pacemaker) Left atrium 2 Internodal pathway 3 Atrioventricular node Purkinje fibers 4 Atrioventricular bundle (bundle of His) Bundle branches Interventricular 5 Purkinje fibers septum 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 node and spread across the myocardium in a coordinated manner, other regions of the heart may also initiate beats. 28.7 Cardiac output is determined by stroke These ectopic foci, or ectopic pacemakers, may send waves volume and heart rate. of depolarization across the myocardium that compete To understand how medications act on the heart and to with those from the normal conduction pathway. The tim- predict the consequences of pharmacotherapy, it is essen- ing and synchronization of atrial and ventricular contrac- tial to have a comprehensive knowledge of normal cardiac tions may be affected. Although healthy hearts occasionally physiology. This includes a thorough understanding of experience an extra beat without incident, ectopic foci in factors that determine the amount of blood pumped by the diseased hearts have the potential to cause dysrhythmias, heart and the forces acting on the chambers. 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- Stroke volume: Stroke volume is the amount of blood ply increasing the total amount of blood in the vascular pumped by a ventricle in a single contraction. What types system (increased blood volume). Drugs or other mecha- of factors might cause a ventricle to eject more blood dur- nisms that constrict veins or increase blood volume will ing a contraction? To understand these factors, a simple therefore increase stroke volume and CO. Conversely, comparison to a rubber band is useful. If you stretch a drugs that dilate veins or reduce blood volume will lower small rubber band 2 inches, it will snap back with a certain CO. 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 Cardiac muscle fibers are analogous to rubber bands. If include quinidine and beta-adrenergic antagonists such as you fill the chambers with more blood, the fibers will have propranolol. 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, What causes the chambers to fill up with more blood, increase stroke volume, and result in less workload for the become stretched (more preload), and contract with greater heart. Preload and afterload are illustrated in Figure 28.6. (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 Blood pressure = CO × peripheral resistance SA node, and heart rate is determined by which fibers are firing at a greater rate at any given moment. Circulating CO is determined by heart rate and stroke volume as hormones such as epinephrine and thyroid hormone also discussed in Section 28.7. From the preceding equation, it is affect heart rate. In theory, drugs that increase heart rate easy to see that as CO increases, blood pressure also will increase CO, although compensatory mechanisms increases. This is important to pharmacology because med- may prevent this effect (see Section 28.8). In addition, a ications that change the CO, stroke volume, or heart rate very rapid heart rate may not give the chambers sufficient have the potential to influence a patient’s blood pressure. time to completely fill, thus reducing CO. As blood speeds through the vascular system, it exerts force against the walls of the vessels. Although the lining of CONNECTION Checkpoint 28.2 the blood vessel is extremely smooth, friction reduces the From what you learned in Chapter 12, predict what effect the fol- velocity of the blood. Further friction is encountered as the lowing would have on heart rate: sympathomimetics, parasympa- stream of fast-moving blood narrows to enter smaller ves- thomimetics, adrenergic agonists, and anticholinergics. Answers sels, divides into two channels (arteries), or encounters to Connection Checkpoint questions are available on the faculty fatty deposits on the vessel walls (plaque). Blood flow may resources site. Please consult with your instructor. exhibit turbulence, a chaotic, tumbling motion that greatly increases friction. The friction that blood encounters in the arteries is called peripheral resistance. Arteries have Hemodynamics and Blood smooth muscle in their walls, which controls the total Pressure peripheral resistance. For example, if the smooth muscle constricts, the inside diameter or lumen of the arteries will 28.8 The primary factors responsible for become smaller and create more resistance and higher blood pressure are cardiac output, peripheral blood pressure. A large number of medications affect vas- resistance, and blood volume. cular smooth muscle. Some of these drugs cause vessels to The homeostatic regulation of blood pressure is a key topic constrict, thus raising blood pressure, whereas others relax in pharmacology because HTN is so prevalent in the popu- smooth muscle, thereby opening the lumen and lowering lation. Regulation of blood pressure is complex with many blood pressure. diverse factors, both local and systemic, interacting to An additional factor responsible for blood pressure is maintain adequate blood flow to the tissues. The three pri- the total amount of blood in the vascular system, or blood mary factors that regulate arterial blood pressure—CO, volume. Although the average person maintains a relatively peripheral resistance, and blood volume—are shown in 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 nervous system nervous Contractility ADH Angiotensin II system Afterload 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 It is critical for the body to maintain a normal range of heart, thus increasing CO and arterial blood pressure. Drugs blood pressure and for it to be able to safely and rapidly are frequently used to adjust blood volume. For example, change pressure as it proceeds through daily activities infusion of intravenous (IV) fluids quickly increases blood such as sleep and exercise. Hypotension can cause dizzi- volume and raises blood pressure. This is used to advantage ness and lack of adequate urine formation, whereas when treating hypotension due to shock. On the other hand, extreme HTN can cause vessels to rupture, resulting in diuretics cause fluid loss through urination, thus decreasing ischemia of critical organs. Figure 28.8 illustrates how the blood volume and lowering blood pressure. body maintains homeostasis during periods of blood pres- PharmFACT sure change. The central and autonomic nervous systems are It is estimated that all the blood vessels in an adult stretch intimately involved in regulating blood pressure. On a through about 60,000 miles of internal body landscape minute-to-minute basis, blood pressure is regulated by a (Marieb & Hoehn, 2016). cluster of neurons in the medulla oblongata called the (CUVTGURQPUG 'NGXCVGF DNQQF 5NQY RTGUUWTG T G UR Q PU G %CTFKQXCUEWNCT EQORGPUCVKQP 4GPCN EQORGPUCVKQP +PETGCUGF 8CUQFKNCVKQP 5NQY &GETGCUGF WTKPG JGCTV UVTQMG QWVRWV TCVG XQNWOG &GETGCUGF 4GFWEGF DNQQF ECTFKCE XQNWOG QWVRWV *QOGQUVCUKU $NQQFRTGUUWTG TGVWTPUVQPQTOCN 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 Many autonomic drugs dilate or constrict blood vessels. From what blood. The vasomotor center reacts to information from you learned in Chapter 12, which class of autonomic drugs is most baroreceptors and chemoreceptors by raising or lowering commonly prescribed for HTN? Answers to Connection Checkpoint blood pressure accordingly. Nerve fibers travel from the questions are available on the faculty resources site. Please consult vasomotor center to the arteries, where the smooth mus- with your instructor. cle is directed to either constrict (raise blood pressure) or relax (lower blood pressure). As discussed in Chapter 16, 28.10 Hormones may have profound effects sympathetic outflow from the vasomotor center stimu- on blood pressure. lates alpha1-adrenergic receptors on arterioles, causing vasoconstriction. Alpha 2-adrenergic agonists can also Several hormones affect blood pressure, and certain classes decrease blood pressure by their central effects on the of medications are given to either enhance or block the vasomotor center. 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 Antidiuretic hormone (ADH) is a hormone released reflexes that constrict the arterioles and veins and acceler- by the posterior pituitary gland when blood pressure falls ate the heart rate. Together, these actions return blood pres- or when the osmotic pressure of the blood increases. ADH, sure to normal levels within seconds. 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- The renin-angiotensin-aldosterone system (RAAS) is ated heart rate, or reflex tachycardia, may cause the patient particularly important in the drug therapy of HTN. As to experience palpitations. The baroreceptors are not able blood pressure falls, the enzyme renin is released by the to offer a continuous or sustained reduction in blood pres- kidneys. Through a two-step pathway, angiotensin II is sure. Continued administration of an antihypertensive formed, which subsequently increases CO and constricts drug will “overcome” the reflex. In addition, with aging or arterioles to return blood pressure to original levels. Angio- certain disease states such as diabetes, the baroreceptor tensin II also promotes the release of aldosterone from the response may be diminished. 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, Atrial natriuretic peptide (ANP) is a hormone that is such as might occur when large amounts of IV fluids are secreted by specialized cells in the right atrium when large administered. The atrial reflex causes the heart rate and increases in blood volume produce excessive stretch on the CO to increase until the backlog of venous blood (or IV atrial wall. ANP has multiple effects, all of which attempt fluid) is distributed throughout the body. 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 (CUVTGURQPUG &GETGCUGF DNQQF.QPI RTGUUWTG VG T O  TG URQ PUG $CTQTGEGRVQTU #FTGPCNOGFWNNC KPJKDKVGF CEVKXCVGF 4GNGCUGQH TGPKPD[MKFPG[ #%' (QTOCVKQPQH 8CUQOQVQT CPIKQVGPUKP++ EGPVGTKP OGFWNNC 5[ORCVJGVKE TGURQPUG 4GNGCUGQH#&*HTQO 8CUQEQPUVTKEVKQP +PETGCUGF RKVWKVCT[UGETGVKQPQH ECTFKCE CNFQUVGTQPGD[CFTGPCNU QWVRWV 5GETGVKQPQH 9CVGTCPF PQTGRKPGRJTKPG UQFKWOTGVGPVKQP CPFGRKPGRJTKPG *QOGQUVCUKU $NQQFRTGUUWTG TGVWTPUVQPQTOCN Figure 28.9 Endocrine and nervous control of blood pressure. Understanding Chapter 28 Key Concepts Summary 28.1 The cardiovascular system consists of the blood, 28.4 The heart is responsible for pumping blood heart, and blood vessels. throughout the circulatory system. 28.2 Blood consists of formed elements and plasma. 28.5 The coronary arteries bring essential nutrients to the myocardium. 28.3 Hemostasis is a complex process involving multiple steps and a large number of enzymes 28.6 The cardiac conduction system keeps the heart and factors. beating in a synchronized manner.  Chapter 28 Review of the Cardiovascular System 487 28.7 Cardiac output is determined by stroke volume 28.9 Neural regulation of blood pressure includes and heart rate. baroreceptor and chemoreceptor reflexes. 28.8 The primary factors responsible for blood 28.10 Hormones may have profound effects on blood pressure are cardiac output, peripheral resistance, pressure. and blood volume. References Marieb, E. N., & Hoehn, K. N. (2016). Human anatomy and Martini, F. H., Nath, J. L., & Bartholomew, E. F. (2015). physiology (10th ed.). Hoboken, NJ: Pearson. Fundamentals of human anatomy and physiology (10th ed.). San Francisco, CA: Benjamin Cummings. Selected Bibliography D’Amico, D., & Barbarito, C. (2016). Health and physical Silverthorn, D. U. (2016). Human physiology: An integrated assessment in nursing (3rd ed.). Hoboken, NJ: Pearson. approach (7th 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 1. Summarize the link between high blood cholesterol, cc Drugs for Dyslipidemias low-density lipoprotein levels, and atherosclerosis. HMG-CoA Reductase Inhibitors 2. Explain the different types of lipids and how they PROTOTYPE Atorvastatin (Lipitor), p. 496 are transported through the body. Bile Acid Sequestrants 3. Illustrate how lipids are transported through the blood. PROTOTYPE Cholestyramine (Questran), p. 500 4. Compare and contrast the clinical importance of the Niacin different types of lipoproteins. Fibric Acid Drugs 5. Give examples of how cholesterol and low-density PROTOTYPE Gemfibrozil (Lopid), p. 502 lipoprotein levels can be controlled with Miscellaneous Drugs for Dyslipidemias 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 apoprotein, 489 hyperlipidemia, 491 rhabdomyolysis, 496 atherosclerosis, 489 hypertriglyceridemia, 491 steroids, 489 dyslipidemia, 491 lipoproteins, 489 sterol nucleus, 489 high-density lipoprotein low-density lipoprotein triglycerides, 489 (HDL), 489 (LDL), 489 very low-density lipoprotein HMG-CoA reductase, 494 phospholipids, 489 (VLDL), 490 hypercholesterolemia, 491 reverse cholesterol transport, 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 must be specially packaged for transport through the 29.1 Lipids are classified as triglycerides, blood. To accomplish this, the body forms complexes phospholipids, or sterols. 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). The third class of lipids, the steroids, is a diverse group Figure 29.2 illustrates the three basic lipoproteins and their of substances having a common sterol nucleus or ring compositions. 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 GVE %* %* %* %* %* %* %* 1 %* * %* * 1 % % %* %* %* %* %* %* %* %* 1 * 1 % % %* %* %* %* %* %* %* %* %* %* %* %* %* %* %* %* GVE 1 * 1 % % %* %* %* %* %* %* %* %* %* %* %* %* %* %* %* %* GVE * )N[EGTQN (CVV[CEKFVCKNU DCEMDQPG C 6TKIN[EGTKFGU %* %* %* %* %* %* %* 1 %* %* *% 0 %* %* 1 2 1 %* 1 %* %* 1 *% 1 % %* %* %* %* %* %* %* %* 1 *% 1 % %* %* %* %* %* %* %* %* %* %* %* %* %* %* %* %* 2QNCTJGCF )N[EGTQN (CVV[CEKFVCKNU DCEMDQPG D 2JQURJQNKRKFU %* 1* %* *% %* %* %* *1 %* 'UVTCFKQN *% %* 1* %* %* %* %* *1 1 %JQNGUVGTQN 6GUVQUVGTQPG E 5VGTQKFU 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- Very low-density lipoprotein (VLDL) is the primary utes to plaque buildup. LDL is often called “bad” choles- carrier of triglycerides in the blood. VLDL accounts for terol because this lipoprotein contributes significantly to virtually all triglycerides being transported from the liver plaque deposits and coronary artery disease (CAD). Sixty to storage in adipose tissue. Through a series of steps,  Chapter 29 Pharmacotherapy of Hyperlipidemia 491 45–50% 20% (a) High-density 30% 5% lipoprotein 25% 45% (b) Low-density 20% 10% lipoprotein 5–10% (c) Very low-density 10–15% lipoprotein 15–20% Triglyceride 55–65% Phospholipid Protein Cholesterol 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- Several terms are used to describe lipid disorders. vascular disease warrant consistent education on the Dyslipidemia is a general term that refers to abnormal importance of drug therapy and lifestyle changes. 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 genetic dyslipidemias can be so severe as to cause CAD Table 29.1 Standard Laboratory Lipid Profiles and death due to myocardial infarction (MI) in patients as Laboratory Value young as 1 or 2 years (Mose, 2016). For most patients, dys- Type of Lipid (mg/dL) Standard lipidemias are the result of a combination of genetic and Total cholesterol Less than 200 Desirable environmental (lifestyle) factors. 200–239 Borderline high risk 240 or higher High risk Low-density Less than 100 Optimal Measurement and Control lipoproteins 100–129 Near or above optimal of Serum Lipids (LDLs) 130–159 Borderline high risk 160–189 High risk 29.3 Blood lipid profiles are important 190 or higher Very high risk diagnostic tools in guiding the therapy of High-density Less than 40 (men) or 50 Low risk dyslipidemias. lipoproteins (women) (HDLs) Although high levels of cholesterol in the blood are Greater than 60 Desirable associated with cardiovascular disease, it is not enough Serum Less than 150 Normal triglycerides to simply measure total cholesterol in the blood. Because 150–199 Borderline high risk some cholesterol is being transported for destruction, a 200–499 High risk more accurate profile is obtained by measuring the LDL 500 or higher Very high risk and HDL. The goal is to maximize the cholesterol car- From “Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood ried by high-density lipoproteins (HDL-C) and mini- Cholesterol in Adults (Adult Treatment Panel III), Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults,” 2001, JAMA, 285, 2486–2497. mize the cholesterol carried by low-density lipoproteins (LDL-C). This is sometimes stated as a ratio of LDL to HDL. If the ratio is greater than 5 (five times more LDL laboratory number, but is now established for the follow- than HDL), the male patient is considered at risk for car- ing treatment categories: diovascular disease. The normal ratio in women is 1. Patients with atherosclerotic CVD slightly lower at 4.5. 2. Patients with diabetes, ages 40 to 75 years with LDL-C Scientists have further divided LDL into subclasses of levels between 70 and 189 mg/dL lipoproteins. For example, one variety found in LDL, called 3. Patients without CVD but who have LDL-C levels of lipoprotein (a), has been strongly associated with plaque for- 190 mg/dL or higher mation and heart disease. It is likely that further research 4. Patients ages 40 through 75 years without CVD or dia- will find other varieties with the expectation that drugs betes but who have LDL-C levels 70 through 189 mg/dL will be designed to be more selective toward the “bad” and 7.5% or greater 10-year risk of atherosclerotic CVD. lipoproteins. Table 29.1 gives the desirable, borderline, and high laboratory values for each of the major lipids and lipo- Based on the results of hundreds of clinical trials over proteins. These values change periodically as additional many years, the ACC/AHA guidelines specifically recom- research becomes available on the association between mend statins as first-line therapy for all categories (see heart disease and lipid levels. Section 29.5). Follow-up measures of LDL are recom- Establishing treatment guidelines for dyslipidemia mended to determine adherence to the drug regimen. has been challenging because the condition has no symp- The fourth category of the ACC/AHA guidelines, which toms and the progression to cardiovascular disease may bases pharmacotherapy on a 7.5% or greater risk of athero- take decades. Until 2013, treatment guidelines focused on sclerotic CVD, has been controversial. The calculation of risk determining levels of LDL and HDL that could prevent gives heavy emphasis to age, which suggests that most of the the development of cardiovascular disease (CVD). Essen- population over age 60 should be on statin medications. Later tially, if a patient exhibited laboratory values shown to be research suggested this guideline has been effective at pre- at high risk (see Table 29.1), pharmacotherapy was initi- venting CVD in this population (Greenland & Lauer, 2015). ated and continued until these values returned to the Blood lipid profiles are used to classify the different pat- normal range. terns of hyperlipidemias observed in clinical practice. These Major revisions were made to these guidelines by the patterns are shown in Table 29.2. The specific type of dyslipid- American College of Cardiology (ACC) and the American emia exhibited by patients is considered when planning ther- Heart Association (AHA) in 2013 (Psaty & Weiss, 2014). apy. For example, Type I requires dietary restrictions and does The 2013 ACC/AHA guidelines no longer stress specific not respond well to pharmacotherapy. Whereas the remain- target goals for LDL levels. The question of who should be ing types respond to the statins, the hypertriglyceridemias treated for high cholesterol levels is no longer based on a 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 Type IIa LDL and cholesterol increased Common condition, may occur at any age Familial hypercholesterolemia Type IIb LDL, VLDL, cholesterol, and triglycerides increased May occur at any age but more commonly in Combined familial hyperlipidemia adults Carbohydrate-induced hypertriglyceridemia Type III Chylomicrons, VLDL, cholesterol, and triglycerides Uncommon condition, occurs most Familial dysbetalipoproteinemia increased frequently in middle-aged adults Type IV VLDL and triglycerides increased Most common dyslipidemia, occurs in Endogenous hyperlipidemia Cholesterol normal or elevated middle-aged adults; associated with obesity, Carbohydrate-induced hypertriglyceridemia Glucose intolerance excessive alcohol intake, tobacco use, and Hyperuricemia other lifestyle factors Type V LDL, VLDL, cholesterol, and chylomicrons increased Uncommon type, may begin in childhood Mixed hyperlipidemia Triglycerides increased 3 times and manifest in adults Carbohydrate- and fat-induced hypertriglyceridemia Glucose intolerance Hyperuricemia 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 through nonpharmacologic means. CONNECTIONS: Lifespan Even in patients with high risk for whom drug therapy Considerations is indicated, using TLCs is important for reducing choles- terol levels. All drugs for hyperlipidemia have adverse Pediatric Dyslipidemias effects, and implementing TLCs may allow for a reduction and Lipid-Lowering Drugs in drug dosages. Following are the most important lipid- Many people consider dyslipidemia to be a condition that reduction lifestyle interventions: occurs with advancing age. Dyslipidemias are also a concern for some pediatric patients, and multiple research studies Monitor blood lipid levels regularly, as recommended have demonstrated that the early stages of atherosclerosis by the healthcare provider. begin in childhood. With the increasing childhood obesity epi- Maintain weight at an optimal level. demic, there is concern that dyslipidemias, CVD, and meta- Implement a medically supervised exercise plan. bolic syndrome will occur at younger and younger ages. Risk Reduce dietary saturated fats and cholesterol. factors for dyslipidemias in children are similar to those in Increase soluble fiber in the diet, as found in oat bran, adults and include overweight or obesity, family history of dys- apples, beans, grapefruit, and broccoli. lipidemias or premature CVD, hypertension, smoking or pas- Eliminate tobacco use. sive smoke exposure, and known genetic lipid disorders. The 2011 National Heart, Lung, and Blood Institute Integrated The single most important lifestyle factor contributing Guidelines for Cardiovascular Health and Risk Reduction in to dyslipidemia is a high amount of saturated fat in the Children and Adolescents recommended targeted screening diet. Nutritionists recommend that the intake of dietary fat of lipid levels for children ages 2 and older with a positive or be limited to less than 30% of the total caloric intake and unknown family history of dyslipidemia-related CVD or other that cholesterol intake be reduced as much as possible. It is major risk factor and universal screening in those ages 9 to interesting to note that restriction of dietary cholesterol 11 years and again between 17 and 21 years. Additionally, alone will not result in a significant reduction in blood cho- they recommended pharmacologic treatment with statins for lesterol levels. In fact, cutting back on cholesterol consump- children with LDL levels above 190 mg/dL, or above 160 mg/dL tion may actually increase the amount of circulating with the presence of two or more cardiovascular risk factors before age 50 (Expert Panel on Integrated Guidelines for cholesterol. How is this possible? The liver reacts to a low- Cardiovascular Health and Risk Reduction in Children and cholesterol diet by making more cholesterol and by inhibit- Adolescents, 2011). ing its excretion whenever saturated fats are present. 494 Unit 5 Pharmacology of the Cardiovascular System