Regis University Integrated Pharmacotherapy 2 Hypertension Part 1 Fall 2024 PDF

Hypertension, Part I School of Pharmacy Integrated Pharmacotherapy 2 Fall 2024 Facilitators Reading and References Peter Clapp, PhD R...

Hypertension, Part I School of Pharmacy Integrated Pharmacotherapy 2 Fall 2024 Facilitators Reading and References Peter Clapp, PhD Required [email protected] Integrated Pharmacotherapy 2 Acute Kidney Injury course notes Integrated Pharmacotherapy 2 Hypertension course notes (this packet) Optional Chad Martell, PharmD, BCPS Ganong Review of Medical Physiology Chapters 30 - 34 [email protected] Goodman & Gilman’s Pharmacologic Basis of Therapeutics Chapter 6,10 and 32 Basic & Clinical Pharmacology (Katzung) Chapter 6, 10 and 11 DiPiro Pharmacotherapy: A Pathophysiologic Approach Chapter 15 (AccessPharmacy) Netter's Illustrated Pharmacology: Pages 45-47, 53-56, 94-100, 107, 118-127 Learning Objectives 1. Summarize the general function of the parasympathetic and sympathetic nervous systems. 2. Differentiate between the neurotransmitters and receptors of the parasympathetic and sympathetic systems. 3. Compare and contrast cholinergic and adrenergic transmission. 4. Describe the biosynthesis and degradation of catecholamines and acetylcholine. 5. List the different cholinergic and adrenergic receptors. 6. Interpret the equations for mean arterial pressure and cardiac output (e.g., define the relationship between stroke volume and cardiac output). 7. Calculate mean arterial pressure. 8. Diagram the pathway of blood through the chambers of the heart and peripheral circulatory system. 9. Compare and contrast the function of myocardial contractile cells and autorhythmic cells. 10. During each phase of the cardiac cycle, compare and contrast ventricular pressure and blood volume in atria and ventricles. 11. Define end diastolic volume, end systolic volume, isovolumetric contraction, and isovolumetric relaxation. 12. Explain the influence of the parasympathetic and sympathetic nervous system on heart rate and stroke volume. 13. Describe the following factors and their role in regulating stroke volume (and their impact on cardiac output): preload, contractility, and afterload. 14. Describe the length-tension relationship (also known as the Frank Starling relationship). 15. Compare the structure and function of arteries, arterioles, capillaries, venules and veins. 16. Compare how blood viscosity, vessel length, and vessel diameter influence resistance. 17. Define the relationship between cardiac output, blood flow, blood pressure, and resistance. 18. Outline how the baroreceptor reflex maintains blood pressure. 19. Compare and contrast the following hormones and their effect on blood pressure: epinephrine, norepinephrine, angiotensin II, antidiuretic hormone (ADH), atrial natriuretic peptide, and aldosterone. 20. Illustrate the structure and organization of vascular smooth muscle. 21. Outline the steps of smooth muscle contraction with emphasis on the role of calcium. 22. Describe the molecular composition of thick and thin filaments in a smooth muscle cell. 23. Describe the role of smooth muscle cells on influencing vascular tone. 24. Illustrate the role of the autonomic nervous system and other mediators on vascular resistance. 25. Describe the physiologic responses of the autonomic nervous system, the renin-angiotensin-aldosterone system (RAAS), and the kidneys for the regulation of blood pressure. 26. Recognize the pathogenic mechanisms that increase cardiac output and increase total peripheral resistance. 27. Describe the role of peripheral autoregulatory mechanisms, endothelial cells, and electrolytes in the pathophysiology of hypertension. **Objectives will not be covered by the RAT but will be covered by applications and exams  Learning Objectives (Cont.) Integrated Pharmacotherapy 2 2 Hypertension Part 1 INTRODUCTION TO HYPERTENSION Definitions Hypertension (HTN) is very common in the U.S., as nearly a third of our Heart rate (HR): number of heart contractions per minute population has a diagnosis of hypertension. HTN is a major risk factor for Stroke volume (SV): volume of blood pumped from a ventricle of coronary artery disease, stroke, and renal failure. The prevalence of HTN the heart in one beat rises progressively with age, such that more than half of all Americans aged Cardiac output (CO): volume of blood ejected per unit of time; 65 years or older have hypertension, and the lifetime risk of developing CO is dependent on HR and SV and is represented by the following HTN in patients greater than 55 years old is 90%. HTN is more common equation: CO = HR x SV in men before the age of 45, and HTN is more common in women after the Systolic blood pressure (SBP): pressure (measured in mm Hg) in age of 55. the arterial wall during cardiac contraction Risk of stroke, myocardial infarction, angina, heart failure, kidney failure, Diastolic blood pressure (DBP): pressure (measured in mm Hg) in the arterial wall during the filling of the ventricles or early death from a cardiovascular cause is directly correlated with blood pressure (BP). Starting at a BP of 115/75 mm Hg, risk of death from Mean arterial pressure (MAP) : average pressure throughout the cardiac cycle of contraction; Since 2/3 of the time is spent a coronary event doubles with every 20/10 mm Hg increase. For patients in diastole and 1/3 in systole, the MAP is estimated using the below age 50, diastolic blood pressure (DBP) is the major predictor of the following equation: MAP = 1/3 (SBP) + 2/3 (DBP) risk of ischemic heart disease. For patients greater than age 60, systolic blood Total peripheral resistance (TPR): sum of the resistance of all of pressure (SBP) is a stronger predictor of ischemic heart disease. Given the the peripheral vasculature in the systemic circulation prevalence and risk associated with HTN, there is tremendous opportunity Hypertension (HTN): persistent elevation of arterial blood for pharmacists to become involved in identifying patients with HTN and pressure (BP) reducing the risk associated with HTN. Isolated systolic hypertension (ISH): SBP > 140 mm Hg and DBP < 90 mm Hg Pulse pressure: difference between SBP and DBP which indicates arterial wall stiffness; higher pulse pressures are correlated with PHYSIOLOGY increased risk of cardiovascular morbidity and mortality Autonomic Neurophysiology Introduction The nervous system consists of the central nervous system (CNS) comprised of the brain and spinal cord, and the peripheral nervous system (PNS) comprised of nerves that extend out from the CNS to connect with limbs and organs. The nervous system can be divided into two groups: the afferent nervous system and the efferent nervous system. Put simply, the afferent nervous system consists of transmission of nerve signals from the PNS to the CNS and the efferent nervous system consists of transmission of nerve signals from the CNS to the PNS. The efferent nervous system contains the motor portion of the nervous system, and may also be divided into two categories: Figure 1. Efferent nervous system autonomic and somatic (Figure 1). As the name suggests, the autonomic nervous system is generally independent of conscious control. For example, it is responsible for your heart Motor (Efferent) rate and gastrointestinal motility. The somatic nervous system Nervous System involves muscular functions that you can consciously control, such as moving your arms or legs. For example, imagine you are walking outside, and then begin to run. Your heart rate will most likely increase involuntarily. The afferent autonomic nervous system sends a signal to your Somatic Autonomic Nervous System Nervous System brain requesting more oxygen to be sent to your muscles to compensate for your increase in muscle activity. The efferent autonomic nervous system then transmits a signal to your heart to increase its output, and your heart’s pumping rate increases in response to that signal. Conscious Motor Control Unconscious Motor Control Autonomic Nervous System Nerve fibers in the autonomic nervous systems consist of two general sections: preganglionic fibers and postganglionic Parasympathetic Sympathetic fibers. The preganglionic nerve fibers are linked with the Division Division postganglionic nerve fibers at clusters of cell bodies called Integrated Pharmacotherapy 2 3 Hypertension Part 1 ganglia. Nerve signals travel through preganglionic fibers (axons) via propagation of action potentials. When the signal reaches the end, or terminus, of the fiber, it stimulates the release of neurotransmitter at the ganglia. The released neurotransmitter transfers the nerve signal to the postganglionic nerve fibers by activating receptors at the postganglionic nerve fibers. Then, the nerve signal continues through the postganglionic fibers in the form of action potential propagation, and terminates at the organ being innervated by the nerve. As with the terminus of the preganglionic fibers, neurotransmitters are released when the nerve signal reaches the terminus of the postganglionic nerve fibers. Once released, these neurotransmitters bind with receptors at the organ site being innervated. In some cases, the release of neurotransmitter from the postganglionic nerve fiber terminus will be into the blood stream, and the neurotransmitter will travel to a distant site and bind with a receptor. The autonomic nervous system is grouped into two divisions: the parasympathetic division and the sympathetic divisions. Figure 2. Neurotransmission in parasympathetic nervous system Spinal Cord Tissue / Organ Innervated by Parasympathetic Nerves Autonomic Ganglia ACh ACh Preganglionic Nerve Fibers Postganglionic Nerve Fibers Nicotinic ACh Muscarinic ACh Receptors Postganglionic Receptors Parasympathetic Division In the parasympathetic division, acetylcholine (ACh) is the major neurotransmitter involved in nerve signaling (Figure 2). At the autonomic ganglia, presynaptic nerve fibers release acetylcholine, which then binds at receptors on postsynaptic nerve fibers called nicotinic ACh receptors. Neurotransmission through postsynaptic nerve fibers terminates with the release of acetylcholine at the tissue or organ being innervated by the parasympathetic nerve. However, in this case, the acetylcholine binds at muscarinic ACh receptors. Sympathetic Division For the majority of neurotransmission in the sympathetic division, acetylcholine is the major neurotransmitter at autonomic ganglia (Figure 3). As with the parasympathetic division, sympathetic preganglionic fibers release acetylcholine at the autonomic ganglia which binds with nicotinic receptors. However, most postganglionic nerve fibers in the sympathetic division release norepinephrine that binds with adrenergic receptors on the innervated tissues. Some sympathetic postganglionic nerve fibers release dopamine, rather than norepinephrine, which binds with dopaminergic receptors (e.g., renal vascular smooth muscle), while others release epinephrine instead of norepinephrine (e.g., release of epinephrine into the bloodstream). Figure 3. Neurotransmission in sympathetic nervous system Spinal Cord Tissue / Organ Innervated by Sympathetic Nerves Autonomic Ganglia ACh NE Preganglionic Nerve Fibers Postganglionic Nerve Fibers Nicotinic ACh Adrenergic Receptors Postganglionic Receptors Integrated Pharmacotherapy 2 4 Hypertension Part 1 Neurotransmission Cholinergic Transmission The processes that involve the release of the neurotransmitter acetylcholine Figure 4. Acetylcholine Presynaptic Synthesis and Release to bind at either nicotinic or muscarinic acetylcholine receptors is called cholinergic transmission. Overall, this process begins with the biosynthesis Presynaptic Terminal of acetylcholine and terminates with the degradation of acetylcholine. Acetylcholine is synthesized from choline and acetyl-CoA in the cytoplasm of nerve cells (Figure 4 on page 5). Choline is transported from the Acetyl Choline CoA extracellular fluid into nerve cells where it and acetyl-CoA serve as a substrates for choline acetyltransferase, the enzyme that catalyzes the ACh = Acetylcholine Choline Acetyltransferase formation of acetylcholine. Once biosynthesized, acetylcholine is transported ACh Acetylcholine into containers called vesicles. Up to 50,000 acetylcholine molecules may be packaged in a single vesicle. Vesicle Fused With Presynaptic Membrane When a neuronal action potential reaches the nerve terminal, it triggers an influx of calcium ions, leading to the fusion of these vesicles with the ACh ACh ACh ACh membrane at the terminal of nerve cells. Once fused, the vesicle releases ACh ACh ACh ACh its acetylcholine from the presynaptic nerve terminal into the extracellular ACh space separating the presynaptic and postsynaptic neurons. This space is ACh sometimes called the synaptic cleft. Following release, acetylcholine may then Acetate ACh bind with acetylcholine receptors on the postsynaptic cells. Depending on the ACh anatomical site, these receptors will be either muscarinic or nicotinic ACh ACh Choline Acetyl- receptors. cholines terase Cholinergic Receptor Eventually, the acetylcholine released into the synaptic cleft will be degraded Postsynaptic Terminal into choline and acetate by the enzyme acetylcholinesterase. Choline may then be recycled back into the presynaptic nerve cells to once again be used in the biosynthesis of acetylcholine. An important concept to understand is that acetylcholinesterase acts to decrease overall cholinergic neurotransmission by degrading acetylcholine. Adrenergic Neurotransmission Molecules called catecholamines are the neurotransmitters involved in Figure 5. Norepinephrine Presynaptic Synthesis and Release adrenergic neurotransmission and dopaminergic neurotransmission. As mentioned earlier, most postganglionic neurotransmission in the Presynaptic Terminal sympathetic division of the autonomic nervous system occurs by the release of norepinephrine, and in some cases dopamine, from nerve terminals DOPA Tyrosine of postganglionic nerve fibers. Epinephrine, norepinephrine (NE), and DA NE Vesicle dopamine (DA) are catecholamines. Similar to acetylcholine, catecholamines are synthesized inside of neurons DA = Dopamine NE (Figure 5). As with acetylcholine synthesis, this process begins with the NE = Norepinephrine DA importing of a precursor molecule from the extracellular fluid. In this case DA-β-hydroxylase the molecule is the amino acid tyrosine. However, unlike acetylcholine synthesis, the biosynthetic pathways involving tyrosine and catecholamines Vesicle Fused With are more complex. Of note are the number of enzymes involved in Presynaptic Membrane catecholamine synthesis, which, from a drug design viewpoint, represent NE potential targets for drugs that could lead to therapeutic agents useful for NE disease treatment. In most postganglionic neurons of the sympathetic division, catecholamine Presynaptic Autoreceptor biosynthesis terminates with the formation of norepinephrine. In some NE Reuptake anatomical sites, such as the adrenal medulla and some portions of the central Inactivation COMT Channel nervous system, norepinephrine is further modified to form epinephrine. of NE However, in dopaminergic neurons (mostly found in the central nervous Inactivation MAO of NE system), catecholamine biosynthesis terminates with the production of Adrenergic Receptors dopamine. Postsynaptic Terminal Integrated Pharmacotherapy 2 5 Hypertension Part 1 Similar to cholinergic transmission, catecholamines are also packaged into vesicles. When the nerve terminal is depolarized by a neuronal action potential, calcium influx occurs, triggering the fusion of the catecholamine-containing vesicles to the cell membrane and the subsequent release of catecholamine into the synaptic cleft. Once released into the synaptic cleft, catecholamines may bind with adrenergic receptors located on the postsynaptic cells. There are several processes that contribute to the removal of catecholamines from the synaptic cleft, and therefore, contribute to the decrease in effect of the released catecholamine neurotransmitters. Inhibition of these processes is a popular target for drugs involved in the nervous system. The first general process is called "reuptake". As the name suggests, catecholamines, and other related neurotransmitters (e.g., serotonin), may be recycled and repackaged into vesicles in the presynaptic nerve terminal by proteins that transport neurotransmitters from the synaptic cleft back into the presynaptic nerve cell. The second process is enzymatic degradation of the catecholamines. Two major enzymes are involved in this process: catecholamine-O- methyltransferase (COMT) and monoamine oxidase (MAO). The first enzyme, COMT, catalyzes the addition of a methyl group onto the para-hydroxyl group of catecholamines. It is important to understand that only catecholamines are substrates for COMT. There are many endogenous compounds as well as drugs that are chemically similar to catecholamines; however, these compounds are not broken down by COMT. The second enzyme, monoamine oxidase (MAO), oxidizes compounds such as norepinephrine, epinephrine, and dopamine at their terminal amine moiety. Autonomic Receptors Receptors in the autonomic nervous system have been named based on their affinity for selective agonists and antagonists. As agonists and antagonists were discovered that had greater selectivity for subtypes of receptors within a receptor class and with the advancement in molecular biology techniques, the names of receptors were further defined by subscript numbering. Autonomic receptors especially important relative to drug action include cholinergic receptors, adrenergic receptors, and dopaminergic receptors. Cholinergic receptors Table 1. Autonomic Receptor Tissue and Organ Effects Cholinergic receptors bind Sympathetic Activity Parasympathetic Activity acetylcholine and include nicotinic Organ or Tissue Major Receptors Effect Major Re- Effect and muscarinic receptors. As ceptors explained earlier, muscarinic and a1 contracts ------- ------- nicotinic cholinergic receptors were Vascular Smooth Muscle b2 relaxes ------- ------- named by their relative affinity Heart for either muscarine or nicotine. Mostly b1 Some b2 Sinoatrial (SA) node increase rate M2 decreases rate Muscarinic receptors are divided into Contractile Cells Mostly b1 Some b2 increases force M2 decreases force five subtypes: M1, M2, M3, M4, and Respiratory Tract M5. Nasal vasculature a1, a2 contracts ------- ------- Bronchial smooth muscle b2 relaxes M1, M3 contracts Adrenergic receptors Gastrointestinal Tract Adrenergic receptors are divided into Smooth muscle walls a2 b2 relaxes M3 contracts two groups: alpha (α) and beta (β). Smooth muscle sphincters a1 contracts M3 relaxes The α receptors are divided into two Secretions ------- ------- M3 increases subtypes: α1 and α2. The β receptors Genitourinary Tract are divided into three subtypes: β1, Bladder wall b2 relaxes M3 contracts β2, and β3. Of these, the β1 and β2 Sphincter a1 contracts M3 relaxes receptor subtypes are most important Uterus (pregnant) a1, a2 contracts M3 contracts in terms of drug action. Uterus (pregnant) b2 relaxes ------- ------- Eye Table 1 on page 6 is a list of a1 Pupillary dilator (radial) muscle contracts ------- ------- especially important organ sites Pupillary constrictor muscle ------- ------- M3 contracts affected by autonomic pharmacology. Ciliary muscle ------- ------- M3 contracts Within each organ group, functions Ciliary epithelium b1 b2 secretion of ------- ------- are separated by the effect of aqueous humor sympathetic and parasympathetic Metabolic Functions nerve innervation on the organ site Liver a1, a2, b2 gluconeogenesis ------- ------- along with the major receptor types Liver a1, a2, b2 glycogenolysis ------- ------- corresponding to each effect. Please Fat cells b3 lipolysis ------- ------- Kidney b1 Renin release ------- ------- note that this table summarizes the most common receptor subtypes in Adapted from Katzung, Basic and Clinical Pharmacology, 10th edition. Integrated Pharmacotherapy 2 6 Hypertension Part 1 general anatomical regions; within some anatomical categories, there are variations on the general rules based on specific anatomy. As you learn the autonomic drugs that are agonists and antagonists at specific autonomic receptors, this table will be a useful reference for explaining the effect caused by these drugs. Cardiovascular Physiology Overview of the Heart and Circulation The heart (Figure 6) is a fist-sized organ with a mass of 250-350 grams that resides within the mediastinum. It is enclosed by a double- walled sac called the pericardium. The outer wall of the pericardium consists of two layers: a superficial fibrous layer and a thin serous layer underneath. The outer fibrous layer is composed of tough, dense connective tissue that performs the following actions: protects the heart, anchors the heart to surrounding structures, and prevents the heart from overfilling with blood. The underlying serous layer is made up of a thin slippery serous membrane that turns inward at the base of the heart and lines the external heart surface (also referred to as the epicardium), creating an enclosed pericardial cavity. Serous fluid fills this space which allows the two membranes to glide smoothly past one another during normal cardiac functions. Figure 6. Anatomy of the Heart Heart Chambers The heart has four chambers: two atria and two ventricles (Figure 6). The atria are receiving chambers for blood returning to the heart from systemic and pulmonary circulation. They are small chambers with thin walls that contract generating minimal pressure. The ventricles make up the bulk of the heart and provide the pressure to push blood throughout the body. The heart valves are connected to the muscles via connective tissue. Pathway of Blood through the Heart Oxygen-depleted and carbon dioxide-rich blood returning from the systemic circulation enters the right atrium and then passes into the right ventricle (Figure 7 on page 7). The right ventricle pumps blood into the pulmonary artery passing through the lungs where carbon dioxide is unloaded and oxygen is picked up. The freshly oxygenated blood is carried by the pulmonary vein back to the left atrium. The blood passes from the left atrium into the left ventricle. Taken from Human Anatomy & Physiology, 7th Ed., Marieb. The left ventricle then ejects the blood into the aorta with enough pressure that the blood travels through systemic arteries to body tissues. Oxygen is picked up by the tissue in exchange for carbon dioxide. The oxygen-depleted and carbon dioxide-rich blood returns via the systemic veins to the heart where the cycle repeats itself. Heart Valves Figure 7. Blood flow through the heart Heart valves are important structures that maintain unidirectional Pulmonary Circulation blood flow through the heart. Valves are located between the atria and ventricles and between the ventricles and the large arteries leaving the heart (pulmonary artery and aorta). We will spend more time talking about heart valves in future Integrated Pharmacotherapy Right Atrium Left Atrium units. Right Tricuspid Valve Left Bicuspid Valve Cardiac Cells There are primarily two types of cells involved in the contraction HEART of the heart. The most abundant cell type is the myocardial Right Ventricle Left Ventricle contractile cells. These cells makeup about 99% of the heart cells and are primarily involved in contraction. The second cell type is Pulmonary Valve Aortic Valve called pacemaker or autorhythmic cells. These cells are involved in the intrinsic electrical conduction system that is mostly responsible for initiating and conducting the action potentials responsible for contraction. What follows is a brief introduction to these types of Systemic Circulation cells, which will be expanded upon in Integrated Pharmacotherapy 6. Integrated Pharmacotherapy 2 7 Hypertension Part 1 Myocardial Contractile Cells Cardiac muscle is similar to skeletal muscle in that it contracts by the sliding filament mechanism. The sliding filament mechanism consists of thin filaments (polymers of actin, troponin, and tropomyosin) sliding over stationary thick filaments (myosin), thereby, shortening the length of the muscle. Contractile cells have lots of mitochondria and use fatty acids as the primary source of energy. Contraction of myocardial contractile cells is triggered by an action potential (a complete reversal in membrane potential). Basically, an action potential triggers a set of events that results in myocardial contraction. Calcium from both the extracellular fluid and sarcoplasmic reticulum is a necessary component of the contraction process. The coupling of an electrical impulse to contraction is called excitation- contraction coupling. The Role of Calcium in Contraction Calcium enters the cytoplasm of the cell and binds to the troponin-tropomyosin complex that resides on the actin polymer of the thin filaments. This interaction triggers a conformational change allowing actin and myosin to form cross bridges resulting in contraction. During the plateau phase of the membrane potential when cytosolic calcium levels are high, calcium triggers contraction and tension develops for approximately the same amount of time that calcium is present inside the cells. This is sufficient time for contraction and ejection of blood from the heart. Another important aspect of calcium is that it can trigger the opening of a special subset of calcium channels in the membrane of the sarcoplasmic reticulum (ryanodine Ca2+-release channels). This process of calcium activating calcium channels is called calcium- induced Ca2+ release. This ensures Figure 8. The Cardiac Cycle a dramatic increase in cytosolic calcium sufficient to stimulate contraction. As you learn later in these student notes, increased levels of cytosolic calcium can augment the strength of the cardiac contraction. Cardiac Autorhythmic Cells Cardiac autorhythmic cells have an unstable resting membrane potential that leads to spontaneous action potentials. Basically, the difference in charge across the membrane slowly changes (the inside of the membrane becomes less negative than its resting potential). Once the change in potential reaches a critical level, known as threshold (typically between -50 and -55 mV), a rapid depolarization or action potential takes place. An action potential is a brief, rapid, dramatic change in membrane potential during which the membrane potential actually reverses and the inside of the cell transiently becomes more positive than the outside. The action potential is then spread throughout the heart triggering the myocardial contractile cells to contract. The Cardiac Cycle The cardiac cycle consists of alternating periods of contraction and emptying (systole) and Taken from Human Anatomy & Physiology, 7th Ed., Marieb. Integrated Pharmacotherapy 2 8 Hypertension Part 1 relaxation and filling (diastole). The cycle is denoted by a succession of pressure and blood volume changes in the heart. Contraction always follows the electrical events of an action potential moving through cardiomyocytes. Typically, the terms systole and diastole refer to the activity of ventricles. The cardiac cycle (Figure 8) begins and ends with ventricular diastole. Blood flow through the heart is controlled by pressure changes and blood flows down a pressure gradient through any available opening. The pressure changes reflect the alternating contraction and relaxation of the myocardium and direct the heart valves to open or close. Of course, this maintains a unidirectional blood flow through the heart. Phase 1. Ventricular filling: mid-to-late diastole. During the early phases of ventricular diastole, the atria are also in diastole. Blood is passively flowing from the venous system through the atria and open atrioventricular (AV) valves into the ventricles. The aortic and pulmonary (semilunar) valves are closed. Both chambers are relaxed and the volume is slowly rising. Approximately 80% of ventricular filling occurs during the earlier portion of this stage. As the ventricles continue to fill, pressure builds forcing the AV valves toward a closed position. During the late phase of ventricular diastole, the SA node membrane potential reaches threshold and fires an action potential. Atrial depolarization triggers atrial contraction which forces more blood into the ventricles. Approximately 20% of ventricular filling is delivered because of atrial contraction. At this point, atrial contraction has completed and the ventricles are completely full. The volume of blood in the ventricle at the end of diastole is called end diastole volume (EDV). For the remaining time of the cardiac cycle, the atria are in diastole. Phase 2. Ventricular systole: At this point, the action potential has spread into the ventricles and they begin contracting. The pressure inside the ventricles rises sharply and rapidly closing the AV valves. For an instant, during ventricular contraction the ventricles are completely closed chambers, called the isovolumetric contraction phase. As ventricular contraction continues, ventricular pressure finally exceeds the pressure in the larger arteries and the semilunar valves are forced open, thus ending the brief isovolumetric contraction phase. Blood is ejected from the ventricles into the aorta and pulmonary artery. This is called ventricular ejection. The ventricular pressure peaks during this phase. As ventricular blood volume decreases, the ventricular pressure begins to drop from its highest point. Phase 3. Isovolumetric relaxation: early diastole. The ventricles begin to relax and for a brief moment ventricular pressure dramatically drops and blood pressure in the aorta and pulmonary artery forces the semilunar valves closed. Once again, the ventricles are totally closed chambers (remember the AV valves are still closed). The amount of blood remaining in the ventricles is referred to as the end systolic volume (ESV). All during ventricular systole, the atria have been in diastole and blood has been flowing into them. The pressure inside the atria has been rising and when the pressure inside the atria exceeds the pressure inside the ventricles, the AV valves are forced open. This begins ventricular filling and the cycle is completed. On average, the heart beats about 75 times per minute and the length of the cardiac cycle is about 0.8 s. Atrial systole is 0.1 s, ventricular systole is 0.3 s, and the period of heart relaxation is 0.4 s. Cardiac Output Cardiac output is the volume of blood pumped by each ventricle per minute. Remember, cardiac output from each ventricle must be the same. Cardiac output is determined by heart rate (beats per minute) and stroke volume (volume of blood pumped per beat or stroke). The average heart rate is 75 beats/min and normal stroke volume is 70 ml/beat. By placing these numbers into the following equation, cardiac output can be calculated as follows: Cardiac output (ml/min) = heart rate (beats/min) X stroke volume (ml/beat) = 75 beats/min X 70 ml/beat = 5250 ml/min or 5.25 L/min The total blood volume is approximately 5-5.5 liters. This means that each half of the heart pumps approximately the entire blood volume each minute. It is important to remember that this is the cardiac output of a resting healthy human being. Cardiac output can dramatically increase during exercise, up to 20 to 25 liters per minute. This difference between cardiac output at rest and maximum cardiac output is called the cardiac reserve. The reason that the cardiac output can vary dramatically is that both heart rate and stroke volume can vary greatly. Integrated Pharmacotherapy 2 9 Hypertension Part 1 Regulation of Heart Rate Heart rate is primarily controlled by the pacemaker cells of the SA node. The heart is innervated by both the sympathetic and parasympathetic nervous systems. Both divisions of the autonomic nervous system innervates the SA and AV nodes. 1. Parasympathetic Nervous System. Acetylcholine (ACh) released by the parasympathetic nerve fiber (vagus nerve) binds to a muscarinic receptor and is coupled to an inhibitory G protein that reduces the activity in adenylyl cyclase and cAMP production. ACh slows the heart rate by increasing K+ permeability of the pacemaker cells in the SA and AV node. The muscarinic receptor is coupled directly to a K+ channel. Enhanced efflux of K+ hyperpolarizes the SA node membrane because more positive potassium ions leave than normal, making the inside of the cell even more negative. As a consequence, the membrane potential is even farther away from threshold and decreases the rate of spontaneous depolarization. This prolongs the time required to drift to threshold decreasing the heart rate. 2. Sympathetic nervous system. By contrast, the sympathetic neurotransmitter norepinephrine binds with b1 adrenergic receptors to speed up the heart rate. b1 adrenergic receptors are coupled to a stimulatory G protein which increases the activity of adenylyl cyclase and cAMP production in the SA and AV nodes, as well as the pacemaker cells located in the ventricles. The cAMP pathway leads to phosphorylation and altered activity of various proteins within cardiac contractile cells. In the pacemaker cells, increased permeability of Na+ and Ca2+ increase the slope of the drifting membrane potential so that the cells reach threshold more frequently. Again, influx of positive ions into the cell causes the inside of the membrane to become more positive, depolarizing the membrane potential. Sympathetic stimulation of the heart also increases the force of contraction by allowing greater influx of calcium ions into the cell through L-type Ca2+ channels. It also enhances the removal of calcium from the cytosol so that relaxation occurs more rapidly following the previous contraction. As is the case in most tissues, the heart is dually innervated by the parasympathetic Figure 9. Cardiac Cell Length and Tension Relationship and sympathetic nervous system. These systems act in opposition. At any given time, the heart rate is determined by the balance between inhibition of the parasympathetic system and stimulation of the sympathetic nerves. At rest, the parasympathetic system dominates keeping the heart rate around 70-75 beats per minute (or lower depending on fitness capacity). Again, this allows for a dramatic increase in heart rate when the sympathetic nervous system is activated dramatically increasing the capacity of the body to respond to a stressful situation. Regulation of Stroke Volume Stroke volume (SV) is the amount of blood pumped out of each ventricle during each beat. Stroke volume is essentially the difference between EDV (the amount of blood that collects during diastole) and ESV (the amount of blood that remains Taken from Human Anatomy & Physiology, 7th Ed., Marieb. after the heart has contracted). SV can be calculated by the following equation: Stroke volume (ml/beat) = EDV - ESV = 120 - 50 Figure 10. Cardiac Preload and Afterload = 70 ml/beat This equation is very important and should always be referred to when you think about stroke volume and cardiac output. As you can see by the numbers in the equation, with each heartbeat, the ventricles pump out approximately 60% of the blood in its chambers. Stroke volume is primarily influenced by three key factors: preload, contractility, and afterload. As described in detail next, preload affects EDV, whereas contractility and afterload affect ESV. Preload Preload is the pressure in the ventricles that the cardiac cells incur just before they contract. Before we discuss preload, we must first discuss a fundamental principle of muscle cells. A relationship exists between the length of muscle before contraction and tension (amount of force) that a contracting cell can subsequently develop at that length Taken from Human Anatomy & Physiology, 7th Ed., Marieb. (Figure 9). Based on this relationship, every muscle cell has an optimal resting length at which maximum force or tension can be generated. This is a result of an optimal overlap of thick and thin filaments where the maximum number of cross bridges is accessible for cycles of contraction. At a resting length less than the optimal resting length, Integrated Pharmacotherapy 2 10 Hypertension Part 1 less tension can be generated because the ends of the thin filaments become Figure 11. Effect of BP Decrease on Cardiac Physiology overlapped and fewer binding sites are available. If the resting length is greater than the optimal resting length, less tension can be developed because the muscle is stretched reducing the number of cross bridges. Cardiac cells are no different and maintain an optimal length at which the force of contraction is maximal. Cardiac cells are normally shorter than their optimal length. As a result, stretching of cardiac cells allows for a dramatic capacity for contractile force. Venous return or preload is the most important factor causing stretching of cardiac muscle (Figure 10). The greater the diastolic filling, the larger the EDV, and the larger the stretch. The increased length results in a greater force on the subsequent contraction and thus a greater stroke volume. This intrinsic relationship between EDV and stroke volume is called the Frank-Starling law of the heart. In simpler terms, the law states that the heart pumps out what is returned to it. This maintains an equal output of the right and left sides of the heart. This is also advantageous under conditions of stress where cardiac output must be increased and stroke volume can dramatically increase. Of course, the increased venous return increases the amount of stretch and because cardiac cells are shorter than their optimal length, cells can still generate maximum tension. The amount of blood returning to the heart and its ventricles directly impacts the EDV. If the venous return is increased as in the case of exercise or slow heart rate, EDV increases. If there is no change in ESV, then SV increases (and CO also). A slow heart beat allows for more time for filling and exercise speeds up the venous return. In contrast, low venous return as a result of blood loss or an extremely rapid heart rate (> 210 beats per minute) decreases EDV. Again, this reduces SV and CO. When there is a change in EDV or ESV, place the numbers into the equation SV = EDV - ESV to determine its impact on stroke volume. Then take it one more step forward and put the new SV into the equation CO = SV x HR and determine Taken from Human Anatomy & Physiology, 7th Ed., Marieb. the impact on CO. Utilization of these equations in this manner is imperative to understand cardiac physiology. Contractility Contractility is defined as the strength of contraction at any given EDV. Cytosolic Ca2+ can influence the strength of contraction. Increases in Ca2+ can dramatically increase the strength of contraction. An increased strength of contraction results in a greater proportion of blood being ejected from the heart during the contraction. This increases SV. How does increased contraction increases SV? Think about how contractility affects the SV equation. The answer is that if you reduce ESV, you increase SV. Recall that SV = EDV - ESV. As you may recall, the sympathetic nervous system triggers a greater influx in the amount of cytosolic calcium which increases the strength and force of contraction. So not only does the sympathetic nervous system increase the heart rate, but it also increases SV, both of which increase CO. Afterload Because blood is ejected into a closed system of large arteries (aorta and pulmonary artery), there is a pressure that exists called afterload. This pressure is the pressure that the heart has to overcome with each contraction for blood to be propelled. In healthy individuals, afterload is not a major issue because the elasticity of the large arteries reduce the pressure. However, in individuals with hypertension where the elasticity is reduced or the smooth muscles are contracted (reducing the diameter of the vessels), the afterload is elevated reducing the ability of ventricles to eject blood. As a consequence, more blood remains in the ventricles after systole. What is the affect of increased afterload on ESV? SV? CO? The Peripheral Circulation Blood travels continuously throughout the body through a closed network of blood vessels (Figure 12 on page 12). There are three major types of blood vessels: arteries, capillaries, and veins. Arteries carry blood away from the heart branching into smaller and smaller divisions. Arterioles feed into capillary beds which are microscopic vessels with very thin walls. The simple structure of a capillary allows for exchange of gases, nutrients, and waste between blood and the interstitial fluid of tissues. Blood flows from the capillaries into veins and back towards the heart. Integrated Pharmacotherapy 2 11 Hypertension Part 1 All vessels are lined by a thin layer of endothelial cells that is in intimate contact with Figure 12. Peripheral Circulation the blood in the lumen. The endothelium is a continuation of the endothelium lining the heart. This layer provides a slick surface that allows blood to move freely as it glides past and is supported by a thin basement membrane. Surrounding the endothelial cells is a thick wall consisting of mostly circularly arranged smooth muscle cells and sheets of connective tissue. Elastin fibers give the arterial walls elasticity so they can rebound after being stretched. Sheets of collagen provide strength to the vessel wall against the high driving pressure of blood. Arterial System The arterial system is divided into arteries and arterioles. Each have a unique size and function. Arteries distribute blood from the heart to the organs. The arteries located near the heart have large diameters and offer very little resistance to blood flow. Because they have lots of elastic connective tissue, they can act as pressure reservoirs, expanding and recoiling as blood is ejected from the heart during systole and diastole, respectively. Arteries feed into arterioles which are smaller in diameter, are highly muscular, and provide considerable resistance to blood flow. Arterioles have little elastin and convert the pulsating pressure swings in the arteries into the stable pressure present in the capillaries. The smooth muscle layer is under the control of sympathetic nerve fibers and other hormones that control the vessel’s circumference. When the smooth muscle layer contracts, the diameter is reduced, resistance is increased, and flow through the vessel is reduced (vasoconstriction). When the smooth muscle layer relaxes, the diameter is increased, and blood flow through the vessel is increased (vasodilation). Venous System Blood flows from capillaries into venules and then into veins and then into the right Taken from Human Anatomy & Physiology, 7th Ed., Marieb. atrium. Veins have large diameters, thin and compliant walls, and low resistance to flow resulting in the their ability to act as low-resistance conduits for blood flow from the tissues to the heart. Because of the low resistance, peripheral veins contain valves that permit flow only toward the heart. A second function in addition to their role as low-resistance conduits is the diameter of veins can be altered in response to changes in blood volume. Approximately 60 percent of the total blood volume is present in the systemic veins at any given moment and can accommodate large volumes of blood with a relatively small increase in internal pressure. The walls of the veins contain small amounts of smooth muscle innervated by sympathetic neurons. Activation of these neurons release norepinephrine which causes contraction of the venous smooth muscle, decreasing the diameter and compliance of the vessels and raising the pressure within them. Increased venous pressure then drives more blood out of the veins into the right side of the heart. In addition to contraction of venous smooth muscle, the skeletal muscle pump and respiratory pump act to increase movement of blood back to the heart. Contraction of both muscles raises venous pressure locally and the valves permit the blood flow only toward the heart to prevent backflow toward the tissues. Figure 13. Blood Vessel Pressure Gradient Physiology of Circulation Blood circulation is dependent on three factors: blood flow, blood pressure, and resistance. Blood flow is the volume of blood flowing through a vessel in a given time period. The units are typically expressed as milliliters per minute (ml/min). Blood pressure the force of blood exerted on a vessel wall and is expressed in millimeters of mercury (mm Hg). Resistance is the opposition of blood flow as it moves through a vessel. Because most resistance occurs at the level of the arterioles in the peripheral circulation, it is called total peripheral resistance. There are three factors that influence resistance: blood viscosity, vessel length, and vessel diameter. Blood viscosity is the internal friction that exists in all fluid as the molecules slide over each other during the flow of the fluid. The greater the viscosity, the less easily molecules move and the greater the resistance to flow. Blood viscosity is primarily determined by the number of circulating red blood cells. Normally, the red blood count does not change; however, blood viscosity and resistance is affected by an abnormal red blood cell count. When Taken from Human Anatomy & Physiology, 7th Ed., Marieb. Integrated Pharmacotherapy 2 12 Hypertension Part 1 red blood counts increases, viscosity and resistance is increased. A longer vessel length results in greater resistance. This is particularly important when people gain significant amounts of weight and their vessel length is dramatically increased. As a consequence, resistance is increased. Because viscosity and vessel length remain relatively constant, the major determinant of resistance is vessel diameter. Changes in vessel diameter occur frequently. Fluid passes through a large vessel more easily than through a smaller vessel. In a small-radius vessel, more of a given volume of blood comes into contact with much more of the surface area than in a larger-radius vessel, resulting in greater friction and resistance. Resistance varies inversely with the fourth power of the vessel radius (R is proportional to 1/r4). This means that doubling the radius reduces resistance to 1/16 its original value and increases flow through the vessel 16-fold (at the same pressure gradient). Only 1/16 as much blood can flow through the vessel at the same pressure gradient when the radius is reduced by two. Relationship between Blood Flow, Blood Pressure, and Resistance The flow rate of blood (F) through a vessel is directly proportional to the difference in blood pressure between two points in the circulation (∆P). Blood flow (F) is inversely proportional to peripheral resistance (R). Resistance is also designated by total peripheral resistance or TPR. These relationships are expressed by the formula: F = ∆P/R. This indicates that when ∆P increases, blood flow speeds up, and when ∆P decreases, blood flow is reduced. If R increases, blood flow decreases. Systemic Blood Pressure The pumping action of the heart generates enough pressure to mediate blood flow. Of course, blood flow is opposed by resistance. In Figure 13, systemic blood flow is highest in the aorta and decreases to virtually zero by the time it is received by the right atrium. This is a very important concept, blood moves through blood vessels along a pressure gradient, always moving from higher- to lower-pressure areas. Arterial Blood Pressure Arterial blood pressure is influenced by how much elastic arteries near the heart can be stretched and by the volume of blood entering and leaving the arteries. When the left ventricle contracts and ejects blood into the aorta, the elastic aorta stretches and expands. The pressure generated during systole is called the systolic pressure. This is the peak blood pressure. Blood flows from the aorta into distal vessels because the pressure in the aorta is higher than in those vessels. During diastole, the aortic valve closes so that blood cannot flow back into the heart. At the same time, the elastic aorta recoils maintaining sufficient pressure to keep blood flowing forward to distal vessels, and aortic pressure drops to its lowest level. This is called the diastolic pressure. The difference between the systolic and diastolic pressure is called the pulse pressure. As the blood moves farther away from the heart, the fluctuations are gradually phased out. Because the aortic pressure fluctuates up and down with each heartbeat, one must consider the mean arterial pressure (MAP). MAP is the pressure that propels the blood through the body. The MAP is not simply the average between systolic and diastolic pressure because diastole lasts longer than systole. Because of this, MAP is the average pressure throughout the cardiac cycle of contraction; Since 2/3 of the time is spent in diastole and 1/3 in systole, the MAP is estimated using the following equation: MAP = 1/3 (SBP) + 2/3 (DBP) For a person with a blood pressure of 120/80: MAP = 40 + 53 = 93 mm Hg Maintaining a steady flow of blood from the heart is the most important function of the heart and vasculature and it does this by maintaining blood pressure. The main players that regulate blood pressure are cardiac output, peripheral resistance, and blood volume (TPR is also know as systemic vascular resistance or SVR). Recall, F = ∆P/TPR or CO = ∆P/TPR or ∆P = CO x TPR These equations are extremely important. Integrated Pharmacotherapy 2 13 Hypertension Part 1 Because CO depends on blood volume, it is clear Figure 14. Intrinsic and Extrinsic BP Controls that blood pressure varies directly with CO, R, and blood volume. This means that a change in any of these variables directs a corresponding change in blood pressure. In reality, a change in any variable alters normal blood pressure, setting off a cascade of events that compensates for the changed variable to maintain normal blood pressure. Factors That Regulate Blood Pressure There are several mechanisms that regulate blood pressure including short-term neural and hormonal mechanisms and long-term renal mechanisms (Figure 14 on page 14). Short-Term Mechanisms: Neural Controls Short-term or “faster” controls of blood pressure primarily control blood pressure by altering peripheral resistance (and CO). This is done Taken from Human Anatomy & Physiology, 7th Ed., Marieb. through two mechanisms. The first mechanism is the maintenance of MAP through regulation of blood vessel diameter via vasoconstriction. The second mechanism is through altering blood distribution (also via vasoconstriction). For example, during exercise, blood will be temporarily shunted away from the gastrointestinal tract to the skeletal muscles. Neural controls of the vasomotor center receive inputs from baroreceptor-initiated reflexes, chemoreceptors, and higher brain centers. The vasomotor center is a cluster of neurons in the medulla of the brainstem that transmit signals along sympathetic efferent nerves regulating blood vessel diameter through vasoconstriction. This center receives inputs from baroreceptors, chemoreceptors, and higher brain centers. Baroreceptors are neural receptors located in the aortic arch and in the walls of nearly every major artery of the neck and thorax. When stretched more than normal (increase in blood pressure), baroreceptors transmit a signal to the vasomotor center, which initiates vasodilation and a reduction in peripheral resistance and a subsequent decrease in blood pressure. A decrease in blood pressure initiates vasoconstriction and an increase in cardiac output to increase blood pressure back to normal. The baroreceptor response is especially important during acute changes in blood pressure such as those occurring when one stands up after reclining. Chemoreceptors located in the aortic arch and large arteries of the neck measure oxygen content or pH of the blood. Lastly, higher brain centers such as the hypothalamus can regulate blood pressure through the sympathetic nervous system. Long-Term Mechanisms: Renal Controls The long-term or “slower” controls of blood pressure result by controlling blood volume. Recall that blood volume is a major determinant of cardiac output through its influence on venous return, EDV, and stroke volume. An increase in blood volume increases blood pressure. The kidneys primarily regulate blood volume. They can do this through control of GFR and also through the release of renin. Recall that renin release triggers a series of reactions that produce angiotensin II (Figure 19). Angiotensin II is a potent vasoconstrictor increasing blood pressure. It also stimulates aldosterone, a hormone that enhances renal reabsorption of sodium. Angiotensin II also stimulates the posterior pituitary gland to release ADH, which promotes water reabsorption. The net result of these molecules is sodium and water reabsorption to increase blood volume and blood pressure. Smooth Muscle Contraction Smooth muscle cells (Figure 15) are mostly found in the walls of hollow organs and tubes and play a role in the movement of the contents of these structures. Smooth muscle is a type of muscle cell with a spindle shape and a single centrally-located nucleus. A smooth muscle cell is considerably smaller than a skeletal muscle cell and smooth muscle is typically arranged in sheets. Smooth muscle contracts in a manner that is distinctive from skeletal and cardiac muscle cells but shares some of the same molecules. Smooth muscle cells contain both thick and thin filaments that contain tropomyosin but not troponin. These thick and thin filaments are arranged diagonally from side to side in an elongated, diamond-shaped lattice so that they spiral down the long axis of the cell. The thick and thin filaments are anchored to the internal surface of the plasma membrane (sarcolemma) at regular intervals called dense bodies. During contraction, thin filaments slide past the thick filaments causing the lattice to shorten and expand from side to side. As a result, the cell shortens and bulges outward between the connections to the plasma membrane (Figure 16). Integrated Pharmacotherapy 2 14 Hypertension Part 1 Innervation of Smooth Muscle Figure 15. Smooth Muscle Smooth muscle is typically innervated by both branches of the autonomic nervous system. Smooth muscle lacks a defined neuromuscular junction. In contrast, the innervating nerve fibers have numerous bulbous swellings, called varicosities that are spread along the nerve terminal across the surface of one or more smooth muscle cells (Figure 17). The varicosities contain synaptic vesicles loaded with the neurotransmitter molecules that are released as an action potential passes along the terminal. Released neurotransmitter diffuses across the wide synaptic cleft onto the underlying smooth muscle cells where it binds to its receptor on the sarcolemma. Taken from Human Anatomy & Physiology, 7th Ed., Marieb. It is important to point out that other factors (besides autonomic neurotransmitters) influence smooth muscle activity. All factors, through a variety of mechanisms, increase the permeability of calcium channels (cause them to be more open) in the plasma membrane, the sarcoplasmic reticulum, or both. Figure 16. Relaxed and Contracted Smooth Muscle Contraction of Smooth Muscle Entire sheets of smooth muscle contract in slow, synchronized fashion. Smooth muscle is connected by gap junctions allowing for contractions to occur in unison. Smooth muscle contracts by a sliding filament mechanism which includes thin filaments sliding inward over the stationary thick filaments. The main structural component of a thin filament is two polymers of spherical actin molecules twisted together. A thick filament is made up of myosin molecules lying lengthwise parallel to each other. Half are orientated in one direction and half are oriented in the opposite direction. The globular heads protrude at regular intervals along the thick filament, forming the cross bridges. The myosin heads have two important sites crucial for contraction: an actin-binding site and a myosin ATPase (ATP splitting) site. The process of smooth muscle contraction via the actin-myosin cross bridging is Taken from Human Anatomy & Physiology, 7th Ed., Marieb. demonstrated in Figure 18 on page 16. Special Features of Smooth Muscle Contraction Smooth muscle contraction and relaxation cycle is approximately 10-30 times longer than skeletal muscle. Further, smooth muscle can maintain tension for prolonged periods at very low energy costs. This is important because Figure 17. Innervation of Smooth Muscle smooth muscle can maintain moderate degrees of contraction without fatiguing. This result from sluggish ATP splitting by the myosin ATPase, slower calcium removal from the cytosol, and the slow dephosphorylation of myosin light chain. Length-Tension Relationship Smooth muscle has a great range of lengths over which it can develop near maximal tension. This can occur at ~60% to 250% of its optimal resting length. This results from the fact that normal smooth muscle resting length is shorter than skeletal muscle and the thick filaments are extremely long, so that when stretched, cross-bridging can maximally occur and develop tension. This is a key feature of smooth muscle because they can maintain their tone and develop further tension when stretched. Taken from Human Anatomy & Physiology, 7th Ed., Marieb. Stress-Relaxation Response Smooth muscle also has a stress-relaxation response. This is where smooth muscle can adjust to new lengths when stretched. Initially, when the cell Integrated Pharmacotherapy 2 15 Hypertension Part 1 is stretched, it briefly contracts and then Figure 18. Actin-Myosin Cross Bridging inherently relaxes to a similar tension level prior to stretch. This results from a rearrangement of cross bridge attachments. Because of the stress-relaxation response and the ability to develop near maximum tension at varying muscle lengths, smooth muscle can exist at variable lengths with little change in tension. This allows organs to accommodate variable volumes with little change in pressure, and then when required, contract to dramatically reduce organ diameter. Hyperplasia Like other muscle, smooth muscle can undergo hypertrophy (increase in cell size). Smooth muscle can also divide to increase their numbers (hyperplasia), a feature unique to smooth muscle. Other types of muscle have very limited capacity to undergo cell division. This is an important feature because smooth muscle may experience increased pressure, and to compensate, it can undergo cell division to increase its strength and ability to develop tension. As calcium enters the cell, a cascade of activation occurs (using ATP to phosphorylate the myosin head). Shortening occurs, contracting the cell. Then the phosphate is removed and the myosin head detaches from the actin molecule. Taken from Human Anatomy & Physiology, 7th Ed., Marieb. ETIOLOGY AND PATHOPHYSIOLOGY Hypertension is defined as a persistently elevated blood pressure. Hypertension is a major concern because there is a very strong correlation between high blood pressure and morbidity and mortality. Furthermore, patients with high blood pressure have increased risk of stroke, myocardial infarction, angina, heart failure, and kidney failure. Etiology Primary Hypertension Primary HTN (aka essential HTN) describes HTN where the exact underlying abnormality is not known. Numerous genetic and environmental mechanisms have been identified as contributing to the development of primary HTN by increasing CO and/or TPR, so a single mechanism to explain the etiology of primary HTN is not possible. More than 90% of patients with HTN have primary HTN. There is no cure for primary HTN, but primary HTN can be controlled with antihypertensive medications. Integrated Pharmacotherapy 2 16 Hypertension Part 1 Secondary Hypertension Figure 19. RAAS Approximately 5% to 10% of patients with HTN have secondary HTN. Secondary HTN results from certain medications (drug-induced HTN) or an anatomic or pathophysiologic abnormality. For example, patients with primary hyperaldosteronism have excess production of aldosterone. Aldosterone leads to sodium and water retention, ultimately increasing blood volume and blood pressure. Secondary HTN can be resistant to antihypertensive medications, but may be curable by other means. For example, when hyperaldosteronism is treated with aldosterone antagonists, the blood pressure improves significantly. Isolated Systolic Hypertension Isolated systolic hypertension (ISH) occurs more commonly in elderly patients as a result of the aging process. During the aging process, there are changes in the arterial vasculature that result in a decrease in the compliance of the arterial wall. This decreased compliance, or hardening of the arterial wall, results in a higher pressure during systole, as the less elastic arterial wall absorbs little of the pressure generated when blood is ejected from the heart. Additionally, this decreased compliance results in a lower pressure during diastole as the less elastic arterial wall is unable to maintain pressure when the ventricles are filling with blood. Consider ISH as a condition where the patient has blood vessels that are like steel pipes, whereas patients without ISH have blood vessels that are like hoses made from rubber bands. Patients with ISH have an increased risk of cardiovascular morbidity and mortality. Pathophysiology The cause of essential hypertension is unclear, but the following factors could potentially contribute to this disease: humoral mechanisms (RAAS, natriuretic hormones, and insulin), abnormal neuronal mechanisms, defects in peripheral autoregulatory systems, and disturbances in electrolytes (sodium, calcium, and potassium). It is thought that none are solely responsible and all probably play some part in the disease. As you know, blood pressure = cardiac output x total peripheral resistance. Table 2 lists the physiologic causes of increased cardiac output and total peripheral resistance that could potentially lead to hypertension. Humoral Mechanisms Renin-Angiotensin-Aldosterone System (RAAS) The RAAS regulates blood volume and electrolyte balance. Angiotensin II directs peripheral vasoconstriction which increases total peripheral resistance (TPR), and ultimately blood pressure (BP). Angiotensin II also increases cardiac contractility and cardiac hypertrophy, both or which can increase blood pressure. Aldosterone increases sodium and water reabsorption, and ADH increases water reabsorption. A defect in any of the RAAS could lead to hypertension. Natriuretic Hormone The natriuretic hormones normally inhibit sodium reabsorption. However, dysfunction of this system can block the inhibitory effects of sodium reabsorption resulting in increased sodium reabsorption and increased blood volume. As natriuretic hormone levels increase, this also results in increased intracellular sodium levels. This directly causes smooth muscle contraction, increased TPR and increased blood pressure. Insulin Resistance/Hyperinsulinemia It is thought that increased levels of insulin can increase sodium retention, increase smooth muscle hypertrophy, and increase intracellular calcium levels in smooth muscle. All three of these factors could contribute to persistently elevated blood pressure. Integrated Pharmacotherapy 2 17 Hypertension Part 1 Neuronal Mechanisms Table 2. Potential Mechanisms of Pathogenesis Pathologic dysfunction of the autonomic nervous Increased Cardiac Output Increased Peripheral Resistance system, adrenergic receptors, baroreceptors, and central nervous system could also potentially lead to Increased cardiac preload Functional vascular constriction Increased fluid volume from excess sodium Excess stimulation of the RAAS increased blood pressure. intake or renal sodium retention (from Sympathetic nervous system reduced number of nephrons or decreased hyperactivity Adrenergic Receptors glomerular filtration) Genetic alterations of cell membranes Disruption of the normal function of the adrenergic Venous constriction Endothelial-derived factors receptors could chronically increase blood pressure. Excess stimulation of the RAAS Structural vascular hypertrophy Presynaptic neurons release norepinephrine which Sympathetic nervous system hyperactivity Hyperinsulinemia resulting from stimulates the vasoconstriction of the smooth obesity or the metabolic syndrome muscle lining the vasculature. Stimulation of the a2- receptors located on the presynaptic neurons block norepinephrine release. Stimulation of b-receptors also on the presynaptic neuron increases norepinephrine release. On the effector cells, stimulation of a1-receptors causes vasoconstriction of smooth muscle; stimulation of b1-receptors causes increased heart rate and contractility, and stimulation of b2-receptors causes vasodilation. Baroreceptors The baroreceptor mechanism may be dysfunctional, less responsive, or inappropriately too responsive, leading to increased blood pressure. Stimulation of the Central Nervous System Stimulation of specific areas of the central nervous system can increase blood pressure, including the vasomotor center, vagal nuclei, nucleus tractus solitarius, and the area postema. Peripheral Autoregulatory Systems Increased blood pressure can result from a defect in renal-tissue autoregulatory systems. Basically the autoregulatory systems that regulate blood flow to tissues can be dysfunctional leading to vasoconstriction and increased TPR. Vascular Endothelial Cells Endothelial cells synthesize vasoconstrictor molecules such as angiotensin II and endothelin I, and vasodilator substances such as PGI2 (prostacyclin), bradykinin, and nitric oxide (NO). Electrolytes An imbalance of electrolytes can lead to elevated blood pressure. Excessive intake of sodium leads to fluid retention. Contrary to what makes sense physiologically, low levels of calcium increase smooth muscle contraction. It is thought, but not proven, that altered potassium levels play a role in blood pressure. REFERENCES 3. Abramowicz M, Zuccotti G, Rizack MA, et al. Cardiovascular drugs in the ICU. Medical Letter 2002;1:19-21. 4. Agodoa LY, Appel L, Bakris GL, et al. Effect of ramipril vs. amlodipine on renal outcomes in hypertensive nephrosclerosis. Journal of the American Medical Association 2001;285:2719-28. 5. ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuretic. Journal of the American Medical Association 2002;288:2981-2997. 6. American Heart Association. Recommendations for blood pressure measurement in humans and experimental animals. Hypertension 2005;45:142-61. 7. AVOID Study Investigators. Aliskiren combined with losartan in type 2 diabetes and nephropathy. New England Journal of Medicine 2008;358:2433-46. 8. Bakris GL, Gonzalez ER. Case Study: The link between hypertension and diabetes. Journal of Managed Care Pharmacy 2007;13:S17-9. 9. Bakris GL, Weir MR. Angiotensin-converting enzyme inhibitor – associated elevations in serum creatinine. Archives of Internal Medicine 2000;160:685-93. 10. Boehringer SK. Can angiotensin receptor blockers be used in patients who have previous ACE inhibitor-induced angioedema? Pharmacist’s Letter 2004;20. Detail-document #200709. 11. Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: Diagnosis, evaluation, and treatment. Hypertension 2008;51:1403-19. 12. Chobanian AV, Bakris GL, Black HR, et al. Seventh Report of Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VII). Hypertension 2003;42:1206-52. 13. Douglas JG, Ferdinand KC, Bakris GL, et al. Barriers to blood pressure control in African Americans. Postgraduate Medicine 2002;112:51-70. 14. Egan BM, Basile JN, Rehman SU, et al. Plasma renin test-guided drug treatment algorithm for correcting patients with treated but uncontrolled hypertension: Integrated Pharmacotherapy 2 18 Hypertension Part 1  A randomized controlled trial. American Journal of Hypertension 2009;22:792-801. 15. Elliott WJ. Management of hypertension in the very elderly patient. Hypertension 2004;44:800-4. 16. Epstein BJ. Elevations in serum creatinine concentration: Concerning or reassuring? Pharmacotherapy 2004;24:697-702. 17. Gradman AH, Schmieder, Lins RL. Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Circulation 2005;111:1012-18. 18. Gray CL, Ndefo U. Nebivolol: A new antihypertensive agent. American Journal of Health-System Pharmacists 2008;65:1125-33. 19. Haskell WL, Lee I, Pate RR, et al. Physical activity and public health: Updated recommendation for adults from the American College of Sports Medicine and the American Heart Association. Circulation 2007;116:1081-93. 20. HYVET Study Group. Treatment of hypertension in patients 80 years of age or older. New England Journal of Medicine 2008;358:1-12. 21. Izzo JL, Levy D, Black HR. Importance of systolic blood pressure in older Americans. Hypertension 2000;35:1021-4. 22. Khosla N, Chua DY, Elliott WJ. Are chlorthalidone and hydrochlorothiazide equivalent blood pressure lowering medications? Journal of Clinical Hypertension 2005;7:354-6. 23. Nelson ME, Rejeski J, Blair SN, et al. Physical activity and public health in older adults: Recommendation from the American College of Sports Medicine and the American Heart Association. Circulation 2007;116:1094-1105. 24. Nishizaka MK, Zaman M, Calhoun DA. Efficacy of low-dose spironolactone in subjects with resistant hypertension. American Journal of Hypertension 2003:16:925-30. 25. ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. New England Journal of Medicine 2008;358:1547-59. 26. Palmer BF. Managing hyperkalemia caused by inhibitors of the rennin-angiotensin-aldosterone system. New England Journal of Medicine 2004;351:585-92. 27. Rosendorff C, Black HR, Cannon CP, et al. Treatment of hypertension in the prevention and management of ischemic heart disease. Circulation 2007;115:2761- 88. 28. Rodgers PT. Combination drug therapy in hypertension: A rational approach for the pharmacist. Journal of the American Pharmaceutical Association 1998;38:469-79. 29. Saseen JJ, MacLaughlin EJ. Hypertension. In: Dipiro JT, Talbert RC, Yee GC, et al. 7th ed. Pharmacotherapy: A Pathophysiologic Approach. McGraw Hill. 2008. 30. Satish S, Freeman DH, Ray L, et al. The relationship between blood pressure and mortality in the oldest old. Journal of the American Geriatrics Society 2001;49:367-74. 31. Schulman IH, Zhou MS, Raij Leopoldo. Cross-talk between angiotensin II receptor types 1 and 2. Hypertension 2007;49:270-1. 32. Sica DA. Combination angiotensin-converting enzyme inhibitor and angiotensin receptor blocker therapy: Its role in clinical practice. Journal of Clinical Hypertension 2003;5:414-20. 33. Smith RD, Levy P, Ferrario CM. Value of noninvasive hemodynamics to achieve blood pressure control in hypertensive subjects. Hypertension 2006;47:771-7. 34. Stokes GS. Systolic hypertension in the elderly: Pushing the frontiers of therapy – a suggested new approach. Journal of Clinical Hypertension 2004;6:192-7. 35. Taler SJ, Textor SC, Augustine JE. Resistant hypertension: Comparing hemodynamic management to specialist care. Hypertension 2002;39:982-8. 36. Tissot AC, Maurer P, Nussberger J, et. al. Effect of immunization against angiotensin II with CYT006-AngQb on ambulatory blood pressure: a double-blind, randomized, placebo-controlled phase IIa study. Lancet 2008;371:821-7. 37. U.S. Preventative Services Task Force. Screening for high blood pressure: U.S. Preventive Services Task Force reaffirmation recommendation statement. Annals of Internal Medicine 2007;147:783-6. 38. Wright JT, Bakris G, Greene T, et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease. Results from the AASK trial. Journal of the American Medical Association 2002;288:2421-31. Integrated Pharmacotherapy 2 19 Hypertension Part 1