NSG533 / NSG 533 Exam 1 (Latest 2026 /2027) Advanced Pharmacology | Questions and Verified Answers with Rationales | 100% Correct | Grade A - Wilkes

NSG533 / NSG 533 Exam 1 (Latest 2026 /2027) Advanced Pharmacology | Questions and Verified Answers with Rationales | 100% Correct | Grade A - Wilkes What are the five essential components of pathophysiology? 1. Etiology (Causative mechanisms) 2. Epidemiology (risk factors and distribution in populations) 3. Pathogenesis (disease mechanism) 4. clinical manifestations (signs, symptoms and diagnostic criteria) 5. Outcomes (cure, remission, chronicity, or death) The "why" of disease- what is the reason for it- what caused it to happen? May be simple/complex. etiology Looks at the pattern of disease among groups or aggregates or populations. This component of disease represents the relationship between numerous population characteristics (e.g. age, ethnicity, socioeconomic status, geographic location) and the incidence and prevalence of disease. Epidemiology Involves the sequence of events that occurs between the stimulus event(s) and the manifestations of the disease. pathogenesis Tell an individual and their health care provider that something is wrong. e.g. Signs and symptoms Clinical manifestations Are relatively easy to understand if you review their definitions (cure, remission, chronicity, or death) Outcomes What are the 4 common mechanisms that characterize all cell injury and death? Give 2 examples of each. 1. ATP depletion- Ischemia and Anemia 2. Oxygen and oxygen-derived free radicals- Chemical and radiation injury, ischemia reperfusion injury, microbial killing by phagocytes, and cellular aging 3. intracellular calcium and loss of calcium steady state- Ischemia and certain chemicals 4. Defects in membrane permeability- Certain medications that can lead to liver or kidney damage The disease mechanism that is the basis of much of the disease today- and most of the cases involve hypoxia. Refers to the inability of the cell to produce adequate energy to fuel normal activities of that particular cell type (cell membrane pumps and protein synthesis) and function. ATP depletion A very inefficient method of ATP production (yields 2 ATP) glycolysis Is a very efficient method of ATP production (yields 36 ATP) Oxidative Phosphorylation What is the most common method of impairing oxygen and ATP production? hypoxia Can lead to irreversible cell injury directly through impairment of energy production in the cell. Ischemia What are the cellular events that occur with ischemia-induced- hypoxic injury? 1. The amount of ATP production within the mitochondria declines 2. The drop in ATP causes NA-K- ATPase pump on CM to fail. Which then leads to increase in NA+,H2O, and Ca+ in cell and decrease in K+ in cell. 3. Increase in water in cell causes cell and it's organelles to swell. 4. When RER swell it's ribosomes fall off and protein synthesis stops. 5. ATP production through phosphorylation declines and glycolysis (anaerobic metabolism) increases. When glycolysis increases in the cell glycogen stores are depleted. 6. Glycolysis also produces lactic acid as by-product. Glycolysis also = intracellular pH decline ( the cell functions within narrow range of pH and even slight drop can incapacitate the cell). 7. Drop in pH causes clumping of nuclear material called pyknosis. Leads to fragmentation of the nuclear material (karyorrhexis) and then to dissolution of nuclear membrane (karyolysis). Decline in pH= rupture of already swollen lysosomes and release of proteolytic enzymes= autodigestion of cell contents and cell membrane. 8. Disruption of CM also increases Ca+ influx into the cell and organelles= activate proteases, endonucleases, and phospholipases that proceed to destroy the cell. Unstable compounds with an unpaired electron in its outer ring. They have a particular affinity for lipid substances. They combine avidly with cell or organelle membrane. "Drill a hole" in the membrane of cell. They are normal byproducts of cellular metabolism, and they are always present in the body. Free radicals Chemically reactive molecules that are formed as natural oxidant species in cells during mitochondrial respiration and energy generation. Most sources come from the mitochondria. Made during the process of making ATP. Reactive oxygen species (ROS) Remove free radicals and ROS from our system. Antioxidants When free radicals are produced in amounts that overwhelm our antioxidants or when antioxidants are decreased. Oxidative Stress What can occur within the cell when injury is induced by free radicals? 1. membrane damage 2. protein modifications 3. mutations in DNA 4. Damage to cell signaling pathways Genetic disturbances can be _______ if they involve the germ cell line of an individual inherited Genetic disturbances can also be _______ by exposure to some mutagenic/ carcinogenic environmental factors acquired Enzymes secreted by microorganisms can breakdown cell membranes once introduced into the body= _______ Allows the organisms to dissolve surrounding tissues and allows them to move deeper into the tissues, blood, and lymphatics. lysis by enzymes Certain viruses, once they have infected a cell, will cause membrane rupture as newly produced viral particles (virions) leave the host cell= ________. Sometimes referred to as lytic viruses. Examples include HIV and Hep B. Lysis by virus Involve the abnormal accumulation of substances that are normally found in the body (endogenous agents) or not normally found in the body (exogenous agents). Metabolic derangements Give 2 examples of endogenous accumulations in the body. 1. Lipids: Fatty changes occurs most often in liver cells but can also be problem in myocardial cells. Liver handles fats and synthesizes complex fats and lipoproteins. Slow accumulation of fat within hepatic or myocardial cells usually does not impair the function of those cells until the problem is extreme. However, fatty change can occur in acute basis and can lead to acute heart or liver failure. 2. Bilirubin: Pigment released when RBCs break down/destroyed. Bilirubin is released/diffuses into blood where it is called unconjugated (indirect) bilirubin. Unconjugated bilirubin is fat soluble and can't be eliminated through kidney (urine). So, it's taken up by liver cells bound to a substance called glucuronic acid and becomes bilirubin glucuronide or conjugated (direct) bilirubin. Conjugated bilirubin is water-soluble and can be eliminated through the kidney. Describe the 2 ways in which conjugated bilirubin leaves the liver cells. 1. As concentration of conjugated bilirubin in the liver cells increases, it begins to diffuse out of the cell into the blood (down its concentration gradient). 2. In addition, some of the conjugated bilirubin becomes part of a substance called bile; bile exits the liver cell through the hepatic duct and common bile duct and then into the duodenum. Explain 3 problems that may result in hyperbilirubinemia. 1. Excessive amounts of Hgb breakdown occur, as with hemolytic anemia or after birth when babies rapidly destroy their excess RBC mass. This results in excessive amounts of unconjugated bilirubin being delivered to the liver at a rate greater than the liver can handle. Unconjugated bilirubin accumulates in the blood. This is referred to as hemolytic jaundice. 2. Second problem area occurs when the amount of bilirubin released from RBC breakdown is normal, but the liver cells are sick and are unable to uptake unconjugated bilirubin from the blood, conjugate it, and/or excrete it into the bile. This is called hepatocellular jaundice because the problem is within the liver cell. 3. The third problem occurs when there is an obstruction to the flow of bile in the hepatic and/or common bile duct. Conjugated bilirubin accumulates in the liver cell and more diffuses into the blood than normal. This is called obstructive jaundice. In obstructive jaundice, stools will be clay colored and urine very dark. Bilirubin levels may be very high with no apparent ill effect. However, CNS abnormalities can result from extremely high and prolonged levels of bilirubin. Normally, bilirubin crosses the BBB extremely slow and with great difficulty. In infants, especially pre-term infants, bilirubin crosses the BBB much more easily. Bilirubin is extremely toxic to nerve tissue and exposure can lead to significant neurologic deficits/death. What is this condition called? Kernicterus Differential Features of Hemolytic Jaundice 1. Basic Defect= 2.Elevation of serum bilirubin= 3. Type of bilirubin in plasma= 4. Bilirubin in urine (normally absent) = 5. Urobilinogen in urine (normally present at low concentrations) = 6. Bilirubin in feces= 7. Red cell survival= 8. Liver function tests= 9. Bile ducts= 1. Excessive production of bilirubin 2. mild 3. unconjugated 4. absent 5. increased 6. increased 7. decreased 8. normal 9. normal Differential Features of Hepatocellular Jaundice 1. Basic Defect= 2.Elevation of serum bilirubin= 3. Type of bilirubin in plasma= 4. Bilirubin in urine (normally absent) = 5. Urobilinogen in urine (normally present at low concentrations) = 6. Bilirubin in feces= 7. Red cell survival= 8. Liver function tests= 9. Bile ducts= 1. Defective uptake, conjugation, and/or excretion of bilirubin 2. severe gated & unconjugated 4. Present (if the defect is in the biliary excretion) 5. Variable depending on the stage of the disease 6. variable 7. normal 8. abnormal 9. normal Differential Features of Obstructive Jaundice 1. Basic Defect= 2.Elevation of serum bilirubin= 3. Type of bilirubin in plasma= 4. Bilirubin in urine (normally absent) = 5. Urobilinogen in urine (normally present at low concentrations) = 6. Bilirubin in feces= 7. Red cell survival= 8. Liver function tests= 9. Bile ducts= 1. Obstruction of bile ducts 2. severe 3. conjugated 4. present 5. decreased (absent) 6. decreased 7. normal 8. variable 9. obstructed disorganized sequence of events that that stimulate the inflammatory process and signals us that cell death is occurring. Cell necrosis Quiet, organized, programmed process resulting in elimination of individual cells. May be physiologic or pathologic. Not associated with inflammation. Apoptosis (type I programmed cell death) Features of Necrosis 1. Cell size= 2. Nucleus= 3. Plasma membrane= 4. Cellular contents= 5. Adjacent inflammation= 6. Physiologic or pathologic role 1. enlarged (swelling) 2. pyknosis- karyorrhexis- karyolysis 3. disrupted 4. Enzymatic digestion; may leak out of cell 5. Frequent 6. Invariably pathologic (culmination of irreversible cell injury) Features of Apoptosis 1. Cell size= 2. Nucleus= 3. Plasma membrane= 4. Cellular contents= 5. Adjacent inflammation= 6. Physiologic or pathologic role 1. Reduced (shrinkage) 2. Fragmentation into nucleosome-size fragments 3. Intact; altered structure, especially orientation of lipids 4. Intact; may be released in apoptotic bodies 5. no 6. Often physiologic, means of eliminating unwanted cells; may be pathologic after some forms of cell injury, especially DNA damage Liquefactive necrosis (occurs in the brain; formation of cysts): commonly results from ischemic injury to neurons and glial cells in the brain. Dead brain tissue is readily affected by liquefactive necrosis because brain cells are rich in the digestive hydrolytic enzymes and lipids, and the brain contains little connective tissue. As the cells are digested by their own hydrolases, the tissue becomes soft, liquefies, and is walled off from healthy tissue, forming cysts. Can also result from bacterial infections e.g., staphylococci and E.coli Coagulative necrosis (Most common type, e.g., usually replaced by scar/fibrous tissue) Occurs primarily in the kidneys, heart, and adrenal glands, commonly results from hypoxia caused by severe ischemia or hypoxia caused by chemical injury, especially ingestion of mercuric chloride. Coagulation is caused by protein denaturation, which causes the protein albumin to change from a gelatinous, transparent state to firm. The necrotic tissues appear firm and slightly swollen. Also referred to as infarct. Caseous necrosis commonly results from tuberculous pulmonary infection, particularly mycobacterium TB, is a combination of coagulative and liquefactive necrosis. The dead cells disintegrate, but the debris is not digested completely by hydrolases. Tissues appear soft and granular and resemble clumped cheese, hence its name. A granulomatous inflammatory wall encloses areas of caseous necrosis. Fat Necrosis (Occurs in pancreatitis): Occurs in the breast, pancreas, and other abdominal structures, is cellular dissolution caused by powerful enzymes called lipases. Lipases break down triglycerides, releasing free fatty acids, which then combine with calcium, magnesium, and sodium ions, creating soaps (process known as saponification). The necrotic tissue appears opaque and chalk white. Gangrenous necrosis (wet & dry) Usually involves interruption of the arterial blood supply to a tissue. Results from severe hypoxic injury, commonly occurring because arteriosclerosis or blockage of major arteries, especially in lower leg. - Dry gangrene- area that is free of infection and in which the line of demarcation between live and dead tissue is apparent. Tissue undergoing dry gangrene becomes dry and shrunken= mummified - Wet gangrene- Infection is present in the area between live and dead tissue. The presence of an acute inflammatory reaction and inflammatory exudate are responsible for the 'wet' component. Wet gangrene is often malodorous and the line of demarcation between live and dead tissue is unclear until the infection is arrested. "Eating of self" is self-destructive process and a survival mechanism. Salvages key metabolites to promote homeostasis. Is important in many different types of tissues. In healthy cells becomes less discriminating and harmful agents accumulate leading to aging. Autophagy (type II programmed cell death) When confronted with a decrease in work demands or adverse environmental conditions, cells __________ or reduce their size and revert to a lower and more efficient level of functioning. Atrophy An increase in work demands may result in _________ an increase in tissue size brought about by an increase in cell size and functional components within the cell--or by _________ an increase in the number of cells in an organ or tissue that is still capable of mitotic division. Hypertrophy, hyperplasia Hypertrophy, hyperplasia, and atrophy- These three types of cell adaptations may be __________ (disappear when stressor removed) or _________ (remain when stressor removed) physiologic, pathologic The fourth type of cell adaptation which often occurs in response to chronic irritation and represents the substitution of one type of normal cell with another type of normal cell, but one that is not normally found in that tissue. These replacement cells are better able to survive under stressful circumstances in which original cell type may succumb to injury or death. Metaplasia Give an example of Metaplasia. Is metaplasia reversible? Metaplasia of laryngeal respiratory epithelium can occur in a smoker. The chronic irritation can lead to an exchanging of one type of epithelium (the normal respiratory epithelium) for another (the more resilient squamous epithelium). Metaplasia is not a normal physiologic process and may be the first step toward neoplasia (the uncontrolled, abnormal growth of cells or tissues in the body AKA tumor) Is metaplasia reversible? Yes, if offending stimulus to cellular alteration is removed. Is the fifth type of cell adaptation but is really maladaptation. Is characterized by deranged cell growth and differentiation within a specific tissue. It results in cells that vary in size, shape, and appearance and is a precursor for cancer. Dysplasia Give an example of Dysplasia Cellular dysplasia in the uterine cervix can occur. The normal cervical squamous epithelium can become transformed to a more disorderly growth pattern, or dysplastic epithelium. This is farther down the road toward neoplasia, but dysplasia is still a potentially reversible process. Define aging and its relationship to cellular function/structure and genetic and environmental factors. Aging is distinct from disease in that the lifespan is limited by the aging process rather than by disease. Aging is thought to be a result of accumulation of DNA and metabolic (free radical) damage. Cells may age more quickly when DNA repair mechanisms are faulty and when metabolic damage is excessive because of reduced antioxidants. Aging is the progressive loss of tissues and organs over time. Possible causes of aging are genetic, epigenetic, inflammatory, oxidative, stress, and metabolic origins. Age related changes in body systems can generally be described as ____________. a decrease in functional reserve and a reduced ability to adapt to environmental changes. What is aging associated with? Inflammation, hypercoagulability, and immune changes. Diet is thought to play a major role in the development of age-related diseases. A clinical syndrome that describes someone vulnerable to falls, functional decline, disability, disease, and death. May involve oxidative stress, inflammation, malnutrition, physical inactivity, and muscle changes. Frailty- Age related disease What are the two ways in which cells die? 1. Killed by injurious agents 2. Induced to commit suicide Describe a cell's death by injury and the series of changes they go through 1. Mechanical damage 2. Exposure to toxic chemicals Changes= 1. They swell 2. Cell contents leak out leading to 3. inflammation of surrounding tissues What happens to cells that are induced to commit suicide? 1. Shrink 2. develop bubble-like blebs on their surface 3. Have chromatin (DNA and protein) in their nucleus degraded 4. Have their mitochondria break down with the release of cytochrome c 5. Break into small, membrane-wrapped, fragments 6. release ATP and UTP (mammalian cells) 7. These nucleotides bind to receptors on wandering phagocytic cells like macrophages and dendritic cells and attract them to the dying cells (a "find me" signal) 8. Phospholipid phosphatidylserine, which is normally hidden in the inner layer of the plasma membrane, is exposed on the surface 9. this "eat me" signal is bound by other receptors on the phagocytes which then engulf the cell fragments. 10. The phagocytic cells secrete cytokines that inhibit inflammation Pattern of events in death by suicide. Is orderly. Programmed cell death (PCD)/ Apoptosis Why should a cell commit suicide? 1. Programmed cell death is as needed for proper development as mitosis is. e.g., The formation of the fingers and toes of the fetus requires the removal, by apoptosis, of the tissue between them. 2. Programmed cell death is needed to destroy cells that represent a threat to the integrity of the organism. e.g., cells infected with virus (cytotoxic T lymphocytes kill virus-infected cells by inducing apoptosis) What makes a cell decide to commit suicide? 1. The withdrawal of positive signals-signals needed for continued survival e.g., GF of neurons, IL-2 2. The receipt of negative signals e.g., increase levels of oxidants within the cell, ultraviolet light, x-ray Describe the 3 mechanisms involved on the process of apoptosis. 1. Apoptosis triggered by internal signals: the intrinsic or mitochondrial pathway 2. Apoptosis triggered by external signals: the extrinsic or death receptor pathway 3. Apoptosis- Inducing Factor (AIF) Describe apoptosis triggered by internal signals: the intrinsic or mitochondrial pathway 1. In a healthy cell, the outer membranes of its mitochondria display the protein Bcl-2 on their surface. Bcl-2 inhibits apoptosis. 2. Internal damage to the cell causes a related protein, Bax, to migrate to the surface of the mitochondrion where it inhibits the protective effect of Bcl-2 and inserts itself into the outer mitochondrial membrane punching holes in it and causing cytochrome c to leak out 3. The released cytochrome c binds to the protein Apaf-1 (apoptotic protease activating factor-1) 4. Using the energy provided by ATP these complexes aggregate to form apoptosomes 5. Apoptosomes bind to and activate caspase-9 6. Caspase-9 cleaves and, in so doing, activates other caspases. 7. The activations of these "executioner" caspases creates an expanding cascade of proteolytic activity which leads to digestion of structural proteins in the cytoplasm, degradation of chromosomal DNA, and phagocytosis of the cell Describe Apoptosis triggered by external signals: the extrinsic death receptor pathway 1. Fas and the TNF (tumor necrosis factor) receptor are integral membrane proteins with their receptor domains exposed at the surface of the cell 2. Binding of the complementary death activator (FasL and TNF respectively) transmits a signal to the cytoplasm 3. That leads to activation of caspase 8 4. Caspase 8 (like caspase 9) initiates a cascade of caspase activation 5. Leading to phagocytosis of the cell Give example of apoptosis triggered by external signals: the extrinsic death receptor pathway When cytotoxic T cells recognize (bind to) their target, 1. they produce more FasL at their surface 2. This bind with the Fas on the surface of the target cell leading to death by apoptosis - The early steps in apoptosis are reversible- In some cases final destruction of the cell is guaranteed only with its engulfment by a phagocyte. Describe apoptosis- Inducing Factor (AIF) 1. Neurons, and perhaps other cells, have another way to self-destruct that- unlike the two paths described- does not use caspases 2. Apoptosis inducing factor (AIF) is a protein that is normally located in the intermembrane space of the mitochondria 3. When the cell receives a signal telling it that it is time to die, AIF - is released from the mitochondria -migrated into the nucleus -binds to DNA which -triggers the destruction of the DNA and cell death Describe the relationship of apoptosis to cancer 1. Some viruses associated with cancers use tricks to prevent apoptosis of the cells they have transformed. e.g., HPV virus that causes cervical cancer produces protein E6 that binds and inactivates the apoptosis promoter p53 2. Cancer cells produced without the participation of viruses may have trick to avoid apoptosis e.g., Some B-cell leukemias and lymphomas express high levels of Bcl-2, thus blocking apoptotic signals they may receive. - Melanoma cells avoid apoptosis by inhibiting the expression of the gene coding Apaf-1 -Some cancer cells secrete elevated levels of a soluble "decoy" molecule that binds to FasL, plugging it up so it cannot bind Fas, Thus, cytotoxic T cells (CTL) cannot kill the cancer cells. -other cancer cells express high levels of FasL and can kill any cytotoxic T cell (CTL) that try to kill them because CTL also express Fas (but are protected from their own FasL) Describe the relationship of apoptosis and organ transplantation The anterior chamber of the eye and the testes express high levels of FasL at all times. Thus antigen-reactive T-cells, which express Fas, would be killed when they enter these sites. This finding raises the possibility of a new way of preventing graft rejection. If at least some of the cells on a transplanted kidney, liver, heart etc. could be made to express high levels of FasL, that might protect the graft from attack by the T cells of the host's cell mediated immune system. If so, then the present need for treatment with immunosuppressive drugs for the rest of the transplant recipient's life would be reduced or eliminated. Describe physiologic atrophy and give an example Physiological atrophy occurs with early development. For example, the thymus gland undergoes physiological atrophy during childhood. Describe pathological atrophy and give an example pathological atrophy occurs as a result of decreases in workload, use, pressure, blood supply, nutrition, hormonal stimulation, and nervous stimulation. For example, individuals immobilized in bed for a prolonged time exhibit a type of skeletal muscle atrophy called disuse atrophy. Is the result caused by increased demand, stimulation by hormones and growth factors? Give example. Physiological hypertrophy For example, physiological hypertrophy in skeletal muscle occurs in response to heavy work. Pregnancy is also an example of physiological hypertrophy and hormone induced uterine enlargement. Results from chronic hemodynamic overload. Give example. Pathologic hypertrophy For example, hypertension or heart valve dysfunction- cardiac hypertrophy. Is an increase in the number of cells in an organ or tissue resulting from an increased rate of cellular division? Occurs as a response to injury that results when the injury has been severe and prolonged. Main mechanism is production of growth factors which stimulate the remaining cells (after cell loss or injury) to synthesize new cell components and, ultimately, to divide. Another mechanism is increased output of new cells from tissue stem cells. Give example Hyperplasia For example, if the liver cells are compromised, new cells can regenerate from intrahepatic stem cells. Hyperplasia can be physiological or pathological. What are the two types of normal, or physiologic, hyperplasia? 1. Compensatory hyperplasia 2. hormonal hyperplasia An adaptive mechanism that enables certain organs to regenerate. Give example. compensatory hyperplasia (physiological hyperplasia) For example, removal of part of the liver leads to hyperplasia of the remaining liver cells (hepatocytes) to compensate for the loss. Occurs chiefly in estrogen-dependent organs, such as the uterus and breast. Give example Hormonal hyperplasia (physiological hyperplasia) E.g., estrogen stimulates the endometrium to grow and thicken for reception of the fertilized ovum. If pregnancy occurs, hormonal hyperplasia, as well as hypertrophy, enables the uterus to enlarge. Abnormal proliferation of normal cells and can occur as a response to excessive hormonal stimulation or the effects of growth factors on target cells. Give example Pathologic hyperplasia E.g., Pathologic hyperplasia of the endometrium (most common example) which is caused by an imbalance between estrogen and progesterone levels with relative increases of estrogen. Give 3 examples of common diseases/conditions linked to oxygen- derived free radicals. 1. Deterioration noted in aging 2. atherosclerosis 3. Brain disorders- ischemic brain injury 4. AIDS- associated dementia 5. Cancer Discuss how the body handles free radicals and ROS to prevent tissue injury 1. Antioxidants- Endogenous or exogenous either blocks synthesis or inactivates (e.g., scavenges) free radicals; includes vitamin E, Vitamin C, cysteine, glutathione, albumin, ceruloplasmin, transferrin 2. Enzymes- Superoxide dismutase, which converts superoxide to H2O2 catalase (in peroxisomes) decomposes H2O2 glutathione peroxidase*, decomposes OH and H2O2 Also known as infiltrations occur as a result of not only sublethal injury sustained by cells but also normal (but inefficient) cell function. Cellular accumulation List cellular accumulations that can occur in both normal and injured cells- Two categories of substances can cause accumulations. 1. A normal cellular substance (such as water, protein, lipid, and carbohydrate excesses) 2. An abnormal substance either endogenous (such as a product of abnormal metabolism or synthesis) or exogenous (e.g., infectious agents or a mineral.) Describe the pathophysiological basis of reperfusion injury When cells are deprived of oxygen, they use their ATP stores and accumulate purine catabolites hypoxanthine and xanthine. In reperfusion injury these are metabolized into free radicals that cause membrane damage and calcium overload. Cardia ischemia and reperfusion causes excessive reactive oxygen species (ROS), pH alterations, osmotic changes, gap junction changes, inflammatory signaling, and calcium overload of the mitochondria. These changes also lead to the opening of a large conductance pore on the mitochondrial membrane called the mitochondrial permeability transition pore with massive escape of ATP and solutes leading to cell death activation (apoptosis). Discuss systematic manifestations of cellular injury 1. Fever 2. Increased heart rate 3. increase in number of leukocytes (leukocytosis) 4. presence of cellular enzymes in extracellular fluid 5. Lactate dehydrogenase 6. Creatine Kinase (CK) 7. Aspartate aminotransferase (AST) 8. Alanine aminotransferase (ALT) 9. Alkaline phosphatase (ALP) 10. Amylase 11. Aldolase 12. Troponins Explain the pathogenesis and pathophysiologic effect(s) of bilirubin and fat accumulation in the cell Two examples of endogenous accumulations are lipids (fat) and bilirubin. -Fatty changes occur most often in liver cells but can also be a problem in myocardial cells. The liver handles fats and synthesizes complex fats and lipoproteins all the time. Slow accumulation of fat within hepatic or myocardial cells usually does not impair the function of those cells until the problem is extreme. However, fatty change can occur on an acute basis and can lead to acute heart or liver failure. -Bilirubin is essentially a pigment that is released when RBCs break down or are destroyed. This bilirubin is released or diffuses into the blood where it is called unconjugated (indirect) bilirubin. Unconjugated bilirubin is fat-soluble and cannot be eliminated through the kidney (urine). The unconjugated bilirubin is then taken up by the liver cells, bound to a substance called glucuronic acid, and becomes bilirubin glucuronide or conjugated (direct) bilirubin. Conjugate bilirubin is water soluble and can be eliminated through the kidney. How do you calculate incidence and prevalence of a disease? The incidence of a disease, as it is usually defined, is the number of new cases occurring in a given population within a given time period-usually 1 year. For example, the incidence of Down Syndrome in the US is 1 in 690 births (1/690 x 100 = 0.14%) On the other hand, the prevalence of a disease involves the number of cases existing (both old and new) in a given time period. The prevalence of Down Syndrome in the US is 400,000. For a population of about 314 million that is a prevalence of 0.13% (400,000/314,000,000 x 100 = 0.13%). The incidence and prevalence can also be expressed as a percentage. Describe the effect of free cytosolic calcium. A destructive agent. Calcium is normally removed from the cytosol by adenosine triphosphate (ATP)- dependent calcium pumps. In normal cells, calcium is bound to buffering proteins, such as calbindin or paralbumin, and is contained in the endoplasmic reticulum and the mitochondria. If there is abnormal permeability of calcium ion channels, direct damage to membranes, or depletion of ATP (i.e., hypoxic injury), calcium level increases in the cytosol. If the free calcium cannot be buffered or pumped out of cells, uncontrolled enzyme activation takes place, causing further damage. Uncontrolled entry of calcium into the cytosol is an important final pathway in many causes of cell death. The process of nuclear shrinkage. It is irreversible condition of chromatin in the nucleus of a cell wall undergoing necrosis or apoptosis. Pyknosis he destructive fragmentation of the nucleus of a cell- its chromatin is disrupted irregularly throughout the cytoplasm karyorrhexis Complete dissolution of the chromatin of a dying cell due to enzymatic degradation by endonucleases. Karyolysis -these 3 changes (Pyknosis, karyorrhexis, and karyolysis lead to destruction of the nucleus- which will eventually cause the cell to die) Discuss the relationship of apoptosis to AIDS HIV indirectly triggers programmed cell death/apoptosis that contributes to the decline in CD4 T lymphocyte counts throughout the course of HIV infection. The HIV induced; premature destruction of lymphocytes is associated with the continuous production of HIV viral proteins that modulate apoptotic pathways. Viral protein expression predisposes lymphocytes particularly CD4+ T cells, CD8+ T cells, and APCs to evolve into effectors of apoptosis and as a result lead to the destruction of healthy non-infected T-cells. Viral proteins protect HIV-infected cells from apoptosis by increasing anti-apoptotic proteins and down-regulating cell surface receptors recognized by immune system cells. _________ is determined by the total solute concentration in a fluid compartment osmolality refers to the ability of the combined effect of all the solutes to generate an osmotic driving force that causes water movement from one compartment to another. Tonicity Effective osmoles= Sodium, glucose, mannitol, and sorbitol Ineffective osmoles urea Normal fluid osmolality= 280-294 mOsm/Kg 5 essential components of pathophysiology 1. Etiology (the why of disease, the reason for it) 2. Epidemiology (risk factors and distributions in populations, incidence and prevalence in disease) 3. Pathogenesis (disease mechanisms; the sequence of events that occurs between the stimulus event and the manifestations of the disease) 4. Clinical Manifestations (signs, symptoms, diagnostic criteria) 5. Outcomes (cure, remission, chronicity, death) "unknown" etiology of disease idiopathic and cryptogenic Iatrogenic etiology of disease as a result of surgical/medical intervention Incidence the new number of cases in a given population in a specific time period; 1 in 690 births - 1/690 x 100 = 0.14% Prevalence number of cases, both old and new, during a specific time period; 400,000 in a population of 314 million - 400,000/314,000,000 x 100 = 0.13% 4 common mechanisms of cell injury and death 1. ATP Depletion 2. Oxygen and oxygen-derived free radicals 3. intracellular calcium and loss of calcium state 4. defects in membrane permeability The disease mechanism that is the basis of much of the disease today- and most of the cases involve hypoxia. Refers to the inability of the cell to produce adequate energy to fuel normal activities of that particular cell type (cell membrane pumps and protein synthesis) and function. ATP deletion - the inability of the cell to produce adequate energy what are the two phases of ATP production? 1. Aerobic (oxidative phosphorylation) 2. Anaerobic (glycolysis) how many ATP does glycolysis yield? 2 How many ATP does oxidative phosphorylation yield? 36 What is the most common method of impairing oxygen and ATP production? Hypoxia - respiratory abnormalities, flow problems such as ischemia, lack of sufficient hgb to carry (anemia), and hemoglobinopathies Can lead to irreversible cell injury directly through impairment of energy production in the cell. Ischemia What are the cellular events that occur with ischemia-induced- hypoxic injury? 1. Decreased oxygen - decreased ATP production within the mitochondria declines 2. The drop in ATP causes NA-K- ATPase pump on CM to fail. Na and Ca influx into the cell, K diffuses out of the cell. Na and H20 enter freely into the cell. 3. Increase in water in cell causes cell and it's organelles to swell. 4. When RER swell it's ribosomes fall off and protein synthesis stops. 5. ATP production through phosphorylation declines and glycolysis (anaerobic metabolism) increases. When glycolysis increases in the cell glycogen stores are depleted. 6. Glycolysis also produces lactic acid as by-product. Lactic acid increases and pH declines ( the cell functions within narrow range of pH and even slight drop can incapacitate the cell). 7. Drop in pH causes clumping of nuclear material called pyknosis. Leads to fragmentation of the nuclear material (karyorrhexis) and then to dissolution of nuclear membrane (karyolysis). Decline in pH - rupture of already swollen lysosomes and release of proteolytic enzymes - autodigestion of cell contents and cell membrane. 8. Disruption of CM also increases Ca+ influx into the cell and organelles - activate proteases, endonucleases, and phospholipases that proceed to destroy the cell. Pyknosis Karyorrhexis Karyolysis Pyknosis - clumping of nuclear material from drop in pH Karyorrhexis - fragmentation of the nuclear material Karyolysis - dissolution of nuclear membrane Explain what happens when the Na-K-ATPase pump fails due to decreased ATP production normally, most sodium ions are outside the cell and most potassium ions are inside the cell when the pump fails, sodium freely enters the cell with H2O and calcium, and potassium freely exits the cell as a result, the cell swells and and protein synthesis stops where does protein synthesis occur in a cell? Rough ER with ribosomes on the surface explain what happens where there is an increase in glycolysis due to decreased ATP production glycogen is decreased, lactate is increased, intracellular pH is decreased decreased pH results in pyknosis, karyorrhexis, and karyolysis Free Radicals Unstable compounds with an unpaired electron in its outer ring. They have a particular affinity for lipid substances. They combine avidly with cell or organelle membrane. "Drill a hole" in the membrane of cell. They are normal byproducts of cellular metabolism, and they are always present in the body. why are free radicals bad? they bind to the phospholipid bilayer of a cell and drill holes in its membrane Reactive oxygen species Chemically reactive molecules that are formed as natural oxidant species in cells during mitochondrial respiration and energy generation. Most sources come from the mitochondria. Made during the process of making ATP. Antioxidants Remove free radicals and ROS from our system Oxidative Stress When free radicals are produced in amounts that overwhelm our antioxidants or when antioxidants are decreased. What can occur within the cell when injury is induced by free radicals? 1. membrane damage 2. protein modifications 3. mutations in DNA 4. Damage to cell signaling pathways what are three diseases linked to oxygen-derived free radicals? 1. Atherosclerosis 2. Cancer 3. Diabetes 4. Alzheimer's 5. Aging Intracellular calcium and loss of calcium steady state Without the ATP-dependent Ca pumps, Ca cannot be buffered or pumped out of the cells, uncontrolled enzyme activation Defects in membrane permeability Early loss of all selective membrane permeability is found in all forms of cell injury Lysis by enzymes Enzymes secreted by microorganisms can breakdown cell membranes once introduced into the body; allows the organisms to dissolve surrounding tissues and allows them to move deeper into the tissues, blood, and lymphatics. Lysis by viruses Certain viruses, once they have infected a cell, will cause membrane rupture as newly produced viral particles (virions) leave the host cell; Sometimes referred to as lytic viruses. Examples include HIV and Hep B. Metabolic derangements Involve the abnormal accumulation of substances that are normally found in the body (endogenous agents) or not normally found in the body (exogenous agents). Endogenous vs. Exogenous accumulations Exogenous - not normally found in the body Endogenous - normally found in the body two endogenous accumulations 1. Lipids 2. Bilirubin Lipids (fat) Fatty changes occurs most often in liver cells but can also be problem in myocardial cells. Liver handles fats and synthesizes complex fats and lipoproteins. Slow accumulation of fat within hepatic or myocardial cells usually does not impair the function of those cells until the problem is extreme. However, fatty change can occur in acute basis and can lead to acute heart or liver failure. Bilirubin Pigment released when RBCs break down/destroyed. Bilirubin is released/diffuses into blood where it is called unconjugated (indirect) bilirubin. Unconjugated bilirubin is fat-soluble and can't be eliminated through kidney (urine). So, it's taken up by liver cells bound to a substance called glucuronic acid and becomes bilirubin glucuronide or conjugated (direct) bilirubin. Conjugated bilirubin is water-soluble and can be eliminated through the kidney. Describe the 2 ways in which conjugated bilirubin leaves the liver cells. 1. As concentration of conjugated bilirubin in the liver cells increases, it begins to diffuse out of the cell into the blood (down its concentration gradient). 2. In addition, some of the conjugated bilirubin becomes part of a substance called bile; bile exits the liver cell through the hepatic duct and common bile duct and then into the duodenum. Explain 3 problems that may result in hyperbilirubinemia. 1. Hemolytic Jaundice - Excessive amounts of Hgb breakdown occur, as with hemolytic anemia or after birth when babies rapidly destroy their excess RBC mass. This results in excessive amounts of unconjugated bilirubin being delivered to the liver at a rate greater than the liver can handle. Unconjugated bilirubin accumulates in the blood. 2. Hepatocellular Jaundice - the amount of bilirubin released from RBC breakdown is normal, but the liver cells are sick and are unable to uptake unconjugated bilirubin from the blood, conjugate it, and/or excrete it into the bile. This is called hepatocellular jaundice because the problem is within the liver cell. 3. Obstructive Jaundice - occurs when there is an obstruction to the flow of bile in the hepatic and/or common bile duct. Conjugated bilirubin accumulates in the liver cell and more diffuses into the blood than normal. This is called obstructive jaundice. In obstructive jaundice, stools will be clay colored and urine very dark. Kernicterus Bilirubin levels may be very high with no apparent ill effect. However, CNS abnormalities can result from extremely high and prolonged levels of bilirubin. Normally, bilirubin crosses the BBB extremely slow and with great difficulty. In infants, especially pre-term infants, bilirubin crosses the BBB much more easily. Bilirubin is extremely toxic to nerve tissue and exposure can lead to significant neurologic deficits/death Reperfusion Injury when blood flow is restored to ischemic tissues, additional damage can occur resulting in cell death proposed reasons for reperfusion injury (5) 1. oxidative stress 2. nitrogen-based free radicals 3. increased intracellular calcium 4. inflammation 5. complement activation Explain oxidative stress as it relates to reperfusion injury reoxygenation generates ROS and nitrogen species, which damages membrane proteins and phospholipids What happens when nitrogen-based free radicals are formed in reperfusion injury? further damage to the cell membrane occurs and calcium overloads the mitochondria Describe the pathophysiological basis of reperfusion injury In reperfusion injury these are metabolized into free radicals that cause membrane damage and calcium overload. Cardia ischemia and reperfusion causes excessive reactive oxygen species (ROS), pH alterations, osmotic changes, gap junction changes, inflammatory signaling, and calcium overload of the mitochondria. These changes also lead to the opening of a large conductance pore on the mitochondrial membrane called the mitochondrial permeability transition pore with massive escape of ATP and solutes leading to cell death activation (apoptosis). Autophagy Type 2 programmed cell death of "Eating of self"; self destructive process and a survival mechanism, salvages key metabolites to promote homeostasis, critical garbage collecting and recycling process, thought with aging that autophagy becomes less discriminating Apoptosis Quiet, organized, programmed process resulting in elimination of individual cells. May be physiologic or pathologic. Not associated with inflammation. Cells shrink, Often physiologic, means of eliminating unwanted cells; may be pathologic after some forms of cell injury, especially DNA damage Cell Necrosis Disorganized sequence of events that that stimulate the inflammatory process and signals us that cell death is occurring. Cells swell. list five types of necrosis 1. coagulative 2. liquefactive 3. caseous 4. fat 5. gangrenous Coagulative Necrosis (Most common type, e.g., usually replaced by scar/fibrous tissue) Occurs primarily in the kidneys, heart, and adrenal glands, commonly results from hypoxia caused by severe ischemia or hypoxia. Coagulation is caused by protein denaturation, which causes the protein albumin to change from a gelatinous, transparent state to firm. The necrotic tissues appear firm and slightly swollen. Also referred to as infarct. Liquefactive Necrosis (occurs in the brain; formation of cysts) Digestion of dead cells transforming tissue into a viscous liquid, commonly results from hypoxic injury within the CNS, also seen in bacterial infections. As the cells are digested by their own hydrolases, the tissue becomes soft, liquefies, and is walled off from healthy tissue, forming cysts. Caseous Necrosis Commonly results from tuberculous pulmonary infection, is a combination of coagulative and liquefactive necrosis. The dead cells disintegrate, but the debris is not digested completely by hydrolases. Tissues appear soft and granular and resemble clumped cheese, hence its name. A granulomatous inflammatory wall encloses areas of caseous necrosis. Fat Necrosis (Occurs in pancreatitis): Occurs in the breast, pancreas, and other abdominal structures, is cellular dissolution caused by powerful enzymes called lipases. Lipases break down triglycerides, releasing free fatty acids, which then combine with calcium, magnesium, and sodium ions, creating soaps (process known as saponification). The necrotic tissue appears opaque and chalk white. Saponification Process of soap formation in fat necrosis due to lipases breaking down triglycerides -- release fatty acids -- combine with Ca, Mg, and Na ions Gangrenous Necrosis Usually involves interruption of the arterial blood supply to a tissue. Results from severe hypoxic injury, with bacterial invasion, commonly occurring because arteriosclerosis or blockage of major arteries, especially in lower leg or gut with low O2 (anaerobic bacteria). Large areas of tissue death. Dry Gangrene Area that is free of infection and in which the line of demarcation between live and dead tissue is apparent. Tissue undergoing dry gangrene becomes dry and shrunken= mummified Wet Gangrene Infection is present in the area between live and dead tissue. The presence of an acute inflammatory reaction and inflammatory exudate are responsible for the 'wet' component. Wet gangrene is often malodorous and the line of demarcation between live and dead tissue is unclear until the infection is arrested. Gas Gangrene wet gangrene caused by clostridium, an organisms that produces gas within the destroyed tissue. This accumulation of gas produces a distinctive sound on palpation of the area called crepitus Systematic manifestations of cellular injury 1. Fever 2. Increased heart rate 3. increase in number of leukocytes (leukocytosis) 4. presence of cellular enzymes in extracellular fluid 5. Lactate dehydrogenase 6. Creatine Kinase (CK) 7. Aspartate aminotransferase (AST) 8. Alanine aminotransferase (ALT) 9. Alkaline phosphatase (ALP) 10. Amylase 11. Aldolase 12. Troponins Define cell necrosis - irreversible injury - rapid plasma membrane structure loss - organelle swelling - mitochondrial dysfunction What happens in cell necrosis - cell membrane is ruptured - leakage of cell contents - ATP is lost - organelles swell - severe mitochondrial damage - local inflammation Define apoptosis programmed cell death; not associated with inflammation List the three mechanisms of apoptosis 1. Apoptosis triggered by internal signals: mitochondrial pathway 2. Apoptosis triggered by death activators binding to receptors at the cell surface 3. Triggered by dangerous ROS What are two viruses that "trick" apoptosis? 1. HPV 2. Epstein Barr Virus Describe the relationship of apoptosis to cancer 1. Some viruses associated with cancers use tricks to prevent apoptosis of the cells they have transformed. e.g., HPV virus that causes cervical cancer produces protein E6 that binds and inactivates the apoptosis promoter p53 2. Cancer cells produced without the participation of viruses may have trick to avoid apoptosis e.g., Some B-cell leukemias and lymphomas express high levels of Bcl-2, thus blocking apoptotic signals they may receive. - Melanoma cells avoid apoptosis by inhibiting the expression of the gene coding Apaf-1 -Some cancer cells secrete elevated levels of a soluble "decoy" molecule that binds to FasL, plugging it up so it cannot bind Fas, Thus, cytotoxic T cells (CTL) cannot kill the cancer cells. -other cancer cells express high levels of FasL and can kill any cytotoxic T cell (CTL) that try to kill them because CTL also express Fas (but are protected from their own FasL) Describe the relationship of apoptosis and organ transplantation The anterior chamber of the eye and the testes express high levels of FasL at all times. Thus antigen-reactive T-cells, which express Fas, would be killed when they enter these sites. This finding raises the possibility of a new way of preventing graft rejection. If at least some of the cells on a transplanted kidney, liver, heart etc. could be made to express high levels of FasL, that might protect the graft from attack by the T cells of the host's cell mediated immune system. If so, then the present need for treatment with immunosuppressive drugs for the rest of the transplant recipient's life would be reduced or eliminated Describe apoptosis triggered by internal signals: the intrinsic or mitochondrial pathway 1. In a healthy cell, the outer membranes of its mitochondria display the protein Bcl-2 on their surface. Bcl-2 inhibits apoptosis. 2. Internal damage to the cell causes a related protein, Bax, to migrate to the surface of the mitochondrion where it inhibits the protective effect of Bcl-2 and inserts itself into the outer mitochondrial membrane punching holes in it and causing cytochrome c to leak out 3. The released cytochrome c binds to the protein Apaf-1 (apoptotic protease activating factor-1) 4. Using the energy provided by ATP these complexes aggregate to form apoptosomes 5. Apoptosomes bind to and activate caspase-9 6. Caspase-9 cleaves and, in so doing, activates other caspases. 7. The activations of these "executioner" caspases creates an expanding cascade of proteolytic activity which leads to digestion of structural proteins in the cytoplasm, degradation of chromosomal DNA, and phagocytosis of the cell Five examples of cell adaptation 1. atrophy 2. metaplasia 3. dysplasia 4. hypertrophy 5. hyperplasia Atrophy in cell adaptation When there is decreased work demand, the cell decreases in size to work at a more efficient level Hypertrophy in cell adaptation When there are increased work demands, the cell increases in size Hyperplasia in cell adaptation An increase in the number of cells in an organ or tissue that is capable of mitotic division Metaplasia in cell adaptation Response to chronic irritation; substitution of one type of normal cell with another type of normal cell that is better able to survive Dysplasia in cell adaptation maladaptation; deranged cell growth and differentiation within a specific tissue; precursor of cancer aging is thought to be the result of: 1. faulty DNA repair mechanisms ahd metabolic (free radical) damage 2. reduced antioxidants Intracellular fluid all the fluid within the cells (2/3 of total body water) Extracellular fluid all the fluid outside of the cells (1/3 of total body water) Define interstitial fluid component of extracellular fluid that is the fluid surrounding the cells and found in the spaces between cells, but not within the blood vessels define intravascular fluid component of extracellular fluid that is the fluid within the blood vessels (aka blood plasma) Extracellular fluid VOLUME The total amount of sodium in the body is responsible for the extracellular fluid volume Extracellular fluid CONCENTRATION The total amount of water in the body is responsible for the extracellular sodium concentration 3 main systems regulate total body sodium 1. RAAS System - Decreased renal perfusion is sensed by the juxtaglomerular cells in the kidney resulting in increase renin secretion and activation of RAAS. Angiotensin causes vasoconstriction and stimulates the release of aldosterone - promotes sodium retention. 2. Natriuretic Peptide System - Volume receptors in great veins and atria are sensitive to small changes in venous and atrial filling. Increased atrial filling results in release of ANF/ANP and BNF/BNP which promotes sodium excretion. 3. Pressure receptors in the aorta and carotid are stimulated by volume depletion and activate sympathetic nervous system - renal retention of sodium. TWO stimuli for ADH secretion The kidney adjusts water excretion (through ADH) to keep extracellular sodium concentration within its normal range An osmotic and a volume/pressure stimulus 1. Changes in plasma osmolality stimulate osmoreceptors in hypothal. resulting in increase or decrease in thirst, increase or decrease in ADH 2. Changes in circulating BP/blood volume are sensed by volume sensitive receptors and baroreceptors, stimulating an increase or decrease in ADH explain the Renin-Angiotensin-Aldosterone System low BP, decreased renal perfusion, or low sodium concentrations -- juxtaglomerular cells of the kidney are activated -- increase the release of renin -- stimulates the formation of Angiotensin 1 -- ACE in the pulmonary vessels converts Angiotensin 1 to Angiotensin II -- vasoconstriction -- increased BP, increased renal perfusion, increased sodium concentration Solute A substance that is dissolved in a solution. Osmolality Total solute concentration in a fluid compartment Normal body fluid osmolality is 280-294 Isotonic Volume depletion/excess with normal osmolality; same osmolality or concentration of particles Tonicity The effective osmolality of a solution; refers to the ability of the combined effect of all the solutes to generate an osmotic driving force Solutes capable of changing the tonicity are Na, glucose, mannitol, and sorbitol Effective osmolality sustained osmotic activity and depends on the concentration of solutes remaining on one side of a permeable membrane Ineffective osmolality Easily crosses cell membranes and distributes evenly throughout total body fluids why is urea known as an ineffective osmole? it easily crosses cell membranes and distributes evenly throughout total body fluids Equation of calculating serum osmolality 2 x (sodium concentration) + (glucose concentration/18) + (BUN/2.8) What does isotonic fluid loss cause dehydration and hypovolemia Isotonic fluid excess aka hypervolemia; caused by excessive administration of IV fluids Why would you give an isotonic solution? increase ECF due to blood loss, dehydration (vomiting), or surgery why would you give a hypertonic solution? decrease cerebral edema, hyponatremia Hypertonic Volume depletion/excess with increased osmolality; usually the cause is loss of free water or failure to replace water loss; usually hypernatremic; cells shrink in a hypertonic solution Hypotonic Normal volume, depletion, or excess with decrease osmolality; most common d/t impaired renal water excretion of free water excess, usually hyponatremic, hypotonic water pulled into cell, causing cells to swell and burst When would you give a hypotonic solution? dehydration, DKA Hyponatremia with hypotonicity Most common form of hyponatremia, usually caused by decrease renal water excretion in the presence of continued water intake Hyponatremia with hyperosmolality Usually related to severe hyperglycemia, increase in glucose in extracellular fluid moves water from the cells to the extracellular compartment and dilutes the sodium concentration Treatment for hyponatremia (Na 135mEq/L) Fluid restriction Treatment for hypernatremia - oral fluids or isotonic solutions - give slowly to prevent cerebral edema - diuretics to enhance sodium excretion s/s hypernatremia (Na 145 mEq/L) muscle twitching, weakness, hyperactive reflexes Water deficit The difference between ideal TBW and current TBW; replacing fluids Current TBW = weight in kg x (0.4 women), (0.5 men), (0.6 infants) Water deficit = (current Na x TBW)/140 - TBW Water excess The difference between current TBW and ideal TBW = Current TBW = weight in kg x (0.5 women), (0.6 men), (0.7 infants) Water excess = weight in kg x (0.5/0.6/0.7) x (1 - (Na/125)) Edema Excessive accumulation of fluid within the interstitial spaces Hydrostatic pressure Pressure generated on the capillary walls by the fluid in a column of blood, hydrostatic pressure tends to force water OUT of a compartment 4 most common mechanisms of edema 1. Increased capillary hydrostatic pressure 2. Decreased capillary oncotic pressure 3. Increased capillary membrane permeability 4. lymphatic channel obstruction 5. sodium and water retention Increased capillary hydrostatic pressure Forces water out of the capillary and into the interstitial compartment; results from either venous obstruction or sodium and water retention Decreased capillary oncotic pressure Plasma proteins, esp. albumin, are lost or production is decreased, decreased synthesis of plasma proteins occurs with liver disease or protein malnutrition. Decreased oncotic attraction of fluid within the capillary causes more fluid to filter into the interstitial space than is reabsorbed into the systematic circulation through the capillaries Increased capillary membrane permeability Occurs with inflammation and immune response, increased vessel permeability permits significant amounts of proteins to escape from within blood vessels into the interstitial space Lymphatic channel obstruction Lymphatic system normally absorbs interstitial fluid, along with small amounts of protein, when blocked fluids are not reabsorbed and accumulate in the interstitial space causing edema Pitting vs. Non-Pitting edema Non Pitting - if the fluid contains a lot of protein; increased capillary permeability and lymphatic obstruction Pitting - if the fluid contains few proteins; increased capillary venous hydrostatic pressure and decreased capillary oncotic pressure Potassium ECF concentration is approx 3.5 to 5 -Insulin, epi, and alkalosis all facilitate the shift of K into the cells -Aldosterone (part of the RAAS) regulates the potassium concentration; secreted in response to high K; stimulates secretion of K into the urine Renal regulation of K 1. The action of aldosterone 2. Concentration gradient for K at the distal tubule and collecting duct 3. Distal tubule flow rate and distal tubule sodium delivery 4. Changes in pH S/S hyperkalemia (K 5.0 mEq/L) - bradycardia - muscle weakness - anxiety - peaked T waves - oliguria treatment for hyperkalemia - Kayexalate - glucose to stimulate insulin secretion (pushes K back to ICF) - dialysis causes of hypokalemia mostly GI and renal - GI (diarrhea/vomiting) - renal (diuretic use, low plasma Mg, excessive aldosterone secretion) s/s hypokalemia (K 3.5mEq/L) - lethargy - n/v - Flat T wave treatment for hypokalemia Potassium replacement 40-80mEq/day if renal function normal Calcium Ionized calcium is an enzymatic cofactor for blood clotting and is required for hormone secretion and function of cell receptors Calcium levels decrease in alkalosis and increase in acidosis Hypocalcemia Ionized calcium 5.5 - inadequate internal absorption - decreased levels of PTH - decreased levels of Vitamin D -deposition of ionized Ca into bone or soft tissue -Blood transfusions Hypercalcemia Ionized calcium 10.5 - hyperparathyroidism -cancer -sarcoidosis -Vit D. toxicity causes of hypercalcemia CHED Calcium ingestion, Hyperparathyroid, excess Vitamin D s/s hypercalcemia (Ca 10.5mg/dL) - loss of membrane excitability - lethargy - depressed T waves treatment for hypercalcemia - phosphate - calcitonin s/s hypocalcemia (Ca 9.0mg/dL) Convulsions (Chvostek/Trousseau) Arrhythmias (long QT) Tetany Stridor treatment for hypocalcemia - 10% calcium gluconate - decrease phosphate intake function of aldosterone is to retain sodium and promote renal excretion of potassium what is the goal of RAAS? increase BP what is the goal of the Natriuretic Peptide System? decrease BP calculate corrected serum sodium 1.6mEq/L x (calculated glucose concentration) = SS Corrected Sodium is 130 + SS is hydrostatic pressure greater in the arterial end of the capillary or venous end of the capillary? why? hydrostatic pressure is greater at the arterial end (35) than the venous end (18) because you are getting further away from the pressure source (the heart) define hydrostatic pressure force exerted by fluid pressing against capillary wall hydrostatic pressure forces water ____ of a compartment out capillary hydrostatic pressure forces water out of the ________ and into the ________ capillary; interstitial compartment interstitial hydrostatic pressure forces water out of the ______ and into the _______ interstitial compartment; capillary refill define oncotic pressure the force of proteins pulling water into or out of the capillary two main proteins involved in oncotic pressure albumin and globulin for hydrostatic and oncotic pressure, is the pressure greater in the capillary or interstitial space? capillary explain the basics of hydrostatic vs oncotic pressure hydrostatic pressure is the movement of water out of either the capillary or interstitial compartment. Oncotic pressure if the movement of water into either the capillary or interstitial compartment. The arterial pressures are greater than the venous pressures. The capillary pressures are greater than the interstitial pressures. Net arterial hydrostatic pressure results in most of the water out of the capillary, while net arterial oncotic pressure results in most of the water into the capillary why is the balance of ICF K and ECF K so important? - conduction and transmission of nerve impulses - maintenance of cardiac rhythms - contraction of skeletal and smooth muscles what are a few reasons Potassium may leave the cell? - cell lysis - insulin deficiency - aldosterone deficiency - strenuous exercise what is the effect of insulin on blood plasma Potassium concentration? insulin decreases the amount of potassium in the bloodstream by facilitating potassium to enter the cell treatment for severe hyperkalemia insulin with dextrose (to prevent hypoglycemia) what should be a concern if you give a hyperglycemic patient insulin? low plasma potassium levels list a few factors that may lead to HYPOKALEMIA - insufficient intake of K - increased movement of K into the cell - increased excretion of K (laxatives, inc consumption of black licorice, diarrhea, diuretics, inc aldosterone) - insulin administration - treatment of pernicious anemia w/ vitamin b12/folate - spurious hypokalemia (false reading due to insulin admin right before blood draw) serum potassium falls 0.3 for each 0.1 ________________ increase in pH (alkalosis) serum potassium rises 0.3 for each 0.1 _______________ decrease in pH in respiratory acidosis serum potassium