Midterm 1 Pharmacology PDF
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These notes cover fundamental concepts in pharmacology, including the ten rights of drug administration, three checks of drug administration, drug order abbreviations, pharmacokinetics (ADME), pharmacodynamics (DREAMT), routes of administration (enteral, topical, parenteral), and transport across membranes. It includes key topics such as absorption, distribution, metabolism, and excretion.
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Module 1 Pharmacology ○ Pharmacology – study of medications ○ Drug – substance capable of producing a biologic response ○ Medication – a drug given for the purpose of producing a therapeutic response Ten Rights of Drug Administration...
Module 1 Pharmacology ○ Pharmacology – study of medications ○ Drug – substance capable of producing a biologic response ○ Medication – a drug given for the purpose of producing a therapeutic response Ten Rights of Drug Administration ○ Right patient / client ○ Right history and assessment ○ Drug approach and right to refuse ○ Right drug ○ Right dose ○ Right route of administration ○ Right time and frequency of delivery ○ Right documentation ○ Right drug-drug interaction and evaluation ○ Right education and information for patient Three Checks of Drug Administration ○ Prior to administering a drug, the nurse should be checking the drug with the Medication Administration Record (MAR) ○ Check when removing the drug from the storage site of the drug ○ Check when preparing the drug for administration ○ Check again just before administering the drug to the patient Drug Order Abbreviations ○ Common types of orders Single order – to be given once Continuous order – to be given on an ongoing basis Standing order – routine order, prewritten to be used in a particular circumstance PRN order – to be given as required - Pharmacokinetics ○ ADME ○ Ab sorption ○ Distribution ○ Metabolism ○ Ex cretion Pharmacodynamics ○ DREAMT ○ Dr(Drug receptor interaction) ○ E(Efficacy and potency) ○ A(Agonist, Adverse reaction) ○ M(Mechanism of Action) Routes of Administration – Enteral Enteral ○ Refers to oral administration of drugs but also include gastric and nasogastric routes, buccal and sublingual routes ○ Sublingual / Buccal ○ Drug diffuses across mucosal tissues into blood ○ Sublingual absorption faster than buccal Formulations – follow instructions for administration carefully ○ Tablets / Capsules Enteric coated – protection from stomach acid Sustained release – dissolve slowly to extend duration of medication ○ Elixirs / Syrups / Suspensions Ensure drugs are shaken before preparing ○ Gastric / Nasogastric Usually liquids Advantages ○ Most common route; easy to administer ○ Considered to be safest route; drug can be recovered from stomach in case of an error ○ Large surface area for absorption ○ Flexible formulations – enteric coated and sustained release Disadvantages ○ Client must be conscious and able to swallow ○ Can be challenging for some pediatric and geriatric patients with difficulty swallowing ○ Drugs can be rendered inactive by stomach acid and gastric / intestinal enzymes ○ Subject to first pass metabolism if drug absorbed in small intestines ○ GI motility can affect bioavailability Routes of Administration – Topical R efers to administration of drugs onto the surface of the skin or of membranous linings of eye, ear, nose, respiratory tract, urinary tract, vagina and rectum Formulations ○ Dermatologic – creams, lotions, gels, powders, sprays ○ Inhalations for respiratory tract – inhalers, nebulizers, positive pressure devices ○ Instillations and irrigations Local effects – topical administration is often used to produce an effect at the place it is applied ○ Unintended adverse effects usually due to drug being absorbed into circulation Systemic effects – some drugs given topically are absorbed into blood to produce effects throughout the body ○ Slow release preparations Advantages ○ Can be formulated and applied to achieve local or systemic effects ○ Application is directly to the site of intended action ○ Fewer adverse effects than enteral or parenteral routes ○ No first pass metabolism or digestion by enzymes ○ For some routes, patient does not have to be conscious Disadvantages ○ Can be irritating to site of administration ○ Local application can produce systemic adverse effects Routes of Administration – Parenteral Refers to routes in which a drug is injected ○ Subcutaneous, dermal ○ Intramuscular ○ Intravenous, intraarterial ○ Intrathecal ○ Intraosseous ○ Intraperitoneal Advantages Absorption is often more rapid, depending on blood supply to site of injection ○ ○ Intravenous is the standard for measuring bioavailability ○ Alternate route for administration for patients that can’t take drug enterally ○ Effects can be local or systemic depending on preparation and route Disadvantages ○ Risk of infection ○ Irritation at site of injection ○ Once drug has been administered, it cannot be removed if an error has been made Pharmacokinetics R efers to the movement of a drug through the body Describes what the body does to a drug as it enters the blood, as it moves to target tissues, as it is metabolized and as it is removed from the body ○ Drugs must pass a series of barriers to reach target tissue ○ Depends on physiologic processes Four Processes of Pharmacokinetics ○ Absorption How drug reaches the circulation ○ Distribution How drug reaches target tissue ○ Metabolism How drug is altered by body ○ Excretion How drug is removed from body Transport Across Membranes ○ Diffusion Movement of a chemical from an area of higher concentration to an area of lower concentration Does not require energy ○ Simple diffusion Diffusion across a membrane Rate of diffusion affected by concentration gradient, properties of chemical, properties of membrane ○ Properties of drugs that affect diffusion across plasma membranes Concentration gradient Related to dosage of drug Size of drug molecule Smaller molecules absorbed faster Lipid solubility Structure of molecule Ionization of molecule, influenced by pH Lipophilic drugs cross membranes more easily than hydrophilic drugs ○ Facilitated Diffusion Diffusion across a membrane that requires a transport protein Ion channels Cotransporters, antiporters Show specificity and saturation kinetics Do not require energy though concentration gradient for diffusion may be maintained through active transport ○ Osmosis Diffusion of water down its concentration gradient ○ Active Transport Movement of a substance from area of low concentration to area of high concentration Requires a transport protein Requires source of energy, usually ATP Shows specificity and saturation kinetics Absorption ○ Movement of drug from site of administration to circulation Primary factor for determining onset of drug action Quantified as bioavailability ○ Factors affecting rate of absorption Route of administration Enteral, parenteral, topical Increase dose = increases rate of absorption due to increased concentration gradient BIO AVAILABILITY IN BLOOD IS 100% IV Meds have 100% BIOAVAILABILITY FASTEST WAY TO ABSORB MEDICINE IS INHALATION DUE TO LARGE SURFACE AREA ○ Factors affecting rate of absorption GI tract environment Presence of food may decrease absorption Presence of certain foods and drugs may alter rate of absorption Motility – influences time during which absorption can occur Blood flow and surface area.Increase blood flow = increase rate of absorption Increase surface area = increase rate Route of administration Impact of temperature on blood flow Drug ionization Depending on pH of surrounding fluid, most drugs in either charged or uncharged state Acids are absorbed in acids because they are nonionized. Bases are absorbed in bases because they are nonionized. Acid in a basic environment is ionized and therefore less able to cross membrane *NaHCO3 alkaline urine will assist in eliminating acid based medication, this will be on exam* Compartment of distribution ○ Plasma ○ Intracellular compartment 29L of fluid in cell ○ Interstitial fluid 9L of fluid 99% Warfarin binds of Albumin ASA (Aspirin) will take Albumin from Warfarin, resulting in warfarin released. Warfarin will be released and cause bleeding. Distribution ○ Transportation of drugs throughout body to target tissue ○ Factors affecting distribution of drug Blood flow to target tissue Increased blood flow = more drug reaching target tissue Drug solubility Hydrophilic drugs transported in solution L ipophilic drugs – a portion is bound to plasma proteins (ie albumin); a portion of drug is in solution Lipophilic drugs in equilibrium between being in solution and being bound to plasma protein Only portion of drug in solution is available to diffuse to target tissue Properties of drug allow some lipophilicity to bind better to plasma proteins than others – competition for binding sites on plasma proteins can create drug interactions D rug must move from circulation to target tissues to create response Special barriers to drug distribution ○ Blood–brain barrier Does not contain pores Protects brain from pathogens and toxins Only lipid-soluble drugs able to cross Not fully developed in neonates Inflammation can increase permeability. ○ Fetal–placental barrier (FPB) Prevents harmful substances from passing from mother's bloodstream to fetus Permeability of barrier changes during pregnancy However, some drugs can cross (alcohol, cocaine, caffeine, some prescription meds) Pregnancy categories for drugs Must consider if the patient is of childbearing age prior to prescribing a drug. Metabolism ○ General purpose: to convert lipid soluble to water soluble. ○ Also called Biotransformation. ○ Metabolism is a process that changes the activity of a drug and makes it more likely to be excreted. ○ Process by which structure (and function) of drugs, nutrients, vitamins, and minerals is altered Liver is primary site for metabolism (Hepatic Microsomal Enzyme, Most are done by CYP3A4), Liver also makes Albumin, Enterohepatic circulation is the process in which drugs circulate around the liver to be metabolized. Metabolism usually makes drug more excretable (hydrophilic) Drug in solution can be filtered by kidney Drug bound to plasma protein not filtered ○ Structural changes result in functional changes to drug Metabolites may be functional (metabolism activates drug); inactive form is termed “prodrug” Metabolites many be non-functional (metabolism inactivates drug) Metabolites may be toxic *Don’t need to know above, for lecture demonstration purposes only* ○ rugs and toxins are seen as foreign to patients bodies D ○ Drugs can undergo metabolism in the lungs, blood, and liver ○ Body works to convert drugs to less active forms and increase water solubility to enhance elimination ○ Microsomal enzymes in liver carry out most metabolic activities Cytochrome P450 (CYP) An enzyme that metabolizes many drugs Many isoenzyme systems within CYP Determine speed at which drug is metabolized ○ Liver - primary route of drug metabolism ○ Liver may be used to convert pro-drugs (inactive) to an active state ○ Types of reactions Phase I (Cytochrome P450 system) Phase II Phase I reactions types ○ Hydrolysis ○ Oxidation ○ Reduction ○ Demethylation ○ Methylation ○ Alcohol dehydrogenase metabolism Phase II reactions ○ Polar group is conjugated to the drug ○ Results in increased polarity of the drug ○ Types of reactions Glycine conjugation Glucuronide conjugation Sulfate conjugation Phase I reactions ○ Cytochrome P450 system ○ Located within the endoplasmic reticulum of hepatocytes ○ Through electron transport chain, a drug bound to the CYP450 system undergoes oxidation or reduction ○ Enzyme induction (Increase) & Inhibition (Decrease) of CYP. More CYP decreases concentration of drugs (because more drugs are metabolized). Less CYP increases concentration of drugs (because less drugs are metabolized and more are in the system). ○ Drug interactions Contribute to drug‒drug interactions ○ Drugs are substrates for CYP presence of one drug may alter metabolism of another drug by competing for same isoenzyme ○ Drugs can inhibit CYP enzymes Inhibiting isoenzyme could reduce metabolism of another drug → toxic levels ○ Drugs can induce CYP enzymes Inducing isoenzyme could increase metabolism of another drug → reduce amount of functional drug Metabolism ○ Ability of patient to metabolize drugs changes throughout life cycle Infants lack mature microsomal enzyme systems. Enzyme activity often reduced in older adults ○ Ability of patient to metabolize drugs influenced by many factors Decreased metabolism with liver impairment Genetic variations of CYP enzymes Genetic polymorphism. Variation of patient’s genetic ability to metabolize CYP. Excretion ○ Removal of drug from the body Kidney is primary site for excretion Pulmonary, glandular, fecal excretion (secondary excretion type) Rate of excretion influences concentration of drug in blood ○ Renal excretion Most drugs are filtered into the nephron but not reabsorbed (drug remains in urine) pH of urine can influence reabsorption of drug from nephron ○ Renal excretion Damage to kidney usually reduces excretion of drug thus dose reduction may be necessary for renal patient You can check the function of the kidney by level of creatinine and GFR. You can check liver function by ALT and AST. Tylenol is Hepatotoxic (4 grams max a day, 10 grams will kill pt). ○ Pulmonary excretion Gasses and volatile liquids Most drugs excreted unmetabolized Respiratory rate and blood flow affect excretion. ○ Glandular secretion Drugs can be secreted in saliva, sweat, breast milk Consideration for nursing mother ○ Fecal and biliary(bilirubin are conjugated whichmeans water soluble)excretion Drugs taken via enteral route may not be fully absorbed and are excreted in feces Enterohepatic recirculation.Longer duration of action. Lipid soluble drugs can be reabsorbed with bile via enterohepatic recirculation → decreases rate of excretion Time-Response Relationships ○ Goal of nurse is to maintain drug at a concentration (therapeutic range) in blood that produces a therapeutic response Plasma drug levels rise as drug is absorbed and then decrease as drug is excreted If plasma levels exceed the therapeutic range (toxic range), drug is more likely to produce more adverse effects Therapeutic range can be very narrow ○ nset – time from point at which drug is administered until it reaches a therapeutic range O ○ Duration – time period in which drug concentration is in a therapeutic range ○ Termination – time period from when drug is administered until its concentration drops out of a therapeutic range ○ Drug half-life (t1/2). Provides estimate of duration of action Time that it takes for the plasma concentration of a drug to be reduced by 50% Drugs with short half-life have to be given more frequently to maintain drug in therapeutic range Drugs with long half-life can be given less frequently How frequently a drug must be given. How long it will take for the drug to be functionally eliminated. 2 0mg. Time-Response Relationships ○ Most drugs to reach therapeutic levels need 4-5 half lifes. ○ Most drugs to reach below minimum effective levels also need 4-5- half life. ○ Maintaining plasma concentration within therapeutic range requires careful dosing Must consider magnitude and frequency of dose, as well as drug half-life More than 90% of drug is excreted after four half-lives Repeated dosing required to maintain steady plasma concentration of drug Next dose given before plasma concentration dips out of therapeutic range S ○ ometimes it is important for a drug to reach a therapeutic range more quickly ○ Loading dose is given Larger dose that leads to more rapid absorption and shorter onset of action Maintenance doses are given to maintain drug within therapeutic range Pharmacodynamics Refers to what the drug does to the body to create a response R ○ elated to the mechanism of action of a drug ○ Related to how a drug interacts with a target tissue Altering the activity of a cell through interactions with receptor Altering the activity of an enzyme Drug does two actions ○ Agonist: Stimulate ○ Antagonist: Blocker Interpatient Variability ○ Response to dose of drug is normally distributed across a population Some people require a very small dose to produce a therapeutic response (left side of curve in figure 4.1) Some people require a very large dose to produce a therapeutic response (right side of curve) Most require a dose in the middle to produce a therapeutic response Interpatient Variability – ED50 ○ Dose at which 50% of a population exhibit desired therapeutic response ○ Clinical implications Predicts dose range to achieve therapeutic response ED50 may be toxic for some patients and may not produce a meaningful response in others Critical to monitor patient response to assess if dosage adjustment is indicated TD50 and LD50 ○ Normal frequency distributions exist for both the dose of drug at which it is toxic and at which it is lethal for test subjects ○ TD50 refers to median toxic dose ○ Dose at which 50% of test subjects exhibit a response indicative of toxicity ○ LD50 refers to median lethal dose ○ Dose at which 50% of test subjects are killed by drug Therapeutic Index (TI) aka MARGIN OF SAFETY ○ Measure that compares LD50 to ED50 using a ratio ○ TI = LD50 / ED50 ○ If a drug has a large TI, it is considered to be safer (upper panel of figure 4.2) than a drug with a smaller TI (lower panel of figure 4.2. T ake a step back when you have to take / open more than 1 of the same medication, because typically it’s most commonly just 1 vial/tablet. P hase 2 is best range of doses to achieve a safe, therapeutic effect Response to drug usually due to several mechanisms ○ More receptors being affected by drug ○ More enzymes being affected by response ○ Patient symptoms affected by drug ○ ie patient has a headache and feels better after taking medication Phase 1 ○ Few receptors or enzymes affected, therefore response is minimal Phase 2 – linear phase ○ As more receptors or enzymes are affected, intensity of response increases Phase 3 – plateau phase ○ Drug is bound to all receptors or enzymes, or symptoms have been alleviated. Increasing dose has no further effect Potency and Efficacy ○ Even within a pharmacologic class, not all drugs produce the same intensity of response ○ Two measures are commonly used to quantify and compare elements of graded dose-response curves Potency A mount of drug required to produce a particular intensity of response drug that requires lowest dose to produce particular intensity of response is most potent (see figure 4.4, upper panel) Efficacy (EFFICACY IS MORE IMPORTANT CLINICALLY) Maximum intensity of response produced by a particular dose of drug Drug with the greatest intensity of response has the highest efficacy (figure 4.4, lower panel). A ) Both are equally effective,Drug A is more potent. B) A is more potent and more effective, since care about efficacy more therefore Drug A is more effective. Receptor Theory ○ Most drugs influence biological response through interactions with cellular receptors ○ Receptor Cellular molecule to which a medication binds to produce its effects Intrinsic activity – ability of drug to bind receptor and produce biological response Most drugs enhance or inhibit a physiological process. ○ Receptors are only activated or inhibited by chemicals that bind like lock and key ○ When receptor is bound by its ligand, intracellular response is triggered Responses carried out by second messenger systems within the cell Responses can be short term (opening of channels) Responses can be long term (transcription and translation of genes) Mechanism of Hormone Action ○ Water-soluble hormones circulate in free, unbound forms Short-acting response Bind to surface receptors ○ Lipid-soluble hormones are primarily circulating bound to a carrier Rapid and long-lasting response Diffuse freely across the plasma and nuclear membranes and bind with cytosolic or nuclear receptors ○ Hormone receptors Located in the plasma membrane or in the intracellular compartment of the target cell ○ Water-soluble hormones High molecular weight Cannot diffuse across the plasma membrane ○ Lipid-soluble hormones Easily diffuse across the plasma membrane and bind to cytosolic or nuclear receptors Tolerance. When given a hormone for a prolonged period of time, a cell will hide its receptor. ○ Chronic exposure of a receptor to an antagonist typically leads to upregulation (increased number of receptors), while chronic exposure of a receptor to an agonist causes downregulation (decreased number of receptors). Agonists and Antagonists ○ Within a pharmacologic class, some drugs are better at stimulating intracellular responses than others ○ Agonist Mimics the action of endogenous substances; response may be greater than endogenous activity. Partial Agonist Produces weaker responses than endogenous substances ○ Antagonists Prevent action of endogenous substances, usually by competing with endogenous ligand and/or agonist for receptor binding sites Sometimes used to prevent adverse effects of overdoses Antagonists do not usually have intrinsic activity Pharmacogenetics ○ Branch of pharmacology that studies the role of genetic variation in drug responses. ○ Considers underlying genetic expression as reason for why drug therapy not effective for everyone ○ Using data from human genome project, genetic differences in drug-metabolizing enzymes have been discovered; opens door to individualized drug therapy Holistic Approach to Pharmacotherapy ○ Patients can respond differently to the same medication ○ Response can be influenced by psychological, cultural and social variables in addition to biological ones ○ Variations can also be due to individual differences in genes and their expression Genetic Influences on Pharmacotherapy ○ Humans of all races share DNA that is 99.8% identical Remaining 0.2% can result in differences in responsiveness, often along ethnic lines ○ Genetic polymorphism Mutation in gene that codes for a protein resulting in two or more versions of same protein Mutated form of enzyme has changed structure. May increase, decrease speed of drug metabolism or may be non-functional Genetic Testing for CYP450Polymorphisms to PredictResponse to Clopidogrel: current evidence and test availability Application: Pharmacogenomics ○ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2943252/#:~:text=Genetic%20testing%20 to%20 determine%20if,high%20risk%20 for%20 pour%20 outcomes Pharmacogenetics and Pharmacogenomics Pharmacogenetics ○ Study of specific genetic variations that alter patients' responses to medications Pharmacogenomics ○ Network of genes that govern a person's response to drug therapy Gender Influences Current research recognizes gender difference in drug response Factors that influence response ○ Body composition (fat to muscle ratios can affect pharmacokinetics of drug) ○ Cerebral blood flow variations may affect distribution of analgesics to CNS Women tend to pay more attention to changes, and seek health care earlier than men. May affect adherence to medication regimen of drug class ○ Antihypertensive drugs May produce impotence, gynecomastia in men Abrupt withdrawal may cause strokes ○ Estrogen in oral contraceptives Elevated risk of thromboembolic disorders in women Patient Education Characteristics of an Ideal Drug ○ Effectively prevents, treats or cures condition of patient ○ Easy to administer ○ Produces rapid, predictable response at relatively low doses ○ Rapid onset of action ○ Duration of action appropriate to reaching therapeutic goals ○ Rapid elimination of drug ○ No adverse effects ○ No interactions with food or other drugs ○ No contraindications – safe for all patients to take ○ Inexpensive and accessible Classification of Drugs ○ Therapeutic classification Describes the condition for which a medication is being given (ie antihypertensive) ○ Pharmacologic classification Describes the mechanism by which the therapeutic effect is achieved (ie. Beta blockers, diuretics, ACE inhibitors) ○ Medications can have multiple classifications ○ Indication condition or circumstance for which drug has been approved A particular drug may have multiple indications ○ Mechanism of action Means by which drug carries out a therapeutic effect ie a diuretic (pharmacologic class) reduces blood pressure (therapeutic class) by reducing blood volume (mechanism) ○ Both therapeutic and pharmacologic classifications are useful but limited therapeutic class identifies purpose of drug (indication) but not how it works (mechanism of action) Pharmacologic class identifies mechanism but not indication Multiple pharmacologic classes can be used for a single therapeutic class Multiple therapeutic classes can be addressed with a single pharmacologic class ○ Within a pharmacologic class, there are often many different but related versions of a drug ○ Prototype drug – a representative drug from a class that is used as a point of comparison for related versions of that drug Learning one drug can allow nurse to extend knowledge to other similar drugs within that class Nomenclature of Drugs ○ IUPAC – scientific name that describes chemical structure of a drug ie 7-chloro-1,3-dihydro-1-methyl-5-phenyl-1,4- benzodiazepin-2(3H)-one ○ Generic – name adopted by regulatory agencies to describe active ingredient of a drug ie diazepam ○ Trade – proprietary name used by the company that produces a drug ie valium Generic names are preferred as they are accepted internationally to represent a particular drug ○ Drug given an international nonproprietary name (INN) specific for that drug ○ Ensures safety as generic name is used by all health care providers to describe same product; no confusion as to composition of drug ○ Can be multiple trade names for a single generic drug Brand name drugs and generic drugs can usually be found in same dosages ○ Generic drugs are usually less expensive than brand name ○ Differences between brand and generic often present in formulation of drug ○ Best measure to compare is bioavailability (the amount of drug that reaches systemic circulation and that can interact with target tissues) ○ Formulation can affect bioavailability Stress Stress ○ P erceived or anticipated threat that disrupts a person’s well-being or homeostasis ○ May stem from psychological/emotional (fear, social rejection), physical (dramatic temperature changes, abuse), or physiological (infection, Asurion) stimuli that trigger the stress response Cortex: ○ Sex hormone ○ Corticosteroids/Cortisone Medulla: ○ Epinephrine ○ Norepinephrine Homeostasis and Allostasis ○ Homeostasis Remaining stable while staying the same A state in which all systems are in balance A state of equilibrium An ideal “set point” despite alterations within the body ○ Allostasis Ability to successfully adapt to challenges Intricate regulatory processes orchestrated by the brain A dynamic process that maintains or re-establishes homeostasis in light of environmental and lifestyle changes No C orticosteroids kills T cells Historical Background ○ Walter B. Cannon “Fight-or-flight response” ○ Hans Selye Work showed physiological stress involved: Enlargement of adrenal gland Decreased lymphocyte levels Development of bleeding ulcers ○ Concluded that physiological stress impairs ability to resist future stressors General Adaptation Syndrome (GAS) ○ Dr. Selye termed this general stress response the general adaptation syndrome (GAS). ○ He perceived it as primarily physiological. ○ Alarm stage Stressor triggers the hypothalamic-pituitary-adrenal (HPA) axis Activates sympathetic nervous system Arousal of body defenses ○ Resistance/adaptation stage Begins with the actions of adrenal hormones Mobilization contributes to “fight-or-flight” ○ Exhaustion stage (allostatic overload) Occurs only if stress continues and adaptation is not successful Leads to stress-related disorders Enemy of Good is Perfect Adrenergic and Cholinergic hormones ○ Cortisol Secreted during stress Reaches all tissues Stimulates gluconeogenesis Elevates the blood glucose level Affects protein metabolism Powerful anti-inflammatory and immunosuppressive agent Abnormal elevations linked to obesity, sleep deprivation, lipid abnormalities, hypertension (HTN), diabetes, atherosclerosis, and loss of bone density Secretion during stress inhibits initial inflammatory effects Promotes resolution and repair Shown to induce T-cell apoptosis ○ Cortisol Effects Used therapeutically as powerful anti-inflammatory/immunosuppressive agents Influence virtually all immune cells Elevated levels may decrease innate immunity and increase autoimmune responses ○ Catecholamines Released from the adrenal medulla Epinephrine released Sympathetic = adrenergic Parasympathetic = cholinergic α-adrenergic receptors α1 and α2 (Found in blood vessel) ○ A1 Stimulating A1 causes vasoconstriction. ○ A2 Stimulating a2 causes vasodilation. β-adrenergic receptors β1 and β2 ○ B1 In the heart. ○ B2 In the lung. Mimic direct sympathetic stimulation Increases proinflammatory cytokine production ○ Histamine and Other Hormones Peripheral (immune) CRH Proinflammatory Mast cells are targeted Histamine release Induces acute inflammation and allergic reaction while suppressing Th1 and promoting Th2 activity Neuropeptide Y (NPY) Sympathetic neurotransmitter Growth factor Anticholinergic(exam) ○ Can’t see ○ Can’t pee ○ Can’t spit ○ Can’t shit Stress, Personality, Coping, and Illness ○ Stress is a system of interdependent processes moderated by nature, intensity, and duration of the stressor and perception, appraisal, and coping ability of the affected individual. ○ Higher perception of stress associated with reduced Tc-cell cytotoxicity. ○ Psychosocial distress Manifests as physiological, emotional, cognitive, and behavioral changes Individual at risk for immunological deficits Aggression associated with changes in T- and B-cell numbers Linked to chronic disorders if severe Identifying and reducing stress in the clinical setting may help in disease prevention and illness management ○ Coping May be adaptive or maladaptive Strategies beneficial when problem focused and when social support is sought Maladaptive coping may contribute to adverse health effects Week 2 Cell Injury m Eq/L: milliequivalents per liter, Cell Injury ○ If it hits DNA, it’s not reversible. Ischemia Decrease blood supply/perfusion. Decrease oxygen, decrease nutrient, increase waste blood/ H+ or acidosis. Hypoxia Oxygen deprivation. ATP DepletionF ○ Hydropic swelling: cellular swelling due to accumulation of water. Cellular pump will sufferpower failureif it failsto receive ATP, oxygen, and nutrients. Due to the failure of the Na/K pump, Na stays in the cell and water follows into the cell and causes the cell to swell. First manifestation of most forms of reversible cell injury Results from malfunction of sodium-potassium pump with accumulation of sodium ions within the cell Any injury that results in loss of energy (ATP) will also result in swelling ○ Cellular concentration Outside cell concentration: 135-145mEq/l Na, 3.5-5 meq/l K Inside cell concentration: 135-145 mEq/l K, 3.5-5 meq/lt Every measurement of concentration is forOUTSIDEOF CELL. Ca2+ entry / Prolonged Ischemia Ca2+ Normal extra [Ca2+] 10 meq/lt, Intra [Ca] ~0 meq/l. Ca2+ are stored in the endoplasmic reticulum and mitochondria. Request ATP to Ca2+ to store Ca2+ into ER and Mitochondria. Free intracellular Ca triggersapoptosis.BecauseCa damages Lysosomes. Lysosomes produce many enzymes, if lysosomes get damaged by free Ca, then the enzyme gets released outside of lysosomes due to death, enzymes will degranulate lysosomes and cells will die because enzymes will catalyze breakdown of the cell. Reactive Oxygen Species/Inflammation: ○ Neutrophils (Microphages), brings ROS (Reactive oxygen species/Free radicals): H2O2, +OH. Destroys cell membrane and cell structure. Steal electrons and create unstable environment for cells ○ Mitochondrial damage ○ Apoptosis/necrosis of cell (IRReversible). Membrane Damage Protein Misfolding ○ Golgi apparatus misfolds due to age/damage. ○ DNA Damage, proteins may misfold, triggering unfolded protein responsive that activecorrective responses. ○ How cancers are typically prevented through corrective response under normal circumstances. ○ Can lead to cell suicide E levatedLactate/Lactic acidmeansanaerobic metabolism. Intracellular Accumulations ○ Anyform ofintracellular accumulationtriggersinflammation. ○ Excess accumulations of substances in cells ○ Leads to cellular injury due to: Toxicity Immune response Taking up cellular space ○ Characterized by: Accumulation of excessive amounts of normal intracellular substance Accumulation of abnormal substances from faulty metabolism or synthesis Accumulation of pigments or particles that cell is unable to degrade Common accumulation site: Liver Liver has a preference for the metabolism of alcohol instead of lipid. As a result, fat deposits build up. Cellular Adaptation B ○ efore cells die they try toadapt. ○ Adaptation methods: Atrophy : Cells shrink and reduce their differentiated functions in response to normal and injurious factors Hypertrophy: Cell enlargement. Typically compensation for mechanical stress. Such as cardiac hypertrophy. Hyperplasia: Increase the number but they look normal. Such as increased erythropoiesis. Chronic irritation, such as callus. Metaplasia(Reversible): Cell is replaced with another that is better suited, such as tolerated to persistent injury. Example: ○ Such as lung cells in smokers that get changed due to smoking. Normal columnar ciliated epithelium by stratified squamous epithelia cell. ○ ○ GERD Dysplasia(reversible) Wannabe cancer (huge potential to be cancerous) Not a true adaptation. Represents adaptation gone astray. Significant potential to transform into full cancerous cells (preneoplastic lesions) HPV dysplasia is reversible. Dysplasia is reversible; once the transformation to neoplasia has been made, the process is not reversible. Irreversible Cell Injury ○ Necrosis / Cell Death Usually ischemia or hypoxia ○ Four types: 1) Coagulative necrosis: Begin with solid organs. Heart, Liver Muscles 2) Liquefactive: Brain, CNS, Spinal cord. Stroke 3) Fat necrosis: Intestines, pancreatitis. ○ Death of adipose tissue. 4) Caseous necrosis: Lung. Pulmonary embolism. ○ Gangrene: Necrosis is a large area of tissue. Result in interruption from blood supply. Types: Dry Gangrene: ○ Coagulative necrosis. Wet Gangrene: ○ Liquefactive necrosis. Gas gangrene: ○ Bacterial Infection of necrotic tissue be clostridium. Formation of gas bubbles in damaged muscle tissue. C Diff (Clostridium difficile) ○ Pungent smell ○ Can be fatal. Apoptosis Vs Necrosis: ○ 5 Necrosis: Messy and inflammation. Apoptosis Clean and tidy, is good and needed to conform the cell to the standard (Quality assurance). ○ Irreversible Cellular Damage Apoptosis is cell death resulting from activation of intracellular signaling cascade that cause cell suicide Apoptosis is tidy and is not usually associated with systemic manifestations of inflammation D ifferent type of metabolism = Anything you eat gets consumed to glucose. ○ ○ Pyruvic acid is made everytime glucose is consumed. ○ Pyruvic acid is made into ATP when there is oxygen in the mitochondria. ○ When no oxygen, pyruvic acid is made intolactateacid ○ Any shock can produce lactic acid. Etiology of Cellular Injury ○ Ischemia and Hypoxic Injury Tissue hypoxia is most often caused by ischemia; causes power failure in the cell Ischemia is the most common cause of cell injury and injures cells faster than hypoxia alone Combination of disruption of oxygen supply with accumulation of metabolic waste ○ Ischemia Cellular events lead to lactic acidosis Cellular proteins and enzymes become more dysfunctional Up to a point, ischemic injury is reversible, but cell death occurs when plasma, mitochondrial, and lysosomal membranes are critically damaged. Ischemia-reperfusion injury Too much oxygen is made Calcium overload Formation of free radicals Subsequent inflammation Cellular injury mechanism ○ Free radicals and reactive oxygen species Electrically uncharged atom or group of atoms having an unpaired electron that damage: Lipid peroxidation Alteration of proteins Alteration of DNA Mitochondrial damage ○ Nutritional Injury Adequate amounts of fats, carbohydrates, proteins, vitamins, and minerals are essential for normal cellular function Certain cell types more susceptible to injury than others Nutritional deficiencies may result from: Poor intake Altered absorption Impaired distribution by circulatory system Inefficient cellular uptake Common causes of malnutrition Poverty Chronic alcoholism. Lipid prefers alcohol instead of fat, and results in fatty liver disease. Acute and/or chronic illness Self-imposed dietary restrictions Malabsorption syndromes Nutritional excesses primarily result from excessive intake BMI greater than 27 kg/m2: health risk BMI greater than 30 kg/m2: obesity ○ Infectious and Immunologic Injury Bacteria and viruses can injure cells in a variety of ways depending on it’s virulence Added injury may occur indirectly by triggering body’s immune response ○ Chemical Injury T oxic chemicals or poisons can cause cellular injury both directly and by becoming metabolized into reactive chemicals by the body ○ Physical and Mechanical Injury Factors Extremes in temperature Abrupt changes in atmospheric pressure Mechanical deformation Electricity Ionizing radiation ○ UV damage DNA peptide bond Genetic mutation Apoptosis ○ Gamma rays ionize molecules and form free-radicals. Leads to Acute cell destruction and necrosis Cellular/Organ marker: ○ Heart: Troponin, ○ Liver: ALT, ○ Kidney: GFR, Creatinine Cellular Aging ○ Physiologic Changes of Aging Age-related decrease in functional reserve Inability to adapt to environmental demand ○ Pyrogen increase temperature Cancer Cancer ○ Diseases in which abnormal cells divide without control and are able to invade other tissues D ○ erived from Greek word for crab, karkinoma ○ Tumor Also referred to as a neoplasm—new growth ○ Neoplasia Means “new growth” Implies abnormality of cellular growth/tumor Malignantneoplasm is cancer Has collagenases/proteases/lipases, thus can spread. Benigngrowth is generally easily cured Do not have collagenases/proteases/lipases Malignant cancer may not be survivable Cancer is associated with alteredexpressionof cellulargenes Genetic Mechanisms of Cancer ○ Carcinogen Potential cancer-causing agent ○ Proto-oncogene Enhance growth-producing pathways ○ Oncogene Proto-oncogene in its mutant overactive form Accelerator ○ Tumor suppressor gene: Break Inhibits cell proliferation Cancers may arise when tumor suppressor gene function is lost or abnormally inhibited Proto-Oncogenes ○ Normal cellular genes that can be transformed into oncogenes by activating (gain-of-function) mutations ○ Gain-of-function mutations code for ○ Growth factors Receptors Cytoplasmic signaling molecules Nuclear transcription factors From Proto-Oncogene to Oncogene ○ Proto-oncogenes Become activated oncogenes when mutations alter their activity so that proliferation-promoting signals are generated inappropriately They becomes immortal Oncogenes introduced to host cell by retrovirus Proto-oncogene within cell suffers a mutagenic event DNA sequence may be lost/damaged and allows proto-oncogene to become abnormally active Error in chromosome replication causes extra copies of proto-oncogene in the genome ○ Retrovirus HIV Kaposi’s sarcoma Epstein-Barr virus Burkitt lymphoma Human T-lymphocyte virus type 1 Adult T-cell leukemia/lymphoma Tumor-Suppressor Genes ○ Contribute to cancer only when not present ○ Both copies of tumor suppressor genes are inactivated when cancer develops Back up! Virus or GE will need to disable both to develop cancer. ○ One can inherit a defective copy of tumor suppressor gene At much higher risk for cancer development. ○ Mutations can cause the gene to not function ○ Epigenetic process “Silences” the gene Does not require a mutation Tumor suppressor Gene List: ○ Rb Gene Found in the eye first, retinoblastoma gene Normally “master brake” for the cell cycle Stops mitosis An inactivating mutation of the Rb gene removes restraint on cell division and replication occurs ○ p53 Gene Most common tumor-suppressor gene defect identified in cancer cells Normally p53 inhibits cell cycling Accumulates only after cellular (DNA) damage Binds to damaged DNA and stalls division to allow DNA to repair itself May direct cell to initiate apoptosis Mutated or damaged p53 allows genetically damaged/unstable cells to survive and continue to replicate Chemotherapy/radiation Damages target/cancer cell to trigger p53-mediated cell death Cancer cells that lack functional p53 may be resistant to chemotherapy/radiation ○ BRCA1 and BRCA2 Gene Tumor suppressor genes Associated with breast cancer Family history and inherited defect in BRCA1 increases risk of breast cancer Carcinoma in situ (CIS) ○ Localized cancer tumor ○ Preinvasive epithelial malignant tumors of glandular or epithelial origin that have not broken through the basement membrane or invaded the surrounding stroma Biology of Cancer Cells ○ Cancer is predominantly a disease of aging ○ Multiple mutations are required before cancer can develop ○ Clonal proliferation or expansion As a result of a mutation, a cell acquires characteristics that allow it to have selective advantage over its neighbors Increased growth rate or decreased apoptosis Cancer Pneumatic ○ Im mortal Cells that have proto-oncogenes, but not rb/P53/BRCA will become immortal. Cancer cells have telomerase, which prevents telomeres from getting shorter in mitosis, thus preventing death. ○ Signal They do not respond to signals, nor don't respond to tumor suppressor genes. ○ Uncontrolledgrowth Uncontrolled growth ○ / Metastasis (WORST FEATURE OF CANCER) Process of cancer cells spreads. Tumor release: Collagenases, breaks down collagen. Proteinases, breaks down proteins. Lipases, breaks down fat. After all these are released, it breaks down the basement membrane of the tissue and spreads to neighboring tissue. ○ An giogenesis Cancer cells can release vascular growth factors, causing the formation of new blood vessels. ○ Differentiation, lack of Well differentiatedmeans it looks like original tissue. Lack of differentiationmeans it doesn’t look likeoriginal tissue, don’t know where this came from. Which means this cancer is metastasized or recently metastasized. Lack of differentiationalso calledAnaplasia The Malignant Phenotype ○ Allows malignant cells to ignore growth controlling signals ○ Antisocial behaviors include Proliferate despite lack of growth-initiating signals from the environment Escape signals to die and achieve a kind of immortality in that they are capable of unlimited replication Lose their differentiated features and contribute poorly or not at all to the function of their tissue Genetically unstable and evolve by accumulating new mutations at a much faster rate than normal cells Invade their local tissue and overrun their neighbors Perhaps worst of all: gain the ability to migrate from their site of origin to colonize distant sites where they do not belong Sustained Proliferative Signaling ○ Proto-oncogenes Normal genes that direct protein synthesis and cellular growth ○ Oncogenes Mutant genes ○ Tumor-suppressor genes Encode proteins that in their normal state negatively regulate proliferation Also referred to as anti-oncogenes Evading Growth Suppressors ○ Mutation (inactivation) of tumor-suppressor genes ○ Allows unregulated cellular growth Retinoblastoma (RB) gene Tumor protein p53 (TP53) Telomeres and Immortality ○ Body cells are not immortal and can only divide a limited number of times. ○ Telomeres are protective caps on each chromosome and are held in place by telomerase. Block cell division and prevent immortality ○ Telomeres become smaller and smaller with each cell division. ○ Cancer cells can activate telomerase. Unlimited division and proliferation ○ Chemotherapy Kills all rapidly dividing cells: Hair, Bone marrow, WBC, platelets, skin. Angiogenesis ○ Process by which cancer tumor forms new blood vessels in order to grow ○ Usually does not develop until late stages of development ○ Triggers are not generally understood ○ Inhibition of angiogenesis is important therapeutic goal ○ Growth of new blood vessels ○ Advanced cancers can secrete angiogenic factors (VEGF) Vascular endothelial GF Platelet-derived GF Basic fibroblast GF T Cell Release ○ Release cytokine/pyruvic factor. Tumor necrosis factor ○ Increase fever, metabolism, depresses appetite Inflammation and Cancer ○ Cancer cell released tumor necrosis factor ○ Chronic inflammation is an important factor in the development of cancer Cytokine release from inflammatory cells Increase fever. Increase metabolism. Depresses appetite. Increases protein + fat breakdown. ○ Helicobacter pylori Chronic inflammation associated with: Peptic ulcer disease Stomach carcinoma Mucosa-associated lymphoid tissue lymphomas ○ T Cell release Tumor Necrosis Factors ○ (Not tested below) ○ Tumor-associated macrophage (TAM) Key cells that promote tumor survival. Presence frequently correlates with a worse prognosis. Mimic M2 phenotype. Have diminished cytotoxic response. Develop the capacity to block T-cytotoxic cell and NK cell functions and produce cytokines that are advantageous for tumor growth and spread. ○ (Not tested ends) Immune System and Cancer ○ Normal immune system protects against cancer ○ Immunosuppression fosters cancer Non-Hodgkin’s lymphoma (10×) Kaposi sarcoma (1000×) Release of immunosuppressive factors into the tumor microenvironment increases resistance of the tumor to chemotherapy and radiotherapy Viruses and Cancer ○ Implicated Hepatitis B and C viruses Epstein-Barr virus (EBV) Kaposi sarcoma herpesvirus (KSHV) Human papillomavirus (HPV) Human T-cell lymphotropic virus type 1 (HTLV-1) Local Spread ○ Invasion Cellular multiplication Mitotic rate versus cellular death rate Release of lytic enzymes Collagenases, proteinase, lipases. Decreased cell-to-cell adhesion Increased motility Metastasis ○ Process by which cancer cells escape their tissue of origin and initiate new colonies of cancer in distant sites Specialized enzymes and receptors enable them to escape their tissue of origin and metastasize Specialized enzymes and receptors allow them to replicate at new site Patterns of Spread ○ Cancer cells generally spread via circulatory or lymphatic systems ○ Tumor markers help identify parent tissue of cancer origin Rely on some retention of parent tumor characteristics Some released into circulation Others identified through biopsy ○ Tumor markers help identify parent tissue of cancer origin Enzymes/proteins typically used as tumor markers Help track tumor activity Increased blood levels: progression and proliferation Distant Metastasis ○ Spread through vascular and lymphatic pathways ○ Selectivity of different cancers at different sites Breast cancer -> bones Lymphomas -> spleen ○ Dormancy Benign vs. Malignant Growth ○ Malignant Tumor Can kill host if untreated Confirmed by invasive or metastasizing nature Tissue-specific differentiation (does not closely resemble tissue type of origin) Greater degree of anaplasia indicates aggressive malignancy Grows rapidly May initiate tumor vessel growth Frequently necrotic Dysfunctional ○ Benign Tumor Does not have potential to kill host, but may be life-threatening because of its location Does not invade adjacent tissue or spread to distant sites Many are encapsulated More closely resembles original tissue type Grows more slowly Little vascularity Rarely necrotic Often retains original function ○ Tumor Terminology “-oma” suffix indicates benign tumor (adenoma) “-carcinoma,” “-sarcoma” indicate malignant tumors Carcinoma: epithelial origin (adenocarcinoma)(Outer) Sarcoma: mesenchymal (nerve, bone, muscle) origin(Deep) Leukemia: white blood cells Exceptions (all the following are malignant) Lymphomas Hepatomas Melanomas ○ Initiation Initiating events Genetic mutations ○ Inappropriately activate proto-oncogenes Inactivate tumor suppressor genes Complete carcinogens Capable of initiating cell damage Capable of promoting cellular proliferation Partial carcinogens Promoters that stimulate growth Incapable of causing genetic mutations sufficient to singly initiate cancer ○ Promotion Stage during which mutant cell proliferates Activation of another oncogene Inactivation of tumor suppressor gene Nutritional factors Infection Regulated by many hormonal growth factors (hormones may be promoters for certain cancers) Estrogen Testosterone Cancer cells produce telomerase Allows immortality in cancer cells ○ Progression Mutant, proliferating cells begin to exhibit malignant behavior Cells whose phenotype gives them a growth advantage proliferate more readily Evolved tumor cells differ significantly from the normal tissue Grading and Staging of Tumors ○ To predict clinical behavior of malignant tumor and guide therapeutic management ○ Grading/Degree of cell Degree of anaplasia Histologic characterization of tumor cells 3 or 4 classes of increasing degrees of malignancy Greater degree of anaplasia=greater degree of malignant potential (the uglier = the most serious) ○ Staging Size of the cancer/Tumor size Location and patterns of spread within the host Extent of local growth Lymph node and organ involvement Distant metastasis Effects of Cancer on the Body ○ Depends on location of tumor and extent of metastasis ○ Early stages may be asymptomatic ○ Tumor increases in size and spreads; more symptoms become apparent ○ Warning signs: Change in bowel or bladder. sore that does not heal A Unusual bleeding or discharge. Th ickening or lump in breast or elsewhere. Indigestion or difficulty swallowing. Obvious change in wart or mole. Nagging cough or hoarseness Pain ○ ommon and feared complication C ○ May be due to metastasis, tissue destruction/inflammation ○ May be caused by cancer treatment ○ Usually controlled with analgesics Patient controlled analgesia C achexia and Immune System Deficits ○ Cachexia Overall weight loss and generalized weakness Loss of appetite (anorexia) (Tumor necrosis factor) Increased metabolic rate Nausea/vomiting ○ Immune system suppressed by cancer cell secretions ○ Some cancers can elude immune system detection TAN ○ Thrombocytopenia: Bone marrow suppression(myelosuppression)due totumor spreading/taking over bone marrow. Or due to chemotherapy Normal platelets value (150,000-450,000 unit/ccm) Bleeding. ○ Anemia: Fatigue ○ Neutropenia(Most important for nurses): Decrease of neutrophil, suppressed immune system. Infections kill cancer patients. (ex: e-coli and candida) Bone Marrow Suppression ○ Contributes to anemia, leukopenia, and thrombocytopenia ○ Due to invasion and destruction of bone marrow cells, poor nutrition, and chemotherapy ○ Anemia: Deficiency in circulating red blood cells Leukopenia ○ Deficiency in circulating white blood cells Primary cause Malignant invasion of bone b marrow Contributing factors Malnutrition Chemotherapy ○ Opportunistic organisms can only infect immunocompromised host (E-Coli in stomach goes to blood and cause sepsis) ○ Infections difficult to manage Try to prevent ○ May cause changes in chemotherapy treatment May be suspended until WBC count recovers Thrombocytopenia ○ Deficiency in circulating platelets Important mediators in blood clotting Predispose to life-threatening hemorrhage, esp., if count is below 20,000 ○ Anemia, leukopenia, thrombocytopenia can all be managed by blood replacement therapy Rapidly proliferating cells. ○ 1) Bone Marrow (TAN) ○ 2) GI -> Stomatitis (Inflammation of oral cavity membrane) ○ 3) Hair Loss / Alopecia Other Effects ○ Hair loss and sloughing of mucosal membranes ○ Complications of chemotherapy and radiation therapy Damaged mucosa primary source of cancer pain and anorexia May provide a portal for infection ○ Paraneoplastic syndromes: tumor production of hormones or cytokines Hypercalcemia Cushing syndrome secondary to ACTH secretion Hyponatremia and water overload secondary to excess ADH secretion Certain tumor released ADH. Result in higher water retention, diluting ion, and cause decrease [Na] Constitutional questions (B signs): ○ 1) Have you lost weight? Intentional or unintentional? ○ 2) Night sweat? ○ 3) Low grade fever/feel warmer? Cancer Therapy Cancer Therapy ○ Early detection best prognosis for cure ○ Mainstays of therapy Surgery Radiation therapy Hitting H-bond in DNA. Drug therapy/chemotherapy ○ Emerging therapies Immunotherapy Targeted molecular therapies Stem cell transplantation Chemotherapy ○ Only work when cells are rapidly dividing. Rapidly proliferating cell ○ Only two types Cell cycle specific chemotherapy Hits S phase, interrupt DNA synthesis Non cell-cycle specific chemotherapy Everywhere ○ Assuming 100,000,000,000 cancer cells. ○ Induction: Decrease to 100,000,000 cancer cells. Bone marrow is also affected by chemotherapy. (myelosuppression) RBC: 5 million -> 2 million. WBC: 5k-10k -> 2k WBC. Platelets: 150k-450k -> 60k ○ Wait for bone marrow to recover. (the longer the wait period, the higher mortality rate) ○ Consolidation: Another period of chemotherapy so take off another 1,000. ○ Maintenance dose: Continue chemotherapy as needed to kill more cancer cells. Surgery ○ Majority of patients wit
