Week Two Pathophysiology PDF

Week Two – Sept. 10, 2024: Cellular Basis of Disease (cont.) & Normal Function of the Central Nervous System Acid Base Balance - Acid – compound that donates H+ to solution o Strong acids fully ionize at lower pH o Weak acids partially ionize § Example – acet...

Week Two – Sept. 10, 2024: Cellular Basis of Disease (cont.) & Normal Function of the Central Nervous System Acid Base Balance - Acid – compound that donates H+ to solution o Strong acids fully ionize at lower pH o Weak acids partially ionize § Example – acetic acid (vinegar) Donates H+ in solution and becomes acetate - Base – compound absorbs H+ to solution o Weak Acid = acetate (negatively charged) § Can absorb H+ and become acetic acid - pH – measure of H+ concentration o pH = - log [H+] o Neutral – 7 o Acidic – 1-6 o Alkalinity – 8-14 o Proteins greatly affected by pH § Alter funx § Includes enzymes o Normal Arterial blood pH – 7.38-7.42 § Normal PCO2 – 35-45 § Normal HCO3- – 21-28 - Buffer Systems – weak acids/bases as conjugate pairs o Funx – regulate pH of every fluid in body o Primary (active) buffer systems – kidneys and lungs o Other Major Buffer Systems § Bicarbonate Base – HCO3- Acid – H2CO3 (carbonic acid) Most important buffer system Regulated by lungs and kidneys o 𝐶𝑂! + 𝐻! 𝑂 < 𝑐𝑎 > 𝐻! 𝐶𝑂" 𝐻𝐶𝑂"# + 𝐻$ § ca = carbonic anhydrase enzyme in all cells that metabolizes 𝐶𝑂! + 𝐻! 𝑂 𝐻! 𝐶𝑂" § reversible rxn, rxn goes both ways to compensate for pH dependent on mass action (amount of product in fluid) o if H+ low 𝐶𝑂! + 𝐻! 𝑂 < 𝑐𝑎 > 𝐻! 𝐶𝑂" o if H+ high 𝐻! 𝐶𝑂" 𝐻𝐶𝑂"# + 𝐻$ § Lungs perform regulation by changing RR and depth Increase RR blows off CO2  o Decreases PCO2, decreasing pH Decrease RR preserves COS o Increasing PCO2 accumulation, decreasing pH Rapid effect – mins-hrs § Kidneys perform regulation by controlling reabsorption of HCO3- and secretion of H+ Increased reabsorption and secretion, increase in pH Decreased reabsorption and secretion, decreased pH Slow effect – hrs-days 60% of CO2 from blood in this form § Hemoglobin Base – Hb- Acid – HHb (hemoglobin w/ H) § Proteins Base – Pr- Acid – HPr Both intracellularly and extracellularly § Phosphate Acid – HPO4 = o Double negative charge Base – H2PO4- Phosphate is found all over body, including in ATP o Buffers systems have a working range where they operate/activate § Allows wider range of pH maintenance abilities - Respiratory/Metabolic Acidosis/Alkalosis o Respiratory Acidosis § Disturbances – low pH, high PCO2, normal HCO3- § Compensations – increasing pH, high PCO2, high HCO3- § Causes – hyperventilation, poor gas exchange r/t accumulation of CO2 and carbonic acid (from inability to escape or overproduction) due to respiratory dysfunction, renal will need to compensate o Respiratory Alkalosis § Disturbances – high pH, low PCO2, normal HCO3- § Compensations – decreasing pH, low PCO2, low HCO3- § Causes – hyperventilation, depletion of CO2 and carbonic acid Due to respiratory dysfunction, renal will need to compensate o Metabolic Acidosis § Disturbances – low pH, normal PCO2, low HCO3- § Compensations – increasing pH, low PCO2 (increased RR), low HCO3- § Causes Increased non-carbonic acids  o Ketoacidosis – over production of keto acids, found when fat break down o Uremia – renal failure causes uric acid to build up in blood due to inability to excrete via urine o Ingestion – increased consumption of acid products Bicarbonate Loss o Diarrhea – r/t loss of electrolytes o Renal failure o Proximal tubule acidosis – renal insufficiency causing increased loss of HOC3- and retain too much acid § If due to renal dysfunction, respiratory ill need to compensate o Metabolic Alkalosis § Disturbances – high pH, normal PCO2, high HCO3- § Compensations – decreasing pH, high PCO2 (decreased RR), high HCO3- § Causes Excess loss of non-carbonic acids o Prolonged vomiting – r/t loss of hydronic acids o GI suctioning – removes GI acids o Hyperaldosteronism – promotes acid loss o Diuretic therapy Excess bicarbonate intake o Compensation Methods for Metabolic Imbalances Cell Metabolism - Cell metabolism – chemical rxn in the body - Energy metabolism – breakdown of nutrients for energy (ATP) o Steps § 1. Glycolysis Occurs in cytosol of cell ATP yield = 2 § 2. Citric acid/Krebs cycle Occurs in mitochondria ATP yield = 2 § 3. Oxidative Phosphorylation Occurs in mitochondria ATP yield = ~32 o Biggest pay off o Only step that REQUIRES OXYGEN as final e- acceptor § Only purpose of O2 in body o Different foods enter at different steps of energy metabolism Cell Transport - Passive Transport – movement of molecules that do not require energy o Simple diffusion – movement of molecules across membrane down their gradient § Example – O2, CO2 o Osmosis – movement of water across the membrane towards high solute concentration § Example – water following Na  o Facilitated Diffusion – movement of molecules across membrane with aid of carrier proteins or protein channels § Example – glucose - Active Transport – movement of molecules that require energy o Secondary Active Transport – uses ATP to move molecules against their gradient § Example – Na-K Pump o Primary Active Transport – relies on the electrochemical gradient created by primary active transport to drive the movement of another substance against its concentration gradient § Example – Na glucose cotransporter Cellular Stress and Injury - Stress/Overt injury leads to either: o Increased functional demand § Persistent stress leads to adaptation Adaptations – hypertrophy, hyperplasia § Relief of stress returns cell to normal structure and funx Limit to window, must be reversed early o Reversible cell injury § Persistent stress leads to adaptations Adaptations – atrophy, metaplasia, dysplasia, storage § Relief of stress returns cell to normal structure and funx Limit to window, must be reversed early § In serve cell injury, irreversible cell injury leads to coagulative necrosis (cell death) - Low level stressor – changes cell funx demands but don’t cause overt injury or cell death o Can still bring clinical manifestation - Coagulative necrosis – cell death from external cause, general tissue death o Coagulative – refers to coagulation of proteins and cell components o Necrosis – refers to death of tissue o Results in big, bloated cells § Intracellular elements clump and coagulate § Cell loses shape due to disorganized cytoskeleton § Dilated ER § Nuclear changes Pyknosis – shrink of nucleus, typically the 1st change Karyorrhexis – nucleus on pieces Karyolysis – lack of nucleus - Liquefactive Necrosis – collection of cells that have dies and liquefied o Tissue appears liquifies and like a cyst § Due to no connective tissue holding it together o Occurs in regions with little connective tissue (ex. Brain) - Caseous Necrosis – not liquefactive but partially liquefied o Occurs with loose network of connective tissue holds death together o Found in lymph nodes from TB in lungs o Named like “casein” a protein in cheese bc looks like cottage cheese - Fat necrosis – cell death that occurs in tissue rich in fatty deposits  o Common in pancreas, breast tissue o When intracellular contents release, they react with fatty deposits and undergo saponification (soapy deposits in tissue) - Apoptosis – programmed cell death, programed in every cell genome o Purpose – organism protection from cells turning cancerous o Steps § 1. Activation intrinsically/extrinsically § 2. Cell shrinkage and chromatin condensation (proteins start chopping up DNA) § 3. Nuclear collapse – cells appear imploded and collapse on itself § 4. Apoptotic body formation – remnants of the cells § 5. Lysis of apoptotic bodies o Triggers § Viral infection § DNA damage r/t excessive DNA error (from external factors or normal mutation) DNA repair proteins scan DNA for error o Bind to errors found, repair and prevent transcription and translation § certain membrane/mitochondrial damage § cell stress (ER) § induction by immune cells (WBC instruct cell to apoptosis) - Mechanisms of Cell Injury o Hypoxic Injury – injury that occurs when area of body does not receive enough O2 § Ischemia – decrease in blood flow resulting int decrease in O2 flow Causes o Decrease in Na/K Pump funx § Increase in Intracellular Na § Increase in extracellular K o Increase in intracellular Ca § Ca ATP pumps stop working o Increase in intracellular eater § Follows Na § Leading to increase in acute swelling Swelling on both cell and organelles o Swelling of mitochondria causes inability to produce ATP § Leading to cell death o Increase in glycolysis o Decrease in glycogen o Increase in lactate (lactic acid) o Decrease in pH § Proteins denature § Increase in lysosomes swelling and explosions  Lysosomes = “stomach of the cell”, contain digestive enzymes o Bursting leads to autodigestion of the cell § Anoxia – complete loss of blood flow, resulting in complete loss in O2 delivery Typically, due to blockage of blood flow Reperfusion injury – injury from returned blood to other areas of body due to trigger inflammatory rxn (inflammatory mediators) in injured cells o Inflammation damages tissue Is quickly followed by Coagulative necrosis o Free Radical (reactive O2 Species) injury – injury from any element w/ unpaired e- in outer shell attempting to steal e- § These elements are highly reactive § Most common free radical is free oxygen Normally a byproduct of metabolism and inflammatory rxn o As O2 oxygen is nonpolar and oxidized o Metabolism will produce a reactive oxygen species o Normally cells have enzymes that neutralize reactive oxygen species to prevent them from creating an issue o However oxidative stress increases production of reactive oxygen § Reason when antioxidants slow cell aging § Injuries cause Lipid peroxidation – injury to plasma membrane from stolen e- o Effects § Increased membrane rigidity § Decreased activity of membrane bound enzymes and other proteins in membrane Example – Na/k Pumps § Altered activity of membrane receptors § Altered permeability Disruption of polypeptide chains – damage to protein DNA damage – damage to DNA o Creates increased risk of cancerous cell formation § Common Free Radicals Superoxide anion O2- Peroxide O2(-2) Hydroxyl Radical OH § Formations of free radicals Metabolism Inflammation – Neutrophils and macrophages releases reactive oxygen to attack bacterial species o Creates collateral damage in organism’s tissue  Air Pollution – release O3 that react w/ UV light creating reactive oxygen Smoking – releases reactive oxygen species Ionizing Radiation – releases reactive oxygen species UV light – releases reactive oxygen species o Other injuries § Mechanical (example crushing) § Extreme temperature § Foreign chem rxn exposure - Adaptations o Hypertrophy – larger cells, same number of cells § Not cell swelling, changes in cellular contents remain proportional § r/t increased funx demands, increased hormonal stimulation § often occur with Hyperplasia § Example – weight training Causes increase demand in muscle cells o Non pathological, health and adaptive § Example – pancreas cells in DM II Allows for increase in insulin release § some cells cannot divide so cope with hypertrophy Example – myocardial hypertrophy o Pathological o r/t HTN or aortic stenosis o Hyperplasia – increase in cell number, cell size remains the same § Often occurs with hypertrophy § r/t increased funx demands, increased hormonal stimulation, chronic injury/tissue repair § example – psoriasis (autoimmune disorders) o Atrophy – smaller cells, same number of cells § Not shrinking, changes in cellular contents remain proportional § r/t decreased funx demands, decreased hormonal § Example – disuse atrophy Atrophied Liver cells r/t protein/calorie deficit (starvation) § Can occur in tissue that responds to hormonal support if there is a decrease in hormonal production Example – reproductive system o Cells can atrophy due to decrease in hormones § Perimenopausal stage may lead to issues with fibroids Most common tx = hysterectomy Often not told that w/ s/sx tx until after menopause fibrous will shrink and issue will go away o Metaplasia – increase in premature cell division of normal cells, results in unharmful but dysfunctional cells § Reversible, adaptive  § r/t chronic injury in tissue § most common in epithelial tissue due to increased rate of replacement § Example – smoker’s lung Ciliated epithelium replaced w/ simple squamous cells o Simple squamous can endure injury and replace faster § Allows tissue to cope § Returns to original structure once healed o Simple squamous lacks functional maturity (cilia, mucus production) § Clinical manifestations Thick mucus Difficultly coughing up mucus o Increases risk of infection § Example – cervical metaplasia Can be r/t HPV o Viruses enters cells and tells cells to increase virus production killing cells o Can lead to dysplasia and cervical cancers in some forms § May cause exertion mutagenesis Genes in HPV can make cell cancerous o Dysplasia – increase in unregulated premature cell division, results in harmful dysfunctional cells § Irreversible, non-adaptive, thought of as a consequence § Precancerous Rapid cell division can lead to cell mutations leading to cancer o Cell division from stem cells include differentiation steps to mature cell until terminally differentiated § Key Features to Terminal differentiated Cell Most funx mature Loose ability to divide Will have an expiration/death day o Will be replaced by new cell § No self-control in cellular division or funx § most common in epithelial tissue due to increased rate of replacement § Example – lung cancer o Changes to cell storage § Normal cell storage – fat/energy, glycogen, vesicles of water Storage accumulation may occur due to lack of digestive funx (by decreased/immobilized enzymes) o This occurs in tattoos § Accumulations Water o r/t hypoxic injury or other injury impairing osmosis across membrane § results in expanded mitochondria and ER Lipids  o Example – brain in Tays Sachs disease § Deficiency in enzyme specific to specific lipid leads to lipid accumulation in neural cells of brain Cannot break them down so cell stores them Lipid Accumulation in Liver o Example – fatty liver disease § Hepatocytes of liver accumulate fat in cytoplasm § r/t chronic ethanol exposure (EtOH) when metabolized by liver creates byproduct acetaldehyde o acetaldehyde blocks liver’s ability to digest fat liver can manage mild-moderate drinking § Clinical manifestations Increase in liver enzymes Fatty liver in biopsy Enlarged yellowish liver § Hydropic Swelling Normal Function of Nervous System - Homeostatic Control System (figure 2.1) o CONTROLED VARIABLE DEVIATED FROM SET POINT § Sensor § Integrator § Effector § Compensatory rxn o CONTROLLED VARIABLE RETURNED TO SET-POINT § Controlled with negative feedback system to turn off effector - Control Systems: Nervous System v. Endocrine Systems o Function of control systems – control, regulate, maintain homeostasis o Nervous System § Anatomic Arrangement – wired system, specific structural arrangement between neurons and target cells § Chemical Messenger – neurotransmitters (NT) § Distance of Action – short distance (diffusion across synaptic cleft) § Specificity of Action – depends on anatomic relationship between nerve a § Speed of rxn – rapid (msec) § Duration of Action – brief (msec) § Major Funx – coordinate rapid, precise rxn § Influence on other major control system – yes o Endocrine § Anatomic Arrangement – wireless system via endocrine glands throughout the body unrelated to target cells § Chemical Messenger – hormones released in blood stream § Distance of Action – long distance § Specificity of Action – demands on specific of target cell binding and responsiveness to hormone, can have multiple targets  § Speed of rxn – slow (min-hours) § Duration of Action – long (mins to days+) § Major Funx – control activities that req. long duration § Influence on other major control system – yes - Divisions of the Nervous system o Central Nervous System – brain and spinal cord o Peripheral Nervous System – nerves around the body § Afferent (sensory) division – receives sensory information Sensory (somatosensory) stimuli – stimulation we are aware of o Includes touch, heat, pain, etc. Visceral Stimuli – stimulation we are typically unaware of effecting the status of visceral funx o Example – BP, blood volume, blood osmolarity § Efferent (motor) division – carries out motor command Somatic Nervous system – voluntary movement o Controls motor neurons that operate skeletal muscles Autonomic Nervous System – voluntary movement, visceral funx o Sympathetic Nervous System – fight/flight, triggered by stress § Controls smooth/cardiac muscle, glands o Parasympathetic Nervous System – rest and digest, dominant most times § Controls smooth/cardiac muscle, glands - Nervous Tissue o Ramón y Cajal § Neuroscientist, late 18000s, Spain § Pioneered the Golgi stain Specific stain to neuro cells with detail and sporadically Gave ability to create drawings of neuro cells o Neurons and muscle cells are only two cells in body that can be “excited” § Meaning can fire AP AP – explosive movement of charged ions across membrane for electrical impulses, creating flow of NT o Neuron = nervous system cells § Cell body (soma) – contain all cellular contents/organelles and make vesicles of NT § Dendrites – received information from other cells that causes cell to fire AP § Axon hillock – where AP starts § Axon – arm of neuron § Axon terminal – ends of axon § Presynaptic terminal – ending bud of neuron where NT are released § Myelination – insulation of an axon on most neurons Ensure flow of AP and increases AP rate and preserve signal Nodes of Ranvier – spaces between myelinated cells where AP occurs in myelinated cells  Schwann cell – flattened myelination of cells in PNS Oligodendrocytes – myelination of cells in CNS § Types of Neurons Afferent (sensory) Neuron – carry sensory message into CNS o Cell body on PNS o Receptor in sensory organ/tissue o Axon terminal in CNS moving towards CNS Interneurons – connect afferent and efferent neurons o V. diverse o Funx – process afferent signal and create efferent command o Can terminate on many targets Efferent neurons – carry command from CNS to target organ/gland/muscle o Cell body in CNS - Resting Membrane Potentials o Dominant Ions at Rest § ICF – K, A- (anions, neg charged ions) %&'(()* K= + § ECF – Na, Cl, Ca o Na/K Pump – maintains ion distribution § 3 Na out, 2 K in o K leak channels – allows K+ to move freely out of cell dependent on gradients o Electrostatic gradient – movement f ions to keep electrical equilibrium o Equilibrium potential based on both concentration gradient and cell permeability to ion o Nernst Equation – establishes equilibrium for each ion [-).])01 § Single charge ions 𝑉( = 61.5𝑥 log( [-).]-. ) [-).])01 § Double charged ions 𝑉( = 30.75𝑥 log( [-).]-. ) & § K = 𝑉( = 61.5𝑥 log 9 %&': ≈ −92𝑚𝑉 & § Ca2+ = 𝑉( = 30.75𝑥 log 9 '.''%: ≈ −123𝑚𝑉 %4! § Na = 𝑉( = 61.5𝑥 log 9 %' : ≈ 67𝑚𝑉 %'" § Cl - 𝑉( = 61.5𝑥 log 9 4 : ≈ −86𝑚𝑉 Negative charge of Cl changes answer to negative to match o Ion charges and movement § K = -92mV, moving out (90%) § Ca2+ = 123mV, moving in (1%) § Na = 67mV, moving in (1%) § Cl- = -86 mV moving in (8%) o Resting Membrane Potential (see figure 2.2) [#$%]$'( § ∑((𝑉! = 61.5𝑥 log( [#$%]#% ))𝑒𝑎𝑐ℎ 𝑖𝑜𝑛 𝑥 % 𝑖𝑜𝑛 𝑚𝑜𝑣𝑒𝑚𝑛𝑡 𝑎𝑐𝑟𝑜𝑠𝑠 𝑚𝑒𝑚𝑒𝑏𝑟𝑎𝑛𝑒) - Action Potentials (AP) o An electrical signal within a cell  o Neurotransmitter (NT) – binding to dendrites open ion channels for charged ion movement creating the AP in the axon hillock o Net charge of cell = -65mV at rest o Steps of AP (see figure 2.3) § 1. NT binds to ligand § 2. Na channels open and depolarize the cell Excitatory postsynaptic potential (EPSP) – creates positive net charge Inhibitory postsynaptic potential (IPSP) – creates more negative net charge o Typically completed when NT causes Cl channels to open (repolarization) § 3. Membrane meets Threshold potential (-55mV) Minimal charge needed to create an AP § 4. AP is carried down axon in chain rxn of Na channels opening until membrane reaches 40mV Stages of Na channels o Closed – channel closed and not blocked, no Na flow o Open – channel open and not blocked, free Na movement o Inactivated – channel open and blocked, no Na movement § Aids in ending depolarization § Specific to Na channel § 5. Hyperpolarization – cell drops charge to -75mV Voltage gated K channels open at 40mV allowing K to move out o Slow rxn to open/close § Reason Na channels got inactive § Reason why we have hyperpolarization Na/K Pump continues to operate to help with repolarization and maintaining resting potential § 6. Refractory Periods Absolute refractory period – moment where Na channels remain inactive to rxn o Keeps from AP happening too close together or moving backwards Relative refectory period – moment where Na channels are closed by cell is hyperpolarized (-75mV) and will take a stronger stimulus to create AP o Saltatory Conduction – conduction of signal in myelin § Na ions “bump” into Na ions already packed into myelin and push others out other side Not diffusion Giving the illusion of AP jumping nodes of Ranvier - Interneural Communication o Communicate via electrically or chemically via synapses § Chemical communication – excitatory/inhibitory NT by presynaptic cell to post synaptic cells  Neurotransmitter s o Amino Acids § Glutamic Acid (glutamate) – stimulant, found in many places § Aminobutyric Acid (GABA) – generic inhibitory NT § Glycine – generic inhibitory NT o Monoacids – derived by dingle chemical modified amino acids § Acetylcholine § Serotonin § Histamine o Catecholamines – derived from tyrosine, a monoamine § Dopamine § NE § Epi Neuroactive peptides – not proper NT but peptides that may be released w/ NT and modify response in Postsynaptic cell o Typically, shorter chains of proteins o V. diverse o Funx – moderate rxn of NT § Example – causes increase/decrease in production/effect of receptor for NT in postsynaptic cell Causes greater sensitivity o Somatostatin, gonadotropin-releasing hormone, substance P, neurotensin, gastrin-releasing peptide, vasoactive intestinal peptide, oxytocin, angiotensin II, thyrotropin- releasing hormone, met-enkephalin, leu- enkephalin, endorphin, adrenocorticotropic hormone, arginine vasopressin, cholecystokinin-like peptide Steps of chemical message o 1. AP travel to axon terminal o 2. AP triggers depolarization to stimulate Ca2+ voltage ion channel o 3. Ca2+ stimulated exocytosis of NT vesicles (regulated exocytosis) § NT vesicles stored in axon terminal, produced in cell body, travel via microtubules o 4. NT released in synaptic cleft o 5. NT binds to receptor on postsynaptic cell § In NMJ acetylcholine will open ion (cation) channels on skeletal muscles Allows positive charged ions (ex. Na) into cell § Triggers AP in next cell  In NMJ causes muscle contraction Example – neuromuscular junction o Electrical Synapses (gap junctions) – direct electrical spread of AP Figure 2.1 Figure 2.2 Figure 2.3