Acid-Base Disorders Notes PDF

Acid-Base Disorders MUDr BOKANG MASWABI M.D, PhD  Acid-Base Balance Necessary to sustain life The pH determines properties of proteins – enzyme activity – part of the cell structure permeability of membranes – distribution of electrolytes pH is kept between 7.35 and 7.45...

Acid-Base Disorders MUDr BOKANG MASWABI M.D, PhD  Acid-Base Balance Necessary to sustain life The pH determines properties of proteins – enzyme activity – part of the cell structure permeability of membranes – distribution of electrolytes pH is kept between 7.35 and 7.45 pH levels 7.8 are not compatible with life  Electrolyte An electrolyte is a substance which develops an electrical charge in the presence of water Cation Anion  Acid base Homeostasis On a typical Western diet, approximately 15,000 mmol of carbon dioxide (which can generate carbonic acid as it combines with water) and 50 to 100 mEq of nonvolatile acid (mostly sulfuric acid derived from the metabolism of sulfur-containing amino acids) are produced each day. Acid-base balance/homeostasis is maintained by pulmonary and renal excretion of volatile acid/carbon dioxide and nonvolatile acid, respectively.  Acid Electrolyte that forms a hydrogen cation and an anion in the presence of water. Weak acid – partially ionizes in water – H2CO3 Strong acid – Totally ionizes in water – HCl  Base A substance that can accept hydrogen ions Weak base – do not bind well with hydrogen – HCO3- Strong base – binds well with hydrogen – OH-  pH Ranges from 0 - 14 Neutral pH (7) Acidosis refers to a pH less than 7.35 Alkalosis refers to a pH greater than 7.45 Physiological pH (7.4 ± 0.05)  Volatile Acids Can be eliminated as CO2 gas Physiological Example – Carbonic acid Carbonic acid dissociates to – CO2 and H20 Volatile acids are eliminated through the lungs. Common nonvolatile acids in humans are lactic acid, phosphoric acid, sulfuric acid, acetoacetic acid, and beta-hydroxybutyric acid.  Nonvolatile Acid An acid that cannot be eliminated as CO2 gas Example – Lactic acids – Ketoacids Acetoacetate 3-hydroxybutyrate Common nonvolatile acids in humans are lactic acid, phosphoric acid, acetone sulfuric acid, acetoacetic acid, and beta-hydroxybutyric acid  Buffers A buffer is an aqueous solution made of a mixture of a weak acid and its conjugate base or a weak base and its conjugate acid. Its pH changes very little when a small amount of strong acid or base is added. It is used to prevent any change in the pH of a solution. Functions of buffers – control pH – converts a strong acid into a weak one – converts a strong base into a weak one  Bicarbonate Buffers Bicarbonate – most important one – operates both in the lung and the kidney Consists of – H2CO3 and HCO3- – CO2 is excreted or retained as needed – HCO3 is excreted or retained as needed H2O + CO2 H2CO3 HCO3- + H+  Protein Buffer System Protein Buffer System – Proteins carry a negative charge – They can combine with H+  Hemoglobin Buffer System Hemoglobin is an example of the protein buffering system – H+ combines with Hgb to form HHgb – HHgb combines with CO 2 to form HHgbCO2 HHgb is a weak acid - H H Hb + + H HbO2 + + H -  Phosphate Buffer Systems Phosphate buffer system Important Buffer – Red blood cells – Renal tubules Consists of H3PO4 (phosphoric acid) – H2PO4- (dihydrogen phosphate)  Renal Buffer System Kidneys regulate pH via 3 ways – Reabsorbtion of filtered HCO3- – formation of titrable acid of H2PO4- / HPO4– – Excretion of ammonia in Urine (as ammonium)  Role of the Liver in ABB - Detoxification of ammonia(NH3) in the liver is done via two ways (ammonia is produced during deamination of amino acids 1) Via urea production CO2 + 2NH4+ CO(NH2)2 + 2H+ + H2O 2) Via glutamine 4NH4+ + H + lactate + 3O2 2glu-NH2 + 2CO2 + H2O Role of the Liver in ABB  ABB AND IONS Electroneutrality must be maintained Acid Base Imbalances thus Cl– affect mineral metabolism Variations in the Na+ concentration of ions is most easily compensated by changing the HCO3- concentration of HCO3- prot- K+ SO42-, HPO42-, Ca2+ Mg2+ lactate, ketone bodies Cellular Shifts in Buffer System Acidosis – potassium leaves the cell – hydrogen ion enters the cell Alkalosis – hydrogen leaves the cell – potassium enters the cell  Regulation of pH Biarbonate Buffering system – within seconds Respiratory system – 20-30 minutes Renal system – several days  Respiratory Control of pH Acidosis – respiratory rate increases Alkalosis – respiratory rate decreases Response time – 20-30 minutes  Acidosis Increased hydrogen ions Decreased bicarbonate ions Decreased pH  Alkalosis Decreased hydrogen ion concentration Increased bicarbonate concentration Increased pH  Normal ABG Values pH 7.4 (7.35 - 7.45) pCO2 40 (35-45) mmHg HCO3- 24 (22-26) mEq/L Base Excess 0 (-2 to +2 mEq/L) pO2 (75-100 mmHg) Saturation O2 98 %  Oxygen saturation Oxygen Saturation (greater than 95%) Dependent on SAO2 Which delivers more oxygen to the tissue – Sat 95% Hgb 15 gm/dl – Sat 95% Hgb 10 gm/dl  Interpretation of Arterial Blood Gases Look at the pH. – normal 7.35 - 7.45 – acidosis 7.45  Interpretation of Arterial Blood Gases Look at the respiratory component. normal pCO2 (35 - 45 mm Hg) – increased pCO2 --> respiratory acidosis – decreased pCO2 --> respiratory alkalosis  Interpretation of Arterial Blood Gases Look at the metabolic component – normal HCO3- (22 - 26 mm HG) – Increased HCO3- metabolic alkalosis – Decreased HCO3- metabolic acidosis  Respiratory Acidosis Mechanism – Hypoventilation – increased CO2 – increased H2CO3 – increased H+  Respiratory Acidosis Laboratory Values – pH < 7.35 – pCO2 > 45 mm Hg – HCO3- unchanged  Respiratory Acidosis Etiologies – Obstructive Lung Diseases – Restrictive Lung Diseases – Hypoventilation narcotics inappropriate ventilator settings  Respiratory Acidosis Signs and symptoms – Cyanosis – Shallow breathing – Dyspnea – Confusion – Cardiac dysrhythmias  Respiratory Alkalosis Mechanism – Hyperventilation – Low carbonic acid level – Low CO2  Respiratory Alkalosis Laboratory Values – pH > 7.45 – pCO2 < 35 mm Hg – HCO3- unchanged  Respiratory Alkalosis Hyperventilation – anxiety – panic attacks Increased respiratory center activity – fever  Respiratory Alkalosis Signs and Symptoms – Light headedness – Paraesthesias – Twitching – Chvostek’s sign – Trousseau’s sign  Metabolic Acidosis Mechanism – Retention of nonvolatile acids – Excessive loss of base Laboratory : HCO3-, pH, later: pCO2  Metabolic acidosis Metabolic Acidosis with Metabolic Acidosis with - increased AG normal AG Lactic acidosis Diarrhea and other losses from the GIT hypoxia, reduced lactic Renal tubular acidosis ;HCO3- acid degradation resorption disorders in renal tubule - Ketoacidosis diabetes, starvation, Dilution acidosis alcoholism… administration of large quantities - Renál acidósis infusion without buffer system? Accumulation of sulphates (constant pCO2, HCO3-is quickly - Intoxications diluted) NH4Cl overdose  Metabolic Alkalosis Mechanisms – Increased levels of HCO3- – Decreased levels of H+ Laboratory Values – pH > 7.45 – HCO3- > 26 mEq/L Laboratory : HCO3-, , pH Later : paCO2  Metabolic Alkalosis Laboratory Values – pH > 7.45 – HCO3- > 26 mEq/L Laboratory : HCO3-, BBs, BE, pH later : paCO2  Metabolic Alkalosis Ingestion of large amounts of sodium bicarbonate Parenteral administration of NaHCO3 Vomiting of gastric contents Nasogastric suctioning Potassium wasting diuretics – thiazide diuretics – loop diuretics  Potassium Imbalances in Acidosis Kidney – In acidosis there is an excess of H+ – In acidosis the kidneys preferentially eliminate H+ – When a H+ is eliminated a K+ is retained. – Increased K+ retention leads to hyperkalemia  Potassium Imbalances in Acidosis Cellular – In acidosis H+ is buffered in the cell – As H+ moves into the cell, K+ moves out of the cell – Increased K+ in the ECF produces hyperkalemia  Potassium Imbalances in Alkalosis Kidney – Alkalosis is related to decreased H+ concentration or increased base. – In alkalosis the kidneys preferentially retain H+. – When H+ is retained, a K+ is excreted. – Increased excretion of K+ leads to hypokalemia.  Potassium Imbalances in Alkalosis Cellular – H+ moves from the cell to the extracellular fluid. – When H+ moves from the cell, it is replaced by a K+. – The result is hypokalemia.  Calcium Imbalances in Acidosis Causes increased release of Ca++ from plasma proteins Hypercalcemia  Calcium Imbalances in Alkalosis Causes increased binding of Ca++ to plasma proteins Hypocalcemia  Compensation for Respiratory Acidosis The kidneys are the major compensatory mechanism for respiratory acidosis. The kidneys retain increased HCO3- Serum HCO3- rises above 26 mEq/L pH returns to normal  Compensation for Respiratory Alkalosis The kidneys are the major compensatory mechanism for respiratory alkalosis. The kidneys excrete more bicarbonate. The HCO3+ falls below 22 mEq/L This balances the acid-base ratio. CO2 ----> H2CO3----> H+ + HCO3  Compensation for Metabolic Acidosis The respiratory system is the major compensatory mechanism for metabolic acidosis. Hyperventilation occurs CO2 is blown off. pH returns to normal CO2 ----> H2CO3----> H+ + HCO3  Compensation for Metabolic Alkalosis The respiratory system is the major compensatory mechanism for metabolic alkalosis. Hypoventilation pH returns to normal CO2 ----> H2CO3----> H+ + HCO3  Metabolic Acidosis Treatment & Management Sodium bicarbonate (NaHCO3) is the agent most commonly used to correct metabolic acidosis. The HCO3- deficit can be calculated by using the following equation: HCO3- deficit = deficit/L (desired serum HCO3- - measured HCO3-) × 0.5 × body weight (volume of distribution for HCO3-) To minimize the risk of hypernatremia and hyperosmolality, – two 50-mL ampules of 8.4% NaHCO3 (containing 50 mEq each) are added to 1 L of 0.25 normal saline – or three ampules are added to 1 L of 5% dextrose in water.  Metabolic Alkalosis Treatment & Management The management of metabolic alkalosis depends primarily on the underlying etiology and on the patient’s volume status. E.g In the case of vomiting, administer antiemetics, if possible.  Respiratory Acidosis and Alkalosis Treatment & Management Treatment of respiratory disorders is primarily directed at the underlying disorder or pathophysiologic process.  INFECTION AND IMMUNITY 2 PHYSIOLOGY OF IMMUNE RESPONSE – Department of Biomedical Sciences Faculty of Medicine  Introduction  Immunology is the study of physiological mechanisms that are used to defend the body from invasion by foreign or infectious agents  In response to diseases caused by infectious agents, the body develops cells dedicated to defense – these form the immune system  Protective immunity takes time to develop, while microorganisms can rapidly multiply and cause disease  Immunity involves two responses, the flexible but specific defenses of the adaptive immune response and the fixed defenses of the innate immune response Role of the Immune System in Homeostasis  Bidirectional interaction with other systems  Reproduction ◼ “Self control” to prevent rejection of the fetus ◼ Stimulation of placental growth ◼ Linked to breeding success (rodents!)  Endocrine ◼ Immune (autoimmune) diseases  CNS ◼ Repair ◼ Neurogenesis ◼ Neurotransmitter/cytokine production and utilization Bob Luebke ITB/ETD/NHEERL US EPA  Role of the Immune System  In distinguishing “self” from “nonself,” immune defences  (1) protect against infection by microbes—viruses, bacteria, fungi, and parasites;  (2) isolate or remove nonmicrobial foreign substances;  (3) destroy cancer cells that arise in the body, a function known as immune surveillance. Bob Luebke ITB/ETD/NHEERL US EPA  Immunity-The Immune Response  People who survive a specific infection become immune to it – protective immunity  To provide protective immunity, the immune system must first engage the microorganism  There is lag time between infection and protection  The first infection is the most dangerous one  This leads to immunization or vaccination  Disease is prevented by prior exposure to an attenuated infectious agent  Defense: Barriers against infections  Skin  Mucosal surfaces  Skin is first line of defense  Mucosal surfaces are bathed against infection in mucus; thick fluid containing  Tough impenetrable barrier glycoproteins, proteoglycans, and enzymes - protective  Skin continuous with epithelia  Lysozyme in tears and saliva lining – antibacterial  respiratory  Respiratory tract mucus is  gastrointestinal continuously removed to clear unwanted material  urogenital tracts  Stomach, vagina, skin acidic – protective When skin and mucosal barriers are breached - immune system responds  Means of acquiring immunity 1. ACTIVE: make own antibody chance encounter w/Ag a) natural pregnancy vaccination b) artificial introduce Ag via treatment  Means of acquiring immunity 2. PASSIVE: transfer preformed antibody a) Natural : mother to fetus (6 months protection) placental vs colostral b) Artificial: immune therapy  Type of immune response  Innate  Adaptive/acquired  defense we are born  Develops with with exposure/time  phagocytic cells  Serum antibodies  complement  T cells (CMI) proteins  anatomical [skin, mucosal surfaces]* * 1st line of defense  Nonspecific Immune Defences -Innate  Do not recognise specific identities  Recognise a general property of the microbes  Carbohydrates and lipid based  Based on use of interferons, body surface defenses and inflammation  Cells included NK cells Nonspecific Immune Defences -Innate Nonspecific Immune Defences -Innate Principle Characteristics of Innate and Adaptive Immunity  Two Arms of The Immune System Innate Immunity Adaptive Immunity Phagocytes Lymphocytes Neutrophils Macrophages T lymphocytes B lymphocytes pathogens pathogens Antigen Antigen presentation presentation TH1 Cytokines chemokines TH1 Cytokines TH1 or TH2 Cytokines Cytotoxicity Antibodies © Jeanne L. Burton, Michigan State University  Mechanisms of immunity  Cellular mediated  Humoral mediated  cells responsible for  Antibodies are protection responsible for  lymphocytes protection  phagocytes  Cells of the Immune System  Lymphoid cells:  20-40% of white blood cells  There are 1011 lymphocytes in the human body  Mononuclear phagocytes:  Monocytes that circulate in the blood and macrophages found in tissues  Granulocytic cells, classified as neutrophils, eosinophils and basophils based on morphology and cytoplasmic staining characteristics  Dendritic cells, whose main function is the presentation of antigen to T cells Cells of the Immune System Cells of the Immune System Organs of the Immune System - cells Bone Marrow: source of immune system cells  Haematopoiesis: blood cell formation 20 STEM CELLS Multipotential Multipotential myeloid cells lymphocytic cells Differentiate & mature into 6 Differentiate & mature into 3 Types of blood cells Types of lymphocytes red cells basophils T lymphocytes neutrophils monocytes B lymphocytes eosinophils platelets Natural Killer Cells 31/10/2024  Site of Hematopoiesis in Humans Changes During Development  The site for hematopoiesis changes with age  In early embryo, blood cells are first produced in the yolk sac and later in the fetal liver  From months 3-7 of fetal life the spleen is the major site of hematopoiesis  As bones develop (4-5 months) hematopoiesis shifts to the bone marrow Hematopoiesis is active  In adults hematopoiesis occurs throughout life because mainly in the bone marrow blood cells are both vital and short-lived  Macrophages Response to pathogens  Bacterial component binding to a cell-surface receptor sends a signal to the macrophage’s nucleus  this initiates the transcription of genes for inflammatory cytokines [IL-6, IL-12, TNF, INOS, IFN-  Inflammation in immune response Vasodilation increases leak of plasma into tissues, causing expansion of local fluid volume leading to swelling and pain  The Complement System  Serum proteins of the complement system are activated in the presence of a pathogen, forming a bond between complement protein and the pathogen  The attached piece of complement marks the pathogen as foreign material  The soluble complement fragment attracts a phagocytic white blood cell to the site of complement activation  The effector cell (macrophage) has a surface receptor that binds to the complement fragment attached to the pathogen  The receptor and its bound ligand are taken up into the cell by endocytosis, which delivers the pathogen to an intracellular vesicle called a phagosome, where it is destroyed The Complement System Pause  T Lymphocytes Recognize Ag only with MHC proteins Produce Lymphokines (not antibodies) Cell Mediated Immunity  T-Cell Subpopulation CD-4 CD-8 T-Cell Help B-Cells produce Antibody Cytotoxicity Reactions  Cell mediated immunity – T - cells  3 Types of T-cells  Only recognize and  Helper T cells (CD4) respond to processed  Cytotoxic T cells (CD8) fragments of protein.  Memory T-cells  Suited for cell to cell  Activation of T cells: interaction and target  T cell receptors bind to body cells infected by antigen presented by the virus, bacteria and antigen-MHC complex abnormal or cancerous  CD4 and CD8 proteins body cells or cells that interact with antigen and help maintain MHC-antigen are transplanted or coupling infused 30 Antigen-presenting cells Antigen-presenting cells  T-Cell Activation Goal: “ Activation and clonal expansion of CD4 and CD8 Cells”  T – cell recognition  Antigen recognition:  Must recognize non-self (antigen) and self (MHC protein of a body cell)  Co-stimulation by binding to other proteins on APC  Cytokines (IL 1 and 2) are released by APC or T cell following co-stimulation  T- Helper Subsets ❑ Th-1 ❑ Hypersensityvity Reactions ❑ Produce IL2 and Gamma IFN ❑ Cell mediated cytotoxicity (virucidal activity) ❑ Th-2 ❑ Principal role in B-cell activation ❑ Produce IL-4 and IL-5 (no IL-2 or Gamma IFN) ❑ Antibody mediated activity (bactericidal activity)  Lymphocytes characteristics  B lymphocytes  Natural Killer cells  Binds soluble antigens  5% of lymphocytes  Nonspecific cytotoxicity  Constitutively expresses MHC II  No TCR/CD3  Induced to express B7  Not MHC restricted  No memory  HUMORAL IMMUNITY  Antigen + Macrophage + T cell + B cell cytokines  Antibodies or Immunoglobulins SPECIFICITY!  MEMORY  (immunity: short, long, or no term) Antibodies are produced by antigen-activated B lymphocytes Fab = antigen binding = Fab variable region IgM () L L IgG1 (1) IgG2 (2) IgG3 (3) Fc = biological IgA () constant region function IgE () (Fc-) H H L = light chain H + heavy chain Antibody structure  Functions of the structures of Ab  Variable region (Fab) bind specifically-neutralize, agglutinate [antigen binding region]  Constant region (Fc)  Activate effector receptors or complement  Macrophage receptors [Opsonin]  Immunoglobin classes and responses  Classes  IgD is attached to B- cell plasma membrane  IgM is released during primary response  IgG functions in late primary and secondary response  IgA found in body secretions First exposure Re-exposure  IgE causes release of Time histamine Type # Ag binding Site of action Functions sites IgG 2 Blood Increase Tissue fluid macrophage activity Can cross placenta Antitoxins Agglutination IgM 10 Blood Agglutination Tissue fluid IgA 2 or 4 Secretions (saliva, Stop bacteria tears, small intestine, adhering to host vaginal, prostate, cells nasal, breast milk) Prevents bacteria forming colonies on mucous membranes IgE 2 Tissues Activate mast cells → HISTAMINE Worm response  Antibody defense mechanisms: PLANe  Precipitation  Lysis: Complement fixation and activation  Agglutination  Neutralization  Enhancing phagocytosis  Opsonization  Free IgG binds Fc receptors with low affinity  IgG bound to Ag, binds to Fc receptors with high affinity  Cross-linking receptors sends signal INFECTION AND IMMUNITY I THE MICROBES Department of Biomedical Sciences Faculty of Medicine  The Ubiquitous Enemy- Microbes  Microbes survive on animal & plant products  Release digestive enzymes  Grow on living tissues (extracellular) where they are bathed in nutrients  Other intracellular microbes infect animal/human cells, utilizing host-cell resources  Some microbes are harmless and some even helpful (e.g. E. Coli in intestines)  Others cause disease (human pathogens)  There is a constant battle between invading microbes and the immune system Pathogens that Cause Human Disease  Besides viruses, two other acellular forms exist:  Viroids: obligate intracellular but acellular parasites of plants; naked RNA; no human diseases.  Prions: acellular particles associated with Kuru, etc.; insensitive to nucleases.  Abnormal prion proteins (PrP) modify folding of normal prion-like proteins found in the body (coded for by human genes).  Epidemiology-Normal Flora  Is found on body surfaces contiguous with the outside environment  Is semi-permanent, varying with major life changes.  Can cause infection  misplaced, e.g., fecal flora to urinary tract or abdominal cavity, or skin flora to catheter  or, if person becomes compromised, normal flora may overgrow (oral thrush).  Contributes to health  protective host defense by maintaining conditions such as pH so other organisms may not grow  serve nutritional function by synthesizing: vitamin K and B vitamins Pathogenicity (Infectivity and Toxicity)  Pathogenicity is the ability to cause infection and disease (harm the host)  Virulence, refers to the degree of pathology caused by the organism  Infectivity is the ability of a pathogen to establish an infection i.e. to be present and to multiply  Colonisation means establishing a prescence  Toxicity; the ability to cause damage Obligatory steps for infectious microorganisms  Pathogenicity- Major mechanisms  Colonisation  Adherence to cell surfaces  Adherence to inert materials , biofilms  Avoid immediate destruction by innate defense  Anti phagocytosis  IgA proteases  Hunting and gathering nutrients (siderophores)  Ability to survive intracellularly (TB. Listeria)  Invasins-surface proteins that allow an organism to bind to and invade normally non-phagocytic human cells, escaping the immune system  Damage from viruses is largely from intracellular replication, which either kills cells, transforms them  Pathogenicity- Inflammation or Immune- Mediated Damage  Cross-reaction of bacterial induced antibodies with tissue antigens causes disease. Rheumatic fever is one example.  Delayed hypersensitivity and the granulomatous response stimulated by the presence of intracellular bacteria is responsible for neurological damage in leprosy, cavitation in tuberculosis, and fallopian tube blockage resulting in infertility from Chlamydia PID (pelvic inflammatory disease).  Immune complexes damage the kidney post streptococcal acute glomerulonephritis.  Peptidoglycan-teichoic acid (large fragments) of Gram-positive cells:  Serves as a structural toxin released when cells die.  Chemotactic for neutrophils.  Pathogenicity Mechanisms Physical Damage  Swelling from infection in a fixed space damages tissues; examples: meningitis and cysticercosis.  Large physical size of organism may cause problems; example: Ascaris lumbricoides blocking bile duct.  Aggressive tissue invasion from Entamoeba histolytica causes intestinal ulceration and releases intestinal bacteria, compounding problems.  Pathogenicity Mechanisms -Toxins Toxins may aid in invasiveness, damage cells, inhibit cellular processes, or trigger immune response and damage. Endotoxin (Lipopolysaccharide=LPS).  LPS is part of the Gram-negative outer membrane.  Toxic portion is lipid A: generally not released (and toxic) until death of cell.  Mechanism  LPS activates macrophages, leading to release of TNF-alpha, 1L-l, and 1L-6.  - IL-l is a major mediator of fever.  Macrophage activation and products lead to tissue damage.  Damage to the endothelium from bradykinin-induced vasodilation leads to shock.  Coagulation (DIC) is mediated through the activation of Hageman factor.  Pathogenicity Mechanisms -Toxins Exotoxins  Are protein toxins, generally quite toxic and secreted by bacterial cells (some Gram +, some Gram -)  can be modified by chemicals or heat to produce a toxoid that still is immunogenic, but no longer toxic so can be used as a vaccine  A-B (or "two") component protein toxins  B component binds to specific cell receptors to facilitate the internalization of A.  A component is the active (toxic) component (often an enzyme such as an ADP ribosyl transferase).  Exotoxins may be subclassed as enterotoxins, neurotoxins, or cytotoxins.  Cytolysins: lyse cells from outside by damaging membrane.  C. perfringens alpha toxin is a lecithinase.  Staphylococcus aureus alpha toxin inserts itself to form pores in the membrane. Major exotoxins  1 CENTRAL NERVOUS SYSTEM Faculty of Medicine 8/5/2024  Learning objectives 2  To understand the structure and anatomy of the central nervous system  To describe the functions of the central nervous system  To understand abnormalities of the central nervous system  Blood brain barrier 8/5/2024  Nervous system 3  The nervous system obtains and processes sensory information ◼ And sends commands to effector cells, such as muscles, that carry out appropriate responses Sensory input Integration Sensory receptor Motor output Brain and spinal cord Effector cells Peripheral nervous Central nervous system (PNS) system (CNS) 8/5/2024  Neurons 4  The basic unit of the nervous system is the individual nerve cell, or neuron.  Nerve cells operate by generating electric signals that pass from one part of the cell to another part of the same cell and by releasing chemical messengers— neurotransmitters—to communicate with other cells.  Neurons serve as integrators because their output reflects the balance of inputs they receive from the thousands or even hundreds of thousands of other neurons that impinge upon them. 8/5/2024  Neurons 5 8/5/2024  Neuron types 6 8/5/2024  Neurotransmitters and neuromodulators 7  Different chemicals which neurons use to communicate 8/5/2024  Nervous system 8  Central nervous system  Peripheral nervous system [PNS]  Consists of:  Collection of peripheral signals ◼ Brain ,nerve ganglia & specialised ◼ Spinal cord structures  Integrate, coordinate and  Carry sensory and motor information control sensory & motor between CNS and all organs and tissues information in the body  Consists of:  Responsible for higher  Sensory (Afferent) division neural functions e.g. memory,  Motor (efferent division learning and emotion ◼ Somatic nervous system ◼ Autonomic (visceral) nervous system 8/5/2024  Blood brain barrier 9  group of anatomical barriers and transport systems in brain capillary endothelium that controls kinds of substances entering brain extracellular space from blood and their rates of entry  A complex group of mechanisms which closely control both the kinds of substances that enter the extracellular fluid of the brain and the rates at which they enter.  These mechanisms minimize the ability of many harmful substances to reach the neurons, but they also reduce the access of the immune system to the brain.  The blood-brain barrier, which comprises the cells that line the smallest blood vessels in the brain, has both anatomical structures, such as tight junctions, and physiological transport systems that handle different classes of substances in different ways. 8/5/2024  Blood brain barrier 10 8/5/2024  The brain 11  Weighs 1.5kg  Brain parts  75% water,  Contains100 billion neurons  Utilizes 20% of body Cerebral cortex oxygen Cerebrum Forebrain Thalamus Hypothalamus Pituitary gland Midbrain Pons Hindbrain Medulla Spinal oblongata cord Cerebellum 8/5/2024  Brain stem 12  Cerebellum:  Located inferior to the occipital lobes of cerebrum  Located posterior to pons & medulla oblongata  Coordinates muscloskeletal movements, balance and muscle tome 8/5/2024  Brain stem 13  Brain stem consists of:  Midbrain ◼ Visual reflexes  Pons ◼ Located be tween midbrain & medulla oblongata ◼ Controls respiratory functions  Medulla oblongata ◼ Contain centres that regulate heart, respiratory, swallowing, cough reflexes, vomiting & sneezing 8/5/2024  Cerebrum and diencephalons 14  Cerebrum  Diencephalons  Two hemispheres located above cerebellum  Deeper portion of the brain containing: each consists of:  Thalamus  Parietal lobe  Hypothalamus  Frontal lobe  Epithalamus  Temporal lobe  Ventral thalamus  Occipital lobe  Act as relay centres for regulation of:  Heart rate  Outer portion is cerebral cortex  Blood pressure  Hemispheres connected by bridge of nerves:  Temperature corpus callosum  Behavioral responses  Digestive functions  Water & electrolyte balance 8/5/2024  Cerebrum 15 Right cerebral Left cerebral hemisphere Frontal lobe Parietal lobe hemisphere Somatosensory Frontal association association Speech area area Taste Reading Speech Hearing Smell Visual Auditory association association area area Vision Temporal lobe Occipital lobe Corpus Basal callosum ganglia 8/5/2024  Reticular formation 16  Receives data from Data to cerebral cortex sensory receptors and sends useful data to the cerebral cortex Input from ears Eye Reticular formation Input from touch, pain, and temperature receptors 8/5/2024  The limbic system 17  Is a functional group of integrating centers in the cerebral cortex, Thalamus thalamus, and Hypothalamus Prefrontal Cerebrum hypothalamus cortex  Is involved in emotions, memory, and learning Smell Olfactory Hippocampus bulb Amygdala 8/5/2024  Summary functions of the brain 18 8/5/2024 19 8/5/2024  Peripheral nervous system 20  PNS can be divided into Somatic & autonomic nervous systems Peripheral nervous system Somatic Autonomic nervous nervous system system Sympathetic Parasympathetic Enteric division division division 8/5/2024  Peripheral nervous system 21  The somatic nervous system ◼ Carries signals to and from skeletal muscles, mainly in response to external stimuli  The autonomic nervous system ◼ Regulates the internal environment by controlling smooth and cardiac muscles and the organs of various body systems 8/5/2024  Peripheral nervous system – cranial nerves 22 Sn Cranial nerve Function 1 Olifactory Sense of smell 2 Optic Visual sense 3 Oculomotor Eye movements 4 Trochlear Aids muscles that moves the eyes 5 Trigeminal Eyes, tear glands, scalp, forehead, teeth, gums, lips, mouth muscles 6 Abducens Muscle conditioning 7 Facial Taste, facial expressions, tear, salivary glands 8 Vestibular Hearing and equilibrium 9 Glossopharyngeal Pharynx, tonsil, tongue & carotid arteries, stimulates salivary glands 10 Vagus Speech, swallowing, heart muscle, smooth muscles, glands 11 Accessory Muscles of soft palate, pharynx, larynx & neck 12 Hypoglossal Tongue movement 8/5/2024  Disorders of the central nervous system 23  Schizophrenia  Sleep disorders  Characterized by psychotic episodes in which patients  Depression lose the ability to distinguish ◼ Major depression reality ◼ Bipolar disorder  Hallucinations:  Visual  Alzheimer’s disease (AD)  Smell ◼ Characterized by  Tactile confusion, memory loss, and a variety of other symptoms 8/5/2024  Disorders of CNS 24  Parkinson’s disease  Motor disorder characterised by: ◼ Difficulty in initiating movements ◼ Slowness of movement ◼ Rigidity 8/5/2024  Disorders of CNS- hemiplegia 25 8/5/2024  Disorders of the CNS - hemiplegia 26 8/5/2024  Upper motor neuron lesion - hemiplegia 27 Definition  It is the damage of upper motor neuron in the higher center or the descending motor tract Causes 1. Trauma 2. Tumour 3. Vascular disorders as thrombosis or hemorrhage Sites:  Most common site of UMNL is the internal capsule 8/5/2024  Upper motor neuron lesion 28 8/5/2024  Features – Motor loss 29 ❑ Contralateral paralysis  Spasticity (increased ❑ Loss of only voluntary muscle tone) of the movements) of the distal muscles of the limbs, skeletal ms due to lower facial and the increased tongue supraspinal Contralateral paresis facilitation to - ❑ ❑ Weakness i.e., the muscles retains some movements of motor neurons the axial ms and upper  facial ms. 8/5/2024  Features of UMNL 30 ❑ Exaggerated tendon jerk & clonus: due to increased supraspinal facilitation. ❑ Positive Babinski's sign 8/5/2024  Sensory loss 31  Contralateral hemianaesthesia i.e. loss of all sensations on the opposite side of the body 8/5/2024  Lower motor neuron disorders 32 ❑ Definition  Effects ❑ It is damage of the lower  Structural changes motor neurons (the spinal ◼ In Nerve (degeneration Anterior horn cells and the and regeneration cranial motor nuclei or their ◼ In muscle (atrophy and axons) resulting in skeletal increase Ach receptors muscle paralysis ❑ Functional changes ❑ Causes ❑ Flaccid paralysis ❑ Trauma ❑ Fasciculation and ❑ Neuropathy fibrillation ❑ Denervation super- sensitivity ❑ Reaction of degeneration 8/5/2024  Lower motor neuron features 33  Flaccid paralysis Fasiculations:  Paralysis of denervated muscles with loss of all types of movements;  Synchronous visible contraction of the motor "voluntary, postural and reflex". unit (all muscle fibers) supplied by the injured  All reflexes are lost including stretch axon. reflex resulting in loss of muscle tone  Result from spontaneous generation of action and tendon jerk (flaccidity) potential (injury potentials) in distal segment of  The extent of paralysis is usually the injured axon limited to a small group of muscles Fibrillations:  As degeneration of the injured axon continues,  Fasiculations and fibrillations: the axon terminals are now separate from the main axon and hence, from each other.  Appears few days or weeks  Injury potentials are still generated along the after denervation terminals leading to asynchronous contraction of the individual ms fibers attached to  Disappear when the motor nerve terminals. completely degenerates or  Invisible to the observer and detected only by successful re-innervation of the electromyogram (EMG). muscle 8/5/2024  LMNL features 34 Denervation supersensitivity: ❑ Reaction of degeneration:  Denervated ms becomes ❑ Abnormal response of supersensitive to the denervated muscle to acetylcholine electric stimulation  This is due to increase in the number of Acetylcholine receptors which cover the entire surface of muscle cell membrane 8/5/2024 35 8/5/2024 36 8/5/2024 37 8/5/2024  Infection and immunity 3 Immune System Disorders  Introduction  Hypersensitivities (≈ Allergies)  I) Anaphalactic  II) Cytotoxic  III) Immune Complex  IV) Cell-mediated (Delayed)  Autoimmune Diseases  Transplant Rejection  Hypersensitivity  Anaphylactic Hypersensitivity:  Results from a second exposure to what could be normally harmless antigen (≈ allergen).  The second response is not an appropriate normal one. The immune system goes too far.  I) Anaphalaxis Allergies to pollen, pet dander, insect venoms, fungal spores, dust mites, peanuts, & penicillin. Localized: (asthma, allergic rhinitis; true food allergies) Systemic (anaphalactic shock): vasodilation throughout body, BP drops; capillaries become porous; edema; constricts brachioles; fatality. IgE from first exposure to antigen (≈ allergen) bind to mast cells and basophils; the person is “sensitized”. Mechanism of action in hypersensitivity  Treatment of Anaphalaxis Short-Term: - anti-histamines; epinephrine - leukotriene receptor blockers Long-Term: - Controlled repeat exposures; boost IgG  II) Hypersensitivity: Cytotoxic  IgG and IgM antibodies bind to foreign antigens on the surface of otherwise healthy human blood cell types.  This results in activation of the complement cascade via the classic pathway, which leads to cytolysis of blood cells with the foreign antigen.  Further antibody and complement C3b binding results in opsonization (i.e. enhanced phagocytosis by phagocytes) of the blood cells with the foreign antigen.  Which foreign antigens will cause a cytotoxic reaction?  AB red blood cell (RBC) antigens & Rh RBC antigen  Drugs (haptens) that bind to blood platelets to become antigenic. Transfusion Rh Incompatibility & Hemolytic Disease of the Newborns  Thrombocytopenic purpura = thrombocyte Intracerebral hemorrhaging Stroke Bruising due to low platelet count; poor clotting favors hemorrhages.  III) Immune Complex The right proportions of antigen to IgG antibody results in small immune complexes that avoids phagocytosis and instead get stuck beneath endothelial cells of capillaries. Damaging to kidney glomeruli (glomerulonephritis)  IV) Cell-Mediated (Delayed) Takes days not hours or minutes; requires T cell and macrophage migration to foreign antigen exposure sight. Allergic Contact Dermatitis: Latex gloves Poison ivy TB skin test is cell-mediated.  Autoimmune Diseases  Lymphocytes become involved in attacking the bodies own cells (antigens)  Self-tolerance of lymphocytes is lost: B cells produce antibodies and T cells activate their cytotoxicity Causes:  Similarities between viral and self antigens (Hepitius C autoimmunity)  Cell malfunction due to antibody binding (Grave’s Disease; thyroid gland).  Immune complex forms (rheumatoid arthritis; joints)  Cell-mediated destruction of specific cell types (insulin-dependent diabetes mellitus; insulin-secreting cells of pancreas).  Some individuals are genetically predisposed (higher risk) due to specific human leukocyte antigen (HLA) gene alleles that they possess.  Transplant Rejection  Non-self hypothesis:  If the Human Leucocyte Antigen (HLA) classes do not match there will be rejections by T cell, antibody, and complement attack on transplant blood vessels; see Graft-versus-Host (GVH) disease  This does not apply for privileged sites; those that are non-vascular (cornea, heart valves); rare exceptions  Grafts are the new tissues transplanted to a target site  Autographs  isographs  allographs  xenographs  Immunosuppression by cyclosporine to minimize transplant rejection; its action is suppression of IL-2 release. Other IL-2 receptor blockers are also available (rapamycin).  Immunodeficiency diseases  A. Primary immunodeficiency states  B. Secondary immunodeficiency states  A. Primary immunodeficiency states  Experiments of nature, extremely rare  X-linked agammaglobulinemia (Bruton's disease)  Inability of pre-B cells to differentiate into mature B-cells  Decrease in circulating B-cells, no germinal centers in LN, rudimentary Peyer's patches  Recurrent bacterial infections (H. influ., Str. pneumon., Staph. aur.) Isolated deficiency of IgA  Most frequent (1:700)  Recurrent sinopulmonary infections, diarrhea Thymic hypoplasia (DiGeorge's syndrome)  Congenital malformation of 3rd and 4th branchial pouches  Vulnerability to viral, fungal and protozoal infections Severe combined immunodeficiency  X-linked or autosomal recessive B. Secondary immunodeficiency states  More common  In malnutrition, infection, cancer, renal disease, malignancies  Patients treated by immunosupressive drugs  AIDS  Acquired immunodeficiency syndrome (AIDS)  Viral etiology (HIV, RNA retrovirus)  Severe immunosupression - opportunistic infections, secondary tumors, neurologic symptoms  First recognized 1981 - Los Angeles - pneumocystic pneumonia in 5 young homosexuals - 2 died  Pneumocystis carinii (interstitial pneumonia in premature infants)  Onset of epidemic  1998 - 33,4 million of infected (22,5 mil in sub-Saharian Africa)  Number of both infected and ill patients increases - USA, Africa (2/3 of all cases in the world), Southeast Asia (Thailand, India, Indonesia)  Transmission  1. sexual contact (lymphocytes in semen)  2. parenteral - blood + derivates, drug abusers sharing needles  3. mother-to-infant - transplacental, intrapartum, breast-feeding  HIV cannot be transmitted by casual personal contact !!!  No transmission from patient to doctor (and vice versa) by casual contact !!!  Prevention of injury - needle sticks, etc.; operation or autopsy - special precautions  HIV epidemiology  Homosexual males  HIV-1 and HIV-2 - (60%) closely related  Intravenous drug  long incubation period abusers (24%)  tropism for lymphocytes  Hemophiliacs (1%) and nervous system  Other blood recipients  immunosupression - (2%) CD4+ T-cells (helpers)  Heterosexual partners  slowly progressive fatal of other high-risk groups outcome members  Children of parents from groups 1.-3.  Opportunistic infections in AIDS  Protozoal (pneumocystosis-lungs; toxoplasmosis-lungs or CNS)  Fungal (candidiasis-GIT, respiratory tract; cryptococcosis-CNS; histoplasmosis-dissem.)  Bacterial (mycobacteriosis-frequently atypical; nocardiosis-lungs, CNS)  Viral (CMV-lungs, GIT, kidneys, CNS; HSV; varicella- zoster; slow viruses)  Neoplasms in AIDS  Kaposi's sarcoma (sarcoma idiopathicum hemorrhagicum multiplex) - related to HSV infection  Non-Hodgkin's Myeloid Leukaemia (Burkitt's or immunoblastic)  Primary ML of CNS  Invasive cancer of uterine cervix Autonomic Nervous System Dr Bokang Maswabi MD PhD  ANS The autonomic nervous system (ANS) is so called because its functions are normally not subject to direct voluntary control. One of the primary regulators of homeostasis  ANS-Function The autonomic nervous system regulates the function of the internal organs in response to the changing internal and external environment. The autonomic nervous system can be divided anatomically into the sympathetic parasympathetic Enteric nervous system  Somatic vs Autonomic Somatic is 1 neuron pathway- myelinated axon from the ventral horn of the spinal cord all the way to effector muscle Target of somatic is skeletal muscle  Somatic vs Autonomic Target of ANS is smooth muscle, cardiac muscle and the glands One of the primary regulators of homeostasis  ANS Divided into sympathetic and parasympathetic. Central clusters of nerves which control the ANS are found in the brainstem, limbic system, periaqueductal gray substance and hypothalamus, reticular formation and spinal cord tracts which in turn receive input from cortex  ANS-Afferent connection Information enters the ANS via – Spinothalamic tract – Spinocerebellar tract – Spinoreticular – Corticothalamic tract – Circumventricular organs= changes in chemical composition of CSF (fever, angiotensin II, cholecystokinin)  Spinocerebellar tract Spinocerebellar tract transmits unconscious proprioceptory information from skeletal muscles (muscle spindles), tendons and ligaments (Golgi tendon organs) and joints (fibrous capsules) to the cerebellum. The cerebellum then integrated this information with other sensory input to help maintain balance, eye movements, assist in locomotion and keep movements smooth and precise. Tract| Description Proprioception from joints, tendons Ventral spinocerebellar and ligaments in the lower body Rostral spinocerebellar Same as above but in the upper body Proprioception from muscle, joints, Dorsal spinocerebellar tendons and ligaments in the lower body Cuneocerebellar Same as above but in the upper body Spinocerebellar tract  Spinothamlamic tract The spinothalamic tract sends conscious sensations of pain, temperature, crude touch and firm pressure from skin to the thalamus and then to the primary somatosensory cortex. Spinoreticular pathway (to the medullary and pontine nuclei) helps to inhibit pain, assists in motor responses to pain Also assists in emotional responses to pain Important in directing attention to painful stimuli  Sympathetic-Efferent connection Projections from the hypothalamus and brain stem, particularly from the brain stem reticular formation, travel to the lateral horn of the spinal cord, where they form synapses onto the sympathetic neurons of the spinal cord. The latter, in turn, project preganglionic fibres to the sympathetic ganglia.  Parasympathetic-Efferent connection The parasympathetic neurons receive input from higher centers and project in turn to parasympathetic ganglia that are generally located near the end organs they serve. The main excitatory neurotransmitter is glutamate and the main inhibitory is Gamma amino butyric acid (GABA) Modulating neurotransmitters include acetylcholine, purines and nitric oxide Neurotransmitters.  Parasympathetic efferents Parasympathetic spinal neurons lie in the brain stem (with projections along CN III, VII, IX, X) and the sacral spinal cord (S2– S4), and are collectively termed the craniosacral system. The intestine has its own autonomic ganglia, which are located in the myenteric and submucous plexuses  Parasympathetic Efferents The parasympathetic preganglionic fibers are long; they project to ganglia near the effector organs, which, in turn, give off short postganglionic processes. The sympathetic preganglionic fibers (unmyelinated; white ramus communicans) travel a short distance to the paravertebral sympathetic chain, and the postganglionic fibers (unmyelinated; gray ramus communicans) travel a relatively long distance to the effector organs. An exception to this rule is the adrenal medulla: playing, as it were, the role of a sympathetic chain ganglion, it receives long preganglionic fibers and then, instead of giving off postganglionic fibers, secretes epinephrine into the bloodstream  Parasympathetic ganglia The parasympathetic system is responsible for stimulation of "rest-and-digest" or "feed and breed“ activities that occur when the body is at rest, especially after eating, including sexual arousal, salivation, lacrimation(tears), urination, digestion and defecation  Neurotransmitters. Acetylcholine is the neurotransmitter in the sympathetic and parasympathetic ganglia. The neurotransmitters of the postganglionic fibers are norepineprhrine (sympathetic) and acetylcholine (parasympathetic). Neuromodulators include neuropeptides (substance P, somatostatin, vasoactive intestinal peptide) Neurotransmitters.  Sympathetic trunk Ganglia Paired vertical chain on either spine Also called vertebral chain Innervate organs above the diaphragm Head neck shoulders and heart Superior middle and inferior cervical ganglia Sympathetic prevertebral Ganglia Also called collateral ganglia Single row in front of the spine, close to the large abdominal arteries Innervate organs BELOW the diaphragm Sympathetic system mediated the fight or flight or freeze response Neurotransmitters. ANS Effects Autonomic Disorders  Heart and circulation Neurogenic arrhythmias may be of supraventricular or ventricular origin and are commonly associated with subarachnoid and intracerebral hemorrhage, head trauma, Neurogenic ECG abnormalities (ST depression or elevation, T-wave inversion) can occur in the setting of cerebral hemorrhage or infarction but are often difficult to distinguish from changes due to myocardial ischemia. Hemodynamic abnormalities. Hypertension: Cerebral hemorrhage, Cushing reflex (accompanied by bradycardia) in response to elevated ICP, porphyria, Wernicke encephalopathy (accompanied by arrhythmia), and posterior fossa tumors. Hypotension: Head injuries, spinal lesions (syringomyelia, trauma, myelitis, funicular vmyelosis), multisystem atrophy, progressive supranuclear palsy, Neurocardiogenic syncope (vasovagal  Thermoregulation Central hyperthermia is an elevation of body temperature due to impaired thermoregulation by the central nervous system. Its mechanism may involve either excessive heat production, excessive heat absorption (e. g., in a hot environment), or inadequate heat elimination. central hyperthememia may be due to hypothalamic lesion( infarction or hemorrhae, tumors, encephalitits) anticholinegic agents  Gastrointestinal system Neurological diseases most commonly affect gastrointestinal function by impairing motility, less commonly by impairing resorptive and secretory processes.  Sexual function Sexual Function The genital organs receive sympathetic (T11–L2), parasympathetic (S2–S4), somatic motor (Onuf’s nucleus), and somatosensory innervation (S2–S4) and are under supraspinal control, mostly through hypothalamic projections to the spinal cord. Hormonal factors also play an important role Neurological disease often causes sexual dysfunction (erectile dysfunction, ejaculatory dysfunction) in combination with bladder dysfunction. Isolated sexual dysfunction is more often due to psychological factors (depression, anxiety), diabetes mellitus, endocrine disorders, and atherosclerosis.  PATOPHYSIOLOGY OF RENAL DISORDERS I. ) Physiology of the Urinary system The kidneys regulate the composition and volume of the plasma water. This in turn, determines the composition and volume of the entire extracellular fluid compartment. Kidneys receive 20% of total cardiac output but make 1% of total body weight GFR is about180L/24hrs/1.63m2 Definitive urine is about 1.5L/1.73m2  Functions of kidneys and urinary tract Selective excretion / elimination – water – electrolytes – catabolites (small compounds, middle-size compounds 500 - 3000 D) 2. Selective retention of filtrated molecules – aminoacids – proteins vitamins –... 3. Endocrine activity – Epo 1,25-OH-D3 vitamin Functions of kidneys and urinary tract Homeostasis - water, electrolyte, AB, nutritive Elimination of toxic products (and drugs) Blood pressure regulation Hematopoiesis regulation Ca++ metabolism Gluconeogenesis  Kidneys - anatomy Cortex Medulla 1,25 mil. nephrons 6-18 pyramids Blood supply  Blood supply Short wide a. afferens Long narrow a. efferens High hydrostatic pressure in capillary Nephron Functions 1. Formation of glomerular filtrate 2. Reabsorption of organic substances 3. Reabsorption of water and ions 4. Tubular secretion of ions and catabolites Exchange of water and solutes in different parts of nephron  Glomerulus Function: Production of glomerular filtrate (composition practically similar to plasma without proteins)  Proximál tubule Active reabsorption of nutrients, proteins, ions from filtrate and their release into peritubular space Proximal tubule allows reabsorbtion of 60-70% filtrate Majority of organic compounds is reabsorbed Active + passive reabsorption of Na+ and other ions Water reabsorption Small rate of secretion in proximal tubule  Loop of Henle Descending limb Ascending limb  Countercurrent multiplication mechanism between descending and ascending loops Osmotic gradient in medulla Facilitation of passive reabsorption of water and solutes from primary urine Loop of Henle Descending limb Ascending limb Osmotic gradient in medulla Loop of Henle Descending limb Ascending limb  Loop of Henle Descending limb Ascending limb  Distal tubule Active secretion of ions, toxic products, drugs Reabsorption of Na+ from filtrate Depends on hormonal activity (aldosterone)  Distal tubule Active secretion of ions, toxic products, drugs Reabsorption of Na+ from filtrate Active secretion / absorption final urine composition Active resorption of Na+ and Cl- via exchange for K+ a H+ (secretion)  Collecting ducts Aldosterone and ADH regulate the loss of water and solutes... facultative reabsorption of H2O, Na+ Reabsorption: Na+, HCO3-, urea Maintenance of pH balance: secretion of H+, HCO3-  Filtration ~ 180 L / day primary urine  Filtration Limiting factors: ~ 180 L / day primary urine Filtration pressure Glomerular membrane properties  Filtration Filtration pressure short wide a. afferens narrow long a. efferens  + - hydrostatic pressure hydrostatic pressure in capillary in Bowman´s space - + oncotic pressure oncotic pressure in capillary in Bowman´s space  Filtration Filtration pressure autoregulation NO, PG, ANP, ET... sympathetic n.s....preserve perfusion, protect kidneys against pressure damage aldosterone ADH  Filtration Filtration pressure  filtration pressure + Juxtaglomerular apparatus Renin + Erytropoetin synthesis  Filtration pressure Negative feedback  Filtration Evaluation = amount of filtrated blood/time physiologically... 2 ml /s normal limits... > 1,3 ml / s If 1/2 we have Renal insufficiency If 1/10 we have Renal failure Creatinine Urea Creatinine clearance Inulin clearance  Filtration Evaluation = degradation product of creatine Creatinine (which is important component part of muscles) Normal limits:  male < 124 mol/L  female < 115 mol/L (due to smaller muscle mass) Urea = degradation product of protein catabolism Influence of GF, proteocatabolism, protein intake, dehydration, diurnal cycle Normal limits: < 7,5 mmol/L  Filtration Evaluation Creatinine stabile 24-h concentrations independent on protein intake independent on physical activity Urea  Filtration Evaluation Creatinine clearance = GFR; Glomerular filtration rate GFR = (Cu ×V°u) /Cp (mg/ml) × (ml/min) / (mg/ml) = ml/min. = (U-creatinine x U-volume) / P-creatinine = cca 2 ml / s (120 ml / min.) Normal limits:  male: 97 - 137 ml / min.  female: 88 - 128 ml / min. Filtration Evaluation Inulin clearance = Inulin filtration through glomerular membrane for 1 min. = GFR × Cp/0.94  Filtration Evaluation 51Cr - EDTA clearance 99mTc - DTPA clearence Quick methods for evaluation of glomerular filtration I.v. administration of isotope. Monitoring of decreased plasma activity. Without urine collection.  Transport Systems Transport via transport proteins is limited by maximal transport capacity (TM), when a transport system fully saturated - in case of glucose in plasma concentrations of 10 mmol/l - in case of AA there is low TM , AA are secreted to urine Active transport mechanisms (ATP-ase systems) - Na reabsorption, K secretion  Transport Systems disorders Metabolic renal tubular disorders Bartter's sy AR K, polyuria,PRA,  aldosterone Liddle's sy AR K,  aldosterone familiar nephrogenic diabetes XL polyuria, ADH-resistance insipidus RTA type 1 AD defect of H+ excretion RTA type 2 AR defect of HCO3- reabsorption RTA type 4 acquired combined deficit oncogenic osteomalacia acquired defect of PO4 reabsorption hypophosphatemia X-linked vitamin D-resistant XL defect of PO4 reabsorption rickets hypophosphatemia vit. D-resistant rickets type 1 AR defect of vit. D hydroxylation vit. D-resistant rickets type 2 AR defect of vit. D receptors  Transport Systems disorders Metabolic renal tubular disorders renal glycosuria AD defect of Glc reabsorption isolated hypourikemia AR defect of uric acid reabsorption cystinuria AR defect of diabasic AA reabsorption Hartnup disease AR defect of neutral (monoamino- and carboxyamino-) AA reabsorption iminoglycinuria AR def. of Pro, OH-Pro, Gly reabsorption adult type of Fanconi sy AR defect of HCO3-, Glc, uric acid, PO4-, amino acid reabsorption Lowe sy XL similar to Fanconi sy Hormonal regulation of diuresis ADH Renin Angiotensin Aldosterone ANP BNP CNP Insulin Hormonal regulation of diuresis ADH Regulating via V2 receptors selective water reabsorption in distal tubuli and collecting ducts  Hormonal regulation of diuresis ADH Regulating via V2 receptors selective water reabsorption in distal tubuli and collecting ducts ADH Hormonal regulation of diuresis Low ADH ADH  Diabetes insipidus- Hormonal regulation of diuresis = Syndrome of ADH deficiency 1. Central (hypothalamic) Diabetes Insipidus there is  ADH trauma and surgery 20 %, idiopatic 25 %, pituitary and hypothalamic tumors) 2. Peripheral (nephrogenic) Diabetes Insipidus There is  ADH chronic renal failure congenital abnormalities of ADH receptors...  Diabetes insipidus- Hormonal regulation of diuresis Symptoms polyuria – water diuresis ( 6 L / day) (secondary) polydipsia weight loss headache Laboratory findings Plasma-hyperosmolarity Urine-hypoosmolarity Pathological results of concentration test (36 h; 12 + 4 h)  SIADH Regulation of diuresis Etiology irritation of hypothalamic osmoreceptors (metastases) reflex stimulation via vagus nerve (bronchogenic ca) paraneoplastic production (small cell ca) carcinoid Symptoms retention of water, solutes, edema Laboratory findings: plasma hypoosmolarity  Na,  K,  Cl Hormonal regulation of diuresis Renin Angiotensin Aldosterone Maintenance of Na and K concentrations Maintenance of extracellular volume Via Stimulation of Na+/K+ATP-ase in proximal tubule Reabsorption of Na+ Secretion of K+  Hormonal regulation of diuresis Addison syndrome, Addison's disease Renin Angiotensin Aldosterone = syndrome of adrenocortical insufficiency K+ retention causes muscle weakness, myopathy, ECG, dyspepsia Na+ loss causes osmotic diuresis... dehydration... hypotension, postural hypotension Hyperpigmentation (MSH from pituitary) x depigmentation (vitiligo) Hypoglycemia Hormonal regulation of diuresis Renin Angiotensin Aldosterone Primary / secondary hyperaldosteronism Stimuli for renin synthesis:  kidney perfusion  Na in proximal tubule  renal artery stenosis kidney blood flow (renovascular hypertension) primary hyperreninisms The role of kidneys in renin synthesis secondary hypertension EPH gestosis hyperestrogenism angiotensinogen (Oral contraceptives) synthesis angiotensin 1 ACE Na / Ca intake angiotensin 2 Cushing sy cortisol aldosterone primary hyperaldosteronisms renal failure sodium retention "primary" hypertension ? endothelin vasoconstriction  Hormonal regulation of diuresis Atrial natriuretic peptide (ANP) B-type natriuretic peptide (B and C type natriuretic peptide Natriuretic peptides ANP BNP CNP Natural antagonists of renin - angiotensin - aldosterone system. Important role in water and mineral balance in patients in hemodynamic stress (e. g., cardiac failure). Atrial natriuretic peptide (ANP) B-type natriuretic peptide (B and C type natriuretic peptide Physiological effects:  vasodilation and hypotensive effect  natriuresis and diuresis activation  inhibition of sympathetic nervous system  inhibition of pathol. actions responsible for hypertrophy and remodelation of heart ventricle and vessel wall  positive effect on endothelial dysfunction in relation to atherosclerosis (including clothing cascade regulation and fibrinolysis and inhibition of platelet activities)  PATOPHYSIOLOGY OF RENAL DISORDERS II Tests of the urinary System  Basic screening tests are; Diuresis the serum level of Urea and Creatinine and the investigation of Urine Biochemistry and Sediment.  Special Nephrological Tests Glomerular Function – Creatinine Clearance Tubular Function – Concentrating ability – Urine acidification test  Diuresis In adults with 1,73 m2 diuresis is 1.5 litres/24 hrs/1.73 m2 Oliguria < 400 mL Anuria < 100 mL Polyuria > 3000 mL  Serum biochemistry Blood Urea Nitrogen (BUN) Normal: 2 – 8,3 mmol/l (12-50 mg/dl) Depends on – Big protein intake, GIT hemorrhage – Protein catabolism (increase: sepsis, corticosteroid) – GFR ( increased in low GFR) – Increased in dehydratation  Serum biochemistry-BUN End product of Protein metabolism, produced in the liver Increase without (or more than) increase in creatinine: increased Protein intake increased Protein Catabolism: burns, bleeding to GIT, sepsis, after corticoid administration. Dehydratation decrease : Hyperhydration Protein malnutrition Severe liver disease  Urine biochemistry Dipstick tests pH Glucose Protein Blood Bilirubin Urobilinogen Ketones Nitrite Leukocytes  URINE ANALYSIS- Glucose Negative – diabetes mellitus ith glycemia more than 10 mmol/L – benign glycosuria can occur in setting of normal glycemia  URINE ANALYSIS pH 5–7 Specific gravity 1010-1020 kg/m3 - amount of all substances in urine Proteins up to 0,3 g/L (300 mg/L) - test is specific for albumin (false negative in multiple myeloma) - semiquantitative Sulphosalicylic test is also sensitive for globulins - quantitative proteinuria (24 hours)  URINE ANALYSIS Ketone bodies; must be negative - fasting, diabetes mellitus (1. type) Bilirubin negative - obstructive jaundice (conjugated) - negative in hemolysis (unconjugated bilirubin does not enter urine) Urobilinogen must be negative 3,2 – 16 µmol/l - increased in hemolytic icterus  URINE ANALYSIS Red Blood Cells < 10/µl - chemical test is not decisive, sediment analysis is required for definitive result Leukocytes < 15/µl - Urinary tract infection Nitrites negative - positive in urinary infection by bacterias which reduces nitrates to nitrites (E. coli, Proteus, Klebsiella, Pseudomonas, Staphylococcus, Aerobacter)  Urine biochemistry Proteinuria Physiological levels < 150 mg / 24 h Pathological levels > 500 mg / 24 h Heavy > 3500 mg / 24 h Nephrotic syndrome > 5000 mg / 24 h Protein urinary excretion of > 2 g per 24 h is usually a result of glomerular disease. Young men with proteinuria < 2 g per 24 h and who have a normal creatinine clearance should be tested for orthostatic proteinuria Methods of quantifying proteinuria: urine dipstick test( uses bromophenol Blue) sulphosalicylic acid tests  Proteinuria 1. Prerenal Selective 2. Renál Glomerulár Nonselective Tubulár 3. Postrenal Normal urine proteins 1. Plasma derived Most plasma proteins (> 68,000 dalton's) are not filtered due to the glomerular barrier. Lower MW proteins are filtered, but are usually reabsorbed by renal tubules. Small amounts of albumin, some globulins, and hormones can normally be found in the urine. 2. Urine derived The renal tubules (Tamm-Horsfall mucoproteins, Ig's), and urogenital tract may secrete small amounts of protein that are added to the urine.  Proteinuria Glomerular versus Tubular  Urine biochemistry Proteinuria Glomerular Increased glomerular capillary permeability to protein; Primary or secondary glomerulopathy Tubular Decreased tubular reabsorption of proteins in glomerular filtrate;Tubular or interstitial disease Overflow Increased production of low- molecular-weight proteins less than 68000 daltons Monoclonal gammopathy, leukemia, hemoglobinemia even myoglobinemia  Glomerular Proteinuria Electrophoresis examination: SELECTIVE – albumin (MW 67 000), transferin (Mr 89 000) – damage of podocytes and outer part of basal membrane NONSELECTIVE – all proteins incl. immunoglobulines – damage of mesangium and inner part of basal membrane  Glomerular Proteinuria Index of selectivity (IS)= U-IgG S-transferrin X S-IgG U-transferrin – IS  0,1 selective proteinuria – IS  0,2 nonselective proteinuria – IS = 0,1-0,2 middle selective proteinuria  TUBULAR MICROPROTEINURIA MW less than 70 000 – (microproteins; alpha1-antitrypsin, albumin, beta-2-microglobulin, retinol-binding protein, alpha-1-acid glycoprotein) Due to decreased tubular reabsorption of filtrated proteins in case of chronic intersticial nephritis, acute tubular necrosis, rejection of transplanted kidney, hereditary tubulopathies c) PRERENAL PROTEINURIA Increased plasma proteins: – Bence-Jones proteinuria – monoclonal gamapathy – myoglobinuria – rhabdomyolysis d) POSTRENAL PROTEINURIA – bleeding, -malignant tumors of excretory system -inflammatory disorders of urinary tract.  Urine Biochemistry Nephrotic syndrome Diagnostic Criteria: Heavy proteinuria (>3500g / 24 h) Hypoalbuminémia (