INTRODUCTION PHYSIOLOGY

Transcription

1 INTRODUCTION PHYSIOLOGY - Physiology is the study of normal functions of living organisms. It includes many branches like viral physiology, bacterial physiology, cellular physiology, plant physiology, animal physiology and human physiology. - Human physiology is the branch of physiology which is concerned with the functions of the entire human body; from the sub-cellular components to the organs and organ systems. It is also concerned with how these functions are performed and how they are integrated. HOMEOSTASIS - All living organisms are composed of cells. Cells of the body do not only contain water, but also surrounded by water (= intracellular and extracellular fluid compartments). The extracellular fluid is the link between the external world and the cells. It carries nutrients to the cells and eliminates their waste products. It circulates between all cells in the body and provides for them a homogenous environment. In other words, it is essential for survival of cells. Disturbance of this extracellular fluid impairs functions of cells and results in disease. For this reason it is described as the "internal environment" (Claude Bernard, 19 th century). Later on, the term "Homeostasis" was applied. It indicates that: "all systems in the body, however various, they have one goal; to maintain the constancy of the internal environment (which is the ECF)". Therefore each organ in the body participates in homeostasis by maintaining constant ECF volume, osmolarity, ph, pressure or temperature). The core of medical physiology (1) 3 rd edition Page 1

2 CELL STRUCTURE - Cells are the building blocks of the body (the basic units of each tissue). The entire body contains about 75 to 100 trillion cells. Although these cells are highly specialized in various organs to perform specific functions, the structures inside their cytoplasm (i.e. the organelles) are almost identical in all types of cells. These include the following: The cell membrane: - Phospholipid bilayer (about 25%) with proteins (about 50%); plus some cholesterol (13%), carbohydrates (3%) and other lipids. - The phospholipids have hydrophilic parts "phosphate" facing outside and the hydrophobic parts "fatty acids" in the interior of the membrane. - Thickness = 7.5 nm (75 Angstrom) - It is a semi-permeable membrane (allows passage of lipid soluble substances and prevents passage of water and water soluble ones). However, the protein channels and carriers in the membrane facilitate passage of many substances- see below. - It contains two types of protein: o Peripheral proteins: attached to one surface of the cell membrane (usually the inner surface) o Integral proteins: extends throughout the cell membrane - Functions of proteins in the cell membrane: o Offer structural support to the membrane (cytoskeleton) o Act as adhesion molecules (connect cells together) o Act as enzymes (catalyze chemical reactions on the cell membrane) The core of medical physiology (1) 3 rd edition Page 2

3 o Act as antigens (usually glycoproteins; like the blood group antigens on surface of red blood cells and the HLA antigens (human leukocyte antigens) on surface of all nucleated cells. Notes about the HLA antigens: They are encoded by group of genes in the short arm (P arm) of chromosome 6. These genes are known as the genes of the major histocompatibility complex (MHC). They include different classes (e.g. MHC class I, MHC class II & MHC class III). HLA antigens (also known as MHC antigens) are unique for every person; that s why they are used by the immune system to distinguish self cells or antigens from non-self (they are considered in selection of a donor in organ transplantation). o Act as ion channels for movement of water and ions across the cell membrane (osmosis and simple diffusion) o Act as carriers for passive transport of certain substances across the cell membrane (facilitated diffusion; see below) o Act as pumps for active transport of certain substances across the cell membrane (active transport; see below) o Act as receptors for hormones and neurotransmitters Remember that peripheral proteins act as enzymes whereas integral proteins carry out the other functions. Carbohydrates on the surface of a cell membrane (= glycocalyx) are either attached to proteins (forming glycoproteins) or to lipids (forming glycolipids). The core of medical physiology (1) 3 rd edition Page 3

4 Fig 1: The cell membrane The nucleus - Contains chromatin (DNA) which condenses to form chromosomes before cell division. The DNA replicates during cell division to carry genetic information from the mother cell to the daughter cells. - The nucleus also contains one or more nucleoli rich in ribosomal RNA (the RNA is synthesized from DNA by transcription). The ribosomal RNA diffuses to the cytoplasm to be translated into proteins (in the ribosomes of the rough endoplasmic reticulum). - The proteins may act within the cell or may be packed within vesicles (in the Golgi apparatus) for secretion to the outside. The endoplasmic reticulum - Complex meshwork of canals and vesicles, extending from the nucleus to the exterior of the cell. - Two types: The core of medical physiology (1) 3 rd edition Page 4

5 o Smooth endoplasmic reticulum: - Has no ribosome on its surface - For synthesis of lipids and steroids - Contains enzymes for certain metabolic functions within the cell (e.g. detoxification of foreign substances) o Rough endoplasmic reticulum: - Has ribosomes on its surface - For protein synthesis The Golgi apparatus - Closely associated with the rough endoplasmic reticulum. - For processing and package of proteins synthesized in the rough endoplasmic reticulum into secretory vesicles (most of the packed proteins act as enzymes). The mitochondria - The power houses of cells (provide the energy used by the cell to perform its functions). They are abundant in certain cells like endocrine cells, parietal cells and renal cells (because these cells need energy for synthesis of hormones or active transport of ions). - Each mitochondrion is surrounded by two phospholipid bilayer membranes; the inner one is folded to produce cristae. The cristae and the inner cavity of the mitochondrion (the matrix) contain the respiratory enzymes needed for oxidative phosphorylation of glucose to release large amount of energy in form of ATP (Adenosine diphosphate). - Each mitochondrion contains DNA that plays a role in formation of few intra-mitochondrial proteins (using mitochondrial ribosomes) and in its own replication. The core of medical physiology (1) 3 rd edition Page 5

6 - Abnormalities of mitochondrial DNA may result in certain diseases, usually affecting the high energy tissues (muscle, heart and brain). These diseases are always inherited from mothers (this is because the defective mitochondria are inherited through ova of mothers; whereas sperms of fathers do not contain mitochondria). The lysosomes - Vesicles formed from the endoplasmic reticulum and Golgi apparatus. They contain hydrolytic enzymes (proteases, lipases, carbohydrases & nucleases) that are used in hydrolysis or digestion of engulfed material (e.g. digestion of bacteria within vacuoles of the white blood cells). Fig 2: The cell organelles The core of medical physiology (1) 3 rd edition Page 6

7 TRANSPORT MECHANISMS ACROSS CELL MEMBRANES - There are constant movements of O2, CO2, nutrients, electrolytes and waste products across cell membranes. A variety of transport mechanisms are involved, these are generally classified into passive and active transport mechanisms. Passive transport mechanisms: - Do not consume energy in transport. - Transport substances from areas of higher concentration to areas of lower concentration (i.e. down the concentration or electrical gradient). - Either do not use carrier (= simple diffusion) or use carrier (= facilitated diffusion). Active transport mechanisms: - Consume energy in transport. - Transport substances from areas of lower concentration to areas of higher concentration (i.e. against the concentration or electrical gradient). - Always need carrier for transport. - Transport of a substance against its chemical or electrical gradient, with consumption of energy and usage of a carrier is known as primary active transport. - Transport of a substance with an other one that s transported actively is known as secondary active transport. Here the substance uses the same carrier that s used by the other substance. - Secondary active transport (also known as co-transport) may occur in the same direction of the primary substance (= symport), or in the opposite direction (= antiport). The core of medical physiology (1) 3 rd edition Page 7

8 Substances transported by simple diffusion - Diffusion is the process by which a substance expands, because of the random movement of its particles to fill the available volume. - Non-polar substances transported by simple diffusion include: o Fatty acids o Steroid hormones (synthesized from cholesterol) o Gases (O 2 and CO 2 ) - Simple diffusion of polar substances (water soluble substances) like ions is low. However, it can occur through certain "ion channels" (integral proteins in the cell membrane). - Passive diffusion of water through cell membranes is known as osmosis. It occurs through certain water channels known as aquaporins. Water moves from the side of lower concentration of a solute to the side of higher concentration of the solute. Fig 2: Passive transport The core of medical physiology (1) 3 rd edition Page 8

9 Substances transported by facilitated diffusion - Do not consume energy in the process of transport. - Have a maximum rate of transport that depends on the density of carriers on the cell membrane. The maximum rate is reached when all the carriers are saturated. - Examples include transport of glucose through the basolateral membranes of renal and intestinal cells and its absorption from the ECF by most cells of the body. Substances transported actively - The well known example of primary active transport is the pump that transports sodium and potassium against their concentrations (= The Na + / K + pump). It transports three atoms of sodium from ICF to ECF in exchange to two atoms of potassium from ECF to ICF. Fig 3: Active transport The core of medical physiology (1) 3 rd edition Page 9

10 - The well known example of secondary active transport is the transport of glucose (coupled to sodium) through the luminal membranes of intestinal and renal cells. - Secretion of hydrogen by renal cells is another example of secondary active transport. However, hydrogen moves in the opposite direction to sodium (anti-port). Other transport mechanisms o Endocytosis (active vesicular transport) - Endocytosis is the uptake of molecules into cells. Here a molecule fuses with the cell membrane, invaginates it and then the invagiation is separated from the cell membrane to form of a vesicle. - Special proteins may facilitate the process of endocytosis (clathrin and dynamin). - When the engulfed substance is dissolved in fluid, the process is known as pinocytosis (cell drinking); and when it is a particulate matter or bacteria, the process is known as phagocytosis (cell eating). o Exocytosis (active vesicular transport) - Exocytosis is the release of substances from cells. (i.e. opposite to endocytosis). Proteins synthesized within the cell are usually packed into secretory vesicles and secreted by exocytosis. - Notice that exocytosis requires calcium, energy and certain proteins. o Solvent drag (passive transport) - During diffusion of a solvent, it tends to drag some solute with it. This occurs in capillaries. The core of medical physiology (1) 3 rd edition Page 10

11 Fig 3: Endocytosis & Exocytosis Transport proteins "carriers, pumps & ion channels" - These are highly specialized transmembrane proteins that allow passage of water, ions, glucose, urea and other substances through cell membranes. - The carriers change their shape (configuration) when they bind their substances to move them from one side of the cell membrane to the other side, usually down the chemical or electrical gradients (= facilitated diffusion). - The pumps act as ATPase enzymes to catalyze hydrolysis of ATP. The released energy is used in active transport of substances, against their chemical or electrical gradients. Examples include the Na + / K + ATPase pump, the proton pump and the Ca 2+ ATPase pump. The core of medical physiology (1) 3 rd edition Page 11

12 (Remember that the active transport is either primary active or secondary active, see above). - The ion channels allow simple diffusion (down chemical or electrical gradients). They include: Leak channels - Always open - Example: Potassium leak channels which are responsible for the resting membrane potentials - Resting membrane potentials are found in almost all cells in the body (see chapter two) Voltage gated channels - Have gates that open or close in response to changes in voltage "or potential" in the cell membrane - Examples: voltage gated sodium channels & voltage gated potassium channels which are responsible for the depolarization and the repolarization phases of action potentials respectively - Action potentials are only found in excitable tissues (nerve and muscle) Ligand gated channels - Have gates that open when certain membrane receptors bind to specific neurotransmitters or hormones, and close when these chemicals are released from the receptors Mechano-sensitive channels - Have gates that open in response to direct mechanical stimulation of the cell membrane - They are involved in movement of some cells The core of medical physiology (1) 3 rd edition Page 12

13 QUESTIONS FOR SELF ASSESSMENT-1 (BEST OF FIVE) 1- Concerning the cell organelles: a. mitochondria synthesize proteins b. endoplasmic reticulum is needed for cell division c. nuclei are the power houses of cells d. lysosomes contain hydrolytic enzymes e. Golgi apparatus translates RNA into proteins 2- Water passes through cell membranes by: a. facilitated diffusion b. primary active transport c. osmosis d. co transport e. none of the above 3- Maintenance of constant internal environment is known as: a. endocytosis b. feedback mechanism c. physiology d. homeostasis e. haemostasis 4- Facilitated diffusion: a. occurs against the electrical gradient b. requires energy c. not influenced by the concentration gradient d. has no transport maximum capacity e. mediated by a protein carrier 5- Which of the following can cross the cell membrane passively? a. Proteins b. carbon dioxide c. potassium ions d. calcium ions e. glucose 6- Facilitated diffusion differs from simple diffusion in that it: a. does not require energy b. occurs against the electrical gradient c. is not influenced by the concentration gradient d. is mediated by a protein carrier e. has no transport maximum capacity 7- Which of the following is a passive type of transport: a. solvent drag b. endocytosis c. exocytosis d. co-transport e. antiport The core of medical physiology (1) 3 rd edition Page 13

14 8- Concerning transport of ions across cell membranes, which of the following is not true: a. secondary active transport requires energy b. simple diffusion occurs down the concentration gradient c. facilitated diffusion occurs against the electrical gradient d. active transport is mediated by a protein carrier e. secondary active transport has a transport maximum capacity 9- Concerning transport across cell membranes, all the following require integral proteins to cross cell membranes except: a. water b. glucose c. oxygen d. potassium ions e. calcium ions 10- Leak channels: a. are present in almost all cells in the body b. have gates that open or close in response to changes in potential c. open when a hormone binds to a nearby membrane receptor d. are responsible for the depolarization phase of action potentials e. are activated by mechanical stimulation of cell membranes 11- All of the following substances cross the cell membrane through channels or transporters except: a. sodium b. bicarbonate c. oxygen d. water e. potassium 12- Homeostasis is: a- arrest of bleeding b- maintenance of constancy of the external environment c- formation of a blood clot d- normal ph e- represented by control of body temperature Question Answer d c d e b d a c c a c e The core of medical physiology (1) 3 rd edition Page 14

15 CHAPTER 1 BODY FLUIDS TOTAL BODY WATER (TBW) -Body composition in a 70 Kg young adult male: Water = 60% (of the total weight which is 70 kg) Proteins = 18% Fats = 15% Minerals = 7% Carbohydrates < 1% -Therefore: water is the most important constituent in the body. -With total deprivation of water, survival is limited to a few days, whereas total food deprivation is tolerated for at least a month. -Total body water (in a 70 kg, young adult male): = 60 % of the total body weight = 42 Kg (60/100 x 70) = 42 L (because density of water = 1) Variation in the % of TBW among different subjects -The % of TBW varies according to: 1) Age - TBW decreases with age (e.g. in an embryo it is near to 100%, in a neonate = 80%, in an adult male = 60% and above the age of 60 years = 52% in males). 2) Sex - The % of TBW is higher in males when compared to equivalent females. This is because the female has higher percentage of fat in her body, compared to an equivalent male, with the same age and weight. The core of medical physiology (1) 3 rd edition Page 15

16 - The higher percentage of fat is associated with less percentage of water because fat cells contain less water than other types of cells. For example, water in a fat cell is about 13% whereas in a muscle cell is about 75%. 3) Body size - The % of TBW is higher in thin-tall subjects compared to obese-short subjects. - This is also explained by the higher percentage of fat in the obese subject, and therefore less percentage of water. Table1.1: % of TBW in males and females of different ages Age % of water in a male % of water in a female Embryo Almost 100% Almost 100% Neonate 80% 80% Adult 60% 51% Elderly 52% 46% Body Fluid Compartments - As mentioned in the introduction of this book, cells of the body do not only contain water, but also surrounded by water. - Therefore, total body water is divided into two compartments: 1) Intracellular fluid (ICF): = 2/3 of the total body water or 40% of the total body weight (TBwt). 2) Extracellular fluid (ECF): = 1/3 of the total body water or 20% of the total body weight (TBwt). - ECF is further divided into: a) Interstitial fluid: = 75% of ECF or 15% of TBwt. The core of medical physiology (1) 3 rd edition Page 16

17 b) Intravascular fluid (plasma): = 25% of ECF or 5% of TBwt. c) Trans-cellular fluid: Negligible. Notes about trans-cellular fluid: It includes synovial fluid, pleural fluid, pericardial fluid, peritoneal fluid, cerebrospinal fluid... Its volume is very low, that s why it is not included in calculations of ECF. In abnormal conditions (like pleural effusion, pericardial effusion and ascites) its volume becomes very high. - In a 70 Kg adult male: Total body water = 42 L (60% of the total body weight) ICF = 28 L (= 40% of total body weight) ECF = 14 L (= 20% of total body weight) ISF = 10.5 L (= 15% of total body weight) IVF (Plasma) = 3.5 L (= 5% of total body weight) Question: Calculate the expected body fluid compartments in an average 60 kg adult male Answer: Total body weight= 60Kg, therefore: Total body water = 60/100 x 60 = 36L, ICF = 40/100 x 60 = 24 L, ECF = 20/100 x 60 = 12 L, ISF = 15/100 x 60 = 9 L and IVF = 5/100 x 60 = 3 L. Notes about body fluid compartments in neonates: Total body water constitutes a very high proportion of the total body weight (about 80%) ECF exceeds 30% and ICF volume is less than 40% of total body weight. Therefore, ECF/ICF volume ratio is very high The core of medical physiology (1) 3 rd edition Page 17

18 Differences between ECF & ICF: ECF has: lower volume, higher ph and higher concentrations of sodium, calcium, chloride & bicarbonate. Sodium is the main cation and chloride is the main anion. ICF has: higher volume, lower ph and higher concentrations of potassium, magnesium, phosphate, sulphate and protein. Potassium is the main cation and non-diffusible anions (like organic phosphate and protein) are the main anions. Table 1.2: Differences between ECF and ICF in a 70 kg adult male Difference Extracellular fluid Intracellular fluid Volume 15L 25L Conc. Of Cations: Sodium (Na + ) Potassium (K + ) Calcium (Ca +2 ) Magnesium (Mg +2 ) Conc. Of Anions: Chloride (Cl - ) Bicarbonate (HCO - 3 ) Phosphate (PO -3 4 ) Protein mmol/l 4.0 mmol/l 2.5 mmol/l 2.0 mmeq/l mmol/l 25.0 mmol/l 2.0 meq/l 17.0 meq/l 10 mmol/l 140 mmol/l Negligible (0) 26 mmeq/l 4 mmol/l 10 mmol/l 100 meq/l 65 meq/l ph Temperature 37 c 37 c Osmolarity mosm/l mosm/l The core of medical physiology (1) 3 rd edition Page 18

19 Measurement of body Fluid Compartments - Volumes of body fluid compartments can be measured using the indicator (dye) dilution method. - In this method, a known quantity of a substance (e.g. a dye) is injected and allowed to distribute in the compartment of interest. After distribution, a sample of fluid is taken from the same compartment to measure the final concentration of the dye. Then the volume of the compartment (known as the volume of distribution of the dye) is calculated using the formula: Volume of distribution = Q-e /C Where: - Q is the quantity of the dye injected - e is the amount of the dye excreted or metabolized by cells - C is the concentration of the dye after equilibration - Substances used for measurement of body fluid compartments should have the following characteristics: - Non toxic - Easily measured - Their amounts are not altered by the body (not stored, metabolized, excreted or produced by the body) or the altered amount can be calculated easily - Distribute only in the compartment being measured - Do not affect water distribution in other compartments Remember that: Leakage of a substance into other compartment decreases its final concentration and therefore increases the calculated volume of distribution. The core of medical physiology (1) 3 rd edition Page 19

20 Examples for substances used in measurement of body fluids: Substances used in measurement of total body water: -Deuterium oxide (heavy water) -Tritium oxide ( 3 H 2 O = an isotope of water) -Antipyrine -Aminopyridine Substances used in measurement of extracellular fluid: -Saccharides (inulin, manitol & sucrose) These fail to penetrate the trans-cellular fluid Therefore they underestimate the ECF -Radioactive electrolytes (sodium, chloride & bromide) These easily penetrate the entire ECF and may escape into cells Therefore they overestimate the ECF -Thiosulphate & thiocynate Substances used in measurement of plasma: -Radioactive iodine used to label serum albumin (RISA) -Evan s blue dye (which binds to plasma protein and stay in plasma) -Labeled macroglobulin Substances used in measurement of Blood: -Blood volume can be calculated from plasma and packed cell volume (PCV) by the formula: Blood = Plasma X 100/100-PCV -The PCV is measured by centrifugation of a sample of blood in a capillary tube, and then the percentage of the packed cells at the bottom of the tube is calculated (read about the PCV in chapter 5). The core of medical physiology (1) 3 rd edition Page 20

21 -It is also calculated from red blood cell volume and plasma volume by the formula: Blood = plasma + red blood cell volume. -The red blood cell volume is obtained from the volume of distribution of re-injected red blood cells labeled with radioactive chromium ( 51 Cr). Intracellular fluid and interstitial fluid: - Are measured indirectly by two substances, for two compartments. Then ICF or ISF can be subtracted as follows: ICF = TBW - ECF ISF = ECF - plasma Factors Affecting Body Fluid Compartments Body fluid compartments are affected by: 1. Osmosis 2. Diffusion 3. Gibbs Donnan equilibrium 4. Sodium-potassium pump 5. Starling's forces 6. Abnormalities of water balance 1- Osmosis - Osmosis is the movement of water molecules across a semipermeable membrane, from a region of lower concentration of a solute to a region of higher concentration of the solute (see the introduction). The core of medical physiology (1) 3 rd edition Page 21

22 - All cell membranes and capillaries are semi-permeable membranes (permeable to water and generally not permeable to solute). - For osmosis to occur there should be a difference in solute concentration between the two sides of the membrane, i.e. difference in osmolarity. Fig 1.1: Osmosis 1 Solution A has the same concentration as solution B = No osmosis 2 Solution A has higher concentration than solution B = Osmosis from B to A Osmolarity, Osmolality & Tonicity Osmolarity - Osmolarity is the number of osmoles of solute per one liter of solution. - It is used to describe concentrations of osmotically active particles in a solution. - If a solute dissociates into ions to form an ideal solution, each liberated ion is an osmotically active particle. The core of medical physiology (1) 3 rd edition Page 22

23 - For example: dissociation of one mole of (NaCl) gives one osmole of sodium and one osmole of chloride (i.e. 2 osmoles). - However, one mole of glucose (C 6 H 12 O 6 ) in a solution gives one osmole; because organic substances like glucose are non-ionizable. - Remember that one mole of a substance contains the same number of molecules that are found in one mole of any other substance (= Avogadro's number = x ). - The osmotically active particles can exert osmotic pressure if they are in contact with another solution, but separated from it by a semipermeable membrane (permeable to the solvent but not to the solute). - Osmotic pressure is defined as the pressure necessary to prevent solvent migration (i.e. prevent osmosis). Fig 1.2: The osmotic pressure Osmotic pressure prevents osmosis from solution B to solution A The core of medical physiology (1) 3 rd edition Page 23

24 Osmolality - Osmolality is the number of osmoles per one kilogram of solvent. - It is more accurate than osmolarity since it depends on mass (which is constant) rather than volume (which is affected by changes in temperature and pressure). - In body fluids, where the solvent is water, the concentration of solutes is very low (highly diluted); therefore one liter and one kilogram are equal. More over, temperature and pressure are constant under normal physiological conditions; that s why osmolality and osmolarity are equal in body fluids. - Because of this similarity between osmolality and osmolarity, you may find osmolality expressed in (mosm/l) rather than (mosm/kg). - Osmolality of plasma = ( ) mosm/l. Na + and its anions are responsible for most of this value (Na + determines ECF osmolality). - Osmolality of intracellular fluid = ( ) mosm/l. K + and its anions are responsible for most of this value (K + determines ICF osmolality). Tonicity - This term is used when describing osmolality of a solution relative to osmolality of the plasma. - Accordingly, solutions may be: o Isotonic (with osmolality similar to plasma) o Hypotonic (with osmolality lower than plasma) o Hypertonic (with osmolality higher than plasma) - Intravenous (I.V.) infusion of each type of these solutions affects volumes and osmolarities of body fluid compartments. These effects can be studied from the following figure and table: The core of medical physiology (1) 3 rd edition Page 24

25 Fig 1.3: The effects of different types of solutions on cells: Table 1.3: Effects of I.V. solutions on volumes and osmolarities Solution ECF ICF Osmosis Vol. Osmol. Vol. Osmol. Isotonic The same The same The same Hypotonic Hypertonic - From the above table: - I.V. infusion of an isotonic solution increases volume of ECF with no effect on its osmolarity, and no effect on volume or osmolarity of ICF (i.e. no effect on cells). - I.V. infusion of a hypotonic solution increases volumes of ECF and ICF and decreases osmolarities of ECF and ICF. - I.V. infusion of a hypertonic solution increases volume and osmolarity of ECF, and decreases volume of ICF while its osmolarity is increased. The core of medical physiology (1) 3 rd edition Page 25

26 Calculation of osmolality: A. From the Freezing Point Depression - One osmole depresses the freezing point of a solution by 1.86 ο c - One milliosmole depresses the freezing point by ο c - Number of milliosmoles per liter in a solution = The freezing point depression/ Q: Calculate the osmolality of normal human plasma if the freezing point = ο c Answer: Plasma osmolality = 0.55/ = 295 mosm/l B. From the Molarity Number of osmoles = Number of moles x number of particles (liberated by a single molecule) Q: Calculate the osmolarity of 0.9% NaCl solution and mention the effect of this solution on volume and osmolarity of ICF after its infusion in the plasma? (Molecular weight of NaCl = 58.5). Answer: 0.9% NaCl = 0.9 g/dl, (x 10) = 9 g/l Molarity = [conc. g/l] / MWt of NaCl = 9 / 58.5 mol/l = mol/l, (x 1000) = 154 mmol/l Osmolarity = 154 x 2 = 308 mosm/l (Isotonic, has no effect on ICF) (Remember that: This solution is regarded as isotonic solution although its osmolarity is higher than plasma Osmolarity (> 300 mosm/l). This is because the dissociation of NaCl in plasma is not as complete as in true ideal solutions (dissociation is about 93%). Therefore the osmolarity of 0.9% NaCl solution in plasma is actually less than 308 mosm/l; that s why it is isotonic). The core of medical physiology (1) 3 rd edition Page 26

27 Q: Calculate the osmolarity of 5% glucose solution. If one liter of this solution is infused intravenously, mention the immediate and the later effects on the cells? (MWt glucose = 180). Answer: 5% glucose = 5g/dL = 50 g/l Molarity = [Conc. g/l]/mwt = 50/180 = mol/l (x 1000) = 278 mmol/l Osmolarity = 278 x 1 = 278 mosm/l (Isotonic) Immediate effect on cells: no effect because it is isotonic Later effect on cells: After uptake of glucose by cells the solution becomes hypotonic; water enters cells, it increases volume & decreases osmolarity of ICF. Q: Calculate the osmolality of a solution containing 110 mmol NaCl, 25 mmol NaHCO 3, 2.5 mmol CaCl 2, 5 mmol urea & 5 mmol glucose Answer: Plasma osmolality = (110x2) + (25x2) + (2.5x3) + (5x1) + (5x1) = mosm/l. (Remember that glucose and urea are non-ionizable). C. Using a formula Osmolarity of the plasma can be calculated using the following formula: Plasma Osmolarity = 2([Na] + [K]) + [glucose] + [urea] (All concentrations are in mmol/l) Q: Calculate the osmolarity of the plasma if [Na] = 140 mmol/l, [K] = 4 mmol/l, [Glucose]= 5 mmol/l and [Urea]= 7 mmol/l. Answer: Osmolarity = 2( ) = 300 mosm/l (isotonic). The core of medical physiology (1) 3 rd edition Page 27

28 2- Diffusion - It is expansion or passage of a substance through a cell membrane down its chemical or electrical gradient, due to continuous random movement of its molecules. - Water follows osmotically active particles to inside or to outside the cell, this affects volumes of body fluid compartments. Fig 1.4: Diffusion 3- Gibbs Donnan equilibrium - The presence of non-diffusible anions (protein and organic phosphate) within the cell affects distribution of diffusible ions (both anions and cations); it allows entry of diffusible cations (e.g. Na + ) into the cell and prevents entry of diffusible anions (e.g. Cl - ). Fig 1.5: Gibbs Donnan equilibrium The core of medical physiology (1) 3 rd edition Page 28

29 - The concept was shown theoretically by Gibbs and confirmed experimentally by Donnan (= known as Gibbs Donnan equilibrium). - At equilibrium: 1- Total cations = total anions (on either side of the membrane) 2- The product of diffusible ions on one side equals the product of diffusible ions on the other side of the membrane (This holds for cations and anions of the same valence). - Take this example of two solutions a and b ; in which Na + and Cl - are diffusible cations and anions respectively; X - indicates non diffusible anions. Solution (a) Solution (b) Na + Na + Cl - Cl - X - At equilibrium: 1- [Na + ] a = [Cl - ] a + [X - ] a (i.e. cations in a = anions in a) [Na + ] b = [Cl - ] b (i.e. cations in b = anions in b) 2- [Na + ] a x [Cl - ] a = [Na + ] b x [Cl - ] b [Na + ] a / [Na + ] b = [Cl - ] b / [Cl - ] a From the above relationships: [Na + ] a > [Cl - ] a (Cations on the side of X - are greater than anions on the same side) [Cl - ] a < [Cl - ] b (Diffusible anions on the side of X - are less than on the other side) [Na + ] a > [Na + ] b (Cations on the side of X - are greater than cations on the other side) The core of medical physiology (1) 3 rd edition Page 29

30 [Na + ] a + [Cl - ] a + [X - ] a > [Na + ] b + [Cl - ] b (There is greater number of ions on the side of X - than on the other side). Remember that: The greater number of particles in compartment a exerts an osmotic effect resulting in swelling of this compartment. A similar effect occurs in body fluids, i.e. cells tend to undergo swelling but this is prevented by the Na+/K+ pump. Effects of Donnan equilibrium in the body: 1- Swelling of cells The ICF contains higher concentration of non diffusible anions than the ECF and therefore more particles. This may result in swelling of the cells and eventually their rupture. However, swelling of cells is prevented by the action of the Na + /K + pump and other ion channels. The Na + /K + pump transports 3 sodium ions to outside of the cell and 2 potassium ions to inside; this decreases the total number of ions inside the cell and prevents its swelling (see below). 2- Electrical difference across the cell membrane The asymmetrical distribution of diffusible ions across the cell membrane generates an electrical difference that can be determined for each ion by the Nernst equation. In addition the asymmetrical distribution of non diffusible anions participates in genesis of the resting membrane potential (see chapter two). 3- Slight difference in concentration of ions between plasma and ISF Since plasma contains higher concentration of protein than the interstitial fluid (ISF), it contains slightly higher concentration of The core of medical physiology (1) 3 rd edition Page 30

31 cations (like sodium and potassium) and lower concentration of anions (like chloride and bicarbonate). 4- Slight difference in concentration of ions between the plasma and the glomerular filtrate At the kidney, proteins are not filtered out of the glomerular capillaries. The filtrate is free of plasma protein. Therefore the plasma contains slightly higher concentration of cations (like sodium and potassium) and lower concentration of anions (like chloride and bicarbonate) than in the filtrate. Table 1.2: Differences between plasma and ISF in an adult male Difference Plasma Interstitial fluid Volume 5% of body weight 15% of body weight Conc. Of Cations: Sodium (Na + ) Potassium (K + ) Calcium (Ca +2 ) Magnesium (Mg +2 ) Total cations Conc. Of Anions: Chloride (Cl - ) Bicarbonate (HCO - 3 ) Phosphate (PO -3 4 ) Organic acids Protein Total anions 145 mmol/l 4.1 mmol/l 2.5 mmol/l 1 mmol/l mmol/l 105 mmol/l 25 mmol/l 1 mmol/l 5 mmol/l 16.6 mmol/l mmol/l 140 mmol/l 4 mmol/l 2.1 mmol/l 1 mmol/l mmol/l 110 mmol/l 30 mmol/l 1 mmol/l 5 mmol/l 1.1 mmol/l mmol/l The core of medical physiology (1) 3 rd edition Page 31

32 4- The Sodium-Potassium Pump - Found in all cells of the body. - Transports sodium and potassium actively against their chemical gradients (3 Na + ions to outside and 2 K + ions to inside the cell). Fig 1.6: The sodium potassium pump - It accounts for 20-45% of the total metabolic energy expended by the cell. - Consists of alpha and beta subunits extending through the cell membrane. The beta subunit is a glycoprotein, whereas the alpha subunit is a protein with extracellular binding sites for K + and intracellular binding sites for Na + and ATP. Fig 1.7: Subunits of the sodium potassium pump The core of medical physiology (1) 3 rd edition Page 32

33 - It is the alpha subunit that transports Na + and K + ; however, separation of the two subunits inactivates the pump - The Na + /K + ATPase enzyme releases energy from ATP that s used in transport of 3 sodium ions to outside the cell and 2 potassium ions to inside. This results in accumulation of negative charges inside the cell (i.e. it is an electrogenic pump). Functions of the Na + /K + pump - Participates in genesis of the resting membrane potential (i.e. generates negative charges towards the inner side of the cell membrane (see chapter two)). - Prevents swelling and rupture of cells by removing excess sodium ions to outside (see Donnan effect). Regulation of the pump - The pump is activated by accumulation of Na + ions intracellularly. - Activity is increased by: o Insulin, Aldosterone and thyroid hormones - Activity is inhibited by: o Dopamine and digitalis 5- Starling's forces - As mentioned above, movement of water across cell membranes depends on osmosis. However, movement of water across the walls of capillaries depends, in addition to that, on 4 primary forces (known as Starling s forces) that control fluid exchange between plasma and interstitium. - Although Starling s forces act in all blood vessels, they cause fluid exchange only in capillaries. The core of medical physiology (1) 3 rd edition Page 33

34 - This is because the walls of capillaries, unlike arteries and veins, are characterized by pores between the endothelial cells that allow movement of water (for this reason capillaries are called the exchange vessels ). - Starling forces include: 1- Capillary hydrostatic pressure (HPc) - It is the pressure of plasma acting on the lateral wall of the blood vessel - For filtration (from plasma to ISF) = 35 mmhg at the arteriolar end of capillaries = 15 mmhg at the veniolar end of capillaries 2- Capillary oncotic pressure (OPc): - The osmotic pressure of plasma proteins (also known as colloid osmotic pressure or oncotic pressure) - It is exerted mainly by albumin - For absorption (from ISF to plasma) = 25 mmhg throughout the capillaries (proteins are not filtered and therefore their oncotic pressure is not changed) 3- Interstitial fluid hydrostatic pressure HP ISF : - Acts in the opposite side to HP C ;(i.e. against filtration) 4- Interstitial fluid oncotic pressure OP ISF : - Acts in the opposite side to OP C ; (i.e. against absorption) Notes about osmotic pressure of proteins (Oncotic pressure) Oncotic pressure is mainly exerted by albumin because it is the smallest plasma protein and therefore it has the highest number of particles than other types of plasma proteins. Osmolarity depends on number not size of particles. The core of medical physiology (1) 3 rd edition Page 34

35 - Calculation of filtration pressure: - Both hydrostatic pressure of ISF and oncotic pressure of ISF are of low magnitude, they act against each other and therefore they cancel each other. That s why they are not considered in calculation of the filtration pressure. - The filtration pressure is calculated by subtracting the capillary oncotic pressure from the capillary hydrostatic pressure as follows: o At the arteriolar end= (35-25)= +10 mmhg (i.e. net filtration) o At the veniolar end= (15-25)= -10 mmhg (i.e. net absorption) Fig 1.8: Starling's forces - A filtration pressure of + 10 mmhg indicates that Starling s forces cause filtration of plasma at the arteriolar end of capillaries to the interstitium. The filtered plasma carries nutrients to the surrounding cells & then the fluid is absorbed back at the veniolar end with the waste products. The core of medical physiology (1) 3 rd edition Page 35

36 About 90% of the filtered fluid at the arteriolar end of capillaries is absorbed back to the capillaries at their veniolar end; the remaining 10% of the filtered fluid is also absorbed but by the lymphatics. The lymphatic vessels also absorb small amount of protein that may escape out of the plasma to the interstitium. The lymphatics return this protein together with the 10% of the filtered fluid back to the circulation at the neck where the main lymphatic duct drains into the jugular vein. This keeps balance between filtration and absorption of fluid at the capillaries. Disturbance of this balance between filtration and absorption may result in accumulation of fluid in the interstitium causing edema. Edema - Edema is defined as abnormal accumulation of fluid in the interstitial space. It is caused by many diseases through one or more of the following mechanisms: 1- Increased capillary hydrostatic pressure (HP C ) - Some diseases may cause accumulation of blood in veins; thus increasing the HP C at the veniolar end of capillaries. - When the HP C becomes higher than the OP C, the return of the filtered fluid to the capillaries is prevented causing edema. - Examples include: o Heart failure Left sided heart failure results in accumulation of blood in the lung veins causing pulmonary edema whereas right sided heart failure causes accumulation of blood in systemic veins causing generalized edema. The core of medical physiology (1) 3 rd edition Page 36

37 o Venous obstruction Results in accumulation of blood proximal to the site of obstruction causing localized edema Remember that: Oedema is not caused by hypertension because the hydrostatic pressure of capillaries is not increased at the veniolar end of capillaries, which is the site of absorption Oedema is not caused by arterial obstruction because this decreases blood flow to the capillaries and therefore decreases HP C 2- Decreased oncotic pressure (OP C ) - Some diseases may lower the level of proteins in the plasma. This decreases OP C. - The low OP C prevents absorption of the filtered fluid back to the intravascular space causing edema. - Examples include: o Malnutrition Decreased protein intake (e.g. Kwashiorkor) Results in generalized edema o Malabsorption Decreased absorption of protein (e.g. due to chronic pancreatitis) Results in generalized edema o Liver disease (chronic disease like liver cirrhosis) Decreased synthesis of plasma proteins Results in generalized edema The core of medical physiology (1) 3 rd edition Page 37

38 o Renal disease (nephrotic or nephritic syndromes or renal failure) Loss of plasma proteins in urine Results in generalized edema 3- Lymphatic obstruction - Obstruction of lymphatics results in accumulation of the fluid that s supposed to be absorbed by the lymphatics to be removed from the interstitium. Therefore, it accumulates causing edema. - The obstruction is caused by: o Filaria (worms that live within the lymphatic vessels) Filariasis results in localized edema (very large swelling proximal to the site of obstruction known as elephantiasis) o Surgical removal of lymph nodes (which drain a site of cancer) This is done to prevent spread of secondaries from the cancer o It interrupts the lymph flow resulting in localized edema 4- Increased permeability of capillaries: - Some diseases may increase the permeability of capillaries and allow filtration of plasma proteins to the interstitium thus increasing the OP ISF which absorbs fluid to the outside causing edema. - The capillary permeability is increased by: o Inflammation The increased permeability is due to mediators of inflammation released by white blood cells and the nearby tissues Results in localized edema The core of medical physiology (1) 3 rd edition Page 38

39 o Burn The increased permeability is due to the high temperature Results in localized edema o Allergy The increased permeability is due to histamine which is released by mast cells and basophils Results in localized or generalized edema Types of edema: - Edema can be classified into 2 types (by applying pressure on it in one site using one finger the thumb against bone, for a minute): 1- Pitting edema - The finger leaves a mark (a pit) on the skin - The mark appears because the fluid escapes away from the site of pressure and returns slowly - Causes of pitting edema include: All causes of high capillary hydrostatic pressure All causes of low capillary oncotic pressure 2- Non pitting edema - The finger does not leave a mark on the skin because the escaped fluid returns rapidly. - This is because it is attracted by proteins that are filtered to the interstitium - Causes of non pitting edema include: All causes of increased permeability All causes of lymphatic obstruction The core of medical physiology (1) 3 rd edition Page 39

40 6- Abnormalities of water balance Water balance - In normal physiological conditions, the body loses water in urine to excrete waste products of metabolism and in addition to that, there is insensible loss of water through the skin and in expired air. - These water losses should continuously be replaced by water intake to maintain normal water content of the body. - On the other hand, if water intake is higher than the daily requirement of the body, the excess water should be excreted. - In summary: water loss should equal water intake (= water balance) Fig 1.9: Water balance - Abnormalities of this balance between water intake and output cause disturbances in volumes and osmolarity of body fluid compartments. The core of medical physiology (1) 3 rd edition Page 40

41 Normal water intake occurs through: o drinking 1.3L/day o solid food 0.9L/day o metabolism 0.3L/day Net = 2.5L/day Normal water output occurs through: o urine 1.5 L/day o stool 0.1 L/day o sweating & insensible loss 0.9 L/day Net= 2.5 L/day Note - The average water intake = the average water loss = 2.5 L/day - The above values vary greatly in different physiological and pathological conditions: Examples of the physiological conditions: 1- Type of work E.g. heavy work increases sweating= increased water loss 2- Exercise E.g. strenuous exercise increases sweating and causes hyperventilation (increases insensible water loss in expired air) = increased water loss 3- Degree of water intake Affects urine volume as follows: - High water intake increases urine volume - Low water intake decreases urine volume Remember that the minimum volume of urine required for excretion of waste products of metabolism is 500 ml/day The core of medical physiology (1) 3 rd edition Page 41

42 4- Variation in body temperature and environmental temperature Both affect the amount of sweating, the rate of metabolism and the rate of respiration (see chapter 4) Examples of the pathological conditions: 1- Abnormal water intake through: - increased metabolism (fever, hyperthyroidism) - increased drinking (psychogenic polydypsia) - excess intravenous fluids (fluid overload) - complete water deprivation 2- Abnormal water loss through: - vomiting - diarrhea - polyuria (diabetes mellitus, diabetes insipidus) - excessive sweating (heat exhaustion) - hyperventilation (metabolic acidosis) Regulation of water balance - As mentioned earlier, maintenance of constancy of ECF is the goal of all systems in the body. - Variation in water intake or water loss produces minor changes in extracellular fluid volume and osmolarity. These changes stimulate certain receptors (e.g. volume receptors & osmoreceptors) that activate multiple regulatory mechanisms to restore back the constancy of the ECF. The core of medical physiology (1) 3 rd edition Page 42

43 - The regulatory mechanisms include: 1- Mechanisms for control of water intake - act principally through control of thirst 2- Mechanisms for control of water loss - act principally through control of urine volume Control of water intake - Under normal environmental and physiological conditions, the amount of water gained by metabolism or solid food is almost constant whereas the amount gained by drinking may be variable. That s why water intake is generally regulated through regulation of drinking (= regulation of thirst). On the other hand, water intake through solid food and metabolism is a non-regulatory component. Thirst - Defined as the subjective perception that provides the urge for humans and animals to drink fluids. - Also defined as the conscious desire for water. - Regulated by thirst center located in the hypothalamus. - There are 4 major stimuli to thirst: Angiotensin II: This is an octa-peptide hormone produced in the plasma following release of renin enzyme from the "Juxtaglomerular apparatus" in the kidney (see below). - It acts directly on specific receptors located in circumventricular organs in the brain (neural organs that lie outside the blood-brain barrier) to stimulate thirst. The neuronal pathway from the circumventricular organs to the hypothalamus also uses angiotensin II as a neurotransmitter. The core of medical physiology (1) 3 rd edition Page 43

44 Hypertonicity: Small increases of 1-2% of the effective osmotic pressure of plasma causes shrinkage of osmoreceptors in the hypothalamus (due to osmosis from the osmoreceptors to the ECF). - Shrinkage of the osmoreceptors results in direct mechanical stimulation of the thirst center because its dendrites which are attached to the osmoreceptors are stretched by the shrinkage. Hypovolemia: The volume of ECF is sensed via volume receptors located at the low pressure side of the circulation (i.e. the venous side, at the junction of the right atrium and the vena cava and at the entry of the pulmonary vein into the left atrium). - Hypervolemia stretches these receptors which send inhibitory impulses through the vagus nerve to inhibit thirst. On the other hand, hypovolemia stimulates thirst through reduction of the inhibitory discharge from the volume receptors to the thirst center. Hypotension: The blood pressure is sensed via baroreceptors located at the high pressure side of the circulation (i.e. the arterial side, at the carotid sinus and the aortic sinus which are found at the bifurcation of the common carotid artery and the aortic arch respectively). - Hypertension stretches these receptors which send inhibitory impulses through the vagus and the glossopharyngeal nerves to inhibit the thirst center. On the other hand, hypotension stimulates thirst through reduction of the inhibitory discharge from these receptors to the thirst center. Remember that: Thirst is one of the symptoms of dehydration and shock The core of medical physiology (1) 3 rd edition Page 44

45 The hormone atrial natriuretic peptide (ANP) inhibits thirst! ANP is a peptide hormone released by atria in response to hypervolemia. It inhibits the effect of angiotensin II on thirst to decrease ECF volume. It also decreases ECF volume through inhibition of aldosterone action on the kidney, increasing the rate of glomerular filtration and increasing the rate of sodium excretion in urine (notice that loss of sodium is followed by loss of water). Important note: Drinking stimulates mechanoreceptors in the mouth and pharynx which provide input to the hypothalamus to attenuate the sensation of thirst. This occurs before any reduction in plasma tonicity; thus acting as a safeguard against over-ingestion of water. Control of water loss - Under normal environmental and physiological conditions, the amount of water lost by sweating, respiration and through the skin is almost constant whereas the amount lost by urine is variable. The minimal volume of urine that can be excreted to eliminate the metabolic waste products = 0.5 L/day. The maximal volume depends on water intake. - For this reason water loss is controlled through regulation of urine volume. This involves the kidney and the hormones acting on it. Renal function - The functional unit of the kidney is the "nephron" which consists of: glomerulus, for filtration & tubules: for reabsorption and secretion. - About 180 L of fluid pass through the glomeruli of the kidney each day. However, only 1.5 L is excreted in urine indicating that the renal tubules reabsorb more than 99% of the filtered fluid. The core of medical physiology (1) 3 rd edition Page 45

46 Fig 1.10: The nephron - Reabsorption of water in the renal tubules occurs as follows: - The PCT: reabsorbs 70% of the filtrate following sodium reabsorption. The filtrate remains isotonic - The loop of Henle: water reabsorption occurs in the thin descending limb without sodium reabsorption. The filtrate becomes hypertonic; however it becomes hypotonic at the end of the thick ascending limb because it reabsorbs solutes without water. - The DCT: relatively impermeable to water. About 5% of the filtrate may be reabsorbed. The filtrate remains hypotonic. - The CDs: Completely impermeable to water except at the presence of ADH (see ADH below). The core of medical physiology (1) 3 rd edition Page 46

47 Hormonal activity ADH - Antidiuretic hormone, also known as vasopressin - It is a nona-peptide hormone synthesized in the hypothalamus and stored in the posterior pituitary gland - It is released in response to the same major stimuli of thirst, through similar mechanisms: o Hyperosmolarity (detected by osmoreceptors located at the hypothalamus. They cause mechanical stimulation of ADH) o Hypovolemia (results in less stretch of the volume receptors at the low pressure side of the circulation and therefore less inhibition of ADH release) o Hypotension (results in less stretch of the baroreceptors at the high pressure side of the circulation and therefore less inhibition of ADH release) o Angiotensin II (stimulates ADH release, see below) o Drugs (drugs that stimulate ADH release include barbiturates, clofibrate, nicotine, acetylcholine and others) Functions of ADH - ADH acts on the collecting ducts in the kidney causing water retention. It facilitates reabsorption of 7-13% of the filtrate - When ADH level in plasma is high, it also causes vasoconstriction resulting in elevation of the blood pressure Abnormalities of ADH: - Deficiency of ADH causes polyuria and excessive thirst due to hypovolemia. Urine volume may reach up to 23 L/day. The condition is known as diabetes insipidus (DI). It may result from a problem in The core of medical physiology (1) 3 rd edition Page 47

48 the hypothalamus (neurogenic DI) or a problem in the renal receptors for ADH (nephrogenic DI) - Excessive ADH secretion causes reduction in urine volume, hypertension and edema due to water retention. The condition is known as syndrome of inappropriate ADH secretion (SIADH). It is caused by many problems; these include head trauma, lung tumors, pneumonia and pancreatitis. Aldosterone - Steroid hormone synthesized in the adrenal cortex - It is released in response to the following stimuli: o Hyperkalemia Directly stimulates aldosterone release from the adrenal cortex. o High level of ACTH The adrenocorticotrophic hormone (ACTH) is released by the anterior pituitary gland to stimulate secretion of cortisol (not aldosterone) by the adrenal cortex. But, in high levels (due to endocrine abnormalities) it also stimulates release of aldosterone. o The renin-angiotensin-aldosterone system In this system, renin enzyme which is produced by the Juxtaglomerular apparatus in the kidney results in formation of angiotensin II. The later stimulates aldosterone secretion from the adrenal cortex. The Juxta-glomerular apparatus (JGA) is formed by: - Cells of the afferent arteriole (juxta-glomerular cells) - Cells of the DCT (macula densa cells) - Lacis cells (= extra-glomerular mesangial cells) The core of medical physiology (1) 3 rd edition Page 48

49 Fig 1.11: The juxta-glomerular apparatus (JGA) - This apparatus (specifically the juxta-glomerular cells) secretes renin in response to one of the following stimuli; o Hyponatremia (low [Na]) o Renal ischemia (e.g. due to hypotension or hypovolemia) o Sympathetic stimulation - Renin acts on a plasma peptide known as angiotensinogen (14 amino acids) produced by the liver to form angiotensin I (10 aa). - Angiotensin I is converted to angiotensin II (8 aa) by the action of angiotensin converting enzyme (ACE). - This enzyme is produced by the pulmonary endothelial cells. It is also released to the circulation by lung macrophages. The core of medical physiology (1) 3 rd edition Page 49

50 - Angiotensin II increases ECF volume & pressure because it causes: 1- Vasoconstriction 2- Stimulation of the sympathetic (this stimulates release of renin and renin forms angiotensin I and then angiotensin II and the cycle repeats itself in a positive feedback mechanism) 3- Stimulation of thirst 4-Stimulation of ADH 5- Stimulation of aldosterone - Aldosterone acts on the DCT and CDs in the kidney to stimulate retention of sodium and secretion of potassium. Water follows sodium resulting in increased ECF volume and pressure. - Unlike excessive ADH secretion, excessive aldosterone secretion due to adrenal tumors results in hypervolemia and hypertension but it does not cause edema. The explanation involves ANP as follows: Hypervolemia caused by sodium and water retention stimulates release of ANP from the atria. ANP acts in the kidney to increase sodium and water excretion. This prevents development of edema. This phenomenon is known as aldosterone escape phenomenon. Atrial natriuretic peptide (ANP) - A peptide hormone released by atria in response to hypervolemia. - It reduces ECF volume through the following effects: o Inhibition of the effect of angiotensin II on thirst o Inhibition of the effect of aldosterone on the kidney o Increasing the rate of glomerular filtration o Increasing excretion of sodium in urine (= natriuresis; notice that loss of sodium is followed by loss of water).) The core of medical physiology (1) 3 rd edition Page 50

51 QUESTIONS FOR SELF ASSESSMENT-2 (BEST OF FIVE) 1. The percentage of total body water is higher in: a. females compared to equivalent males b. old subjects compared to children c. infants compared to neonates d. thin subjects compared to obese ones e. male children compared to female children 2. Using the indicator dilution method, ECF volume is measured by: a. heavy water b. RISA c. inulin d. heavy water and RISA e. Evan s blue dye 3. The volume of distribution of substance A in an average adult male was found to be 3.5 litres. This substance could be: a. distributed to all body fluid compartments b. highly exchangeable between plasma and interstitium c. tightly bound to plasma proteins d. rapidly metabolised by cells e. all the above are correct 4. The ECF differs from the ICF because it contains: a. less concentration of sodium b. lower ph c. higher temperature d. osmolarity of about 300 mosm/l e. higher concentration of chloride 5. The interstitial fluid: a. constitutes about 5% of total body weight in adults b. temperature is less than that of the plasma c. osmolarity is determined by Cl - concentration d. volume can be measured by using inulin and manitol e. contains slightly higher concentration of Cl - than plasma 6. In a twenty years old man, the following volumes of distribution are obtained using the indicator dilution method: inulin = 14L and Evan s blue dye = 3L; which of the following is not true: a- intravascular fluid volume is about 3L b- ECF volume is about 14L c- ICF volume cannot be calculated from this data d- ISF volume cannot be calculated from this data e- blood volume cannot be calculated from this data The core of medical physiology (1) 3 rd edition Page 51

52 7. The osmolarity of plasma is a function of: a. calcium concentration b. protein concentration c. sodium concentration d. urea concentration e. glucose concentration 8. The concentration of calcium in the extracellular fluid is about: a. 10 mg/dl b. 5 mmol/l c. 1.5 meq/l d. 1.0 % e Filtration of fluid from plasma to interstitium is increased by: a. increased capillary oncotic pressure b. increased capillary hydrostatic pressure c. increased interstitial hydrostatic pressure d. decreased interstitial oncotic pressure e. lymphatic obstruction 10. Edema due to high capillary permeability results from: a. filariasis b. renal failure c. burn d. hepatic failure e. deep vein thrombosis 11. Gibbs Donnan equilibrium is responsible for: a. higher concentration of Na + in ICF than in ECF b. lower concentration of K + in plasma than in ISF c. slightly higher concentration of HCO 3 - in ISF than in plasma d. lower concentration of Cl - in intracellular fluid than in plasma e. higher volume of interstitial fluid than plasma 12. The ECF/ICF volume ratio is highest in: a- lean males b- obese males c- male children d- female children e- newborns Question Answer d c c e e d c a b c c e The core of medical physiology (1) 3 rd edition Page 52

53 CHAPTER 2 EXCITABLE TISSUES - Nerves and muscles are said to be excitable because they are capable of generating electrical signals known as action potentials. - In addition to action potentials, excitable tissues are also characterized by resting membrane potentials. However, unlike action potentials, resting membrane potentials are found in almost all cells of the body. THE RESTING MEMBRANE POTENTIAL (RMP) - It is the difference in electrical potential between the interior and the exterior of cell membranes at rest, with the interior being more negative relative to the exterior. - The cell membranes are said to be polarized ; i.e. negative inside and positive outside. Fig 2.1: The polarized cell membrane - The difference in potential across the cell membrane can be measured by special devices (e.g. the Cathode Ray Oscilloscope), using electrodes placed in the two sides of the cell membrane. Fig 2.2: Measurement of the resting membrane potential The core of medical physiology (1) 3 rd edition Page 53

54 - The magnitude of the RMP differs in different types of cells, for example: In a skeletal muscle cell = - 90 mv In a cardiac muscle cell = - 90 mv In a nerve cell = - 70 mv Causes of the RMP: a- Potassium efflux b- The Sodium- potassium pump c- ICF non diffusible anions a- Potassium efflux - This is the major cause of RMP. - The cell membrane is more permeable to potassium than sodium (because the hydrated atom of potassium is smaller than the hydrated atom of sodium). - Therefore potassium diffuses to the outside down its concentration gradient through potassium leak channels. Fig 2.3: Potassium efflux - For each atom of potassium that diffuses to the outside, a negative charge is generated inside and a positive charge is generated outside the cell membrane. The core of medical physiology (1) 3 rd edition Page 54

55 - The positive charges outside the cell membrane rebel the potassium ions, forcing them back to the inside through the leak channels (down their electrical gradient from the positive side to the negative side). However, net potassium efflux continues until the chemical gradient which drives potassium to the outside is equal to the electrical gradient that drives potassium to the inside (= stage of equilibrium). b- The Sodium- potassium pump - An electrogenic pump that pumps 3 sodium ions to outside and 2 potassium ions to inside, thus generating negative charges within the cell. Fig 2.4:The sodium potassium pump - Sodium and potassium ions are transported actively against their concentration gradients, using energy released by hydrolysis of ATP (see chapter 1). c- ICF non diffusible anions - Presence of non diffusible anions inside the cell (protein and organic phosphate) contributes to the genesis of RMP by increasing the number of negative charges inside the cell (= very low contribution). The core of medical physiology (1) 3 rd edition Page 55

56 The equilibrium potential: - The equilibrium potential (E) for an ion gives an idea about its role in genesis of the resting membrane potential. Here the ion is placed in a medium similar to ECF and allowed to pass into or out of the cell to reach equilibrium, without contribution of other ions. The membrane potential generated due to difference in concentrations of that ion in ECF and ICF is called the equilibrium potential. However, it does not occur normally because of the contribution of other ions. - The equilibrium potential can be measured by the Nernst equation as follows: for cations: E = 61 log [cation] ECF /[cation] ICF for anions E = 61 log [anion] ICF /[anion] ECF - Examples: E for K + = 61 log 4/140 = - 90 mv (close to the RMP, indicating a major role of K + in the genesis of RMP). E for Na + = 61 log 150/15 = + 61 mv (very far from the RMP, indicating a minor role of Na + in genesis of the RMP). E for Cl - = 61 log 110/8 = - 70 mv (However, there is no evidence that Cl - has an active transport similar to Na + and K + ; so it does not contribute to the RMP). - The Goldman equation can be used for direct calculation of the RMP. It includes the effects of the major ions and their permeabilities (P) across the cell membrane; as follows: RMP (mv) = 61 log P K [K] ECF + P Na [Na] ECF + P Cl [Cl] ICF P K [K] ICF + P Na [Na] ICF + P Cl [Cl] ECF The core of medical physiology (1) 3 rd edition Page 56

57 THE ACTION POTENTIAL (AP) - Occurs only in excitable tissues (nerve & muscle). - Involves alterations in the membrane potential (depolarization and repolarization) following sufficient mechanical, electrical or chemical stimulation. - The action potential can be recorded by special devices (e.g. the cathode ray oscilloscope). - The recorded action potential can be: Monophasic in which the recording electrodes are placed on the surface of cell membrane; or Biphasic in which they are placed on the two sides of cell membrane. Components of the action potential 1- Stimulus artifact - Occurs at the time of stimulation (marks the point of stimulation) - Due to current leakage from the stimulus electrode 2- Latent period - The isopotential interval from the point of stimulation to the start of action potential. - Can be used for measurement of the conduction velocity (CV) in an axon. Conduction velocity = (the distance between the stimulating and recording electrodes) divided by (the latent period). 3- Threshold - The voltage at which the "fast voltage gated sodium channels" open. If not reached, action potential never occurs. The core of medical physiology (1) 3 rd edition Page 57

58 - It is usually about 15 mv less than the resting membrane potential (e.g. -75 mv when the RMP is -90 mv). 4- Depolarization - Due to sodium influx through the "fast voltage gated sodium channels". - The membrane potential moves towards the equilibrium potential for sodium (+60 mv) but it does not reach it because opening of the sodium channels is short lived (the channels rapidly become inactivated and will never open again unless the membrane potential returns back to the resting level); (see the refractory period below). 5- Repolarization - Due to potassium efflux through "voltage gated potassium channels". - Opening of the "voltage gated potassium channels" is slower than sodium channels; that s why potassium efflux occurs after sodium influx. Opening is also more prolonged than sodium channels and this explains the occurrence of after-hyperpolarization (see below). - Additional factors that facilitate repolarization are the inactivation of the "fast voltage gated sodium channels" and the reversal of the membrane potential (becomes positive inside); thus limiting further sodium influx. 6- After- depolarization - The slower fall in the rate of repolarization. - occurs when repolarization is 70% completed. The core of medical physiology (1) 3 rd edition Page 58

59 7- After-hyperpolarization - Slight overshooting in the hyperpolarizing direction, due to excess potassium efflux through the "voltage gated potassium channels", and then restoration of the membrane potential to the resting level (due to the activity of the Na/K pump). Fig 2.5: The action potential Characteristics of action potentials 1- All or none law - Sub threshold stimuli can never generate an action potential whereas threshold and supra threshold stimuli can generate action potentials of the same magnitude (i.e. full action potential). - This indicates that action potentials either occur in a full form or do not occur at all (i.e. all or none). The core of medical physiology (1) 3 rd edition Page 59

60 2- Refractory period - Period of time during which a cell membrane is refractory to excitation, because it is already in a state of excitation. During this period the "fast voltage gated sodium channels" are inactivated - The refractory period is divided into: Absolute refractory period: o Action potential can never be generated even with suprathreshold stimulation. o Its duration from the firing level to the end of one third of repolarization. Relative refractory period: o Action potential can not be generated by ordinary stimulation but it can be generated by supra-threshold stimulation. o Its duration from the end of absolute refractory period to the end of repolarization (i.e. to the start of after-depolarization). Fig 2.6: The refractory period The core of medical physiology (1) 3 rd edition Page 60

61 3- Conduction - Action potential can be propagated (conducted) through axons of neurons. - Conduction is an active, self propagating process that occurs with no change in amplitude or velocity of the action potential. - There are two types of conduction: Conduction in unmylinated nerves (continuous conduction) Conduction in myelinated nerves (saltatory conduction) (jumping of action potential from a node of Ranvier to another). Fig 2.7: Types of electrical conduction The core of medical physiology (1) 3 rd edition Page 61

62 - The velocity of conduction depends on: Degree of myelination: - Faster in thick myelinated > thin myelinated > un-myelinated Distance between nodes of Ranvier: - Faster when the distance is increased Diameter of the axon: - Faster when the diameter is larger The compound action potential - The above description of action potential refers to action potential that s recorded from a single axon. It differs from an action potential recorded from a peripheral nerve (which contains many axons). - The action potential that s recorded from a peripheral nerve is called the compound action potential and it is characterized by multiple peaks. Fig 2.8: The compound action potential - It represents algebraic summation of action potentials of many axons in the nerve. The multiple peaks appear because a peripheral nerve contains different types of fibers with different sizes, thresholds and peaks. The core of medical physiology (1) 3 rd edition Page 62

63 Effects of ECF electrolyte disturbances on excitability Disturbances in sodium ions - Have little effect on the resting membrane potential (RMP). - Hyponatremia decreases the amplitude of the action potential. Disturbances in potassium ions - Affect the resting membrane potential because potassium efflux is the main cause of the resting membrane potential. - Hypokalemia causes hyperpolarization (because it allows more K efflux and therefore the resting membrane potential gets away from the threshold; this decreases excitability. Fig 2.9: Hyperpolarization caused by excessive K efflux - Mild to moderate hyperkalemia limits potassium efflux and therefore the RMP is elevated to become closer to the threshold, this increases excitability. However, severe hyperkalemia elevates the RMP to the level of the threshold and therefore it inhibits excitability (the cell can not respond to stimulation since its RMP is not below the threshold; that s why hyperkalemia prevents excitation of the heart and stops it in diastole). The core of medical physiology (1) 3 rd edition Page 63

64 Fig 2.10: Effect of hyperkalemia on the RMP Disturbances in calcium ions - Calcium ions guard the sodium leak channels, thus preventing sodium influx through these channels during the resting state. - In hypocalcemia sodium ions enter the cells because the leak channels are not guarded, this elevates the RMP and makes the cells more excitable (for this reason hypocalcaemia is characterized by high excitability in neuromuscular junctions resulting in involuntary contraction of some muscles (= this is known as tetany). - Hypercalcemia has an opposite effect; it prevents influx of sodium ions through their leak channels; therefore, it stabilizes cell membranes and decreases excitability. - Severe hypercalcemia may interfere with the normal function of nerves and may result in coma. - Hypercalcemia increases contractility of cardiac muscle but not skeletal muscle; that s because calcium ions in ECF enter cardiac muscle cells and increase contraction (they do not enter skeletal muscle cells). Severe hypercalcemia stops the heart in systole. The core of medical physiology (1) 3 rd edition Page 64

65 Action potential of the cardiac muscle Fig 2.11: - There are two types of muscle in the heart: The cardiac muscle proper: whose AP is characterized by the plateau phase (due to calcium influx). The plateau prolongs the refractory period. The conductive system: whose AP is characterized by the prepotential (unstable resting membrane potential, mainly due to slow potassium efflux). NERVE - Nerves are distributed throughout the body to form the nervous system. The nervous system is subdivided into: Central nervous system (CNS = the brain and the spinal cord). Peripheral nervous system (PNS = the spinal and cranial nerves). - Each nerve consists of many nerve cells (neurons). The core of medical physiology (1) 3 rd edition Page 65

66 - A neuron is the main functional cell in the nervous system. - It consists of: o Cell body (or soma) o Dendrites o Axon Fig 2.12: The neuron - There are about 100 billion neurons in the CNS and about times this number glial cell (neuroglia). - - Neuroglia (= non-excitable cells) are 3 types in the CNS: o Microglia - Phagocytic cells in the brain (resemble tissue macrophages) o Astrocytes (= macrglia) - Provide a supportive matrix around the neurons - Form part of the blood brain barrier (BBB) - Maintain stable ECF concentration of ions (by taking up K + ) - Two types: fibrous astrocytes (in the white matter) and protoplasmic astrocytes (in the gray matter) o Oligodendrocytes (= macroglia) - Form myelin sheath around axons in the CNS The core of medical physiology (1) 3 rd edition Page 66

67 - There is one type of glia in the peripheral nervous system (PNS): o Schwann cells - The only glial cells in the PNS - Form myelin sheath around axons in the PNS - Each cell wraps its membrane around axons up to 100 times to form a myelin sheath Fig 2.13: Myelination Types of nerve fibers - Nerve fibers are divided into 3 groups: (A, B and C). - These groups differ in the axon size and degree of myelination. - The A group is subdivided into: (A, A, A and A ). Group A Thick myelinated = The fastest (especially the A type) Has the largest diameter Carries touch, proprioception and motor impulses Most susceptible to pressure Least susceptible to local anesthetics, that s why touch sensation, which is carried by type A fibers, is not completely depressed by local anesthetics The core of medical physiology (1) 3 rd edition Page 67

68 Conduction velocity of type A fibers: - A = m/s - A = m/s - A = m/s - A = m/s Group B Thin myelinated Found in the preganglionic autonomic neurons Most susceptible to hypoxia than to pressure or local anesthetics Conduction velocity= 3-15 m/s Group C Un-myelinated Mainly carries pain and cold sensations Also found in the postganglionic sympathetic neurons Most susceptible to local anesthetics (that s why local anesthetics depress pain sensation which is carried through type C fibers) Least susceptible to hypoxia and pressure Conduction velocity= m/s Important note - There is another method of nerve fiber classification (Ia, Ib, II, III and IV) However, it is rather confusing. - Here Ia, Ib, II and III are equivalent to the subdivisions of group A fibers whereas IV is equivalent to type C fibers. - This classification is used to describe afferents of the muscle spindle & the Golgi tendon organ (see the motor system). The core of medical physiology (1) 3 rd edition Page 68

69 SYNAPTIC TRANSMISSION THE SYNAPSE - It is a junction between two neurons. It allows transmission of electrical impulses from one neuron to another. - The transmission is called "chemical transmission" because a chemical substance "a neurotransmitter" is released by the first neuron (the pre-synaptic neuron) to bind receptors in the second one (the post-synaptic neuron). However, direct electrical transmission can occur through special synapses. - Unlike electrical transmission through the axons, chemical transmission is uni-directional (i.e. allows conduction in one way only; from the pre-synaptic neuron to the post-synaptic neuron). - The total number of synapses in the CNS is very large; a single axon may divide to form over 2000 synaptic endings. - Most synapses occur between the axon terminals of the presynaptic neuron and the cell body or dendrites of the post-synaptic neuron (axo-somatic and axo-dendritic connections). However, other types of connection may occur (e.g. axo-axonal). Fig 2.14: Synapses The core of medical physiology (1) 3 rd edition Page 69

70 General structure of the synapse Fig 2.15: The presynaptic neuron: Releases a neurotransmitter (NT) through the presynaptic membrane The NT is synthesized in the cell body, packed into vesicles in the Golgi apparatus and then transported through the axon to be stored at the terminal end of the axon. The terminal end of the axon is slightly dilated for storage of the NT. It is called the synaptic knob or button. The postsynaptic neuron: - Contains receptors for the NT. - The receptors are located on the postsynaptic membrane. The core of medical physiology (1) 3 rd edition Page 70

71 The synaptic cleft: - The area that separates the pre and post synaptic neurons - It is about nm wide - The NT has to cross this area to bind its receptors on the postsynaptic membrane - It may contain an enzyme for hydrolysis of the NT and therefore terminates its action (e.g. acetylcholine esterase enzyme for hydrolysis of acetylcholine). Steps of neurotransmitter release to the synaptic cleft 1- Arrival of the action potential to the terminal end of the axon 2- Opening of voltage-gated Ca ++ channels, allowing Ca ++ influx 3- Ca ++ stimulates release of the neurotransmitter (NT) from the vesicles by exocytosis (it increases movement of the vesicles to fuse with the pre-synaptic membrane and facilitates the process of exocytosis) 4- The NT within the vesicles is released to the synaptic cleft. - Note: Ca ++ is then removed from the knob by "Ca 2+ /Na + antiport " Fate of the neurotransmitter at the synaptic cleft Neurotransmitters at the synaptic cleft may: 1- Combine with receptors on the post-synaptic membrane (to exert their effects) 2- Be hydrolyzed by an enzyme in the synaptic cleft 3- Return back to the synaptic knob by endocytosis 4- Diffuse to the plasma (where it is catabolized there or in other tissues) The core of medical physiology (1) 3 rd edition Page 71

72 Fig 2.16: Fate of neurotransmitters at the synapse Notes to remember: Not all of these options are applicable for all types of neurotransmitters. For example: acetylcholine is hydrolyzed in the cleft by acetylcholine-esterase into acetate and choline. Therefore it does not return back to the synaptic knob by endocytosis; however, its metabolite choline returns back. Another example: noradrenaline is not hydrolyzed in the cleft. Therefore it returns back to the synaptic knob by endocytosis and packed again into vesicles to be released later (recycling). Because it is not hydrolyzed in the cleft, the amount of noradrenaline that diffuses to plasma is higher than that of acetylcholine. The core of medical physiology (1) 3 rd edition Page 72

73 ELECTRICAL EVENTS IN THE POSTSYNAPTIC NEURON - When a neurotransmitter combines with its specific receptor, it results in opening or closure of some "ligand gated channels" on the postsynaptic membrane. - This changes the permeability of the postsynaptic membrane to specific ions and results in a postsynaptic potential. - The postsynaptic potential is a local potential that can be excitatory or inhibitory (depending on which type of ion channels is opened). Excitatory post synaptic potential (EPSP): This is a depolarizing potential that increases excitability of the post-synaptic neuron It does not cause a response because it does not reach the threshold It is caused by an excitatory neurotransmitter that opens: - sodium channels causing sodium influx - or calcium channels causing calcium influx Inhibitory post synaptic potential (IPSP): This is a hyperpolarizing potential that decreases excitability of the post-synaptic neuron It is caused by an inhibitory neurotransmitter that opens potassium or chloride channels causing potassium efflux or chloride influx respectively or closes: sodium or calcium channels preventing their influx. Summation of local potentials: - For an EPSP to reach a threshold and cause a response, it should summate with other EPS potentials. - There are two types of summation: spatial and temporal. The core of medical physiology (1) 3 rd edition Page 73

74 Spatial summation: Occurs when multiple EPSPs arrive simultaneously, at the same time, on the post-synaptic neuron. The potentials when added together reach the threshold and produce an action potential. Temporal summation: Occurs when a single synaptic knob is stimulated repeatedly to produce successive EPSPs. These when added together reach the threshold and produce an action potential. Fig 2.17: Summation of local potentials Action potential in the post-synaptic neuron - Summation of several EPSPs generates an action potential in the post-synaptic neuron. - The action potential starts in the generator zone which is situated at the origin of the axon (axon hillock). - It is more excitable than the rest of the axon because: It contains higher number of voltage-gated Na + channels Its threshold is more near to the RMP (-59 mv) The core of medical physiology (1) 3 rd edition Page 74

75 Inhibition and facilitation at synapses Direct inhibition Occurs directly by releasing an inhibitory NT from a presynaptic neuron into a postsynaptic neuron. This direct inhibition on the postsynaptic neuron is called postsynaptic inhibition. Fig 2.18: Direct inhibition Indirect inhibition Occurs indirectly on the neuron Has many forms; for example: o it follows a previous discharge on the postsynaptic neuron (= here the already excited postsynaptic cell is in a refractory period or in after-hyperpolarization (Periods of low excitability) o it occurs in a postsynaptic neuron if the release of the excitatory NT coming from its presynaptic neuron is prevented by direct inhibition from another neuron (this is known as presynaptic inhibition) The core of medical physiology (1) 3 rd edition Page 75

76 Fig 2.19: Indirect inhibition Properties of synapses a- Transmission is uni-directional - From the presynaptic neuron to the postsynaptic neuron. b- Synaptic delay - The minimum time required for chemical conduction from a synaptic knob to its postsynaptic neuron is a bout 0.5 ms. - Measurement of synaptic delay within the CNS gives information about the number of synapses in a pathway. For example if the delay is about 1.2 ms, the number of synapses is probably two. c- Synaptic fatigue - Failure or decrease in frequency of conduction in a synapse following repetitive stimulation. - Due to exhaustion of the NT (release of all vesicles at the synaptic knob) or inactivation of the receptors at the postsynaptic membrane. d- Post-tetanic facilitation - Increased frequency of conduction in a synapse following repeated stimulation. - Caused by increased availability of calcium in the synaptic knob due to repeated stimulation. The core of medical physiology (1) 3 rd edition Page 76

77 e- Convergence and divergence - Most of the inputs to the postsynaptic neurons are multiple (convergence). - Most of the outputs from the presynaptic neurons are multiple (divergence) Fig 2.20: Convergence and divergence The Neuromuscular junction (NMJ) - Special type of synapse (between a neuron and a muscle cell). - The muscle cell membrane that receives the terminal end of the neuron is known as the motor end plate. It is characterized by multiple invaginations (junctional folds) that increase its surface area. - Transmission through the NMJ is similar to chemical transmission through other synapses. - The neurotransmitter is acetylcholine and the receptors are nicotinic. - The local potential produced by binding of acetylcholine to its nicotinic receptors at the NMJ is called the end plate potential. - The end plate potential is always excitatory (caused by sodium influx) and it is regularly capable of generating an action potential (the high amount of acetylcholine released in the cleft is 10 times sufficient for generation of an action potential). The core of medical physiology (1) 3 rd edition Page 77

78 Fig 2.21: The neuromuscular junction Factors affecting neuromuscular transmission Autoimmune destruction of acetylcholine receptors at the NMJ (= Myasthenia gravis): characterized by weak skeletal muscles. Autoimmune destruction of calcium channels at the synaptic knob of the NMJ (= Lambert-Eaton syndrome): similar to Myasthenia but unlike it, the weakness of skeletal muscles is improved by repeated contractions, due to increased Ca ++ level in the knob. Blockers of acetylcholine receptors (e.g. curare and succinylcholine): cause paralysis of skeletal muscles. Snake venoms: block acetylcholine receptors causing paralysis. Organophosphorus compounds (OPC e.g. parathion) & nerve agents (e.g. Sarin, Tabun and VX): inhibit acetylcholinesterase to allow acetylcholine to act for prolonged periods in both nicotinic receptors (causing fasciculations, tachycardia & mydriasis) and muscarinic receptors (causing bradycardia, bronchospasm, salivation, lacrimation, diarrhea and vomiting). OPC are used as insecticides whereas nerve agents are military weapons. Botulinum toxin: released by bacteria (Clostridium botulinum): Prevents release of acetylcholine from neurons causing paralysis. The core of medical physiology (1) 3 rd edition Page 78

79 MUSCLE Types of muscle - There are 3 types of muscle: Skeletal muscle - Striated - Under voluntary control (somatic nervous system) - Has no anatomical connection between fibers - Does not contract in the absence of external stimulation Fig 2.22: Cardiac muscle - Striated - Under involuntary control (autonomic nervous system) - There are connections between fibers (gap junctions and intercalated discs) - Contracts rhythmically in the absence of external stimulation Fig 2.23: The core of medical physiology (1) 3 rd edition Page 79

80 Smooth muscle - Non striated - Under involuntary control (autonomic nervous system) - Connections between fibers may be present (e.g. smooth muscle in viscera) or absent (e.g. smooth muscle in the eye). Fig 2.24: Structure of skeletal muscle - Each muscle consists of bundles of fibers Fig 2.25: - Each fiber is a single cell, composed of myofibrils Fig 2.26: The core of medical physiology (1) 3 rd edition Page 80

81 - Each myofibril consists of filaments, the filaments are: Thick filaments: myosin II Thin filaments: actin, tropomyosin and troponins (I, T & C) Others: actinin and titin Fig 2.27: Striations - Appearance of alternate light and dark bands in skeletal or cardiac muscle fibers when examined under direct polarized light, using the microscope. - Are due to differences in refractive indexes of thick & thin filaments - The light area (I band): Is isotropic to polarized light contains actin only divided into two halves by the Z line - The dark area (A band): is anisotropic to polarized light contains myosin + ends of actin contains lighter area in the middle (H band) that contains myosin only and divided by the M line The core of medical physiology (1) 3 rd edition Page 81

82 - The area between two Z lines is called sarcomere - The sarcomere is the functional unit of muscles. It contains an A band + two halves of I band. Fig 2.28: The thick filaments: Myosin II - Each has 2 heavy chains and 4 light chains forming a tail and 2 globular heads. - Each head of myosin has: Actin binding site ATPase activity Fig 2.29: The core of medical physiology (1) 3 rd edition Page 82

83 The thin filaments : a- Actin: - Consists of two chains that form double helix - Has active sites that act as targets for myosin heads Fig 2.30: b- Tropomyosin: - Lie in the groove between the two filaments of actin - Hides the actin active sites during relaxation of muscle - This prevents binding of myosin heads to actin Fig 2.31: The core of medical physiology (1) 3 rd edition Page 83

84 c- Troponins: - Troponin T: binds other troponin units to tropomyosin - Troponin I: inhibits interaction between actin and myosin - Troponin C: binds calcium which initiates contraction Fig 2.32: The sarcotubular system - Membranous structures in the muscle fiber - Made up of: T tubules & sarcoplasmic reticulum Fig 2.33: The core of medical physiology (1) 3 rd edition Page 84

85 The T tubules: - Are transverse tubules that arise as invaginations from the cell membrane. - Located at the A-I junctions in skeletal muscles (= two per cell); and at the Z lines in cardiac muscles (one per cell). - Inside the cell they are perforated by the myofibrils. - They transmit action potentials from the sarcolemma to the interior of the cell. The sarcoplasmic reticulum: - Forms irregular curtain around the myofibrils. - Has an enlarged terminal on each side of the T tubule "the sarcoplasmic cisternae". These form with the T tubule a triad (T tubule + 2 cisternae on each side). - It stores calcium to be released to the sarcoplasm when an action potential arrives through the T tubule. Molecular basis of contraction (Sliding theory) - Contraction occurs by sliding of the thin filaments over the thick filaments, thus shortening the sarcomers. Steps of muscle contraction: Depolarization of the sarcolemma (by an action potential coming from the neuromuscular junction). Transmission of the action potential to interior of the muscle cell via the T tubules. The passage of the depolarization wave through the T tubules induces opening of dihydropyridine receptors in the membrane of the T tubules. The core of medical physiology (1) 3 rd edition Page 85

86 The dihydropyridine receptors: o in the cardiac muscle they allow influx of calcium & this triggers release of stored calcium in the terminal cisterns. o in skeletal muscle fibers they act as sensors that detect arrival of the depolarizing wave & trigger release of stored calcium. Release of stored calcium from the terminal cisterns to the sarcoplasm occurs via the ryanodine receptors Calcium in the sarcoplasm binds to troponin C This results in: o Weakness of the binding of troponin I to actin o Conformational changes in tropomyosin Tropomyosin moves laterally to uncover the actin active sites Myosin heads bind the uncovered actin active sites ATP is hydrolyzed and the energy released by hydrolysis causes flexion of myosin heads inwards. This causes sliding of actin on myosin resulting in shortening of the sarcomers (= contraction). Fig 2.34: The core of medical physiology (1) 3 rd edition Page 86

87 Notes to remember: - The process by which depolarization of the muscle cell results in contraction is known as excitation-contraction coupling. - Seven active sites in actin are uncovered for each molecule of troponin C that binds a calcium ion. - Contraction of skeletal muscle depends on release of stored calcium from the sarcoplasmic reticulum whereas contraction of cardiac and smooth muscles requires influx of calcium from the ECF. - The calcium binding protein in smooth muscle is known as calmodulin. Unlike troponin, calmodulin initiates contraction immediately. First it activates a kinase enzyme that s needed for phosphorylation of myosin head. This phosphorylation triggers the ATPase activity of the head and this is followed by contraction. Steps of muscle relaxation: Shortly after releasing calcium to the sarcoplasm, the sarcoplasmic reticulum begins to transport it back actively by the Ca-Mg ATPase pump When the level of calcium in the sarcoplasm is lowered sufficiently, calcium is released from troponin C This causes actin & myosin interaction to stop, tropomyosin returns to its position & the muscle relaxes. Remember that: ATP is consumed for both contraction & relaxation. If calcium transport back to the sarcoplasmic cisterns is inhibited, relaxation will never occur (= contracture) The core of medical physiology (1) 3 rd edition Page 87

88 If no energy is available for relaxation (no ATP), the muscle becomes rigid (= rigor). A common example is (rigor mortis) which occurs after death. - Relaxation in smooth muscles follows de-phosphorylation of myosin heads by a phosphatase enzyme. However, contraction may continue in spite of that for some time; this is due to the latch bridge mechanism. - In the latch bridge mechanism, myosin remains attached to actin resulting in a sustained contraction with minimal energy expenditure; as in the vascular smooth muscle. Types of contraction Isotonic contraction: - Isotonic contraction (the same tension) is contraction against a constant load that results in shortening of a muscle. - The muscle develops a constant tension throughout the range of movement (e.g. when lifting a light object). Isometric contraction: - Isometric contraction (the same length) is contraction without appreciable shortening of a muscle. - The tension developed by the muscle is not constant, it is increasing (e.g. when trying to lift a very heavy object). - Since there is no distance of movement (the same length of muscle); no work is done during the isometric contraction (remember that work = force times distance, which is zero). - Standing involves isometric contraction of muscles whereas walking involves both isometric & isotonic contractions. The core of medical physiology (1) 3 rd edition Page 88

89 Single muscle twitch and summation of contractions - A single sufficient stimulation of a muscle fiber results in a single action potential that results in a single contraction followed by relaxation (= single muscle twitch). - The duration of the single muscle twitch is longer than the duration of the action potential. - Repeated stimulation of a muscle fiber results in repeated action potentials that are followed by successive contractions. - Since there is no refractory period for contractions, each new contraction starts before completion of the previous one. This results in summation of these contractions. - The tension developed by summation of contractions is greater than that s developed by a single contraction. - Summation of contractions into one continuous contraction is called tetanus. Tetanus - Tetanus may be complete (with no any relaxation between contractions) or incomplete (with some incomplete relaxations between contractions). - The frequency of stimulation that results in tetanus is determined by the duration of the single muscle twitch. - With a frequency of stimulation just below the frequency of summation, the tension developed is increased by each new stimulus until a uniform tension per contraction is reached. This is called treppe or staircase phenomenon. - Here the increase in tension is not due to summation, it is due to increased availability of calcium to troponin C. The core of medical physiology (1) 3 rd edition Page 89

90 Types of muscle fibers There are two types of muscle fibers: Type one fibers: Called red muscles (darker than other types) Respond slowly to stimulation (i.e. have long latency) Have high oxidative capacity Contract to maintain posture E.g. muscles of the back Type two fibers: Called white muscles Have short twitch duration Respond rapidly (i.e. have short latency) Have high glycolytic capacity Specialized for fine skilled movement E.g. muscles of the hand The oxygen debt mechanism - During severe exercise, the amount of oxygen delivered to skeletal muscle by the circulation is not enough for aerobic metabolism; for this reason skeletal muscle has to find extra oxygen or additional sources of energy; this is achieved as follows: It takes oxygen from myoglobin It metabolizes glucose anaerobically to lactic acid to synthesize ATP It uses phosphorylcreatine to synthesize ATP - Hyperventilation after exercise provides extra amount of oxygen that can be used to repay oxygen taken from myoglobin, to The core of medical physiology (1) 3 rd edition Page 90

91 catabolize lactic acid to carbon dioxide and water, and to replenish phosphorylcreatine. - This extra amount of oxygen consumed after exercise is described as the oxygen debt. - The mechanism of oxygen debt does not occur in the cardiac muscle because it depends exclusively on aerobic metabolism for energy production. QUESTIONS FOR SELF ASSESSMENT-3 (BEST OF FIVE) 1- The resting membrane potential is generated by: a. opening and closure of ligand gated channels b. passage of ions through voltage gated channels c. selective permeability of the cell membrane to potassium d. closure of sodium leak channels by calcium e. the high concentration of phosphates in the cell 2- The following is true about the action potential: a. an external stimulus is not always needed for its initiation b. the depolarization phase is always due to Na+ influx c. its duration is equal in all types of excitable cells d. after-depolarization phase is due to activity of the Na+/K+ pump e. it can be summated in skeletal but not in cardiac muscle 3- Concerning myelination, which of the following is not true: a. synthesized from phospholipids and protein b. found in preganglionic sympathetic neurons c. found in postganglionic sympathetic neurons d. found in the central nervous system e. formed by oligodendroglial cells 4- If ECF K+ concentration is increased from 3.5 to 5.0 mmol/l: a. the resting membrane potential becomes less negative b. the resting membrane potential will not change c. fast voltage gated sodium channels will open d. an action potential will occur spontaneously e. the cell membrane becomes hyperpolarized 5- Leak channels: a. are present in almost all cells in the body b. have gates that open or close during action potentials c. have gates that open when a hormone binds to its receptor d. are responsible for the depolarization phase of action potentials e. gates are closed by the end of the action potential The core of medical physiology (1) 3 rd edition Page 91

92 6- Calcium channels in synaptic knob: a. Allow release of neurotransmitter through them b. Are voltage gated c. Are ligand gated d. Are opened when acetylecholine is released e. Cause termination of the action potential 7- These proteins are involved in skeletal muscle contraction except: a. calmodulin b. actin c. tropomyosin d. myosin e. troponin C 8- The A band in a striated muscle a. is a light area b. contains thick filaments only c. is divided by the M line d. is longer during relaxation than during contraction e. appears due to overlapping between actin and myosin 9- Concerning chemical conduction, which of the following is not true: a. it is unidirectional (one way direction) b. excitatory neurotransmitters open Na + channels c. inhibitory neurotransmitters open Ca++ channels d. GABA opens CI - channels in the postsynaptic neurons e. the post-synaptic neuron is influenced by many pre-synaptic neurons 10- Ryanodine receptors: a. allow influx of calcium from ECF to ICF in cardiac muscle b. allow release of calcium from the sarcoplasmic cisternae to ICF in skeletal muscle c. are found in skeletal but not cardiac muscle d. act as sensors for arrival of excitation through the T tubule e. allow pumping back of calcium to sarcoplasmic cisternae 11- Isometric contraction differs from isotonic contraction in that: a- it does not occur in cardiac muscle b- it occurs during walking c- it does not involve interaction between actin and myosin d- the muscle tension applied is increased during the contraction e- the force applied equals zero Question Answer c a c a a b a c c b d The core of medical physiology (1) 3 rd edition Page 92

93 CHAPTER 3 THE AUTONOMIC NERVOUS SYSTEM INTRODUCTION - The nervous system can be classified into two physiological divisions: The somatic nervous system (SNS) and the autonomic nervous system (ANS) Table 3.1: Comparison between the SNS and the ANS: The somatic nervous system The autonomic nervous system - Controls voluntary functions - Controls involuntary functions e.g. limb movements e.g. cardiac beats - Supplies skeletal muscles - Supplies smooth and cardiac muscles - One neuron connects the - Two neurons connect the central central part with the target part with the target muscle muscle - The two neurons are: preganglionic & postganglionic neurons connected by a ganglion Fig 3.1 Peripheral neurons of the SNS and the ANS The core of medical physiology (1) 3 rd edition Page 93

94 Divisions of the autonomic nervous system - The autonomic nervous system (ANS) is divided into: Sympathetic division Parasympathetic division Differences between the sympathetic and the parasympathetic divisions: * Activators - Stressful stimuli (e.g. fear, pain, exercise ) activates the sympathetic while complete physical and mental rest (e.g. sleep) activates the parasympathetic. * Metabolism - The sympathetic nervous system causes catabolism for immediate release of energy that s used for fight or flight; whereas the parasympathetic is associated with anabolic reactions that store energy until needed by the body. * Anatomical points - The peripheral parts of the ANS are made up of preganglionic (myelinated, type B) and postganglionic (unmyelinated, type C) neurons. - The cell bodies of the preganglionic neurons are located in the lateral horn of the spinal cord or the motor nuclei of the cranial nerves 10, 9, 7 and 3 (= 1973). Their axons pass through the ventral horns to the spinal nerves and then they follow the blood vessels to the target organs. - The preganglionic neurons of the sympathetic are short. They leave the spinal nerve through white rami communicantes to synapse in sympathetic ganglia with postganglionic neurons that return back to The core of medical physiology (1) 3 rd edition Page 94

95 the spinal nerve via gray rami communicantes to be distributed to their targets. They are longer than the preganglionic neurons. Fig 3.2: Origin and course of a preganglionic neuron - The sympathetic ganglia, the site of cell bodies of the postganglionic neurons, are connected together to form the sympathetic trunk that extends parallel to the thoracic and upper lumbar spinal segments. Additional sympathetic ganglia are also found in the neck (superior, middle and stellate ganglia) and in the abdomen (collateral ganglia). - On the other hand, the preganglionic parasympathetic neurons are longer than the postganglionic. The ganglia are found near or within the wall of the target organs. Fig 3.3: The output of autonomic neurons The core of medical physiology (1) 3 rd edition Page 95

96 Output from the CNS - The central parts of the sympathetic and parasympathetic nervous systems originate from certain autonomic centers at the brain (e.g. the hypothalamus or the brain stem) and then descend through the spinal cord. - The peripheral part of the sympathetic passes out through the spinal nerves that originate from the thoracic and some lumbar segments (from T1 to L2); whereas the peripheral part of the parasympathetic passes out through some cranial nerves (number 10, 9, 7 and 3) and some sacral spinal nerves (S2, S3 and S4). - For this reason the outflow of the sympathetic is described as thoraco-lumbar and that of the parasympathetic as cranio-sacral. * Effects - The ratio of a preganglionic neuron to postganglionic neurons is about 1:20 for the sympathetic neurons and 1:1 for the parasympathetic neurons. This indicates that the effects of the sympathetic are generalized (because of divergence of its preganglionic neurons) while those of the parasympathetic are localized. * The neurotransmitters released by the neurons - All preganglionic neurons whether sympathetic or parasympathetic, and all postganglionic parasympathetic neurons release acetylcholine whereas most postganglionic sympathetic neurons release noradrenaline. Others release acetylcholine. - Postganglionic sympathetic neurons that release acetylcholine supply the sweat glands, arterioles of skeletal muscles and piloerectror muscles. The core of medical physiology (1) 3 rd edition Page 96

97 Table 3.2: Comparison between the symp. and the parasymp. Difference Sympathetic Parasympathetic Activator* Stress Rest Metabolism* Catabolic to release Anabolic to store energy for fight or flight energy until needed Pregan. neurons Postga. neurons Ganglia Short Long Near the spinal cord (paravertebral) Long Short Near or within the wall of the organ Output from the Thoracolumbar Craniosacral CNS* Effects* Generalized Localized Neurotransmitter released by the neurons Pregananglionic: = Acetylcholine Postganglionic = Noradrenaline Preganglionic = Acetylcholine Postganglionic = Acetylcholine THE NEUROTRANSMTTERS - The principal neurotransmitters (NT) in the autonomic nervous system are acetylcholine and noradrenaline. Acetylcholine: - Synthesized from acetyl co A and choline in the cell body of cholinergic neurons (i.e. neurons that release acetylcholine). - Synthesis is catalyzed by the enzyme choline acetyltransferase. The core of medical physiology (1) 3 rd edition Page 97

98 - Acetylcholine is released by: o All preganglionic parasympathetic neurons o All postganglionic parasympathetic neurons o All preganglionic sympathetic neurons o Some postganglionic sympathetic neurons (those supplying sweat glands, arterioles of skeletal muscles and pilo-erector muscles) - When released at the synaptic cleft, acetylcholine acts on its receptors. However, its action is terminated by the acetylcholinesterase enzyme which converts it to acetate and choline. Therefore generally no acetylcholine diffuses to plasma. Noradrenaline (= norepinephrine): - Synthesized from the amino acid tyrosine in noradrenergic neurons (i.e. neurons that release noradrenaline) - Steps of synthesis: Tyrosine (from diet or from phenylalanine) is hydroxylated to dopa (by tyrosine hydroxylase in the cytoplasm). Dopa is decarboxylated to dopamine (by dopa decarboxylase in the cytoplasm). Dopamine is converted to norepinephrine (by dopamine beta hydroxylase in the vesicles). - Noradrenaline is also synthesized in the adrenal medulla (an endocrine gland regarded as a modified sympathetic ganglion that lost its postganglionic axons). However, in this gland most of the synthesized noradrenaline (= norepinephrine) is converted to adrenaline (= epinephrine) by the enzyme phenylethanolamine-nmethyltransferase (PNMT). The core of medical physiology (1) 3 rd edition Page 98

99 - Adrenaline, noradrenaline and dopamine are called catecholamines. - In summary, noradrenaline is released by: o Most postganglionic sympathetic neurons (excluding those which release acetylcholine). o The adrenal medulla (releases adrenaline plus some noradrenaline). - When released at the synaptic cleft, noradrenaline acts on its receptors. There is no enzyme for its hydrolysis in the cleft. However, after its diffusion into the plasma, it is hydrolyzed by two enzymes: Monoamine oxidase (MAO) Catechol-O-methyl-transferase (COMT) - The most important metabolite is vanillylmandelic acid (VMA), which is excreted in urine. - Excretion of high amount of this metabolite in urine indicates hyper-production of catecholamines (e.g. by a tumor in the adrenal medulla (= pheochromocytoma)). Fig 3.4: Cholinergic and noradrenergic neurons The core of medical physiology (1) 3 rd edition Page 99

100 Other neurotransmitters: Dopamine: Released by some interneurons in symp. ganglia GnRH: Released by some preganglionic neurons Co-transmitters: (VIP): May be found with acetylcholine (ATP, Neuropeptide Y): may be found with noradrenaline AUTONOMIC RECEPTORS - These are the receptors for the neurotransmitters in the autonomic nervous system (i.e. receptors for acetylcholine and noradrenaline) Acetylcholine receptors 1- Nicotinic receptors (N) - Stimulated by small amount of nicotine (a chemical substance found in tobacco). - Found at the following sites: Sympathetic ganglia Parasympathetic ganglia Neuromuscular junction Adrenal medulla The brain 2- Muscarinic receptors (M) - Stimulated by small amount of muscarine (a chemical substance excreted in urine of tadpoles). - Found at the following sites: All organs supplied by postganglionic cholinergic nerves (these include all organs in the body supplied by autonomic neurons except ventricles of the heart and blood vessels of The core of medical physiology (1) 3 rd edition Page 100

101 the skin, abdominal viscera and the kidney which are supplied only by sympathetic, without parasympathetic supply). The brain Noradrenaline receptors 1- Alpha receptors Sites of alpha receptors: Alpha 1: Blood vessels Dilator pupillae muscle Sphincters Alpha 2: Pancreas Presynaptic membranes 2- Beta receptors Sites of beta receptors: Beta 1: The heart Renin secreting cells Adipose tissue Beta 2: Bronchi Uterus Pancreas Beta 3: Adipose tissue - The core of medical physiology (1) 3 rd edition Page 101

102 Remember that: Both noradrenaline and adrenaline act on α and β receptors. Noradrenaline acts better on α receptors than on β receptors while adrenaline acts better on β receptors than on α receptors. Fig 2.5: Autonomic receptors N = Nicotinic receptors M= Muscarinic receptors EFFECTS OF SYMP. AND PARASYMP. STIMULATION - All postganglionic parasympathetic neurons are cholinergic and most postganglionic sympathetic neurons are noradrenergic. - Therefore sympathetic effects are generally mediated by noradrenaline and parasympathetic effects are generally mediated by acetylcholine. The core of medical physiology (1) 3 rd edition Page 102

103 - Examples of these effects on various organs in the body: Organ Sympathetic effect Parasympathetic effect Eye pupil Dilation (it contracts the dilator pupillae muscle/ alpha receptors) Constriction (it contracts the constrictor pupillae muscle/ muscarinic Rs) Salivary glands Stimulates secretion (small amount, mucus in consistency) Stimulates secretion (large amount, watery in consistency) Bronchioles Bronchodilation/ through beta 2 Rs Bronchoconstriction/ through muscarinic Rs Heart rate Increased (Positive chronotropic)/ beta 1 Decreased (Negative chronotropic/ Muscarin. Contractility of the heart Increased Positive inotropic No direct effect on contractility (it does not supply the ventricles) GIT motility & Secretions Decreased (inhibitory, contracts the sphincters and relaxes the walls) Increased (excitatory, it relaxes the sphincters and contracts the walls) Blood vessels - Vasoconstriction (mediated through alpha receptors) - Vasodilatation of some blood vessels like the coronary artery (mediated through beta 2 receptors). - Does not supply and therefore has no effect on blood vessels of the skin, abdominal viscera and the kidney. - Causes vasodilatation in some blood vessels like the coronary artery) The core of medical physiology (1) 3 rd edition Page 103

104 Organ Sympathetic effect Parasympathetic effect Micturition & Defecation reflexes Not involved in the reflex; but, its stimulation inhibits these reflexes Excitatory (contracts the walls of the bladder & rectum & relaxes their sphincters) Sex organs Mediates the ediates the erection reflex ejaculation reflex Sweat glands Causes sweating No effect (does not supply sweat glands) BLOCKERS - Block the actions of neurotransmitters at their receptors - Two types: Competitive blockers - Compete with the neurotransmitter (NT) for binding with its receptors. - The affinity of the receptor for the blocker is higher than for the NT. - The blocker occupies the receptor without producing any response. Depolarizing blockers - Causes prolonged depolarization of the receptor. - The receptor becomes in state of refractory period, therefore it does not respond to the neurotransmitter. The core of medical physiology (1) 3 rd edition Page 104

105 Blockers of Acetylcholine Nicotinic blockers: - Blockers of acetylcholine at nicotinic receptors - Competitive blockers: o Curare (at the neuromuscular junction) o Hexamethonium (at the ganglia) - Depolarizing blocker: o Large amount of nicotine Muscarinic blockers: Competitive blockers: o Atropine o Scopolamine (hyoscine) Depolarizing blocker: o Large amount of muscarine Blockers of noradrenaline Alpha blockers: o Phentolamine o Prazosin (alpha 1) o Yohimbine (Alpha 2) Beta blockers: o Propranolol - (non selective blocker; blocks beta 1 & beta 2 receptors) o Atenolol - (selective blocker; blocks beta 1) o Butoxamine - (selective blocker; blocks beta 2) The core of medical physiology (1) 3 rd edition Page 105

106 ABNORMALITIES Horner s Syndrome - Results from damage to sympathetic neurons that supply the face - The damage may occur at any site along the course of sympathetic neurons which originate from the hypothalamus, descend through the brain stem, emerge from the upper thoracic segments, synapse at the superior, middle or inferior cervical ganglia and then pass with blood vessels to supply the face. However, the damage usually occurs at the neck (cervical sympathectomy). - Examples of the causes: o Apical lung tumor o Surgical trauma at the neck o Hypothalamic lesions - The syndrome is characterized by the following signs (on the affected side of the face): o Ptosis (drooping of the upper eye lid) o Meiosis (constriction of the eye pupil) o Anhydrosis (dryness, due to loss of sweating) o Enophthalmos (abnormal recession of the eyeball in the orbit) o Rubor (redness, due to vasodilatation) o Calor (hotness, due to vasodilatation) Myasthenia Gravis - Results from damage to acetylcholine receptors at the neuromuscular junctions. - The damage is caused by auto-antibodies induced by unknown mechanism The core of medical physiology (1) 3 rd edition Page 106

107 - Develops in females more than males. - It is characterized by: o Muscle weakness (especially after repeated movement) o Ptosis (drooping of the upper eye lid) o Weakness of respiratory muscles (the patient may die due to respiratory failure). - Treatment: - By anti- acetylcholine esterase (e.g. neostigmine); to decrease break down of acetylcholine at the neuromuscular junction and allow it to act on the remaining receptors. - Other modalities of treatment include: o Use of steroids to inhibit production of the auto-antibodies by lymphocytes o Decrease of further breakdown of acetylcholine receptors by plasmapheresis (a machine that eliminates the autoantibodies from plasma). Table 3.3: Effects of drugs acting on autonomic receptors ATROPINE PROPRANOLOL SALBUTAMOL Mechanism of Muscarinic β1 & β2 blocker β2 agonist action blocker (antagonist) (stimulant) Effects Heart rate GIT motility & secretion - Bronchodilation - Dilatation of the eye pupil - Dries mouth Heart rate & contractility Cardiac output Blood pressure - Vasoconstriction - Bronchoconstriction - Bronchodilation Heart rate (sideeffect, because although it is β2 agonist, it may react with β1 receptors resulting ( saliva) in tachycardia) The core of medical physiology (1) 3 rd edition Page 107

108 QUESTIONS FOR SELF ASSESSMENT-4 (BEST OF FIVE) 1. The somatic nervous system differs from the autonomic nervous system because: a- it has sensory and motor neurons b- its neurons release acetylcholine c- some of its neurons arise from the spinal cord d- it has nicotinic receptors e- it causes skeletal muscle contraction 2. Effects of the parasympathetic nervous system include all the following except: a- meiosis b- penile erection c- increased gastrointestinal motility d- decreased airway resistance e- bradycardia 3. Stimulation of the sympathetic nervous system results in: a- bradycardia b- recruitment in the cardiac muscle c- dilatation of skeletal muscle arterioles d- excessive salivary secretion e- negative inotropic effect 4. Acetylcholine: a- is released by all postganglionic sympathetic neurons b- is released from the adrenal medulla c- causes contraction of skeletal muscles d- is blocked by propranolol e- has alpha and beta receptors 5. The drug that blocks muscarinic receptors results in: a- tachycardia b- excessive salivation c- elevation of blood pressure d- micturition e- sweating 6. Nicotinic receptors are found in: a- arterioles of skeletal muscle b- motor end plates of skeletal muscles c- sweat glands in the skin d- small intestine e- ventricles of the heart The core of medical physiology (1) 3 rd edition Page 108

109 7. The nicotinic cholinergic receptors at the autonomic ganglia are: a- blocked by curare b- stimulated by salbutamol c- stimulated with noradrenaline d- blocked by hexamethonium e- identical to those in skeletal muscles 8. Stimulation of beta 1 receptors results in all the following except: a- breakdown of adipose tissue b- increased cardiac output c- release of renin from the juxta-glomerular cells d- tachycardia e- vasoconstriction 9. Adrenal medullary cells are stimulated by: a- dopamine b- GABA c- adrenaline d- acetylcholine e- nor-adrenaline 10. Dopamine is: a- released by all autonomic ganglia b- an excitatory neurotransmitter c- an acetylcholine derivative d- a noradrenaline precursor e- the main neurotransmitter released by the adrenal medulla 11. Sympathetic nerves a- release noradrenalin from pre-ganglionic fibres b- release adrenalin from post- ganglionic fibres c- are stimulated during sleep d- release of acetylcholine by some postganglionic fibres e- are mostly myelinated 12. Stimulation of the sympathetic nervous system results in: a- tachycardia through β2 receptors b- constriction of skin blood vessels through β1 c- dilatation of the eye pupil through β1 receptors d- contraction of intestinal wall through alpha receptors e- sweating through muscarinic receptors Question Answer e d C c a b d e d d d e The core of medical physiology (1) 3 rd edition Page 109

110 CHAPTER 4 TEMPERATURE AND METABOLIC RATE TEMPERATURE Normal body temperature - The temperature of the internal structures of the body is called the core body temperature. - It equals 37 o C (± 0.5 o C) or 98.6 o F (± 1.3 o F) - The core body temperature differs from the temperature of the skin because: The temperature of the skin is affected directly by the temperature of the external environment. The subcutaneous fat layer beneath the skin acts as insulator. It preserves the core body temperature and prevents the effect of the external environment. Remember that: Skin vasodilatation (as occurs when the core body temperature rises) allows blood to pass through the subcutaneous fat layer and comes under the skin to facilitate heat loss to the outside. The opposite occurs when the core body temperature falls. Measurement of the core body temperature - The device used is the clinical thermometer - The sites used for measurement are: The rectum The most accurate site Not socially acceptable Used in children and unconscious patients The core of medical physiology (1) 3 rd edition Page 110

111 The mouth (under the tongue) The most frequently used site (Socially acceptable) Differs slightly from the core body temperature (less by 0.5 o C ) Affected by hyperventilation, smoking and recently ingested food or drink. Other less frequently used sites: o The axilla (less accurate; affected by the external environment) o The ear (less accurate; affected by the external environment) o Freshly passed urine (more accurate but used for research purposes only ) Regulation of body temperature - Maintenance of normal body temperature is an important goal in homeostasis. - This is because disturbance in body temperature affects: Activity of enzymes Speed of metabolic reactions within the body Activity of the various systems in the body. For example: o The nervous system: higher body temperature increases conduction in neurons whereas lower body temperature decreases conduction. o The cardiovascular system: higher body temperature causes tachycardia and increases contractility whereas lower body temperature does the reverse. o The respiratory system: higher body temperature causes hyperventilation whereas lower body temperature causes hypoventilation. The core of medical physiology (1) 3 rd edition Page 111

112 o The endocrine system: higher body temperature decreases release of thyroid hormones whereas lower body temperature increases release of thyroid hormones. - Regulation of body temperature within narrow limits is not only a characteristic of humans; it is also a characteristic of birds and mammals. For this reason they are described as "warm blooded" or homeothermic. - Other vertebrates like reptiles, amphibia and fish are "cold blooded" or poikilothermic because the range of their body temperature is rather wide. - Invertebrates, on the other hand, can not regulate their body temperature. The temperature regulatory center: - There is a center specialized for control of body temperature located in the hypothalamus, known as the temperature regulatory center. - This center controls heat loss & heat gain (the anterior hypothalamus controls heat loss & the posterior hypothalamus controls heat gain. - Notice that: to maintain constant body temperature, the degree of heat loss should always be balanced by an equivalent degree of heat gain. Heat loss: - Heat is lost from the body by: 1. Conduction - Transfer of heat between objects in contact with each other (From an object with higher temperature to another with lower temperature). The core of medical physiology (1) 3 rd edition Page 112

113 - Conduction occurs for either heat loss or heat gain, depending on the level of body temperature. 2- Convection - Transfer of heat away from a surface by successive currents of air or water (from the object to the air or water currents, if they have temperature lower than that of the object). - Convection occurs for either heat loss or heat gain, depending on the level of body temperature. 3- Radiation - Transfer of heat between objects not in contact with each other (from that of higher temperature to another with lower temperature). - Radiation occurs for either heat loss or heat gain, depending on the level of body temperature, compared to the temperature of the water or air currents. 4- Evaporation - Vaporization of water molecules from a surface, taking heat. - For example, evaporation of sweat from the surface of the body or evaporation of water from the mucus membranes during respiration. - Notice that vaporization of 1g of water removes about 0.6 kcal of heat. - During exercise, sweat secretion may reach 1.6 L/h. Evaporation of this volume results in loss of more than 900 kcal of heat per hour. - Evaporation occurs for heat loss only (heat is always lost, not gained by evaporation). The core of medical physiology (1) 3 rd edition Page 113

114 Heat gain - The body gains heat by: 1- Metabolism - Metabolism of all types of energy substrate, especially brown fat, produces considerable heat. - Brown fat is more abundant in infants than adults. It is found mainly between scapulae and at the nape of the neck. Unlike the white fat, it has rich sympathetic innervation and high metabolic activity. 2- Muscular activity - Contraction of muscles is a major source of heat. This may be induced voluntarily (e.g. exercise) or involuntarily (e.g. shivering) - Shivering is stimulated when the body temperature reaches 35.5 o C. 3- Food intake (Specific dynamic action of food) - Obligatory energy release that occurs during assimilation of food within the digestive system (i.e. before absorption). - The energy release of specific dynamic action of food is highest for proteins than for carbohydrates or fats. 4- From the environment - By conduction, convection or radiation (notice that these mechanisms are suitable for both heat loss and heat gain). - Remember that: In a hot weather, the mechanisms of conduction, convection and radiation are all for heat gain; the only way for heat loss is through evaporation of sweating. However, in a very humid environment sweating occurs without evaporation. Therefore the temperature of the body is not decreased. The core of medical physiology (1) 3 rd edition Page 114

115 Body responses to a hot environment - Due to the direct effect of a hot environment, the temperature of the body starts to rise. - This rise is detected by thermoreceptors located peripherally in the skin and centrally in the spinal cord and hypothalamus. - The peripheral and central chemoreceptors send their impulses to the temperature regulatory center in the hypothalamus. - The center, to correct the body temperature, increases heat loss (by the anterior hypothalamus) & decreases heat gain (by the posterior hypothalamus). - Heat loss is increased by: o Sweating (to increase evaporation from the skin) o Vasodilatation (to increase blood supply to the skin, for radiation) o Increased respiration (to increase evaporation from the mucus membranes). o Behavioral changes to increase heat loss, these include: Stretching at sleep (to increase surface area for radiation) Light clothes and cold drinks - Heat gain is decreased by: o Decreased metabolism, decreased food intake and decreased muscular activity. Body responses to a cold environment - Due to the direct effect of the cold environment, the temperature of the body starts to drop. - This drop is detected by peripheral and central thermoreceptors. The core of medical physiology (1) 3 rd edition Page 115

116 - The thermoreceptors send impulses to activate the temperature regulatory center in the hypothalamus. - The center increases heat gain (by the posterior hypothalamus) & decreases heat loss (by the anterior hypothalamus). - Heat gain is increased by: o Increased metabolism o Increased food intake (the body temperature rises due to the specific dynamic action of food). o Increased muscular activity (shivering and exercise) - Heat loss is decreased by: o Decreased sweating (to decrease evaporation from the skin) o Vasoconstriction (to decrease blood flow to the skin) o Decreased respiration (to decrease evaporation through the mucus membranes) o Behavioral changes that include: Curling up at sleep (to reduce the surface area). Other behavior changes like heavy, dark-colored clothes and hot drinks increase heat gain. Physiological variation in body temperature - Body temperature varies physiologically according to: Age - Higher in neonates> children > adults - The higher temperature in neonates and children is due to heat released by metabolic reactions of the growing tissues Gender - Higher in males than females of the same age and weight The core of medical physiology (1) 3 rd edition Page 116

117 - Due to presence of higher percentage of inactive tissues (fats) in females At and following ovulation - Due to release of progesterone which has thermogenic effect Pregnancy - Due to higher rate of metabolism (fetal tissues) & higher level of progesterone Lactation - Due to higher rate of metabolism (breast tissue) Circulating hormones - Normal variation in levels of thyroid hormones and catecholamines results in equivalent variation in body temperature Circadian fluctuation - Body temperature fluctuates normally throughout the day of o C. It is lowest early in the morning and highest at the evening. Emotions - Due to unconscious tensing of muscles. Sleep and exercise - Body temperature rises with muscular activity and drops at sleep. Abnormalities of temperature regulation Fever (Pyrexia) An important sign of disease (e.g. tonsillitis, pneumonia, typhoid, malaria, malignancies ) Caused by endogenous pyrogens (e.g. cytokines released by phagocytic cells, such as interleukin-1 (IL-1), IL-6 and tumor necrosis factor (TNF ), which act to increase body temperature). The core of medical physiology (1) 3 rd edition Page 117

118 Release of the endogenous pyrogens is induced, in most times, by exogenous pyrogens (substances not synthesized by the body such as bacterial toxins). Interleukins, which can not cross the blood brain barrier to reach the preoptic area in the hypothalamus, induce synthesis of a substance (most probably prostaglandin E 2 ) to reach that area which is the site of temperature setting in the body (= Thermostat). Prostaglandin E 2 resets the thermostat from 37 o C to a higher level (e.g. 40 o C). The subject feels cold, and therefore he develops changes that elevate the body temperature such as shivering, non-shivering thermogenesis (breakdown of brown fat) and skin vasoconstriction; these result in fever. Remember that: Immediately following loss of the prostaglandin effect, the temperature setting point returns back to 37 o C. Since the body temperature is still higher than 37 o C, the subject develops changes to decrease the body temperature such as sweating and vasodilatation of skin blood vessels. Drugs that decrease synthesis of prostaglandins can treat fever (e.g. Aspirin). Heat stroke In a hot dry environment, the only way to lose heat is through evaporation of sweating. Therefore, failure of sweating results in abnormal elevation of body temperature to a degree that affects the activity of the nervous system, resulting in convulsions, coma and even death. The core of medical physiology (1) 3 rd edition Page 118

119 In heat stroke, there is damage to the temperature regulatory center caused by the high environmental temperature. This was confirmed at autopsy. However, the exact mechanism of damage is not well understood. Sometimes, as in severe exercise, heat stroke may result from failure of the temperature regulatory mechanisms to maintain normal body temperature (i.e. inadequate sweating); due to high rate of heat production by the exercising muscles. Failure to reduce body temperature is followed by complications of high temperature (convulsions, coma and death). Treatment should start immediately (e.g. electrical beds to reduce the body temperature gradually or if not available: ice water; However, body temperature should not be lowered quickly). Heat exhaustion In a hot humid environment, even sweating can not reduce body temperature because it fails to evaporate. For this reason subjects should keep themselves in a cold and well ventilated area to lose heat. In heat exhaustion, there is excessive sweating but with no evaporation. The body temperature becomes elevated, the activity of the nervous system is affected and the patient develops dehydration (due to the excessive sweating). If not treated, the temperature regulatory mechanisms eventually fail and the heat exhaustion becomes complicated by heat stroke (permanent damage to temperature center). The core of medical physiology (1) 3 rd edition Page 119

120 Therefore it is important to treat the condition immediately by taking the patient to a well ventilated, cold room and giving him IV fluids (in form of normal saline). Table 4.1: Differences between heat stroke and heat exhaustion Difference Heat stroke Heat exhaustion Classical environment Hot dry Hot humid Temperature center Abnormal Normal Sweating Absent Excessive Skin Hot & dry Hot & wet Dehydration Absent Present Effects of the high temperature Tachycardia Hyperventilation Convulsions & coma Present Present Hypothermia Diagnosed when rectal temperature is < 35 o C. Characterized by loss of consciousness, bradycardia and decreased respiration. Occurs due to the direct effect of cold environments on slim subjects with thin subcutaneous fat layer (e.g. malnourished children and old people); or subjects with immature temperature regulatory mechanisms (e.g. pre-term babies). Treatment by stepwise elevation of body temperature using heavy clothes or electric blankets (because sudden elevation of body temperature is dangerous). The core of medical physiology (1) 3 rd edition Page 120

121 Lesions of the hypothalamus - The anterior hypothalamus controls heat loss (e.g. vasodilatation and sweating) whereas the posterior hypothalamus controls heat gain (e.g. shivering). - Damage involving the anterior hypothalamus causes hyperthermia in hot environments (due to failure of heat loss) whereas damage involving the posterior hypothalamus causes hypothermia in cold environments (due to failure of heat gain). Malignant hyperthermia - This is a life threatening condition that occurs due to a mutation in the gene coding for the ryanodine receptors in skeletal muscles. - Anesthetic drugs such as halothane and suxamethonium trigger excessive release of calcium through these receptors from the sarcoplasmic cisternae into the sarcoplasm, causing prolonged contraction. Calcium causes contraction of muscles, this results in sudden rise in body temperature and eventually death. Heat cramps - These are brief, painful muscle spasms occurring in the abdomen, thigh or calf muscles. - They occur during or after exercise, especially in the un-acclimatized subjects, due to loss of large amounts of water and salts in sweat. - Acclimatization involves elevation of aldosterone level which reabsorbs sodium from sweat glands to prevent its loss in sweat. - Treatment measures include resting of the muscles, rehydration and correction of sodium and potassium loss. The core of medical physiology (1) 3 rd edition Page 121

122 THE METABOLIC RATE - The word metabolism refers to all chemical transformations that occur within the body. - It includes: Anabolic reactions: o Synthesis of complex molecules from simpler ones o Example: glycogen from glucose, protein from amino acids o Involves consumption of energy for synthesis Catabolic reactions: o Degradation of complex molecules to simpler ones o Example: glycogen to glucose, protein to amino acids o Involves release of energy during degradation THE BASAL METABOLIC RATE The metabolic rate is defined as the rate of energy release per unit time. If it is measured at certain standard conditions; it is called the basal metabolic rate (BMR). The standard conditions for its measurement are: o Complete physical and mental rest o Fasting for at least 12 hours o Comfortable temperature The energy released by the body at these standard conditions is used to maintain basal functions in the body such as: o Beating of the heart o Respiration The core of medical physiology (1) 3 rd edition Page 122

123 o Activity of the nervous system o Sodium-Potassium ATPase pump Measurement of the BMR Normal BMR = 2000 kcal/day or 40 kcal/m 2 /h Measurement of the BMR was formerly used to diagnose thyroid problems: o If increased by 15% = it indicates hyperthyroidism o If decreased by 15% = it indicates hypothyroidism BMR is measured by 2 methods: Direct Calorimetry (Not preferred because it is difficult and needs special laboratories) Indirect Calorimetry (Preferred) Direct Calorimetry Involves incubation of a subject in a vessel container for a certain period of time. The vessel container is surrounded by a known volume of water and covered from outside by insulator. The energy released during this period of time, in the form of heat, will raise the temperature of the water around the container. This change in temperature is used to calculate the BMR. Indirect Calorimetry Involves indirect measurement of the BMR by measuring certain substances consumed or produced during the catabolic reactions. For example, take the reaction: The core of medical physiology (1) 3 rd edition Page 123

124 C 6 H 12 O 6 + (6) O 2 = (6) CO 2 + (6) H 2 O + energy (heat) Here the amount of energy released is known Using the above information, the metabolic rate can be calculated indirectly by measuring any of the following during a certain period of time: o the amount of oxygen consumption o the amount of glucose consumption o the amount of carbon dioxide production o the amount of water production Using the oxygen consumption: The amount of energy produced when one liter of oxygen is consumed is called the joule equivalent (JE) It differs according to difference in the foodstuff being oxidized. This is because the ratio of carbon to oxygen atoms differs in different types of foodstuff. The difference in the ratio of carbon to oxygen atoms also results in difference in the respiratory quotients (RQ) of foodstuffs. The RQ of each foodstuff is defined as the ratio of carbon dioxide produced to oxygen consumed in the steady state, when equilibrium is reached at rest. It differs from the respiratory exchange ratio (R) which is the ratio of CO 2 to O 2 at any given time (see below). The RQ for; o CHO = 1, Protein = 0.82, Fat = 0.7, Mixed diet = 0.85 The RQ can be used to calculate the joule equivalent (JE) for each foodstuff as follows: JE = (RQ x 3.5) The core of medical physiology (1) 3 rd edition Page 124

125 Now the BMR can be calculated as follows: BMR = oxygen consumption x joule equivalent (in joule/unit time) BMR = oxygen consumption x joule equivalent/surface area x 4.2 (in kcal/m2 /h). Note: The volume of oxygen consumption should be corrected for standard temperature & pressure (STP) by multiplying it by a factor, obtained from nomograms (e.g. the correction factor at STP when air temperature = 21 c & ambient pressure = 741 mmhg equals 0.883) Notes to remember about the respiratory exchange ratio (R) It is affected by hyperventilation (e.g. during exercise or metabolic acidosis); here R is increased (due to expiration of more CO 2 by the hyperventilation). Then following exercise, R is decreased (due to the oxygen debt mechanism). The respiratory quotient (RQ) and the respiratory exchange ratio (R) of individual organs give information about their activities. For example the RQ for the brain (measured during the steady state) = 0.99; indicating that its main source of energy is glucose. The R for the stomach (measured during active secretion of HCl) is negative, indicating that more CO2 is consumed than produced; this is used in synthesis of HCL (see the GIT in volume 2). Measurement of oxygen consumption Requirement Bell-type spirometer (Benedict s Roth) Kymograph The core of medical physiology (1) 3 rd edition Page 125

126 Method The subject puts the mouth piece of the spirometer in his mouth Firstly, the spirometer is connected to the atmosphere to familiarize the subject to the procedure before recording Then the atmospheric opening is closed to allow the subject to consume the oxygen inside the cylinder of the spirometer Oxygen consumption is obtained from a recording on a kymograph paper of a spirometer by measuring the slope of the line A-B as in this example: Fig 4.1: Measurement of oxygen consumption Calculation BMR = oxygen consumption x correction factor for STP x Joule equivalent/ Surface area x 4.2 The core of medical physiology (1) 3 rd edition Page 126

127 Remember that: If the standard conditions mentioned above are not fulfilled; the value obtained is a metabolic rate (not BMR) To calculate the joule equivalent using the formula (JE = (3.5 x RQ)), the type of foodstuff consumed by the subject over the past few days should be known; this gives the RQ The surface area can be obtained, using the height and weight of a subject, from nomograms or certain equations Factors affecting the metabolic rate Age - Higher in neonates> children > adults> old subjects - Due to increased metabolism of the growing tissues. Here the metabolic rate should be expressed per surface area for comparison. Gender - Higher in males than females of the same age and weight. - Due to presence of higher percentage of fats in females. At and following ovulation - Due to the higher body temperature caused by progesterone. Pregnancy and lactation - Due to presence of more metabolically active tissues (fetal and breast tissues); & higher level of progesterone. Circulating hormones - Normal variation in levels of thyroid hormones and catecholamines results in equivalent variation in the metabolic rate. Emotions - Due to unconscious tensing of muscles. The core of medical physiology (1) 3 rd edition Page 127

128 Sleep and exercise - The metabolic rate rises with activity. Recent ingestion of food (SDA) - Due to the specific dynamic action of food (SDA). As mentioned earlier it is the obligatory energy release following ingestion of food, due to its assimilation within the GIT. However, its exact cause is unknown. It lasts for 6 hours. The rise in metabolic rate is highest following protein ingestion and lowest following fat ingestion. Body temperature and environmental temperature - The relation between environmental temperature and the rate of metabolism is generally an inverse relationship (increased environmental temperature = decreased metabolic rate). However, the relation between body temperature and the rate of metabolism is a direct relationship (increased body temperature = increased metabolic rate). - The relation between the environmental temperature and the rate of metabolism is explained by the body responses to hot or cold environment. - For example, the rate of metabolism rises in a cold environment and drops in a hot one (see above). - However, when the environmental temperature rises enough to elevate the body temperature or drops enough to decrease the body temperature, the metabolic rate increases or decreases respectively (i.e. the relation becomes a direct relationship). - It is calculated that for each one Celsius degree rise in body temperature, the metabolic rate increases by 14%. The core of medical physiology (1) 3 rd edition Page 128

129 QUESTIONS FOR SELF ASSESSMENT-5 (BEST OF FIVE) 1. The most accurate site for measurement of body temperature is: a. The mouth b. The axilla c. The rectum d. The nose e. The skin 2. Whenever the body temperature is lower than the set point of the thermostat in the hypothalamus: a. Sweating is increased b. Skin blood vessels dilate c. Rate of metabolism is increased d. Subjects feel hot sensation e. Appetite to food is inhibited 3. Features of heat stroke include all the following except: a. Hypotension b. Dehydration c. Low urine output d. Absence of sweating e. Convulsions 4. Heat exhaustion: a. Occurs in hot dry environments b. Is due to failure of sweating c. Is best treated with ice water immersion d. Is associated with low plasma osmolarity e. Is associated with dehydration 5. At the onset of fever, patients develop: a. Hot sensation b. Sweating c. Convulsions d. Skin vasoconstriction e. Nausea and vomiting 6. Exposure to a cold environment is not excepted to cause: a. Release of thyroid hormones b. Peripheral cyanosis c. Acceleration of metabolism d. Reduction in blood pressure e. Reduction in heart rate 7. The main way for heat loss from a body in a hot dry environment is through: a. Sweating b. Hyperventilation c. Evaporation The core of medical physiology (1) 3 rd edition Page 129

130 d. Radiation e. Conduction 8. Concerning regulation of body temperature: a. Birds and mammals are poikilothermic b. The temperature regulatory centre is located in the medulla c. Convection never causes heat gain d. Shivering occurs when body temperature falls below 36.5 C e. Damage to the posterior hypothalamus is expected to cause hypothermia 9. Heat stroke differs from heat exhaustion because it: a. Usually occurs in both dry and humid environments b. Is associated with elevated core body temperature c. Causes tachycardia and impaired level of consciousness d. Is not characterized by dehydration e. Is not associated with sweating 10. Measurement of the basal metabolic rate requires: a. fasting for two hours b. ingestion of a heavy meal c. moderate exercise during measurement d. normal body temperature e. suitable environmental temperature 11. Basal metabolism is mainly accounted for by: a. Energy spent by cardio-respiratory functions b. Secretions in the endocrine system c. The sodium-potassium pump d. Maintenance of body temperature e. Renal tubular mechanisms 12. In the body the metabolism of 10 grams of protein would produce approximately: a. 10 kcal b. 53 kcal c. 41 kcal d. 90 kcal e. 20 cal 13. For measurement of the basal metabolic rate all the following conditions are required except: a. mental rest b. physic rest c. normal body temperature d. 12 hours fasting prior to measurement e. comfortable room temperature 14. The specific dynamic action of food is due to: a. an increase in core body temperature b. amino acid metabolism in the liver The core of medical physiology (1) 3 rd edition Page 130

131 c. energy expenditure during digestion d. hypothalamic sympathetic stimulation e. secretion of insulin 15. The basal metabolic rate: a. is about 500 kcal/ kg body weight / day b. is measured during exercise c. is measured during exposure to cold environment d. rises during menstruation and lactation e. is usually measured two hour following a meal 16. All the following conditions are expected to increase the rate of metabolism in a young woman EXCEPT: a. Fasting b. Fever c. Menstruation d. Second trimester of pregnancy e. Cold environment 17. The respiratory exchange ratio is: a. The ratio of CO2 production to O2 consumption during steady states b. Used to calculate the joule equivalent c. Used to calculate oxygen debt of organs d. Negative for the stomach during active secretion of HCL e. Negative for the brain at rest 18. The metabolic rate is increased by all of the following except: a. Rise in body temperature b. Rise in environmental temperature c. Increased sympathetic outflow d. Stress e. Hyperfunction of the thyroid gland 19. Which of the following is the main consumer of energy under basal conditions? a. Heart activity b. Respiratory muscle activity c. Sodium-potassium pump d. Skeletal muscle activity e. Liver metabolism Question Answer c c b e d d c e e e Question Answer c c c c d a d b c The core of medical physiology (1) 3 rd edition Page 131

132 CHAPTER 5 HEMATOLOGY BLOOD - Blood is a type of connective tissue. - Like other types of connective tissue it consists of: Cells and intercellular substance - The cells are: Red blood cells (RBCs) or erythrocytes White blood cells (WBCs) or leukocytes Platelets or thrombocytes - The intercellular substance is called plasma - Volume of blood is about 5L in an average adult male (= 8% of total body weight). - Volume of plasma is about 3.5L (= 5% of total body weight). - The cells in blood can be separated from plasma by centrifugation. - The percentage of cells in blood is called the packed cell volume (PCV) or the hematocrit. The PCV PCV is the percentage of blood occupied by cells. Most of these cells are RBCs (more than 90%). Normal values = 40-50% in males [average = 45%] = 37-47% in females [average = 42%] Low PCV indicates anemia High PCV indicates polycythemia. The core of medical physiology (1) 3 rd edition Page 132

133 Fig 5.1: The packed cell volume Functions of blood 1. Transport of: Gases (e.g. oxygen and carbon dioxide) Nutrients (e.g. glucose, amino acids and free fatty acids) Waste products (e.g. urea and uric acid) Hormones (e.g. catecholamines, insulin, cortisol and thyroid hormones) 2. Defense by WBCs 3- Homeostasis (maintenance of the constancy of the internal environment, which is the ECF): Control of temperature (by distribution of heat by the blood) Control of ph (by buffers in the blood, e.g. HCO - 3, proteins and hemoglobin) 4- Hemostasis Prevention of blood loss & maintenance of blood in the fluid state. Blood loss is prevented by arrest of bleeding (e.g. by platelets and clotting factors) and maintenance of blood in the fluid state occurs by the natural anticoagulants. The core of medical physiology (1) 3 rd edition Page 133

134 Formation of blood (hematopoiesis) Sites of hematopoiesis During pregnancy, blood is formed at the following sites: Yolk sac: - Forms blood during the intrauterine life, first trimester Liver & spleen: - Form blood during the intrauterine life, second trimester - After delivery, the liver and spleen may resume their hemopoietic activity in children suffering from chronic anemia [this is known as extramedullary hematopoiesis] Bone marrow): - Forms blood during the intrauterine life, third trimester (and then after delivery); called red marrow (active marrow) - Found in almost all bones during pregnancy After delivery, blood is formed at the following sites: The red bone marrow - After delivery, the red bone marrow starts to be replaced gradually by yellow marrow (inactive marrow) - At about the age of 20y the red marrow is confined to: o Flat bones - Skull, sternum, ribs, scapula, vertebrae & iliac bone o Ends of long bones epiphyses not the shaft diaphysis o Small bones of hands & feet - About 75% of the cells in the red bone marrow are WBC precursors and only 25% are RBC precursors; inspite of the fact that RBC count is over 500 times more than the WBC count. This indicates the longer life span of RBCs. The core of medical physiology (1) 3 rd edition Page 134

135 THE RED BLOOD CELLS Characteristics of RBCs Shape: Biconcave disks Diameter: 7.5 micrometer Thickness: 1 micrometer (center), 2 micrometer (edges) Fig 5.2: Contents: o No nucleus - Therefore no reproduction - Their life span is about 120 days o No organelles - e.g. no mitochondria and therefore no aerobic glycolysis. However, they use anaerobic glycolysis to generate small amount of energy for maintenance of the integrity of the cell membrane o Contain hemoglobin - A red pigment found within RBCs - Important for transport of oxygen - The volume of a red blood cell is larger than its contents. This allows it to squeeze itself through the narrow capillaries. The core of medical physiology (1) 3 rd edition Page 135

136 Count of RBCs - In males: million/mm 3 & in females: million/mm 3 Functions of RBCs Transport oxygen (bound to iron in hemoglobin) Transport carbon dioxide (bound to globin in hemoglobin) Buffer (a function of hemoglobin) Contain antigens on its surface that determine the type of blood group Stages of erythropoiesis Can be divided into: Replication phase o The increase in number of RBCs Maturation phase o The decrease in size of RBC precursors o Loss of contents (nucleus and organelles) o Acquisition of hemoglobin Stages in the bone marrow: Pluripotent non-committed stem cells - Nucleated cells that divide to form 2 major types of committed stem cells: lymphoid and non-lymphoid (myeloid & erythroid) cells Committed stem cells (or progenitor cells) - Nucleated cells that divide to form only one type of blood cells (e.g. the lymphoid forms lymphocytes and the erythroid forms RBCs, and the myeloid forms other WBCs granulocytes, monocytes and precursors of platelets megakaryocytes ). The core of medical physiology (1) 3 rd edition Page 136

137 Proerythroblasts (or Normoblasts) - The erythroid committed stem cells divide to form nucleated cells known as proerythroblasts (or normoblasts). - These divide many times and start to form hemoglobin; that s why they are described as early, intermediate & late or according to the stain as basophilic and polychromatophilic. - The normoblasts lose the nucleus & other organelles to become reticulocytes. Stages in the blood: Reticulocytes - The first non-nucleated red blood cell precursors. - They have no organelles except some ribosomes (so they are still able to synthesize hemoglobin from ribosomal RNA). - After their formation they stay in the bone marrow for 1-2 days; then they enter the peripheral blood for the first time and stay for another 1-2 days before they become mature erythrocytes. - They constitute about 1% of total RBCs. - High reticulocyte count (>2% = reticulocytosis) indicates hyperactivity in the bone marrow (i.e. rapid synthesis of RBCs to replace the lost ones) as occurs in: o Hemolytic anemia (reticulocytosis indicates RBC hemolysis) o Recent treatment of anemia (e.g. following vitamin B12 injections) Erythrocytes - The mature red blood cells. The core of medical physiology (1) 3 rd edition Page 137

138 CONTROL OF ERYTHROPOIESIS Normal erythropoiesis requires: - Normal bone marrow - Cytokines and colony stimulating factors - Erythropoietin & other hormones (e.g. thyroid hormones) - Certain nutrients (e.g. iron, vitamin B12 and folic acid) Normal bone marrow - Normal bone marrow is essential for normal erythropoiesis. - Diseases affecting the bone marrow usually results in abnormal erythropoiesis (see anemia). Cytokines and colony stimulating factors - Interleukins: IL-1, 1L-3, IL-6 and GM-CSF (Granulocyte- Monocyte Colony Stimulating Factors) stimulate proliferation and conversion of pluripotent stem cells into committed stem cells. - These growth factors are produced by bone marrow stromal cells such as fibroblasts, endothelial cells, activated T cells and macrophages. Erythropoietin (= the principal regulator of erythropoiesis) Characteristics: - Glycoprotein (contains 24% carbohydrates and 76% protein). - Have single chain with 165 amino acids. - MWt: Site of production: - In adults: produced mainly in the kidneys (90%) & in the liver (10%). - In fetal life: the liver is the main site of production. Stimulus: - Hypoxia (low oxygen at the tissue level). The core of medical physiology (1) 3 rd edition Page 138

139 Function - Stimulates replication of stem cells and formation of erythroblasts. - Erythropoietin dose not influence the maturation stages of RBCs. Abnormalities Erythropoietin excess (= results in polycythemia) - Caused by: o High altitudes: people living at high altitudes have physiological polycythemia due to the low oxygen tension at these sites. o Renal problems (e.g. renal tumors or polycystic kidney disease): these pathological problems are characterized by excessive release of erythropoietin causing pathological polycythemia. o Chronic respiratory problems: When these problems cause hypoxia, patients develop polycythemia (e.g. lung fibrosis). - Erythropoietin deficiency (= results in anemia) - Anemia caused by erythropoietin deficiency is characterized by low count of RBCs but with normal shape and color normocytic normochromic anemia. The chief cause is chronic renal failure. Other hormones needed for normal erythropoiesis: o Androgens (= male hormones that increase bulk of muscles, e.g. testosterone). Muscles are more active than fats, they consume more oxygen. This stimulates erythropoietin production and therefore RBC formation. That s why RBC count is higher in males than females of the same age (notice that this difference between males and females is absent before puberty!). o Growth hormone o Cortisol o Thyroid hormones The core of medical physiology (1) 3 rd edition Page 139

140 Nutrients needed for erythropoiesis o Amino acids: for formation of globin (Hb) o Iron: for formation of heme (Hb). Its deficiency causes microcytic hypochromic anemia o Vitamin B 12 & folic acid: for DNA synthesis (cell division). Deficiency causes macrocytic normochromic anemia o Vitamin C: for iron absorption (it is a reducing factor that maintains iron in the ferrous state) o Other B vitamins: Co factors in the metabolic reactions o Vitamin E: for maintenance of RBC membrane (an anti-oxidant that protects the cell membrane from oxygen radicals). Deficiency causes hemolytic anemia. o Trace elements: - Copper: promotes iron absorption - Cobalt: Needed for vitamin B 12 synthesis in animals. It may stimulate erythropoietin production. Iron metabolism Distribution in the body - Total amount in the body is about 3-5 grams. Distributed in: o Heme of hemoglobin (65-75%) o Cellular enzymes (catalase, cytochrome oxidase) (3%) o Storage (ferritin, hemosiderin) (>20%) o Plasma (transferrin) (< 1%) Dietary sources - Animal products: e.g. liver, meat, egg - Plant products: e.g. vegetables, beans - The average diet provides mg/day The core of medical physiology (1) 3 rd edition Page 140

141 Daily requirements - About 1 mg/day in an adult man, 2 mg/day in an adult woman - The daily requirements are increased during: o Pregnancy o Lactation o Infancy (the first year of life) Absorption - Amount absorbed = 10-15% of ingested iron; however, it is highly increased in patients suffering from iron deficiency anemia. - Site of absorption: upper small intestine (duodenum). - Mechanism of absorption: 2 ndary active transport (Fe 2+ -H + symport). - Factors that increase absorption: o Ferrous state (Fe 2+ ) o Gastric acidity (HCl), maintains iron in the ferrous state o Vitamin C, also maintains iron in the ferrous state o Iron in heme - Factors that decrease absorption: o Presence of phosphates, oxalates or phytates in diet o Achlorohydria (low hydrochloric acid due to gastric atrophy) o Diarrhea o Clay o Fever o Tetracycline Iron in plasma - Concentration= microgram/dl - Transported in plasma by a beta globulin known as transferrrin - Transferrin is normally 30-40% saturated with iron The core of medical physiology (1) 3 rd edition Page 141

142 Storage - Sites of storage: Intestinal mucosa, liver, spleen and bone marrow. - Forms of storage: ferritin &hemosiderin. - Ferritin is the main form of storage. It stores 65% of stored iron in a soluble form that s easily mobilized whereas hemosiderin stores 35% of stored iron in an insoluble form that s slowly mobilized. Function of iron: formation of heme in Hb - Iron found in ferrous (Fe2+) form - Each Hb molecule contains 4 (Fe2+) - Each atom of iron binds 2 atoms of oxygen (Therefore each Hb molecule carries 8 atoms of oxygen (or four molecules). Excretion - Total daily loss of iron= 1 mg/day in adult men, 2mg/day in adult women (i.e. daily intake = daily loss). - Routes for iron loss: Feces, skin, urine and menstruation Abnormalities o Iron deficiency anemia= (microcytic hypochromic anemia) - Characterized by: Low Hb, small & pale RBCs (microcytic hypochromic anemia), low concentration of iron in plasma, low plasma ferritin and high total iron binding capacity (TIBC). o Iron overload: 1 о : Hemochromatosis & 2 о : Hemosiderosis - Hemochromatosis is a common hereditary condition characterized by excessive iron absorption resulting in abnormal accumulation of iron in many organs causing damage (e.g. liver cirrhosis, gonadal atrophy, cardiomyopathy, skin pigmentation and diabetes mellitus). - Hemosiderosis describes iron overload secondary to certain causes (e.g. repeated blood transfusions and excessive iron therapy). The core of medical physiology (1) 3 rd edition Page 142

143 Vitamin B 12 - Cyanocobalamin - Water soluble vitamin Sources and requirement - Found in food of animal origin (notice that vitamin B12 is formed by micro-organisms that contaminate animal tissues, it is not found in food of plant origin unless it is contaminated by these microorganisms). - Daily requirements are very low (about 1-2 microgram/day) Site of absorption - Terminal ileum - Absorption is assisted by the intrinsic factor (produced by parietal cells in the stomach). This binds iron in the stomach and travels with it to the terminal ileum to be absorbed together by pinocytosis. Storage - In the liver, the amount stored is enough for at least 3 years without intake. Functions o DNA synthesis: (needed for red blood cell replication) o Myelination of nerves Abnormalities o Deficiency causes: - Macrocytic normochromic anemia (megaloblastic anemia) - Sub-acute combined degeneration of the cord (demyelination) o Causes of deficiency: - Low intake (rare cause of deficiency except in strict vegetarians) - Resection of the terminal ileum (decreases absorption) The core of medical physiology (1) 3 rd edition Page 143

144 - Gastrectomy (removal of the stomach decreases absorption because there is no intrinsic factor). - Gastric atrophy (caused by auto-antibodies that attack parietal cells or the intrinsic factor); this is known as pernicious anemia. Folic acid - Water soluble vitamin Sources and requirement - Found mainly in food of plant origin - Daily requirement is about 100 microgram/day - Requirements are increased during: o Pregnancy o Lactation o Infancy Absorption - In the small intestine (especially the jejunum) Function - DNA synthesis (needed for red blood cell replication) Abnormalities - Deficiency causes: macrocytic normochromic anemia - Causes of deficiency: o Decreased intake: malnutrition o Decreased absorption: villous atrophy o Increased requirements: - Pregnancy - Drugs (e.g. methotrexate) The core of medical physiology (1) 3 rd edition Page 144

145 HEMOGLOBIN - The red pigment found in RBCs. - Molecular weight is about Concentration o g/dl in adult males o g/dl in adult females o g/dl in neonates Structure - Consists of 4 subunits. Each subunit consists of heme + a polypeptide chain. [Hb = 4 heme + 4 polypeptide chains] - Each heme is synthesized from glycine and succinyl- CoA. It has a porphyrin ring containing iron in the reduced state (Fe 2+ ). - Each polypeptide chain is identical to another chain in Hb; therefore the 4 polypeptide chains are 2 pairs; e.g. 2 alpha + 2 beta chains or 2 alpha + 2 gamma chains or 2 alpha + 2 delta chains. The 4 chains are called collectively globin (i.e. Hb = 4 heme + globin). Fig 5.3: The four subunits of hemoglobin The core of medical physiology (1) 3 rd edition Page 145

146 Functions of Hb o Carries 98% of oxygen in the blood o Carries some carbon dioxide o Buffer Normal types of Hb Hb A - Adult Hb: constitutes about 98% of all Hb in adults - Contains 2 alpha & 2 beta chains (α 2 β 2 ) - Each alpha chain contains 141 aa (formed by genes on chromosome 16) whereas each beta chain contains 146 aa (formed by genes on chromosome 11) Hb A2 - Adult Hb: constitutes about 2.5% of all Hb in adults - Consists of 2 alpha & 2 delta chains (α 2 δ 2 ) - Delta chain is similar to beta chain, but differs in 10 aa. It is also formed by genes on chromosome 11 Hb F - Fetal Hb - Starts to be replaced Hb A before birth. - At birth, it constitutes about 70% of total Hb. This decrease to less than 2% (i.e. replacement is almost complete) by the age of 6 month. - Hb F has higher affinity to oxygen than Hb A. This is because it binds 2,3 DPG (di-phospho-glycerate) less avidly (in other words: 2,3 DPG does not occupy the sites available for oxygen binding as occurs in Hb A. - This facilitates delivery of oxygen from the mother to her fetus through the placental membranes. The core of medical physiology (1) 3 rd edition Page 146

147 - Consists of 2 alpha & 2 gamma chains (α 2 γ 2 ) - Gamma chain is similar to beta chain except in 37 aa. It is also formed by genes on chromosome 11. Hb A1c (Glycated Hb) - Subtype of Hb A - Its terminal amino acid (valine) can bind glucose - Normally it constitutes about 5% of total Hb - Higher percentage of Hb A1c indicates poorly controlled diabetes mellitus Embryonic hemoglobins - Types of hemoglobin during the first 8 weeks of pregnancy include: Gower 1 Hb: consists of 2 zeta and 2 epsilon chains (ξ 2 ε 2 ) Gower 2 Hb: consists of 2 alpha and 2 epsilon chains (α 2 ε 2 ) Portland Hb: consists of 2 zeta and 2 gamma chains (ξ 2 γ 2 ) Abnormal types of Hb Hb S - Sickle cell Hb - It is Hb A but the amino acid number 6 in beta chains (glutamic acid) is replaced by (valine) - Hb S precipitates in cases of hypoxia. This changes the shape of RBCs to a sickle shape - Complications of the sickle shape: o Hemolytic crisis: hemolytic anemia known as sickle cell anemia o Jaundice: pre-hepatic jaundice due to the excessive hemolysis o Vaso-occlusive crisis: obstruction of small capillaries causing atrophy of organs supplied with these blood vessels The core of medical physiology (1) 3 rd edition Page 147

148 - Symptoms appear after the age of 6 month when HbF is almost totally replaced by Hb A (This is because Hb F prevents sickling of RBCs since it does not contain beta chains) - The disease is less severe in heterozygotes (who have one chromosome affected and therefore 50% of their Hb is Hb S) than homozygotes (who have defect in the two chromosomes that form Hb A and therefore most of their Hb is Hb S). Notes to remember about Hb S & sickle cell disease: In these patients, Hb F persists in high concentrations after the age of 6 month and until adulthood as compensation. The disease in heterozygotes is known as sickle cell trait whereas in homozygotes as sickle cell disease Sickle cell disease is a well known problem in certain tribes in Western Sudan and Western Africa. It exists especially in malaria endemic areas; this is explained by the fact that hemoglobin S cannot be digested by malaria parasites (i.e. Hb S patients the sicklers are rarely infected with malaria). Thalassemia - Decreased production of globin chains; e.g. deficiency of alpha chains (alpha thalassemia) or beta chains (beta thalassemia). - Thalassemia is characterized by excessive hemolysis of RBCs resulting in hemolytic anemia. - The type of anemia is microcytic hypochromic anemia. Other abnormal types of hemoglobin - Are numerous. They include Hb C, E, D and H. - The abnormal types of Hb can be identified by electrophoresis (use of an electrical current to separate normal and abnormal types of The core of medical physiology (1) 3 rd edition Page 148

149 hemoglobin in the blood, because they have different electrical charges and different rates of movement). Remember the following abnormal conditions of Hb: Methemoglobin - Here iron is oxidized (from the ferrous state (Fe 2+ ) to a ferric state (Fe 3+ )) by some oxidizing agents (e.g. drugs). Normally this is converted back by NADH- Methemoglobin Reductase System within the RBCs. Congenital absence of this enzyme causes hereditary methemoglonbinemia. - The ferric state can not bind oxygen in a reversible reaction as the ferrous state. - Methemoglobin gives the skin a dark color resembling cyanosis. Carboxyhemoglobin - Formed by reaction of hemoglobin with carbon monoxide. - The affinity of Hb for CO is very high. That s why it displaces oxygen from its sites resulting in reduction of oxygen carrying capacity of the blood (= anemic hypoxia). RBC DESTRUCTION Stages of destruction - Every second, a large number of RBCs are broken down in the tissue macrophage system (previously known as the reticuloendothelial system); e.g. the spleen. - At the same time the same number is replaced by new RBCs produced in the bone marrow. - Anemia occurs if breakdown is more than production whereas polycythemia occurs if breakdown is less than production. The core of medical physiology (1) 3 rd edition Page 149

150 In the spleen (the main site of RBC destruction) - Old and abnormally shaped RBCs that cannot pass through small capillaries in the spleen are destroyed by macrophages and the main product of destruction is hemoglobin which gives heme and globin. - Globin is hydrolyzed into amino acids which are reutilized. - Heme releases iron which is needed by the body for synthesis of new RBCs. The remaining porphyrin ring is converted to biliverdin and then to bilirubin. - Bilirubin, a yellow pigment that s water insoluble, is transported towards the liver carried by albumin. - Carriage of the insoluble bilirubin in the blood by plasma proteins prevents its appearance in urine (can not be filtered). In the liver and bile - In the liver, bilirubin is conjugated to glucouronic acid to be water soluble. - Conjugation is catalyzed by the enzyme glucouronyl transferase. - Conjugated bilirubin is then secreted in bile. It gives bile its yellowish color. - For this reason it is called bile pigment. However, some of it escapes into the systemic circulation and appears normally in urine. In the intestine - When bile reaches the intestine, bilirubin is converted by bacteria to stercobilinogen & urobilinogen (both called urobilinogens). - Stercobilinogen is excreted in stool, giving it its characteristic color. - Urobilinogen is absorbed to the entero-hepatic circulation. However, some of it escapes into the systemic circulation and appears normally in urine. The core of medical physiology (1) 3 rd edition Page 150

151 Fig 5.4: Excretion of bilirubin Jaundice - Yellowish coloration of the skin, sclera & mucus membranes. - Occurs due to high level of bilirubin in the plasma (normal bilirubin level is about 1mg/dL). - Jaundice appears when the concentration is higher than 2mg/dL Types of Jaundice o Pre-hepatic (hemolytic) o Hepatic o Post-hepatic jaundice (obstructive) Pre-hepatic Jaundice - Caused by excessive hemolysis of RBCs resulting in excessive release of unconjugated bilirubin (gives indirect reaction in the van den Bergh test). - The high amount of unconjugated bilirubin exceeds the capacity of the liver for conjugation and excretion into bile. For this reason the The core of medical physiology (1) 3 rd edition Page 151

152 unconjugated bilirubin appears in blood causing the yellowish color. However, it does not appear in urine because it is bound to albumin in the blood (acholuric jaundice). - Conjugated bilirubin that s secreted by the liver in bile is higher than normal. Therefore production of urobilinogens in the intestine and consequently its excretion in urine are also higher than normal. - Prehepatic jaundice is usually associated with hemolytic anemia. - Causes include: Abnormal RBC shape o Sickle cell anemia (due to Hb S) o Congenital spherocytosis (Due to lack of spectrin) o Congenital elliptocytosis (due to lack of spectrin) Lack of RBC enzymes o Glucose 6 phosphate dehydrogenase deficiency o Pyruvate kinase deficiency Mechanical destruction of RBCs o Malaria o Hypersplenism Other causes like T o Thalassemia o Autoimmune hemolytic anemia Hepatic Jaundice - Caused by liver cell damage or lack of enzymes resulting in failure of bilirubin conjugation in liver cells (thus increasing unconjugated bilirubin in the blood) or failure of bilirubin secretion in bile after its conjugation (thus increasing conjugated bilirubin in the blood). - i.e. Bilirubin in hepatic jaundice may conjugated or unconjugated. The core of medical physiology (1) 3 rd edition Page 152

153 - Conjugated bilirubin appears in urine whereas unconjugated bilirubin does not (because it is bound to albumin). - Causes of hepatic jaundice include: o Viral hepatitis (e.g. A, B, C, ) or alcoholic liver disease; cause cell damage = failure of conjugation = unconjugated jaundice o Dubin Johnson & Rotor syndromes: due congenital defect in the mechanism of bilirubin secretion in bile = conjugated jaundice o Crigler-Najjar syndrome (type I & II); due to congenital deficiency of the conjugating enzyme = unconjugated jaundice o Gilbert's syndrome; due to decreased activity of the conjugating enzyme= one of the commonest causes of unconjugated jaundice Post-hepatic Jaundice - Caused by obstruction of the biliary tracts. This prevents conjugated bilirubin from reaching the intestine. Therefore it appears in blood causing the characteristic yellowish color. - The conjugated bilirubin, which is water soluble, appears in urine (Choluric jaundice). It gives urine a characteristic dark yellowish color. Urobilinogen is not produced in the intestine and so it is absent from urine. - Since bile does not reach the intestine, stool becomes pale (due to absent bile pigments like bilirubin) and full of fat (due to absent bile salts which are essential for fat digestion and absorption). - Causes of obstructive jaundice include: o Gall stones obstructing the common bile duct o Parasites obstructing the common bile duct o Tumors obstructing the common bile duct (e.g. carcinoma head of the pancreas) The core of medical physiology (1) 3 rd edition Page 153

154 ANEMIA Definition - State of reduction in hemoglobin concentration below the normal range (according to age and sex) - This occurs because of: o low Hb within each RBC (and/or) o low total count of RBCs Classification of anemia o Decreased production of RBCs o Increased destruction of RBCs o Blood loss 1- Anemia due to decreased RBC production Diseases of the bone marrow - Examples include: o Bone marrow infiltration - Tumors (primary tumors like leukemias or secondary tumors from other sources like the bone or the thyroid) - Myelofibrosis o Bone marrow failure (Aplastic anemia) - Congenital (Fanconi's anemia) - Drugs (e.g. chloramphenicol) Lack of nutrients (Nutritional anemias) - Examples include: o Iron deficiency anemia o Vitamin B12 deficiency anemia o Folic acid deficiency anemia o Deficiency of proteins The core of medical physiology (1) 3 rd edition Page 154

155 Lack of hormones - Examples include: o Erythropoietin deficiency (e.g. chronic renal failure) 2- Anemia due to increased RBC destruction - Causes include: Abnormal RBC shape o Sickle cell anemia (due to Hb S) o Congenital spherocytosis (Due to lack of spectrin) o Congenital elliptocytosis (due to lack of spectrin) Lack of RBC enzymes o Glucose 6 phosphate dehydrogenase deficiency o Pyruvate kinase deficiency Mechanical destruction of RBCs o Malaria o Hypersplenism Other causes o Thalassemia, Autoimmune hemolytic anemia 3- Anemia of blood loss Acute blood loss - Acute bleeding occurs following trauma - The drop in Hb concentration does not occur immediately. It occurs after about 3 days (i.e. after restoration of plasma volume and before restoration of cells). The cells take about 4 weeks to be restored. - Severity of anemia is best assessed by history (information given by the patient or his relatives about the blood loss). Chronic blood loss The core of medical physiology (1) 3 rd edition Page 155

156 - Occurs due to daily loss of small amount of blood over long period of time. This results in iron deficiency anemia (due to loss of iron with blood; about 0.5 mg iron in each ml of blood). - Examples include: Worms like ankylostoma (the hook worm), chronic peptic ulcer and bleeding from a GIT tumor. Diagnosis of anemia Step 1 (symptoms): - Anemia is suspected when patients complain of: o Fatigability, palpitations, breathlessness and headache. Remember that: Mild anemia and even severe anemia that s developed gradually over long time, may be asymptomatic due to compensatory mechanisms. Step 2 (signs): - Doctors do clinical examination looking for: o Pallor of mucus membranes o Tachycardia o High pulse pressure (increased systolic and decreased diastolic pressure) o Signs of the cause or signs of complications - During clinical examination, doctors look for signs of a cause that may be responsible for the anemia (e.g. jaundice indicates hemolytic anemia and severe loss of weight indicates malignancy). At the same time they look for a possible complication of anemia, especially if it is severe. A well known example is anemic heart failure presenting with generalized edema. The core of medical physiology (1) 3 rd edition Page 156

157 Step 3 (investigations): Investigations are required to confirm the diagnosis of anemia. These include: Hb estimation, PCV and RBC count Investigations are also needed to know the cause of anemia. Examples include: o Peripheral blood picture - The shape and color of RBCs under the microscope may give clue about the cause of anemia, look at this table: Table 5.1: Shape of RBCs Color of RBCs Possible causes Microcytic Hypochromic Iron deficiency Thalassemia Macrocytic (Megaloblastic) Normochromic Vitamin B12 deficiency Folic acid deficiency Normocytic Normochromic Anemia of chronic illness Chronic renal failure - Direct microscopy may give additional information. For example fragmented RBCs indicate hemolysis. - High reticulocyte count and bilirubin level in plasma indicate hemolytic anemia. RBC indices - Can be calculated to give similar information as the microscopic peripheral blood picture (i.e. information about the shape and color of RBCs). - They include the following indices: MCV (Mean corpuscular volume) = PCV x 10/RBC; normally = fl (may be up to 100 fl) The core of medical physiology (1) 3 rd edition Page 157

158 - RBCs with higher results are described as macrocytic, lower results are microcytic and normal results are normocytic. MCH (Mean corpuscular hemoglobin) = Hb x 10/RBC - Normally = pg - RBCs with lower results are described as hypochromic while normal results are normochromic. MCHC (Mean corpuscular hemoglobin concentration) = Hb x 100/PCV - Normally = 34% (or 34 g/dl) range: g/dl - RBCs with lower results are described as hypochromic while normal results are normochromic. Investigations for specific causes - For example: o Investigations for iron deficiency like TIBC, iron concentration and ferritin level in plasma (see iron metabolism). o Investigations for chronic renal failure like serum creatinine, urea and electrolytes. o Investigations for leukemia like total WBC count and differential count. Treatment of anemia 1- Treatment of the cause (e.g. stop the site of bleeding) 2- Replacement of the deficient nutrient (e.g. iron and/or folic acid) 3- Correction of the low Hb by blood transfusion (if Hb is very low). This is important to prevent anemic heart failure. However, if heart failure has already developed, it is preferred to transfuse packed cells rather than whole blood, to avoid additional fluid overload. The core of medical physiology (1) 3 rd edition Page 158

159 QUESTIONS FOR SELF ASSESSMENT-6 (BEST OF FIVE) 1. A male fetus during the second trimester of intra-uterine life has: a. about 60% of his total body weight as water b. red blood cells synthesized in the liver c. Gower type of haemoglobin d. anti A antibodies if he is blood group B e. anti D antibodies if he is rhesus negative 2. All the following about haemoglobin s are correct except: a. it consists of two alpha and two beta chains b. its alpha chains are normal c. it is absent in all neonates carrying the genes of sickle cell disease d. it precipitates due to hypoxia causing sickling of leucocytes e. it results in sickle cell anemia 3. Iron: a. is found in high amounts in mother s milk b. is absorbed mainly in the terminal ileum c. is transported in plasma with albumin d. is not stored in the liver e. deficiency causes reduction in volume and color of red blood cells 4. Which of the following is NOT a characteristic of obstructive jaundice: a. pale fatty stool b. normal urine color c. absent urobilinogen from urine d. high conjugated bilirubin in blood e. bleeding tendency 5. The principal hormone needed for red blood cell formation is: a. cortisol b. thyroxin c. vitamin D d. erythropoietin e. parathyroid hormone 6. Iron deficiency anemia is characterized by: a. high PCV b. aplastic bone marrow c. pale fatty stool d. low ferritin level in the plasma e. macrocytic normochromic RBCs The core of medical physiology (1) 3 rd edition Page 159

160 7. Concerning folic acid, it is: a. a fat soluble vitamin b. found in green leafy vegetable c. absorbed better in presence of reducing factors d. antagonized by vitamin B12 e. required for myelin formation 8. Hemolytic jaundice is characterized by: a. high concentration of conjugated bilirubin in urine b. high concentration of unconjugated bilirubin in plasma c. absence of urobilinogen in urine d. pale and fatty stool e. abnormal function of the liver 9. The red bone marrow in an adult is found at all these sites except: a. skull b. ribs c. pelvic bones d. shaft of the femur e. sternum 10. Reticulocytes are: a. precursors of white blood cells b. not present in normal blood c. increased in bacterial infections d. decreased in haemolytic anemia e. increased following correction of nutritional anemia 11. The mature red blood cell in children: a. is synthesized in the spleen b. has few mitochondria c. its volume increases in folic acid deficiency d. of males has more hemoglobin than that of females e. lives for about 8 hours 12. Concerning the packed cell volume (PCV), it is: a. the percentage of RBCs out of total cells in the blood b. higher in neonates than in infants c. normally about 37% in the adult male d. high in patients with haemolytic anemia e. low in all subjects living at high altitude 13. Erythropoietin: a. is stimulated by increased oxygen tension. b. Is needed for Hb synthesis c. reduces maturation time of red blood cells. d. its level is always high in people living at high altitudes e. its level is always low in patients with chronic kidney failure. The core of medical physiology (1) 3 rd edition Page 160

161 14. Hb S: a. is similar to Hb F b. is characterized by abnormal alpha chains c. starts to appear in normal children after the age of 6 months d. precipitates when there is hypoxia e. is an important protective mechanism against malaria 15. Regarding iron absorption, it is: a. hormonally controlled b. decreased by HCL c. Increased by intrinsic factor of the stomach d. decreased by penicillin e. about 10% of daily ingested iron 16. Hyperactivity in the bone marrow is indicated by: a. jaundice b. anaemia c. leucocytosis d. thrombocytosis e. reticulocytosis 17. Microcytic hypochromic anemia occurs due to: a. acute renal failure b. hepatic cirrhosis c. congestive heart failure d. chronic peptic ulcer e. filariasis 18. Vitamin B12: a. is found in green vegetables b. is absorbed in the stomach c. is needed for haemoglobin synthesis d. deficiency causes normocytic normochromic anemia e. deficiency results in demyelination neuropathy 19. Hb concentration in a pregnant lady is 9 g/dl, PCV is 36% and RBC count is 3 x 10 6 cell/mm 3. Which of the following is not true: a. mean corpuscular hemoglobin is normal b. iron status is probably normal c. volume of red blood cells is above normal d. this lady most probably suffers from vit. B12 deficiency e. folate deficiency is expected in this patient Question Answer b d e b d d b b d e Question Answer c b e d e e d e d The core of medical physiology (1) 3 rd edition Page 161

162 LEUCOCYTES Definition - The motile units in the blood that protect the body against invaders. Count /mm 3 - Higher count (leucocytosis) is caused by leukemia, infections, inflammation... - Lower count (leucopenia) is caused by certain diseases of the bone marrow and certain infections (e.g. typhoid fever). Formation of WBCs Site: bone marrow Stages: (Proliferation & Maturation) - Like other types of cells, formation starts by differentiation of pluripotent stem cells into committed stem cells (progenitor cells). - There are separate committed stem cells for lymphocytes, basophils and eosinophils, whereas neutrophils and monocytes have a common precursor. Regulation: by certain colony stimulating factors (GM-CSF) and cytokines (IL3, IL4 and IL5). Classification - According to presence or absence of cytoplasmic granules, they are classified into two major types: o Granulocytes o Agranulocytes The granulocytes: - Have granulated cytoplasm - Have polysegmented nucleus The core of medical physiology (1) 3 rd edition Page 162

163 - known as poly-morpho-nuclear leucocytes [PMNL]). - Have very short life span (Hours) - Have 3 types (according to reaction of the cytoplasmic granules with acidic or basic dyes): 1- Neutrophils: the granules react with basic and acidic dyes 2- Eosinophils (Acidophils):the granules react with acidic dyes (e.g. eosin dye) 3- Basophils:the granules react with basic dyes (e.g. mythelene blue dye) Neutrophils - Constitute 50-70% of total WBCs (the most abundant type) - Nucleus: segmented (3-5 lobes) - Cytoplasm: granulated - Granules: react with acidic and basic dyes, purple in color Fig 5.5: Neutrophil - Can phagocytose bacteria and then perform intracellular killing (see below). - Increased in: o Bacterial infections o Stressful stimuli o Hormones (adrenaline/cortisol) The core of medical physiology (1) 3 rd edition Page 163

164 Eosinophils (Acidophils) - Constitute 1-4% of total WBCs - Nucleus: segmented (2-3 lobes) - Cytoplasm: granulated - Granules: bright red in color. React with acidic dyes (like eosin). Fig 5.6: Eosinophil - Increased in: o Parasitic infections (attack parasites that are too large to be phagocytosed). o Allergic reactions (e.g. asthma). - They release proteins, cytokines and chemokines that can induce inflammation and kill microorganisms (e.g. Major basic protein and Leukotriene C 4 ) Basophils - Constitute (0-0.4%) of total WBCs (i.e. they are the least abundant WBCs) - Nucleus: may be segmented but hidden by the granules - Cytoplasm: granulated. The granules: rough, dense and dark blue in color. They obscure the nucleus behind them. The core of medical physiology (1) 3 rd edition Page 164

165 Fig 5.7: Basophil - The granules contain heparin and histamine (similar to mast cells). They react with basic dyes like methylene blue dye. - They release their contents in response to stimulation from T lymphocytes. - They are essential in immediate hypersensitivity reactions - Generally increased in allergic reactions (e.g. allergic rhinitis and allergic dermatitis). Agranulocytes - Generally have non-granulated cytoplasm (they may have few fine granules). - Have one nucleus (not segmented) - Have longer life span (days, months or years) - Two types: Monocytes and lymphocytes Monocytes - Have larger diameter than other types of WBCs - Constitute 2-8% of total WBCs - Nucleus: kidney shaped - Cytoplasm: not granulated - They can phagocytose bacteria and kill it intracellularly The core of medical physiology (1) 3 rd edition Page 165

166 Fig 5.8: Monocyte - They stay in the circulation for (2-3 days) and then enter the tissues where they transform into tissue macrophages. However, the life span of tissue macrophages is uncertain; may be 3 months or more. - Tissue macrophages include: Kupffer cells in the liver, Langerhans cells in the skin, Microglia in the brain, Osteoclasts in bone and Alveolar macrophages in the lung (= members of the mononuclear phagocyte system, used to be known as reticulo-endothelial system). - Functions of the tissue macrophages (or the phagocyte system): Phagocytosis (activated of phagocytes by T lymphocytes) Presentation of antigens to lymphocytes Release of cytokines and other substances (see immunity). Lymphocytes - Constitute 20-40% of total WBCs - Size: may be small or large - Nucleus: rounded - Cytoplasm: scanty and not granulated. The core of medical physiology (1) 3 rd edition Page 166

167 Fig 5.9: Lymphocyte - Before birth, they are produced in the bone marrow as lymphocyte precursor cells. - Then after birth, some still arise from bone marrow. However, most lymphocytes are formed in the lymph nodes, thymus or spleen, from the original precursor cells that developed in the bone marrow and processed in one of the following sites: Thymus gland or Burza of Fabricius (in birds) /or burza equivalent tissues like the fetal liver and the bone marrow (in humans) - Accordingly there are 2 types of lymphocytes: - T-Lymphocytes (processed in the thymus gland) & - B-Lymphocytes (processed in the Burza equivalent tissues). The two types circulate between blood and lymph. T-Lymphocytes: - Constitute about 80% of total lymphocytes - Mature in the thymus gland - Types: Helper T cells (CD4 cells) & cytotoxic T cells (CD8 cells). - When activated, the T lymphocyte form memory T cells; for future recognition of the invader (= the secondary immune response) - They are responsible for cell mediated immunity (see below) The core of medical physiology (1) 3 rd edition Page 167

168 B-Lymphocytes: - Constitute about 20% of total lymphocytes. - Maturate in the bone marrow - When activated, they differentiate into plasma cells (for production of antibodies) and memory B cells (for future recognition of the invader, = the secondary immune response) - Responsible for humoral immunity; i.e. secretion of antibodies that are mixed with body fluids (see below) How can white blood cells perform their functions? Chemotaxis - Attraction of neutrophils to the site of infection by certain substances including components of the complement system (C5a), leukotrienes and products of damaged tissues, bacteria or leucocytes. Diapedisis - Passage of white blood cells from the blood to the tissues through the wall of capillaries (e.g. neutrophils, basophils, eosinophils and monocytes). Opsonization - Preparation for eating or making the foreign cell palatable or tasty for phagocytosis. Opsonins that coat foreign cells include IgG and some proteins of the complement system. Phagocytosis - The process of ingestion of bacteria or any abnormal cell by a phagocytic cell (e.g. neutrophils, Monocytes or macrophages). - Preceded by recognition and followed by intracellular killing. The core of medical physiology (1) 3 rd edition Page 168

169 Intracellular killing - Fusion of cytoplasmic granules in the phagocytic cell with the phagocytic vacuole, then release of the antimicrobial agents found within these granules into the vacuole. - The antimicrobial agents found within the granules of neutrophils include: o Defensins o Proteases (elastase, metalloproteinases) - Other antimicrobial agents released by neutrophils: o Toxic oxygen metabolites (O - 2, H 2 O 2 ) o Oxidants (HOCl, HOBr, ) - - The toxic oxygen metabolites (O 2, H 2 O 2 ) are oxidants formed following activation of a cell membrane bound enzyme (NADPH oxidase). - It is associated with a process known as the respiratory burst, characterized by marked increase in oxygen uptake and metabolism in the neutrophil. - Steps of formation: NADPH + H + + 2O 2 = NADP + + 2H O 2 O O H + + H + = H2O2 + O 2 (The second step is catalyzed by the enzyme superoxide dismutase (SOD)) - Formation of the other oxidants (HOCl, HOBr) is catalyzed by the enzyme myeloperoxidase. - Notice that certain types of bacteria can resist intracellular killing and remain viable within the WBCs. The core of medical physiology (1) 3 rd edition Page 169

170 IMMUNITY - The physiological process by which the body destroys or neutralizes foreign particles. Includes two types: o Non specific immunity (Innate immunity) (Does not depend on recognition of the invader (i.e. non specific)) o Specific immunity (Depends on recognition of the invader) Non specific immunity (Innate immunity) - The first line of defense against invaders. It includes: Natural barriers Inflammation Natural killer cells Complement system Natural barriers: - Prevent invasion of tissues by microorganism. They include: o Anatomical barriers (e.g. skin and mucus membranes) o Biochemical barriers (e.g. saliva, tears and gastric acid) o Mechanical barriers (e.g. cough and vomiting) Inflammation: = The response of the body to infection. It acts to localize infection. It involves: o Attraction of WBCs to the site of infection o Release of active substances by WBCs o The active substances destroy the microorganisms. However, they also damage tissues and result in changes in blood vessels (e.g. vasodilatation and increased permeability). - Signs of inflammation: redness, swelling, pain & loss of function. The core of medical physiology (1) 3 rd edition Page 170

171 Natural killer cells (= NK cells) - A small fraction of circulating lymphocytes is neither T nor B lymphocytes; most of these are natural killer cells (NK cells). - They resemble cytotoxic lymphocytes in killing their targets by releasing granules containing cytolytic enzymes (perforins). However, they differ from them in that: o They kill naturally (generally they do not need activation, however, they may become activated by interferons α and β. o They attack cells which lack class I MHC antigens on their membranes; these include some virus infected cells (because some viruses inhibit expression of MHC-I antigens) & tumor cells (because these have low or no class I MHC expression). The complement system - Group of proteins (30 or more), activated to produce a cell killing effect. - They include: (C1 (has 3 subunits: q, r and s), C2, C3a, C3b, C4, C5, C6, C7, C8, C9, factor B, factor D, factor H, factor I ). - Most of these proteins are inactive beta globulins (= 5% of all globulins). - They are activated by: Classic pathway - Triggered by antigen-antibody complexes. - The first factor to be activated is C1 (see fig 5.10). Alternative pathway - Triggered by the surface of pathogens like bacteria or viruses. - The first factor to be activated is C3 (see fig 5.10). Lectin pathway The core of medical physiology (1) 3 rd edition Page 171

172 - Triggered by contact of lectin with certain carbohydrate groups (mannose) in bacterial wall (mannose-binding lectin (MBL)). - MBL acts like C1q it activates C2 & C4, then other steps follow. Fig 5.10: Activation of the complement ystem Mechanism of action: - The cell killing effect of the complement proteins is achieved by: Opsonization (e.g. by C1q and C3b) Chemotaxis (e.g. by C5a) Cell lysis (by the perforating complex C5b6789) Degranulation of mast cells to release histamine (e.g. by C3a) The core of medical physiology (1) 3 rd edition Page 172

173 Remember that: - Complement proteins are tightly regulated by complement control proteins that inhibit their damaging effects on the normal cells. - Deficiency of some of the complement proteins may predispose to repeated infections (e.g. meningitis). Specific immunity - Depends on the action of lymphocytes which, in addition to their immediate defensive role, form memory cells for future recognition of the invaders. - This explains the fact that a secondary immune response (induced by subsequent exposure to an antigen) is always more rapid and stronger than a primary immune response (induced by first exposure to the antigen). - Antigens are presented to lymphocytes by antigen presenting cells which, after phagocytosis, present some of the invader antigens on their surface; to be recognized by the lymphocytes. - The antigen presenting cells are: o Dendritic cells (found in lymph nodes spleen and skin) o Macrophages (in different tissues) o Native B lymphocytes (can bind antigen directly through IgM antibodies expressed on their surface. However, they need T helper cells for full activation (see below)). - After recognition of the antigen, the lymphocytes proliferate and mediate two types of specific immunity: o Cell mediated immunity (mediated through activation and proliferation of T lymphocytes). The core of medical physiology (1) 3 rd edition Page 173

174 o Humoral immunity (mediated through activation and proliferation of B lymphocytes). Cell mediated immunity - T helper lymphocytes recognize antigens presented by the antigen presenting cells when these antigens are linked with the major histocompatibility proteins type II (MHC-II). - Certain markers on the surface of T helper cells (known as cluster of differentiation 4 or CD4) facilitate this recognition. Fig 5.11: Proliferation of T helper cells - The activated T helper cells release cytokines for activation of T cytotoxic lymphocytes, natural killer cells and macrophages. These attack primarily virus infected cells, intracellular bacteria, fungi, protozoa and cancer cells. In addition they play an important role in rejection of transplanted organs. The cytokines also activate the B lymphocytes. The core of medical physiology (1) 3 rd edition Page 174

175 - The Cytotoxic T cells can recognize antigens presented by the virus infected cells when these antigens are linked with the major histocompatibility proteins type I (MHC-I). - Certain markers on the surface of cytotoxic T cells (known as cluster of differentiation 8 (CD8)) facilitate this recognition. They kill their targets by releasing proteins known as perforins into them. These make pores into the virus infected cells and initiate apoptosis. Fig 5.12: Proliferation of cytotoxic T cells - It is important to notice that T helper lymphocytes are two types: o T helper 1 (T H1 ): the principal cells activated in cellular immunity o T helper 2 (T H2 ): interacts with B lymphocytes in relation to humeral immunity - Examples of the cytokines released By T H1 : o IL-2 (activates lymphocyte proliferation (autocrine effect), natural killer (NK) cells and macrophages) o Interferon (IFNγ activates macrophages and inhibits T H2 ) The core of medical physiology (1) 3 rd edition Page 175

176 - Examples of the cytokines released by T H2 : o IL 4 (activates B lymphocytes to produce IgE antibodies) o IL-5 (stimulates differentiation of eosinophils) - Human immuno-deficiency virus (HIV) attacks CD4 cells (T helper cells); resulting in failure of cytokine production and therefore failure of activation and proliferation lymphocytes and macrophages. This causes acquired immune-deficiency syndrome (AIDS) and renders the body susceptible for infection (with even the nonpathogenic bacteria) and cancer. Humoral Immunity - Activated B-lymphocytes transform into plasma cells and produce large number of antibodies - The antibodies attack the invaders in different ways (see below). - Unlike cell mediated immunity, humoral immunity is directed mainly against extracellular organisms like bacteria). Note: - Proteins of the major histocompatibility complex (MHC) are encoded by genes located on the short arm of chromosome 6. These proteins are found on the outer surface of body cells and they are unique for each person. In humans they are known as human leukocyte antigens (HLA). - The MHC genes are classified into 3 classes: Class I o Encodes for MHC-I proteins, which are coupled with antigens formed within the cell (e.g. formed by intracellular virus). These proteins are found on all nucleated cells. They are recognized by CD8 cells. The core of medical physiology (1) 3 rd edition Page 176

177 Class II o Encodes for MHC-II proteins, which are coupled with antigens of extracellular organisms like bacteria. The antigens are selected after phagocytosis of bacteria and then presented in association with MHC-II proteins. Therefore these proteins are found on antigen presenting cells. They are recognized by CD4 cells. Class III o Encodes for some immunological proteins (e.g. some cytokines and complement proteins). The cytokines - Cytokines are proteins produced by a wide variety of immune and non-immune cell types. - They are involved in regulation of growth, development, and activation of immunity and in the mediation of inflammation. - A single cytokine can be released by different cells and different cytokines may have similar functions and can act on different cells. - Actions of cytokines may be: o Autocrine: the cytokine acts on the same cell that secretes it o Paracrine: the cytokine acts on a nearby cell o Endocrine: the cytokine circulates in blood and acts on distant cells - Cytokines have names that describe their targets or their functions. For example, cytokines acting on leucocytes are interleukins (IL-1, 2, 3, 4 ); whereas cytokines stimulating hematopoiesis are colony stimulating factors (granulocyte-monocyte colony-stimulating factor). The core of medical physiology (1) 3 rd edition Page 177

178 - Chemokines are cytokines that regulate cell movement (e.g. Chemotaxis which is regulated by the chemokines IL-8 & RANTES). Table 5.2: Examples of some cytokines and their functions Cytokine Cell source IL-1 Macrophages Epithelial cells Fibroblasts Function Hematopoiesis Fever & hepatic acute phase proteins Activation of WBCs IL-2 T cells Activation & proliferation of T cells Activation of B cells, NK cells and macrophages IL-3 IL-4 T cells NK cells T cells Mast cells Hematopoiesis Stimulation of B cells to secrete antibodies Stimulation of T H2 proliferation Activation of eosinophils IL-5 T cells, mast cells & eosinophils IL-6 B cells Fever & induction of acute phase Epithelial cells proteins from the liver Fibroblasts T & B cell differentiation IL-8 Macrophages, Chemotaxis WBCs, fibroblasts Release of histamine from basophils & endothelial cells IL-12 Macrophages Induces T H1 cell formation Neutrophils IFN α & β All cells Anti-viral activity. Stimulate T cell, macrophage, and NK cell activity. Direct anti-tumor effects IFN γ (interferon - γ) TNFα (tumor necrosis factor α) RANTES T cells NK cells Macrophages Most WBCs Epithelial cells Fibroblasts Macrophages, T cells, fibroblasts & basophils Regulates macrophage and NK cell activations. Stimulates immunoglobulin secretion by B cells Fever, anorexia, shock, capillary leak Leukocyte cytotoxicity, enhanced NK cell function, acute phase protein synthesis, pro-inflammatory cytokine production Chemotaxis Induces release of histamine from basophils The core of medical physiology (1) 3 rd edition Page 178

179 The antibodies - Gamma globulins, called immuno-globulins or (Ig); produced by activated B-lymphocytes (known as plasma cells). Structure of the basic unit of antibodies: - 2 heavy chains & 2 light chains connected by disulfide bridges. - Each chain consists of both variable (V) and constant (C) regions. - The C regions form the Fc portion for cell binding whereas the V regions form the Fab portion for antigen binding. - The variable regions have variable sequences of amino-acids; this makes the Fab portion in each immunoglobulin molecule differs from Fab portions in other molecules. That s why antibodies secreted against specific antigen do not attack other antigens. Remember that: Each antibody attacks only one specific antigen by its antigen binding site (Fab portion). Fig 5.13: The basic structure of antibodies The core of medical physiology (1) 3 rd edition Page 179

180 - The immunoglobulins (Ig) are classified according to the types of heavy chains into 5 types: G, M, A, E and D; therefore they are described as IgG, IgM, IgA, IgE and IgD. IgG: - The most abundant (constitutes more than 75% of total immunoglobulins in plasma). - The smallest type (monomer: has two sites for binding antigens) - The only type that can cross the placenta from the mother to the fetus to protect him from micro-organisms (= passive immunity) - IgG is the main antibody in the secondary immune response (i.e. the immune response following exposure to an antigen for the second time or more) IgM: - The largest type - Pentamer (5 of the basic units connected together) - It is the main antibody in the primary immune response (i.e. the immune response following exposure to an antigen for the first time). The secondary immune response is more faster and stronger than the primary immune response due to presence of memory cells formed during the primary response. They immediately react with the antigen and result in secretion of adequate amounts of IgG antibodies against the antigen IgA: - Monomer, dimer or trimer - In addition to plasma, it is also found on the mucosal surfaces (e.g. mucosa of the GIT, genitor-urinary and respiratory systems), The core of medical physiology (1) 3 rd edition Page 180

181 and in body secretions like saliva, milk and tears. For this reason it is called the secretory immunoglobulin. - Plays an important defensive role at these sites against colonization of mucosa by pathogens. IgE: - After its formation during a primary immune response induced by certain allergens, it becomes attached to membranes of mast cells & basophils through the Fc portion. Then during a subsequent exposure to the same allergen, it binds the allergen through the Fab portion. This induces release of histamine from these cells causing symptoms and signs of immediate hypersensitivity reaction and sometimes a severe anaphylactic shock due to profound vasodilatation. - In addition to its role in allergic reactions, it also offers protection against parasites (e.g. worms). IgD: - Has unknown function; may be antigen antibody recognition (may act as antigen binding receptor on B lymphocytes). Mechanisms of action of the immunoglobulins Opsonization of bacteria to facilitate phagocytosis (e.g. IgG) Neutralization of some toxins Blocking attachment of some viruses and bacteria to cells Activation of the complement system (IgG and IgM antibodies) Agglutination of group of cells or substances together to prevent their spread; to be captured by phagocytes in one action Precipitation of some antigen-antibody complexes Degranulation of mast cells and basophils (release of histamine) The core of medical physiology (1) 3 rd edition Page 181

182 QUESTIONS FOR SELF ASSESSMENT-7 (BEST OF FIVE) 1. Concerning the white blood cells, which of the following is true: a. neutrophils are increased in viral infections b. basophils are increased in parasitic infections c. eosinophils have kidney shaped nuclei d. monocytes phagocytose bacteria e. lymphocytes release histamine 2. B- Lymphocytes are: a. phagocytic cells produced by the bone marrow b. premature cells activated in the thymus gland c. the dominant type of lymphocytes d. responsible for humeral immunity e. increased in bacterial infections 3. The major basic protein is: a. found in the granules of eosinophils b. involved in allergic reactions c. an anti-parasitic substance d. a cause of bronchospasm in asthmatic patients e. all the above statements are true 4. Which of the following antibodies is found in mother s milk: a. IgA b. IgM c. IgG d. IgD e. IgE 5. A stained blood film of a patient with hypersplenism shows: a. neutropenia with reticulocytosis b. thrombocytopenia with erythroblastosis c. anemia with neutrophilia d. anemia with agranulocytosis e. pancytopenia with reticulocytosis 6. Concerning natural killer cells, which of the following is not true: a. they are non T, non B lymphocytes b. they attack tumor cells c. they attack antigens presented with class I MHC proteins d. they kill virus infected cells by releasing perforins e. they are similar to T-cytotoxic lymphocytes 7. B lymphocytes differ from T lymphocytes in that they: a. have large oval nuclei b. may act as antigen presenting cells c. form memory cells d. populate lymph nodes e. play an important role in immunity The core of medical physiology (1) 3 rd edition Page 182

183 8. Regarding T-Lymphocytes, which of the following is correct: a. helper cells recognize antigens when presented in association with MHC class I b. cytotoxic cells expose CD4 molecules on their membranes c. major cytokines are released by the CD8 cells d. TNFα is immediately released by T helper cells after their activation e. T lymphocytes constitute the majority of lymphocytes in circulation 9. Acute bacterial infections are characterized by high count of: a. neutrophils b. basophils c. monocytes d. lymphocytes e. both a & c 10. A stained normal blood film shows: a. 20% nuetrophils. b. 4% basophils. c. 8% lymphocytes. d. 4% monocytes. e. 11% eosinophils. 11. "T Lymphocytes" differ from "neutrophils" in all the following except: a. their cytoplasm is not granulated b. they are not markedly increased in bacterial infections c. they are attacked by the Human Immunodeficiency Virus (HIV) d. they cannot produce antibodies e. their nuclei are not segmented 12. Neutrophils: a. have granules containing heparin b. are produced in the thymus gland c. can leave the blood and enter tissues d. live up to three days e. are increased in viral infections 13. Immunogloblin: a. D has the largest size b. E is found in milk c. G is found mainly in primary immune response d. M is the only type that activates complement proteins e. A is found in the mucosa of the respiratory tract 14. Immunoglobulin M (IgM) is: a. described as the secretory immunoglobulin b. most abundant in the secondary immune response c. the dominant type of immunoglobulin in plasma d. the antibody type directed against antigens of the ABO system e. found on surface of mast cells The core of medical physiology (1) 3 rd edition Page 183

184 15. The following cytokine is not released by T lymphocytes: a. IL-1 b. IL-2 c. IL-3 d. IL-4 e. IFNγ 16. Attraction of neutrophils to the site of infection occurs by: a. phagocytosis b. coagulation c. diapedesis d. agglutination e. Chemotaxis 17. Phagocytosis is the major function of: a. B lymphocytes b. neutrophils c. endothelial cells d. basophils e. eosinophils 18. Development of acquired immunity requires all the following except: a. B lymphocytes b. T lymphocytes c. Macrophages d. Major histocompatibility complex e. Basophils 19. This cell presents antigens to T helper with MHC class II proteins: a. virus infected cell b. tumor cell c. dendritic cell d. mast cell e. NK cell 20. Which of the following factors is not a chemotactic agent: a. IL-8 b. C5b c. RANTES d. C3a e. Leukotrienes Question o o o o o o o o o o Answer d d e a e c b e a d Question o o o o o o o o o o Answer d c e d a e b e c d The core of medical physiology (1) 3 rd edition Page 184

185 BLOOD GROUPS AND BLOOD TRANSFUSION BLOOD GROUPS = Antigens found on the surface of red blood cells Importance - Blood transfusion - Exclusion of paternity (paternity can be excluded by blood groups; however, its confirmation requires DNA fingerprinting). Types - There is large number of these antigens. - The most important are: ABO system & rhesus system. - Others (of less importance): MNS, Lutheran, Kell, Kidd, Duffy The ABO System Antigens (Agglutinogens): A & B - Two antigens on surface of RBCs: A & B. - Accordingly there are 4 blood groups: Blood group A has antigen A Blood group B has antigen B Blood group AB has both antigens A & B Blood group O has neither antigen A nor B. -These antigens are also found in other tissues (salivary glands, kidney, liver, lung, pancreas, testes and amniotic fluid). - They are glycosphingolipids in RBCs but glycoproteins in the other tissues. - Basically, all groups have H antigens. In individuals with blood group O, all the H antigens persist without conversion into antigen A or B. In individuals with blood group A or B, the H antigens are converted into antigens A or B respectively. This is achieved by The core of medical physiology (1) 3 rd edition Page 185

186 adding N-acetylgalactosamine to H antigens in blood group A, or adding galactose to H antigens in blood group B. - A and B glycoproteins are secreted by tissue cells into the circulation. Some individuals are non-secretors. They are susceptible to a variety of infections because the glycoproteins may bind to polysaccharides on cells and block attachment of bacteria to these polysaccharides. Antibodies (Agglutinins): anti A & anti B - Anti A and anti B antibodies (of IgM type) are acquired naturally after birth by unknown mechanism. - Suggested mechanisms for their formation in neonates after birth: Food contains antigens similar to A & B antigens. Ingestion and absorption of these antigens induce the immune system to attack them by antibodies that circulate in the blood as anti A & anti B antibodies. Certain intestinal bacteria contain antigens similar to A & B antigens. If these bacteria infect the neonate, the immune system will form antibodies against the bacterial antigens. These antibodies circulate as anti A and anti B antibodies. - The most interesting fact is that: The body forms antibodies against the ABO antigens not present on surface of red blood cells. For example a subject with group A has antigen A on RBC membranes, so his body forms antibodies against B antigen (anti B antibodies). - Accordingly, plasma contains the following types of antibodies: Anti A antibodies in subjects with blood group B Anti B antibodies in subjects with blood group A Anti A & anti B antibodies in subjects with blood group O The core of medical physiology (1) 3 rd edition Page 186

187 No antibodies in subjects with blood group AB Donors (In blood transfusion) - Selection of a donor depends on absence of antigens on RBCs of the donor that may react with antibodies in plasma of the recipient (i.e. reactions between donor s cells & recipient s plasma or serum ). - On the other hand, reaction between the donor s plasma and recipient s cells is neglected. This is because the volume of blood collected from the donor is about 500 ml and therefore the amount of antibodies in the plasma of this blood is very small. In addition to that, it will become diluted in the plasma of the recipient. - Accordingly, donors are selected for each blood group as follows: Donors for blood group (A) are those with blood groups A & O Donors for blood group (B) are those with blood groups B & O Donors for group (AB) are those with blood groups A, B, AB, O Donors for blood group (O) are those with blood group O Notes to remember about the donors: Subjects with blood group AB can receive blood from every blood group (they are described universal recipients) Subjects with blood group O can give blood to every blood group (they are described as universal donors). Inheritance: Autosomal dominant - Blood group antigens are inherited from each parent as autosomal dominant characters in chromosome 9p (i.e. A & B antigens are inherited in the two copies of chr 9, from the father and the mother). - Therefore, the genotype for each blood group will be as follows: Blood group A: the genotype is [AA] or [AO] Blood group B: the genotype is [BB] or [BO] The core of medical physiology (1) 3 rd edition Page 187

188 Blood group AB: the genotype is [AB] Blood group O: the genotype is [OO] - If a father and his wife have blood groups A and B respectively, their children may have any type of blood groups (A, B, AB or O). But, if they are A and A, their children may have either A or O only. Distribution (%) - The ABO blood groups are distributed as follows: Blood group A is found in about 42% of population Blood group B is found in about 8% of population Blood group AB is found in about 3% of population Blood group O is found in about 47% of population Notes to remember about distribution of blood groups: The most dominant blood group is O (blood group of the universal donors) and the least dominant is AB (blood group of the universal recipients). The Rhesus System - First studied in the rhesus monkeys. Antigens: D - Include antigens C, c, D, E, e. - Unlike the ABO antigens, these proteins are only found on RBCs (not found in other tissues). - The most important of these antigens is antigen D (has the highest antigenisty). - Accordingly, there are (2) types of rhesus groups: Rh +ve (antigen D is present on RBC surface) Rh -ve (antigen D is absent from RBC surface) The core of medical physiology (1) 3 rd edition Page 188

189 Antibodies: anti D - Unlike the anti A & anti B antibodies, antibodies of the rhesus system (anti D antibodies) are of the IgG type (i.e. the smallest type that can cross the placenta from maternal blood to fetal blood). - Also unlike anti A and anti B antibodies, anti D antibodies are not naturally acquired after birth. - They develop only in (Rh -ve) subjects (never in Rh +ve subjects). - Causes of their development in rhesus ve subjects: Blood transfusion of Rh +ve blood to Rh ve subjects Delivery of (Rh +ve) baby by Rh ve mothers (During labor, the placenta separates from the uterus resulting in bleeding and entrance of some fetal blood in maternal circulation Donors - Rh +ve subjects do not have anti D antibodies. They can receive blood from Rh +ve & Rh ve subjects. - Rh -ve subjects do not have anti D antibodies unless they receive Rh +ve blood. Therefore, they should receive Rh -ve blood only. - During emergencies, Rh ve blood is not always available; that s why rhesus ve subjects may receive Rh +ve blood for the first time. This induces formation of anti D antibodies in his plasma within 3 days after the transfusion. - Therefore, any future transfusion of Rh +ve blood is contraindicated because it will be associated with severe reaction. Inheritance - Autosomal dominant character in chromosome 1. - Chrmosome 1 carries E or e plus D or without D (absence of D is indicated as d) plus C or c. For example: Cde or cde or CdE The core of medical physiology (1) 3 rd edition Page 189

190 - Since antigen D determines the rhesus group, genotype for each group (chromosomes from father and mother) will be as follows: Rh +ve genotypes: DD or Dd Rh ve genotype: dd Remember that: A child of a rhesus +ve father & rhesus +ve mother can be either Rh +ve or a Rh ve (if the genotype of both father and mother is Dd ). A child of a rhesus -ve father & rhesus -ve mother should be Rh ve. Distribution (%) - Percentage of subjects with Rh +ve blood group, in all populations, is far higher than that of Rh ve subjects. - For example: 99% are Rh +ve & only 1% are Rh ve in Europe. In other communities, the percentage of rhesus positive subjects is about 85% and 15% for Rh ve subjects. Remember that: In the ABO system of blood grouping, transfusion of a mismatched blood (e.g. group A subject receiving blood group B) is always associated with severe reaction. In the Rhesus system, blood transfusion reactions are: - Never expected for Rh +ve subject receiving Rh ve blood - Not expected in the first blood transfusion for Rh -ve subject receiving Rh +ve blood - Always expected in subsequent transfusions for Rh ve subject receiving Rh +ve blood The core of medical physiology (1) 3 rd edition Page 190

191 Hemolytic disease of the newborn - Also known as erythroblastosis fetalis because the early stages of RBCs (erythroblasts) appear in fetal blood together with reticulocytes as compensation to the excessive hemolysis. - It occurs in Rh +ve neonates of Rh ve mothers. - During delivery of the first Rh +ve neonate, some of his blood enters maternal circulation. The delivered neonate is normal; but the mother forms anti D antibodies of IgG type to get rid of the baby s RBCs (i.e. she becomes immunized). - When she becomes pregnant again with a Rh +ve fetus, these antibodies cross the placenta, enter the fetal circulation and attack RBCs of the fetus who develops hemolytic anemia and jaundice. - The hemolytic anemia is associated with hyperactive bone marrow to replace the lost RBCs. This results in appearance of the early stages of RBC in fetal blood (erythroblastosis & reticulocytosis). - Anemia may become complicated by heart failure associated with generalized edema (hydrops fetalis) and the fetus may die in utero. - The jaundice is caused by unconjugated bilirubin which is insoluble in water. It may precipitate in the basal ganglia in the brain causing Kernicterus (characterized by motor problems and may be associated with mental retardation). - If the newborn is delivered with jaundice, he can be treated with: Phototherapy: converts the insoluble bilirubin to a water soluble substance, lumirubin, that s soluble (do not precipitate in the brain) and can be excreted easily in urine Exchange transfusion: taking Rh +ve blood from the neonate and giving him Rh ve blood The core of medical physiology (1) 3 rd edition Page 191

192 Plasmapheresis: usage of a machine that extracts the antibodies from blood of the neonate - Prevention is better than cure. Here an injection of anti D antibodies given to the mother immediately following labor and not more than 72 hours after it will attack fetal RBCs that carry the rhesus antigen and therefore prevent formation of anti D antibodies by the mother herself. Remember that: Antibodies injected to a subject stay in the circulation for short time and then disappears completely. Antibodies formed by a subject himself stay in the circulation for very long time because memory cells continue to secrete the antibodies for life. - Sometimes, ABO incompatibility between the mother and the neonate offers some natural protection against the hemolytic disease. For example when the mother is blood group A and the neonate is blood group B, here the naturally occurring anti B antibodies in maternal blood attack RBCs of the neonate as soon as they enter maternal circulation and therefore prevent formation of anti D antibodies. The core of medical physiology (1) 3 rd edition Page 192

193 Blood transfusion Precautions - When blood is infused intravenously into patients, plasma of the patients should not contain antibodies that may react with blood group antigens on RBCs of the donor. - To achieve this, suitable donors should be selected for each blood group, and this is further confirmed by cross matching test. - In cross matching test the plasma of the recipient (containing antibodies) is mixed with the donor's blood and then examined under the microscope for evidence of agglutination of the RBCs. Agglutination indicates that the blood of the donor is not suitable for the recipient. - In spite of this, errors may occur and unfortunate patients may receive mismatched blood by accident. For this reason, blood transfusion should always be taken seriously, with certain precautions, including release of a few drops at first to make sure that there is no reaction and close follow up of the process, putting life saving drugs at reach beside the patient. Complications of mismatched blood transfusion Agglutination of RBCs, followed by hemolysis: o In mild cases, agglutination of RBCs may be complicated by posttransfusion jaundice. o In severe reaction, a few ml of blood are sufficient to cause severe pain in the back or in other sites and tightness in the chest (due to block of capillaries by the agglutinated RBCs). This is also followed by hemolysis of the RBCs and release of hemoglobin in plasma. The core of medical physiology (1) 3 rd edition Page 193

194 Acute renal failure: o Some of the intravascular hemoglobin is filtered at the glomeruli and excreted in urine (hemoglobinuria). o Some precipitates in the renal tubule resulting, in addition to the low blood pressure, in acute renal failure. o Acute renal failure is characterized by low urine output, high urea and high potassium ions. Death may occur in few days. Disseminated intravascular coagulation (DIC): o In severe cases, antigen-antibody reactions may result in activation of coagulation causing DIC and therefore fatal bleeding due consumption of the clotting factors. Complications of compatible blood transfusion o Hyperkalemia due to potassium released from hemolysed RBCs during storage of blood o Hypocalcemia due to excess anticoagulant (e.g. citrate, which is a calcium chelating agent) o Fever (febrile reaction) due to pyrogens and/or cytokines in the donor s blood o Allergy (allergic reaction) due to allergens in the donor s blood; sometimes severe anaphylaxis may occur. o Transmission of infection due to transfusion of infected blood (e.g. HIV, Hepatitis B, malaria ) o Air embolism o Thrombophlebitis at the injection site o Fluid overload especially in patients with heart failure o Iron overload due to repeated blood transfusions (hemosiderosis) The core of medical physiology (1) 3 rd edition Page 194

195 HEMOSTASIS Definition - Prevention of blood loss by arrest of bleeding and maintenance of blood in the fluid state. Mechanisms (or steps) of hemostasis following injury o Vasospasm o Formation of platelet plug o Formation of blood clot (Coagulation) o Fibrinolysis or fibrous tissue formation Vasospasm - Occurs immediately following injury due to: o Myogenic response (the vascular smooth muscle responds to trauma by spasm) o Humoral factors (serotonin & catecholamines like epinephrine and norepinephrine cause vasoconstriction) o Neural factors (neural reflex involving the sympathetic neurons) - The vasospasm is expected to be weak in cases of: o Hypoxia o Metabolic acidosis o Small surface area (spasm caused by a knife is weaker than that caused by a stone; because the surface area of blood vessels injured by the knife is smaller than by the stone) Formation of platelet plug - Aggregation of platelets to close a hole in the blood vessel - Enough to close small holes in blood vessels - Large holes need the third step: blood coagulation The core of medical physiology (1) 3 rd edition Page 195

196 Platelets (Thrombocytes) - Small cells (2-4µm in diameter) - Count: (200, ,000/mm 3 ) - Life span: about 5 days (up to 10 days) - Arise from stem cells & then megakaryocytes in the bone marrow. - The cytoplasm of each megakaryocyte breaks down into large number of platelets (i.e. they are non-nucleated). - Formation is regulated by colony stimulating factors and a hormone known as thrombopoietin, a protein released by the liver and kidneys. - About one third are stored in the spleen. That s why splenectomy (removal of the spleen) is sometimes used for treatment of thrombocytopenia to increase platelet count. - Their membranes contain receptors for collagen and von Willebrand factor (vwf); both are important for attachment of platelets to collagen at sites of blood vessel injury. Also they have receptors for ADP and fibrinogen. - Platelets contain two types of granules: o Alpha granules (contain protein substances like the clotting factor number 13, platelet derived growth factor (PDGF) which is a potent stimulus for wound healing & vwf which is synthesized by megakaryocytes and also by endothelial cells) o Dense granules (contain non-protein substances like serotonin and ADP) - Functions of platelets: Participates in the various mechanisms of hemostasis as follows: o Vasospasm: they release a vasoconstrictor (serotonin) o Platelet plug formation: major function of platelets (see below) The core of medical physiology (1) 3 rd edition Page 196

197 o Blood coagulation (platelets release some clotting factors (e.g. factor 13 and platelet factor 3 phospholipids ) Clot retraction: after formation of a blood clot and incubation of blood for half an hour or so, platelets contract because they contain actin and myosin fibers in their cytoplasm. This decreases the size of the clot (to about 10% of its original size), and expresses serum (read table 5.2). - Platelet deficiency (thrombocytopenia) results in increased bleeding tendency. A count less than 50,000 cell/µl is associated with hemorrhage after minor injuries and possibly multiple petechial hemorrhages under the skin and mucus membranes thrombocytopenic purpura ; however, purpura is very common when the platelet count is less than 20,000 cell/µl. - On the other hand, high count of platelets (thrombocytosis) predisposes to thrombotic problems. Mechanism of platelet plug formation: 1. Platelets attach to collagen fibers (this step is facilitated by collagen receptors on platelets & vwf) 2. Activation of platelets (attachment to collagen fibers activates platelets to swell, become irregular in surface and become sticky) 3. Release of contents (serotonin, thromboxane A 2 TXA 2, ADP...) 4. Aggregation of platelets (serotonin causes vasospasm whereas TXA 2 & ADP activate nearby platelets to swell and stick to the previous ones and release the same contents, then TXA 2 & ADP activate other platelets and the cycle repeats itself in a form of positive feedback mechanism until the small hole in the blood vessel is sealed by the plug (large holes need coagulation). The core of medical physiology (1) 3 rd edition Page 197

198 Table 5.2: Comparison between serum and plasma Difference Plasma Serum Formation By centrifugation of blood By incubating a clotted sample for sometime Clotting proteins Present Absent (consumed) (e.g. fibrinogen) Serotonin Low High (released by activated platelets) Blood coagulation - Biochemical reactions that involve activation of clotting factors (present in blood in inactive form) in a cascade way to form a blood clot. - The clotting factors are indicated by roman numbers from I to XIII or by names; for example: o Fibrinogen Factor I o Prothrombin Factor II o Tissue factor Factor III or tissue thromboplastin o Calcium Factor IV o Factor V Proaccelerin or labile factor o Factor VII Serum prothrombin conversion accelerator (SPCA) or stable factor o Factor VIII Anti-hemophilic factor A o Factor IX Christmas factor or antihemophilic factor B o Factor X Stuart factor o Factor XI Antihemophilic factor C The core of medical physiology (1) 3 rd edition Page 198

199 o Factor XII Hageman factor o Factor XIII Fibrin-stabilizing factor - Most of these factors are produced by the liver (exceptions include factors: III, IV and XIII). - Remember that: there is no clotting factor known as factor VI. - Activation of the clotting factors occurs through two pathways: o Intrinsic pathway o Extrinsic pathway The intrinsic pathway - All factors involved are present in the blood (i.e. there is no need for an extrinsic factor from the tissues). - Factors activated through this pathway include: XII, XI, IX, VIII, X, V, II and I; plus calcium ions (factor IV) & phospholipids (provided by platelets as platelet factor 3). - The first factor to be activated is factor XII; it is activated when blood comes in contact with collagen or wettable negative surface like glass. See the other steps in figure 5.14: The extrinsic pathway - It is called extrinsic because a tissue factor (known as thromboplastin or factor III) is needed for its activation. This factor consists of phospholipids and protein. - Factors activated through this pathway include: VII, X, V, II and I; plus calcium ions (factor IV) & phospholipids (provided by the tissue factor). - This pathway is faster than the intrinsic pathway. - The first factor to be activated is factor VII; it is activated by the tissue factor. See the other steps in figure The core of medical physiology (1) 3 rd edition Page 199

200 - Factor X, II, I and V are activated through both intrinsic and extrinsic pathways; that s why they are described as factors of the common pathway. Fig 5.14: The pathways of coagulation The core of medical physiology (1) 3 rd edition Page 200

201 Important notes about coagulation Calcium ions are needed in all steps of coagulation except the first two steps of the intrinsic pathway which need high molecular weight kininogen (HMWK) and Prekallikrein (PK). Phospholipids are needed in many steps (e.g. activation of factor X and II). Phospholipids in the intrinsic pathway are provided by platelets and in the extrinsic pathway are provided by the tissue factor. Factor V and VIII are cofactors, their activation by thrombin results in amplification and repetition of the reactions through a positive feedback mechanism. Thrombin, the active form of factor II, is an alpha globulin synthesized in the liver as prothrombin. Its activation requires many factors: ax, av, calcium and phosplolipids. All these factors are known collectively as prothrombin activator complex or thrombokinase. Activation of prothrombin to thrombin is the most important step in coagulation. Actions of thrombin include: o Activation of fibrinogen (factor I) o Activation of factor V o Activation of factor VIII o Activation of plasminogen (see below) o Activation of platelets o Activation of protein C (through thrombomodulin, see below) Thrombin activates fibrinogen to form fibrin strands. These combine together to form a net at the site of injury. The net catches cells and protein until it is completely sealed as clot. The core of medical physiology (1) 3 rd edition Page 201

202 The blood clot is stabilized by factor XIII (fibrin stabilizing factor) and Ca ++. Factor XIII is released by platelets. It forms covalent bonds between fibrin strands. Fig 5.15: The blood clot Fibrinolysis - After formation of the blood clot, bleeding stops; but the clot causes partial obstruction within the blood vessel. Therefore, it should be removed by the process of fibrinolysis; however, some clots may become invaded by fibroblasts (invited by platelet derived growth factors). These cells convert the clot into a permanent fibrous tissue. - Fibrinolysis involves enzymatic degradation of fibrin by the enzyme plasminn resulting in formation of fibrin degradation products. - Plasmin is produced by the liver as an inactive protein (Plasminogen). - Plasminogen is activated by factors called (Plasminogen activators) - These factors can be obtained from: o Blood o Tissues o Urine o Bacteria The core of medical physiology (1) 3 rd edition Page 202

203 Plasminogen activators in blood - These are: axii and thrombin. - Although they are responsible for formation of the blood clot, they participate in its lysis by activating plasminogen into plasmin. However, lysis does not occur immediately following blood clot formation because plasmin is inhibited by a plasma protein known as α 2 anti-plasmin. The level of plasmin has to increase gradually until it becomes sufficient to cause lysis of the clot, this usually occurs after 48 hours. During this time regeneration occurs and the hole in the blood vessel is closed. Plasminogen activator in the tissues - This is the tpa (tissue Plasminogen activator). It is released by the tissues, e.g. vascular endothelium, to cause lysis of the clot. - It can be synthesized by recombinant DNA from melanoma cells for medical purposes (to be used for treatment of acute myocardial infarction). However, it is very expensive to be used in the developing countries. Plasminogen activator in urine - This is urokinase which is synthesized by the transitional epithelium of the urinary tract and released in urine. - Its physiological significance in urine is unknown, may be to cause immediate lysis for clots that may obstruct the renal tubules. Plasminogen activator from bacteria - This is streptokinase, a toxin produced and released by streptococci to break clots formed by the body to limit its spread. - The bacteria are cultured and streptokinase is extracted for treatment of acute myocardial infarction. It is rather cheaper than The core of medical physiology (1) 3 rd edition Page 203

204 tpa. However, since it is extracted from bacteria, its IV infusion induces formation of antibodies against it. Therefore, its future use in the same patient requires certain precautions. The normal endothelium can activate plasminogen - The endothelial cells have Plasminogen receptors on their surface. These activate Plasminogen when it binds them. ANTICOAGULANTS Natural anticoagulants - These are present naturally within the body. They prevent clotting within the circulation. - Abnormalities associated with a defect or absence of one or more of these factors are usually associated with intravascular clotting. - They include: The normal endothelium - Prevents clotting by the following: o Smooth surface prevents activation of the clotting factors o Release of prostacycline & nitric oxide (these cause vasodilatation and inhibit platelet aggregation) o Have plasminogen receptors on their surface that activates plasmin when it binds them o Thrombomodulin (see below) The blood flow - Rapid blood flow inhibits coagulation whereas stasis of blood favors coagulation. Stasis may occur due to: o Mechanical obstruction of a blood vessel o Prolonged sitting (e.g. during prolonged flight or bus journey) The core of medical physiology (1) 3 rd edition Page 204

205 o Prolonged lying down (e.g. comatose patients or those with fractures) Anti-thrombin III - An alpha globulin synthesized by the liver. - Inactivates IX, X, XI and XII. - Its activity is increased about 1000 times by heparin. For this reason it is called the heparin cofactor - Hemoglobin may also facilitate the activity of antithrombin III. Heparin - Sulfated polysaccharide (MWt: 15,000-18,000) - Found in the granules of mast cells and basophils - Acts through activation of antithrombin III - Its low level in plasma indicates that it is not very important as a natural anticoagulant at normal conditions. - It is very important for prevention of coagulation in containers used for blood collection and when given intravenously in therapeutic doses (e.g. in cases of deep vein thrombosis (DVT)). - When given accidentally in toxic doses, protamine sulphate is used to neutralize it (= antidote). Alpha II macroglobulin - Similar to anti-thrombin III - Inactivates some clotting factors. Thrombomodulin - A protein expressed on surface of most endothelial cells (except those in cerebral capillaries) - Binds thrombin to form a complex that activates protein C. The core of medical physiology (1) 3 rd edition Page 205

206 Protein C and its cofactor: protein S - Produced by the liver - Require vitamin K for their synthesis. - Inactivate the following: o Factor V o Factor VIII o Inhibitor of tissue Plasminogen activator (i.e. activates tpa and therefore increases plasmin) Fibrin, plasmin and FDPs - Fibrin adsorbs some clotting factors and this prevents propagation of the clot within the blood vessel. - Plasmin breaks down fibrin resulting in dissolution of clots. - Fibrin degradation products (FDPs) also inhibit coagulation (by inhibiting thrombin). Synthetic anticoagulants Vitamin K antagonists - For example warfarin (Coumarin derivative) - This interferes with the action of vitamin K that s needed for synthesis of the following clotting factors in the liver (1972): o Factor II (prothrombin) (2) o Factor VII (7) o Factor IX (9) o Factor X (10) - Warfarin is the only anticoagulant that can be taken orally. It is used for prevention of thrombosis and embolism. - Warfarin interacts with many drugs that may potentiate or inhibit its effects (e.g. aspirin); that s why drugs taken with it should be revised. The core of medical physiology (1) 3 rd edition Page 206

207 - Warfarin therapy should be monitored by testing the INR (International Normalized Ratio). This is calculated from prothrombin time (PT) as follows: INR = (PT test/pt control) ISO Where ISO is the international sensitivity index. Very important notes to remember: Effects of warfarin start to appear 3 days after initiating therapy. That s because warfarin acts through inhibiting synthesis of vitamin K dependent clotting factors in the liver, but factors already present in blood continue to act during the first few days. In addition to that, coagulation tendency is sometimes increased when starting warfarin therapy, rather than decreased! That s because warfarin inhibits activity of the anticoagulants protein C & S which are also vitamin K dependent factors. Therefore, the best way to anti-coagulate the patient during this period is to give heparin together with warfarin when starting treatment and to monitor warfarin effects with INR; then stop heparin and continue with warfarin. Calcium chelating agents - These include: oxalate, citrate and EDTA. - They bind calcium and make it unavailable for coagulation - Not used in vivo because they may decrease calcium concentration in the plasma and cause tetany. Remember that: Anticoagulants used only in vitro: Calcium chelating agents Anticoagulants used only in vivo: Vitamin k antagonists Anticoagulants used in vitro and in vivo: Heparin - The core of medical physiology (1) 3 rd edition Page 207

208 TESTS FOR HEMOSTATSIS Bleeding time (BT) - A test for platelets because it is done by causing small hole in a blood vessel (a pinprick at the lobe of the ear or the anterior surface of the forearm, using a lancet) - Normally takes 1-7 minutes. - It is prolonged in the following conditions: o Thrombocytopenia o Thromboasthenia o Von Willebrand disease o Vitamin C deficiency Clotting time - A test for the clotting factors of the intrinsic pathway or common pathway (because it involves collection of blood in a test tube and then initiation of coagulation by contact of blood with glass). - Normally takes less than 10 minutes. - It is prolonged in the following conditions: o Hemophilia o von Willebrand disease o Vitamin K deficiency o Chronic liver disease o Afibrinogenaemia o Obstructive jaundice Prothrombin time (PT) - A test for the clotting factors of the extrinsic pathway because blood is collected in a tube containing citrate to remove Ca ++ ; then Ca ++ & thromboplastin are added to allow blood to clot (= extrinsic pathway). The core of medical physiology (1) 3 rd edition Page 208

209 - Normally takes seconds. - It is prolonged in the following conditions: o Vitamin K deficiency o Chronic liver disease o Afibrinogenaemia o Obstructive jaundice - As mentioned above, it is used for calculation of the international normalized ratio (INR). Activated partial thromboplastin time (aptt) - A test for the clotting factors of the intrinsic pathway. - It is activated to shorten the time of coagulation by adding certain substances like kaolin and it is called partial because thromboplastin is not added. - It normally takes seconds. - It is prolonged by the same causes that prolong the clotting time. EXAMPLES OF BLEEDING TENDENCIES Hemophilia - Occurs due to deficiency of: o Factor VIII (hemophilia A, classical, 85% of cases). o Factor IX (hemophilia B, less common, 15% of cases, also known as Christmas disease). - Inherited as X- linked recessive (therefore it is more common in males). - Characterized by normal BT and prolonged clotting time and aptt. - Treatment: factor VIII injections or fresh frozen plasma or blood. The core of medical physiology (1) 3 rd edition Page 209

210 Von Willebrand disease - vwf is a glycoprotein produced by endothelial cells and megakaryocytes. - It is needed for stabilization of factor VIII and for attachment of platelets to collagen. - Congenital deficiency of this factor causes bleeding tendency with prolonged bleeding time and clotting time. Afibrinogenaemia - Deficiency of fibrinogen may be congenital (since birth), or acquired later in life by a disease (e.g. placental abruption during pregnancy results in clotting of blood behind the placenta. This consumes fibrinogen and causes its deficiency). - Characterized by prolonged clotting time and prothrombin time; however, the best test is thrombin time (TT) which gives information about availability of fibrinogen. Chronic liver diseases - Impairs synthesis of the clotting factors which are synthesized in the liver. Obstructive jaundice - Impairs absorption of vitamin K. which is a fat soluble vitamin that needs bile for its absorption from the intestine. - Vitamin k is needed for synthesis of clotting factors the II, VII, IX and X (1972). Therefore obstructive jaundice causes deficiency of these factors. For this reason, patients with obstructive jaundice should receive vitamin K injections daily for 5 days before surgery. The core of medical physiology (1) 3 rd edition Page 210

211 Examples of clotting tendencies (thrombosis): Due to congenital problems - Deficiency of protein C, protein S or antithrombin III Due to atherosclerotic blood vessels - Atherosclerosis may be complicated by complete occlusion of a blood vessel. - It is predisposed by systemic diseases like diabetes and hypertension. - Most dangerous at the coronary, renal and cerebral arteries Due to sluggish blood flow - Follows prolonged periods of bed ridden (e.g. due to operations, delivery or fractures). - May be complicated by detachment of the clots (embolization). - A large embolus detached from a lower limb vein that obstructs the pulmonary artery usually causes immediate death. - This is known as pulmonary embolism. Due to wide spread deposition of fibrin in the circulation - This is known as disseminated intravascular coagulations (DIC). - It is caused by septicemia, disseminated cancers or massive tissue injuries. These stimulate formation of multiple clots within the intravascular space. - The clots consume the clotting factors and therefore patients bleed from the skin, GIT and respiratory tract (usually fatal). The core of medical physiology (1) 3 rd edition Page 211

212 PLASMA - The fluid part of the blood Volume - About 5% of total body weight in a 70 kg adult male (= 3.5 L) Contents Water (= 90%) Inorganic substances (minerals, electrolytes ) Organic substances (proteins, glucose, fats, bilirubin, urea ) Plasma proteins - Types: Albumin Globulins (, and ) Fibrinogen - Synthesis The liver (synthesizes most plasma proteins) Plasma cells (Synthesizes gamma globulins which are not synthesized by the liver (also known as immunoglobulins or antibodies) - Concentration: Total = 6-8 g/dl Albumin: g/dl Globulins (, and ): 2.3 g/dl Fibrinogen: 0.3 g/dl - Functions: Oncotic pressure (albumin because its particles are smaller and larger in number than other types of plasma proteins) The core of medical physiology (1) 3 rd edition Page 212

213 Viscosity of blood (globulins and fibrinogens because of the asymmetrical shape and large size of their particles) Clotting (fibrinogen and some globulins- most clotting factors are beta globulins but prothrombin is an alpha globulin) Transport of hormone like thyroid, adrenocortical and gonadal hormones (albumin and globulins) Carriage of ions, metals, bilirubin (e.g. albumin carries bilirubin and the beta globulin transferrin carries iron) Protection by antibodies (gamma globulins) Buffer (= 15% of the buffering capacity of the blood, by the COOH and NH2 groups in all proteins) QUESTIONS FOR SELF ASSESSMENT-8 (BEST OF FIVE) 1. The intrinsic pathway of blood coagulation: a. is triggered by contact of factor X with collagen b. is faster than the extrinsic pathway c. utilizes 50% of the clotting factors present in the blood d. requires tissue thromboplastin for its activation e. is never completed in the absence of Ca++ 2. Platelets: a. are non nucleated biconcave cells b. arise from megakaryocytes in the bone marrow c. always stop bleeding d. their count is higher than red blood cells e. their size is larger than white blood cells 3. A child whose both father & mother are group B-positive may be: a. blood group A positive b. blood group A negative c. blood group AB positive d. blood group O-negative e. blood group AB negative 4. Vitamin K deficiency causes low production of factor: a. I b. VII c. VIII The core of medical physiology (1) 3 rd edition Page 213

214 d. XI e. XII 5. Prolonged clotting time is found in all the following except: a- heparin therapy b- obstructive jaundice c- congenital afibrinogenaemia d- thrombocytopenia e- chronic liver disease 6. The following is not a function of thrombin: a- breakdown of fibrinogen b- activation of protein C c- activation of factor VIII d- activation of plasminogen e- activation of factor XI 7. The following is not a primary function of globulins: a- blood coagulation b- transport of iron c- immunity d- colloid osmotic pressure e- blood viscosity 8. A woman who is blood group O Rh -ve: a- has no any antigens on surface of RBCs b- has anti-a, anti-b and anti D antibodies in plasma c- acts as a universal donor d- can never have a rhesus +ve child e- usually gives birth to a jaundiced baby 9. The following statement about the extrinsic pathway is not true: a- it is triggered by tissue trauma b- it involves factor II c- it requires calcium ions d- it is prolonged in haemophilia e- it is normal in von Willebrand disease 10. The following anticoagulant acts in vitro and in vivo : a- heparin b- warfarin c- thrombomodulin d- EDTA e- citrate 11. Bleeding tendency commonly occurs due to all the following except: a- warfarin therapy b- obstructive jaundice c- hypocalcaemia d- thromocytopenia The core of medical physiology (1) 3 rd edition Page 214

215 e- chronic liver disease 12. The following is not transported by plasma proteins a. iron b. oxygen c. carbon dioxide d. bilirubin e. thyroxine 13. This factor is not activated through the intrinsic pathway? a. I b. II c. V d. VII e. VIII 14. Plasminogen is activated by all of the following except: a. Urokinase b. Streptokinase c. Tissue plasminogen activator (tpa) d. thromboplastin e. thrombin 15. All the following are natural anticoaguans except: a. thromboxane A2 b. prostacycline c. protein C d. antithrombin III e. plasminogen 16. Hemophilia is: a. more common in males than females b. due to congenital deficiency of Hageman factor c. characterized by normal bleeding time d. characterized by low level of vwf e. diagnosed when the INR is higher than normal 17. Anti-thrombin III: a. is a beta globulin b. activity is inhibited by heparin c. is similar in structure to alpha 2 macroglobulin d. deficiency causes bleeding tendency e. level in plasma is decreased by warfarin Question Answer e b d b d e d c d a Question Answer c b d d a c c The core of medical physiology (1) 3 rd edition Page 215

216 THE CARDIAC MUSCLE Fig 6.1: The heart CHAPTER 6 THE CARDIOVASCULAR SYSTEM Human heart consists of: o 4 chambers 2 atria (thin walled, receive blood from major veins and allow it to fill the ventricles) 2 ventricles (thick walled, pump blood to pulmonary and systemic circulation) o 4 valves 2 Atrio-ventricular valves (AV valves): - Mitral (left) and Tricuspid (right) 2 Semilunar valves: - Aortic (left) and Pulmonary (right) The core of medical physiology (1) 3 rd edition Page 216

217 Properties of the cardiac muscle - The cardiac muscle contains two types of muscle fiber: Cardiac muscle proper Conductive system - It has special properties that characterize it from other types of muscles, these properties include: 1- The histology of the cardiac muscle - Unlike skeletal muscle, there are anatomical connections between the myocardial fibers (intercalated discs and gap junctions); and unlike smooth muscle, the cardiac muscle is striated. Fig 6.2: The muscle differences in histology 2- Functional syncytium - Stimulation of one cardiac muscle cell results in stimulation of all the cells. This occurs due to presence of gap junctions & intercalated discs between the fibers (which are areas of low electrical resistance that allow movement of ions and therefore transmission of action potential easily between cells). - Therefore, the heart contracts as one unit (as a syncytium which is multiple cells grouped together as one unit within a common cell membrane forming a single multi-nucleated cell). - Remember that the heart is not an anatomical syncytium but it is a functional syncytium. The core of medical physiology (1) 3 rd edition Page 217

218 Fig 6.3: The cardiac muscle histology 3- The main source of energy - The cardiac muscle consumes fat as the main source of energy. Under basal conditions, 60% of the caloric needs are provided by free fatty acids, 35% by carbohydrates and 5% by ketones and amino acids. - On the other hand, skeletal muscles utilize carbohydrates as the main source of energy, especially during exercise. 4- Blood flow (supply) - The cardiac muscle receives its blood supply mainly during diastole (unlike skeletal muscles which receive their blood supply mainly during systole). - The left ventricle receives its blood supply during the diastolic phase only whereas the right ventricle receives its blood supply during both systole & diastole. - This is explained by many physiological & anatomical mechanisms: Physiological explanation: During systole, aortic pressure= 120 mmhg, left ventricular pressure= 120 mmhg and right ventricular pressure= 25 mmhg; therefore blood flows from the aorta through the right coronary artery but not the left one. On The core of medical physiology (1) 3 rd edition Page 218

219 the other hand, during diastole, aortic pressure= 80 mmhg, left ventricular pressure= 0 mmhg and right ventricular pressure= 0 mmhg; therefore blood flows from the aorta through both right and left coronary arteries. Anatomical explanation: during systole, leaflets of the aortic valve obstruct openings (sinuses) of coronary arteries. 5- Oxygen extraction - At basal conditions, the cardiac muscle extracts higher amount of oxygen than skeletal muscle. It consumes about 9 ml O2/ 100 g tissue/minute. This is approximately about 70-80% of the oxygen delivered by each unit of blood. 6- Metabolism - The cardiac muscle depends on aerobic metabolism for generation of energy. Anaerobic metabolism provides less than 1% of the total energy. This figure may increase slightly during hypoxic states; however, there is no oxygen debt mechanism (obstruction of the coronary artery reduces oxygen delivery to the cardiac muscle and results in its necrosis and death). On the other hand, skeletal muscle depends on both aerobic & anaerobic metabolism for generation of energy, and there is oxygen debt mechanism (oxygen debt is the extra amount of oxygen consumed after exercise to repay oxygen taken from myoglobin & to get rid of lactate accumulating in muscle. 7- Electrical activity (action potential) - Action potential of the cardiac muscle proper is characterized by the plateau phase (due to calcium influx), and that of the conductive system is characterized by the prepotential (see below). Theses phases are not found in action potentials of other types of muscles. The core of medical physiology (1) 3 rd edition Page 219

220 Fig 6.4: Actions potentials in the cardiac muscle 8- The refractory period - Is prolonged in cardiac muscle ( ms) due to presence of the plateau phase. This protects the heart from tetanus (summation of contractions during successive stimulation) and therefore allows the cardiac muscle to relax; because relaxation is essential for ventricular filling. The refractory period in skeletal muscles is about 5-20 ms. Fig 6.5: the refractory periods in muscles 9- ECF calcium: - Contraction of the cardiac muscle depends on both ICF & ECF calcium, whereas contraction of skeletal muscle depends on ICF calcium only. The T tubules in the cardiac muscle allow influx of calcium during action potentials to stimulate contraction. Therefore, The core of medical physiology (1) 3 rd edition Page 220

221 increasing ECF calcium increases contractility in cardiac muscle and may stop the heart in systole. 10- No Recruitment in cardiac muscle - Increasing strength of stimulation in skeletal muscles results in recruitment (i.e. it increases number of stimulated fibers) whereas in the cardiac muscle there is no recruitment (no increase in the number of stimulated fibers). That s because stimulation of one fiber in cardiac muscle results in stimulation of all the fibers. 11- Automaticity - The various parts of the conductive system can discharge action potential spontaneously. This is explained by the prepotential phases that characterize action potentials of the different structures of the conductive system (the conductive system has no resting membrane potential but gradual elevation of prepotential towards the threshold, see below). This results in spontaneous generation of action potentials by the conductive system (especially the sino-atrial node). However, the cardiac muscle proper, which has no prepotential, can discharge action potentials spontaneously, but in abnormal conditions (e.g. ischemia). This is known as idio-ventricular rhythm. 12- Rhythmicity - The cardiac muscle undergoes regular rhythmic contractions due to presence of the conductive system, which controls these rhythmic contractions whereas skeletal muscle cannot contract rhythmically. 13- Conductivity - This is again a characteristic of the conductive system, which generates rhythmic action potentials and conducts it to the whole parts of the cardiac muscle (see below). The core of medical physiology (1) 3 rd edition Page 221

222 The conductive system - The conductive system is formed of cardiac muscle fibers that are less striated and lack definitive boundaries. - It consists of the following structures: Sino-atrial node (SA node) Atrio-ventricular node (AV node) Internodal atrial pathways Bundle of His 2 Bundle branches (BB): o Rt Bundle branch (RBB) o Lt Bundle branch (LBB). - The left BB is divided into anterior & posterior fascicles o Purkinje fibers Fig 6.6: the conductive system The core of medical physiology (1) 3 rd edition Page 222

223 The sino-atrial node (SA Node) - The SA node is found in the right atrium, at the opening of the SVC. - It can discharge action potential spontaneously (the discharge probably originates from small rounded cells in the SA node called P cells). - It is supplied by sympathetic neurons from the right side (because it is developed from structures in the right side of the embryo). The sympathetic neurons increase its rate of discharge. - Similarly, it is supplied by parasympathetic neurons from the right vagus. The parasympathetic neurons decrease its rate of discharge. - Without innervation, its rate of discharge = 100/min, with innervation (symp & parasymp) = 70/min. This indicates that the parasympathetic effect is more dominant than the sympathetic effect on the SA node. - The rate of discharge of the SA node is faster than other parts in the heart, e.g.: AV node [45 /min] and Ventricles [15-35 /min]. That s why the SA node determines the heart rate (because it is the fastest). For this reason it is regarded as the cardiac pacemaker. - Its action potential is characterized by the prepotential (gradual elevation of the membrane potential towards the threshold) due to low K + efflux through the K + leak channels (remember that potassium efflux generates the resting membrane potential). In addition to that, the prepotential is completed by some Ca ++ influx (through transient Ca ++ channels (T channels). - The depolarization phase is due to Ca ++ influx (through long lasting calcium channels (L channels)); with some sodium influx; whereas the repolarization phase is due to potassium efflux through the K + voltage gated channels. The core of medical physiology (1) 3 rd edition Page 223

224 - The sympathetic makes the prepotential more vertical and therefore increases heart rate whereas the parasympathetic makes the prepotential more horizontal and therefore decreases the heart rate. Fig 6.7: Effects of neurons on the prepotential The AV Node - The AV node is found in the Rt atrium on the right side of inter-atrial septum, above the fibrous ring that separates atria from ventricles. - It delays conduction from atria to ventricles (because its muscle fibers have lower number of gap junctions and smaller diameter than the SA node). - This delay allows atrial contraction to precede ventricular contraction and therefore completes ventricular filling with blood. - When the SA node is diseased as in fibrosis of the SA node in old subjects (known as sick sinus syndrome), the AV node becomes the cardiac pacemaker. Here the heart rate decreases to about 45 beats/ min). - When the AV node is damaged, ventricular rate becomes 15-35/min The core of medical physiology (1) 3 rd edition Page 224

225 THE ELECTROCARDIOGRAM (ECG) - It is a record of the electrical activity of the heart from the surface of the body using electrodes. - The record represents the sum of all action potentials of myocardial fibers at the time of recording as follows: o The sum of all atrial depolarizations o The sum of all atrial repolarizations o The sum of all ventricular depolarizations o The sum of all ventricular repolarizations - All these events appear in the ECG as waves and intervals. The waves are indicated by the letters p, q, r, s, t and sometimes u. Methods of Recording - The ECG is recorded by two types of recording: o One active electrode + an inactive electrode (= unipolar recording) o Two active electrodes + an inactive electrode (= bipolar recording) - The inactive electrode is the reference electrode that gives the isoelectric line in the ECG; it is usually attached to the right foot. - The isoelectric line determines whether a wave is positive or negative. A positive wave is that recorded above the isoelectric line whereas a negative wave is that recorded below it. - A current of depolarization or repolarization coming towards an active electrode produces a positive ECG wave whereas a current passing a way from an active electrode produces a negative wave. - The active electrodes are placed on the forearms, legs and chest; at different locations to detect abnormalities in different sites of the The core of medical physiology (1) 3 rd edition Page 225

226 heart. Abnormalities appear as changes in the normal configuration of the different waves and intervals in the ECG. o The unipolar leads - These are readings obtained by unipolar recording (i.e. each reading is recorded by one active electrode). They include: Limb leads (recorded by electrodes placed on the limbs): o avr (augmented vector of the right arm) o avl (augmented vector of the left arm) o avf (augmented vector of the left foot, remember that the reference electrode is placed on the right foot) Chest leads (recorded by electrodes placed on the chest): o V1 (Vector of electrode placed on the 4th intercostal space to the right of the sternum) o V2 (Vector of electrode placed on the 4th intercostal space to the left of the sternum) o V3 (Vector of electrode placed midway between V2 & V4) o V4 (Vector of electrode placed on the 5th intercostal space at the mid-clavicular line) o V5 (Vector of electrode placed on the 5th intercostal space at the anterior axillary line) o V6 (Vector of electrode placed on the 5th intercostal space at the mid-axillary line) o The bipolar leads - Readings obtained by bipolar recording (2 active electrodes) - Include three limb leads (I, II & III): o Lead I is recorded by two active electrodes placed on the right and left arms. The core of medical physiology (1) 3 rd edition Page 226

227 o Lead II is recorded by two active electrodes placed on the right arm & the left foot. o Lead III is recorded by two active electrodes placed on the left arm & the left foot. Einthoven s triangle - An imaginary equilateral triangle formed by the three bipolar electrodes (I, II and III). The heads of the triangle are the points of attachment of the unipolar leads avr, avl and avf; with the assumption that the heart lies in the center of this triangle. - It is well known in electricity that: "In an equilateral triangle, with a source of electricity in the center, the summation of potentials at the heads of the triangle = zero". - Taking Einthoven's triangle: (avr+ avl + avf = zero) or (I + III = II) - Einthoven s triangle is used to determine the cardiac axis (i.e. the orientation of the heart relative to the horizontal plane), which lies normally between the angles -30 & +90 degrees (or up to + 110). - Left ventricular hypertrophy deviates the axis to the left of -30 whereas right ventricular hypertrophy deviates the heart to the right of 110 degrees. Fig 6.8: Einthoven s triangle The core of medical physiology (1) 3 rd edition Page 227

228 Importance of the ECG The ECG is used to: o Calculate the heart rate o Assess the size of the heart o Diagnose diseases of the heart (e.g. ischemic heart disease (IHD), myocardial infarction, pericardial effusion ), o Diagnose arrhythmias o Diagnose electrolyte disturbances (e.g. hyper or hypokalaemia) Remember that: The ECG does not detect the mechanical events in the heart (i.e. it does not show contraction or relaxation of the cardiac muscle); it only detects the electrical activity (i.e. depolarization and repolarization). The standard ECG Fig 6.9 The normal waves o P wave due to atrial depolarization o QRS complex due to ventricular depolarization o T wave due to ventricular repolarization o U wave due to papillary muscle repolarization; however, in sometimes, it may be absent from the ECG or may be present with other abnormal ECG signs indicating hypokalemia. The core of medical physiology (1) 3 rd edition Page 228

229 o Atrial repolarization is not shown in the ECG; it is obscured by the QRS complex. The Intervals o PR interval - From beginning of P wave to the beginning of QRS complex. - Its duration ( s) represents time taken for spreading of depolarization from the SA node to the ventricular septum (through AV node and bundle of His). - Short PR interval indicates tachycardia (e.g. due to Wolf Parkinson White syndrome WPW ) whereas prolonged PR interval indicates 1 st degree heart block (e.g. due to hypokalemia). o QRS duration - From beginning of Q wave to the end of S wave. - Its duration (< 0.1 s) represents time taken for spreading of depolarization throughout both ventricles. - Prolonged QRS duration (described as broad complexes) indicates ventricular ischemia (ischemic heart disease IHD ). o QT interval - From beginning of q wave to the end of T wave. - Its duration (about 0.43 s) represents time of depolarization & then repolarization of both ventricles. - Prolonged QT interval predisposes to ventricular arrhythmias. o ST segment - From the end of S wave to the beginning of T wave. - Equivalent to the plateau phase in action potential of the ventricular muscle; that s why it is affected by changes in Ca ++ ions (prolonged in hypocalcaemia short in hypercalcaemia). The core of medical physiology (1) 3 rd edition Page 229

230 Calculation of the heart rate - The heart rate from the ECG = Paper speed (in mm/s) / duration of one ECG cycle (in mm) - The paper speed = 25 mm/s (unless the other value 50 mm/s is used) whereas the duration of one ECG cycle is best taken as RR interval (in mm). This gives heart rate in beats per second. - To calculate the heart rate in beats per minute rather than per second, the second should be divided by 60; therefore the formula becomes: Heart rate (beat/min) = 25 x 60 /RR interval (in mm) - Remember dimensions of the ECG paper: Fig 6.10 ABNORMAL ECG Normal sinus rhythm - The normal cardiac rhythm is a sinus rhythm (i.e. the pacemaker is the SA node). - Abnormal rhythms like nodal rhythm (pacemaker is AV node) or idioventricular rhythm (pacemaker is the ventricle) occur when the SA node is diseased or when there is complete block of conduction between atria and ventricles (3rd degree heart block). - Presence of normal P wave in the ECG indicates normal rhythm. The core of medical physiology (1) 3 rd edition Page 230

231 Sinus arrhythmia - This is a normal physiological condition in healthy children & young adults. It depends on intact autonomic nervous system. - It is defined as change in heart rate with respiration (heart rate increases with inspiration & decreases with expiration). This variation in the heart rate is lost in patients with autonomic neuropathy. Possible explanations for the sinus arrhythmia: 1- Inspiration = decreased intra-thoracic pressure = increased venous return = Bainbridge reflex or effect (see below) = increased heart rate. 2- Inspiration = discharge of inspiratory impulses from the respiratory center in the medulla = radiation of these impulses to the nearby cardiac center = increased sympathetic discharge from this center to the heart = increased heart rate. 3- Inspiration = inflation of the lung = stimulation of stretch receptors in smooth muscle of bronchioles = inhibitory impulses pass through the vagus to the cardio-inhibitory center in the medulla = decreased parasympathetic supply to the heart = increased heart rate. 4- Inspiration = increased venous return to the right side of the heart but decreased venous return to the left side = decreased cardiac output from the left side = decreased blood pressure = less stimulation of baroreceptors = increased heart rate (read below). Fig 6.13: variation in heart rate with respiration (sinus arrhthmia) The core of medical physiology (1) 3 rd edition Page 231

232 Abnormal sinus rhythm Sinus tachycardia o The heart rate is fast (> 100/min) while the pacemaker is still the SA node. o Causes may be physiological (e.g. motions, pain, hypoglycemia and exercise) or pathological (e.g. hyperthyroidism and drugs like beta adrenergic agonists and muscarinic blockers). Fig 6.11 Sinus bradycardia o The heart rate is slow (< 60 /min) while the pacemaker is still the SA node. o Causes may be physiological (e.g. sleep and athletes) or pathological (e.g. hypothyroidism, hypothermia and drugs like beta blockers and muscarinic stimulators). Fig 6.12 The core of medical physiology (1) 3 rd edition Page 232

233 Arrhythmias - Abnormal rhythm of the heart that may be determined by a new pacemaker. Causes include: o Damage to the normal pacemaker o Appearance of a new, abnormal pacemaker, with a faster discharge (this occurs in atria or ventricles due to ischemia) o Block in the transmission through the conductive system o Abnormal pathways for transmission (e.g. the bundle of Kent in Wolf Parkinson White Syndrome). Types of arrhythmias Atrial arrhythmias: Atrial extrasystole - Premature discharge from an atrial focus (an ECG cycle that appears before completion of a previous one). - Characterized by abnormally shaped P wave (because atrial depolarization is initiated in an abnormal site, not the SA node). - The premature beat occurs once and it is followed by a delay in the new discharge from the SA node (known as compensatory pause). Fig 6.14: Atrial extrasystole showing the abnormal P wave The core of medical physiology (1) 3 rd edition Page 233

234 Atrail tachycardia - Regular rapid discharge with narrow QRS complexes (the narrow complexes generally indicate that there is no problem in ventricles). - The heart rate from the ECG= the radial pulse and may reach about 200 beat/min. Fig 6.15: Atrial tachycardia Atrial flutter - Regular rapid discharge with narrow complexes. - The rate of atrial discharge (rate of P waves in the ECG) is about ( /min) whereas the radial pulse (= rate of QRS complexes) is less than that. - This is because of the delay in the AV node (every discharge from the SA node is not necessarily conducted to the ventricles; therefore number of P waves is higher than number of QRS complexes). - P waves give a characteristic appearance in atrial flutter (the sawtoothed appearance). Fig 6.16: Atrial flutter showing the saw-toothed appearance The core of medical physiology (1) 3 rd edition Page 234

235 Atrial fibrillation - Irregular rapid discharge with narrow complexes. - The rate of discharge in atria is expected to be ( /min); however, its calculation from the ECG is impossible because P waves are completely absent. - The ventricular rate (i.e. rate of QRS complexes) is slower because of the delay in the AV node. Fig 6.17: Atrial fibrillation Consequences of atrial arrhythmias: - Occasional extrasystoles have no ill effects and do not need treatment; however, other atrial arrhythmias decrease time of the cardiac cycle (because of the tachycardia); this decreases the diastolic time which is necessary for ventricular filling and therefore decreases the stroke volume and the cardiac output. The reduction in cardiac output may cause heart failure. Treatment of atrial arrhythmias: - According to severity of arrhythmia and patient condition, atrial arrhythmias may be treated with simple maneuvers that increase vagal discharge (like carotid sinus massage at the angle of the jaw, eyeball pressure or induction of vomiting); or by anti-arrhythmic drugs (like digitalis, beta blockers ); or by using the defibrillator. The core of medical physiology (1) 3 rd edition Page 235

236 Ventricular arrhythmias Ventricular extrasystole - Premature discharge from a ventricular focus (an ECG cycle that appears before completion of a previous one). - Characterized by abnormally shaped QRS complex (because ventricular depolarization is initiated in an abnormal site, not the normal site which is the septum). Fig 6.18 Ventricular tachycardia - Regular rapid discharge with broad QRS complexes (the broad complexes indicate that there is a problem in ventricles). - Other ECG waves may be hidden by the broad complexes. - The heart rate is very fast. - The commonest cause is ischemic heart disease. Fig 6.19 The core of medical physiology (1) 3 rd edition Page 236

237 Ventricular fibrillation - Very rapid discharge of multiple ventricular foci. - Results in appearance of an abnormal bizarre shaped ECG). - ECG waves are not clear. - It is a cause of death in patients with myocardial infarction. Fig 6.20 Consequences of ventricular arrhythmias: - Occasional extrasystoles have no serous effects and do not need treatment. - Ventricular tachycardia decreases cardiac output because the time available for ventricular filling is decreased and therefore the stroke volume and cardiac output are decreased. This causes heart failure. - In addition to that, ventricular tachycardia may be complicated by ventricular fibrillation. - Ventricular fibrillation is the most dangerous type of arrhythmia. It causes death in minutes because the heart fibrillates without ejecting blood to supply the brain. Treatment: - According to severity of arrhythmia & patient condition, ventricular arrhythmias can be treated with anti-arrhythmic drugs or defibrillators (= electric shock). The core of medical physiology (1) 3 rd edition Page 237

238 Heart Block - Block of conduction from atria to ventricles. - May be: 1- Incomplete heart block: first or second degree 2- Complete heart block: third degree First degree: - Prolonged PR interval (> 0.2s) - Causes include: IHD & hypokalaemia. Fig 6.21 Second degree - Conduction from atria to the ventricles is blocked (e.g. due to IHD). - This results in generation of P wave two or three times before appearance of the QRS complex (2:1 or 3:1 conduction). Fig 6.22 Third degree - Complete block of conduction from atria to ventricles (due to IHD). - Atria continue to contract by the SA node whereas ventricles continue to contract by a ventricular focus (idioventricular rhythm). The core of medical physiology (1) 3 rd edition Page 238

239 - P waves appear at regular intervals with a normal rate (60-100/min) - QRS complexes are not related to the P waves. They appear independently with an abnormal shape and a slow rate (15-35/min). Fig Patients with complete heart block develop Stokes Adams attacks (become immediately unconscious and collapse with a minimal degree of exercise). That s because the low cerebral blood flow is further decreased with exercise due to shifting of blood towards muscles. Myocardial infarction (MI) - Death of myocardial fibers due to interruption of the blood supply (block in the coronary artery or some of its branches). - This produces characteristic changes in the ECG. The changes are explained by the findings that the infarcted area develops rapid repolarization (due to accelerated opening of K + channels) followed by reduction in the resting membrane potential (RMP) and then delayed depolarization. The reduction in the RMP makes the normal area more negative relative to the infarcted area (in the extracellular surface of cells not the intracellular). Therefore the electrical currents The core of medical physiology (1) 3 rd edition Page 239

240 flow from inside the infarcted area to the normal area (from positive to negative). This means that the currents are flowing towards the ECG electrodes overlying the infarcted area. The electrodes develop upward deflection. This appears as ST elevation in the ECG (Note: the currents are flowing away from the electrodes opposite to the infarcted area. This appears as ST depression in other ECG leads). Fig Some days later, the dead muscle becomes electrically silent (after development of scar tissue). Here the infarcted area becomes more negative relative to the normal area (extracellularly). This results in disappearance of the ST elevation and appearance of abnormal Q waves). Fig 6.25 The core of medical physiology (1) 3 rd edition Page 240

241 - The ECG does not only diagnose MI but also localizes its site (according to which lead develops ECG changes). For example: ST elevation in II, III and avf indicates inferior MI ST elevation in V 1, V 2, V 3 and V 4 indicates anteroseptal MI ST elevation in V 4, V 5, V 6, I and avl indicates anterolateral MI Tall R wave and ST depression in V 1 and V 2 indicates posterior MI Remember that: Acute MI is a life threatening problem. It may cause immediate death due to: - Arrhythmia (e.g. ventricular fibrillation) - Severe heart failure - Rupture of the infarcted area. The risk of these complications is highest during the first week following the infarction. That s why these patients should be treated appropriately (e.g. by thrombolytic therapy) in special wards (Coronary Care Units CCU ) for close follow up and monitoring during the acute phase. The core of medical physiology (1) 3 rd edition Page 241

242 ECG changes during electrolyte disturbances Hyperkalemia o Tall, slender peaked T wave o Absent P wave o Wide, slurred QRS Fig 6.26 Hypokalemia o ST segment depression o Appearance of U wave o Prolonged PR interval o T wave inversion. Fig 6.27 The core of medical physiology (1) 3 rd edition Page 242

243 Hypercalcemia: o Short QT interval Hypocalcemia: o Long QT interval Fig 6.28 Important notes Hyponatremia causes low voltage ECG. Hyperkalemia decreases the resting membrane potential (RMP) towards the threshold, making the cells more excitable (causing arrhythmias) and eventually the RMP reaches the threshold, making the cells non excitable. Here the heart stops in diastole. Hypercalcemia increases contractility in the heart because ECF calcium enters the cells to cause contraction. Severe hypercalcemia stops the heart in systole. For this reason IV injection of calcium in patients with hypocalcemia should be slow to avoid injection of large amount of calcium. The core of medical physiology (1) 3 rd edition Page 243

244 THE CARDIAC CYCLE Duration The normal heart rate is about 75 beat/min (i.e. 75 beats in 60 seconds); therefore, each beat takes 60/75 = 0.8 second. Each beat is regarded as one cardiac cycle that involves phases of contraction & relaxation for both atria and ventricles. Therefore, each cardiac cycle (0.8s) can be studied in 3 phases: o Atrial systole (takes 0.1 s) o Ventricular systole (takes 0.3 s) o Atrial diastole (takes 0.7 s) & ventricular diastole (takes 0.5 s) Atrial Systole During the phase of atrial systole, the ventricles are in state of diastole. Therefore, atrial contraction ejects blood to fill the ventricles through the atrio-ventricular (AV) valves. Ventricular filling occurs by two ways: Passive filling (blood flows passively from atria to ventricles) & active filling (BY atrial systole). About 70% of ventricular filling occurs passively. Then atrial systole completes ventricular filling (provides the 30%). Atrial contraction increases atrial pressure and causes reflux of blood through the superior vena cava, causing a characteristic a wave ( a for atrial systole) in both atrial pressure curve and internal jugular venous pressure JVP curve (see figure 6.29). Ventricular Systole Occurs immediately after atrial systole because of the delay in the AV node (i.e. ventricles contract while atria relax). The core of medical physiology (1) 3 rd edition Page 244

245 When the ventricles start to contract, the pressures inside them start to rise, then contraction continues until ventricular pressure exceeds atrial pressure, here the AV valves close to prevent reflux of blood back to the atria. Closure of the AV valves results in the first heart sound S1 (the sound is caused by turbulence of blood due to closure of valves). Then the ventricles continue to contract & their pressures continue to rise, while all valves are closed. This is the isovolumetric contraction phase. It occurs immediately after S1. When pressure in the left ventricle reaches 80 mmhg and in the right ventricle reaches 10 mmhg, the semilunar valves open & blood starts to be ejected into the aorta and pulmonary artery (remember that inspite of the difference in pressure, the two valves open almost in the same time). The ventricles continue to contract & the pressures continue to rise to maintain ejection which starts rapidly at first (rapid ejection phase) and then slows down (slow ejection phase). The maximum pressure reached in the left ventricle is 120 mmhg & in the right ventricle = 25 mmhg (= systolic pressure). About 70 ml of blood is ejected from each ventricle. It is known as stroke volume SV and it is defined as volume of blood ejected from each ventricle per beat. About 50 ml of blood remains in each ventricle at the end of systole. It is known as end systolic volume ESV. About 120 ml of blood is found in each ventricle before ejection. The core of medical physiology (1) 3 rd edition Page 245

246 This 120 ml is known as the end diastolic volume EDV. It is defined as volume of blood that remains in each ventricle at the end of diastole. Remember that: contraction of ventricles pushes cusps of the AV valves backwards towards the atria. This causes a characteristic wave in atrial pressure curve & JVP curve known as C wave ( C for cusp shooting). Look at the following figure. Fig 6.29: The cardiac cycle Atrial & Ventricular Diastole Atrial diastole Precedes ventricular diastole and continues throughout most of the cycle (because it takes 0.7 s and the whole cycle is 0.8 s). During this phase blood enters the atria (venous return). The core of medical physiology (1) 3 rd edition Page 246

247 Accumulation of blood in atria raises atrial & jugular venous pressures and produces V wave in atrial pressure curve and JVP curve ( V for venous return). Ventricular diastole: Ventricular diastole starts during atrial diastole and filling of atria with blood. When the ventricles start to relax, the pressures inside them start to drop. When the ventricular pressures become lower than the pressures in aortic & pulmonary arteries, the semilunar valves are closed to prevent return of blood back to the ventricles. Closure of the semilunar valves results in the second heart sound S2 (the sound is caused by turbulence of blood due to closure of the valves). Then the ventricles continue to relax & the pressures inside them continue to drop, while all valves are closed. This is the isovolumetric relaxation phase. It occurs immediately after S2. When the pressures inside the ventricles become lower than the pressures in atria, the AV valves open. This allows passive filling of ventricles with blood that already filled atria during this period. Then the atria contract to complete ventricular filling and to start a new cycle. The core of medical physiology (1) 3 rd edition Page 247

248 THE HEART SOUNDS - Heart sounds are 4 sounds that result from turbulence of blood flow within the heart during closure of the valves or rapid filling of the ventricles. - The first two sounds are normal sounds, the third is normal in children and young adults and abnormal in older ages (indicates heart failure). The fourth sound is always abnormal (hypertension). The first heart sound (S 1 ) - Caused by closure of the AV valves. - Occurs at the beginning of ventricular systole (i.e. at start of the isovolumetric contraction phase). - It is low pitched and more prolonged than S2. The second heart sound (S2) - Caused by closure of the semilunar valves - Occurs at the start of ventricular diastole (i.e. at the start of the isovolumetric relaxation phase). - It is high pitched and takes less time than S1. - It may split into two components (aortic S2 and pulmonary S2). - In normal states, closure of aortic valve precedes closure of the pulmonary valve (i.e. aortic S2 precedes pulmonary S2). - Wide splitting of S2 occurs during deep inspiration, when closure of the pulmonary valve is delayed because the stroke volume is increased by the extra volume of blood delivered to the heart during deep inspiration (inspiration causes chest expansion, this decreases intra-thoracic pressure and increases venous return and therefore stroke volume). - Splitting of S2 decreases in expiration and pulmonary hypertension. The core of medical physiology (1) 3 rd edition Page 248

249 The third heart sound (S3) - Caused by rapid ventricular filling (turbulence of blood during passive filling of ventricles). - It is normal in children and young adults (filling causes turbulence because the size of ventricles is small). - It indicates heart failure in adults because blood volume of passive filling is added to high end systolic volume in patients with heart failure (the end systolic volume is high in heart failure because of the weak ventricular contractions). - On auscultation, presence of S3 plus S1 & S2 gives a characteristic sound described as Galloping rhythm. - Galloping rhythm is an important sign of heart failure in adults. The fourth heart sound (S4) - S4 is an abnormal sound; it is also known as atrial sound. - It is caused by atrial systole in patients suffering from hypertension. - In normal states, atrial systole does not cause a sound because ventricles expand to receive blood ejected by atrial systole; however, in a hypertensive patient, ventricular wall becomes stiff due to hypertrophy (because they act against resistance). That s why atrial systole results in turbulence of blood and generation of S4. Abnormal sounds - Abnormal musical sounds heard over the heart are known as murmurs. They are generated by turbulence of blood flow within the heart due to valvular lesions. - Abnormal sound heard over arteries is known as bruit (e.g. renal bruit due to renal artery stenosis (narrowing). - Abnormal sound heard over veins is known as venous hum. The core of medical physiology (1) 3 rd edition Page 249

250 - Murmurs are either systolic or diastolic. - Systolic murmurs are caused by: Stenosis (narrowing) of semilunar valves Regurgitation (reflux or dilatation) of atrio-ventricular valves - Diastolic murmurs are caused by: Stenosis (narrowing) of atrio-ventricular valves Regurgitation (reflux or dilatation) of semilunar valves - For example mitral (or tricuspid) stenosis causes mid diastolic murmur and aortic (or pulmonary) regurgitation causes early diastolic murmur whereas mitral (or tricuspid) regurgitation causes pansystolic murmur and aortic (or pulmonary) stenosis causes ejection systolic murmur. Pressure volume curves of the ventricles - This curve summarizes various events in the cardiac cycle. The Y axis represents pressure whereas X axis represents volume. The following figure describes the curve of the left ventricle. Fig 6.30: The pressure volume curve of the left ventricle The core of medical physiology (1) 3 rd edition Page 250

251 - In the above curve: A represents: passive ventricular filling B represents: atrial systole C represents: isovolumetric contraction D represents: rapid ejection phase E represents: isovolumetric relaxation Op1 represents: opening of AV valves Op2 represents: opening of semilunar valves S1-4 represents: sites of heart sounds 50 ml = End systolic volume 120 ml = End diastolic volume THE CARDIAC OUTPUT Definition - Volume of blood ejected by each ventricle each minute (not both ventricles). It is about 5 L/min in an average adult male, at rest (less in females and more during exercise). - The cardiac index (CI) is sometimes calculated to compare between subjects. It equals (COP/surface area) e.g. CI in adults = 5 /1.6 = 3.1 L/m 2. CI in children is higher because surface area is smaller. Measurement - Many methods can be used for measurement of the cardiac output. - These include: Indirect methods (like indicator dilution technique, Fick principle and thermodilution method) Direct methods (using electromagnetic or ultrasonic flowmeter devices). The core of medical physiology (1) 3 rd edition Page 251

252 Indicator dilution technique or Hamilton dye method - In this method, Q amount of a dye is injected in an arm vein; then serial arterial samples are obtained from a peripheral artery to measure the concentration of the dye as it is ejected from the heart to the systemic arteries. - The concentrations are plotted in a graph paper against time. - The resulting curve shows that the concentrations increase to a maximum, and then they start to decrease and then increase again because of recirculation of the dye (look at figure 6.31). - The descending limb at point (x) is extrapolated to the X axis to obtain the time of one circulation (t). The area under the curve is used to calculate the average concentration (C). - Then the COP can be obtained in (L/min) as follows: COP = (Q x 60) / (C x t) Fig 6.31: Hamilton dye dilution method The core of medical physiology (1) 3 rd edition Page 252

253 Fick principle - Fick principle is commonly used for measurement of blood flow to organs (e.g. renal blood flow, cerebral blood flow, liver blood flow ). - It states that the amount of a substance consumed (or added) by an organ in a given time equals the arterial-venous difference in concentration times the blood flow to the organ. - In summary: Q = [A] - [V] x Blood flow to the organ (where Q= the quantity of a substance consumed by the organ, [A] and [V] are the concentrations of the substance in the artery supplying and the vein draining the organ respectively and [A] - [V] is the arterial-venous difference in concentration. - From the above principle the blood flow can be calculated as follows: Blood flow = Q / [A] [V] - If the lungs are taken as an organ, their blood flow = the cardiac output from the right ventricle = the cardiac output (revise definition of COP). Therefore COP = Q / [A] [V] - The substance consumed (actually added) by the lungs is oxygen. - Oxygen added by the lungs = 250 ml oxygen/min, measured by spirometer. - Oxygen concentration in the pulmonary artery (carrying deoxygenated blood) = 150 ml oxygen/l blood (measured using a catheter introduced into the pulmonary artery). - Oxygen concentration in the pulmonary vein (carrying oxygenated blood) = 200 ml oxygen/l blood (measured from any peripheral artery because all arteries have the same concentration of oxygen). - Remember that oxygen concentration in the deoxygenated blood of the pulmonary artery is not taken from peripheral veins. The core of medical physiology (1) 3 rd edition Page 253

254 - By applying the above values to the formula: COP = Q / [A] [V] COP = 250 ml oxygen/min / [50 ml oxygen/l] (Where 50 is the arterial-venous difference between 150 and 200 ml oxygen/l); therefore the COP = 5 L/min. Thermo-dilution technique - This is similar to the dilution method. - A cold saline is injected as an indicator in the right atrium and the change in blood temperature within the pulmonary artery is used for calculation of the COP. Direct methods - Used mainly in experimental animals. - Here surgery is needed to enter the heart through great arteries or veins and measure the cardiac output directly using a flow-meter device (electromagnetic or ultrasonic flow-meter device). Control of the COP - The COP = heart rate x stroke volume. - 5 L/min = 72 beat/min x 70 ml/beat. - Therefore, the two factors that control the COP are the heart rate & stroke volume. Control of the heart rate (HR) - The heart rate is the number of cardiac beats per minute. - It ranges between 60 & 100 beats per min; the average is about 72 beat/min at rest; however, normal heart rate differs according to age (in neonates>infants>children>adults). The core of medical physiology (1) 3 rd edition Page 254

255 - In normal adults, a value less than 60 beat/min is described as bradycardia whereas a value more than 100 beat/min is described as tachycardia. - The term positive chronotropic effect is used to describe increase in heart rate whereas negative chronotropic effect describes the reverse. - Remember that: when the heart rate is increased, the time for ventricular filling is decreased and therefore the stroke volume is decreased, this occurs if contractility of the heart is not affected; however, when contractility is also increased, the stroke volume is increased (i.e. factors that increase the heart rate & contractility: increase the stroke volume; whereas factors that increase the heart rate alone: decrease the stroke volume). Factors affecting the HR are: Neural factors o Sympathetic neurons - Release noradrenaline to act on beta 1 receptors - Activated by stress (fear, pain, emotions ) - Increase heart rate (positive chronotropic effect) o Chemoreceptors - Chemical receptors found in aortic bodies (in aortic arch) & carotid bodies (in carotid bifurcation). - Stimulated by hypoxia, hypercapnia and acidosis - Increase heart rate (positive chronotropic effect) o Bainbridge effect or reflex - Increase in heart rate (positive chronotropic effect) due to increase in venous return that initiates a reflex or effect as follows: The core of medical physiology (1) 3 rd edition Page 255

256 - The reflex is initiated in receptors in the right atrium and integrated in the medulla. It results in stimulation of the SA node to increase its rate of discharge (Bainbridge reflex) - The effect is a direct mechanical effect of the blood on the SA node to increase its rate of discharge (Bainbridge effect) o Parasympathetic neurons - Release acetylcholine to act on muscarinic receptors. - Activated by rest and sleep - Decrease heart rate (negative chronotropic effect) o Baroreceptor reflexes - Stretch receptors found in aortic sinus (in aortic arch) & carotid sinus (in carotid bifurcation). - Stimulated by elevation in blood pressure. - Decrease heart rate (negative chronotropic effect). Hormonal factors: - Many hormones have positive chronotropic effect. - Examples include catecholamines & thyroid hormones. - Thyroid hormones act indirectly by increasing number and affinity of beta1 receptors in the heart to catecholamines. Physiological factors - HR is increased by exercise (which is associated with sympathetic stimulation due to physical stress or excitement emotions ). - It low during sleep (which is associated with parasympathetic stimulation). Physical factors - Changes in body temperature (due to hot or cold environment or due to fever or hypothermia) affect heart rate. The core of medical physiology (1) 3 rd edition Page 256

257 - Elevation in body temperature by one degree centigrade increases heart rate by about 15 beat/min whereas reduction in body temperature does the reverse. Drugs o Atropine (muscarinic blocker): - Blocks the parasympathetic; that s why it increases the heart rate. - It is used in cases of cardiac asystole. o Atenolol & propranolol (beta blockers): - Both drugs decrease HR by blocking beta 1 receptors in SA node. - Atenolol is selective beta blocker (blocks beta1) whereas propranolol is non-selective beta blocker (blocks both beta 1&2). - Salbutamol is a commonly used drug for treatment of asthma. It is a beta 2 agonist. Therefore, it should not increase the heart rate; however, the drug has some effect on beta1 receptors, that s why it increases the heart rate as a side effect. o Digitalis (anti arrhythmic drug that slows conduction): - Decreases the heart rate because it slows the conductive system. - It increases entry of calcium in cardiac muscle (through a mechanism that involves inhibition of the Na + -K + pump). That s why it increases contractility of the heart. Control of the stroke volume (SV) - Defined as the volume of blood ejected by each ventricle each beat. - Normal value is about 70 ml (in an average adult male, at rest); however, it differs according to age, sex and physiological state. - It is smaller in neonates < infants < older children < adults due to gradual increase in the size of the heart with normal development. The core of medical physiology (1) 3 rd edition Page 257

258 - The stroke volume is larger in males compared to equivalent female of the same age and body size because the heart is adapted to eject more blood to more active tissues in males (muscles) compared to more inactive tissues in females (fats). - During stress (emotions, pain, hypoglycemia & exercise), the sympathetic nervous system is activated resulting in increased contractility of the heart, this increases stroke volume. At rest, the stroke volume returns to its normal value 70 ml. - The term positive inotropic effect is used to describe increase in contractility of the heart whereas negative inotropic effect describes the reverse. - When contractility of the heart is increased, subjects become aware of the heart beating, this is described as palpitation. - Remember that: when contractility of the heart is increased, the stroke volume is increased whereas the end systolic volume is decreased. Factors affecting SV are: Neural factors o Sympathetic neurons - Increase the stroke volume (positive inotropic effect). o Chemoreceptors - Increase the stroke volume (positive inotropic effect). o Parasympathetic neurons - Do not supply ventricles of the heart. Therefore they have no direct effect on contractility of the heart or stroke volume. o Baroreceptor reflexes - Decrease the stroke volume (negative inotropic effect). The core of medical physiology (1) 3 rd edition Page 258

259 Hormonal factors: - Many hormones have positive inotropic effect. - Examples include catecholamines & thyroid hormones. - Thyroid hormones act indirectly by increasing number and affinity of beta1 receptors in the ventricles to catecholamines. Physiological factors - SV is increased by exercise (positive inotropic effect). Physical factors - Changes in body temperature (due to hot or cold environment or due to fever or hypothermia) have direct effect on contractility. - High temperature increases the stroke volume (positive inotropic effect); whereas low temperature does the reverse. Drugs o Atropine (muscarinic blocker): - Blocks the parasympathetic; that s why it has no direct effect on contractility and stroke volume. o Atenolol & propranolol (beta blockers): - Both drugs decrease SV by blocking beta 1 receptors in ventricles. They are commonly prescribed for patients with IHD because they decrease cardiac contractility and therefore decrease the need for oxygen by cardiac muscle. o Digitalis (anti arrhythmic drug that slows conduction): - Increases entry of calcium in cardiac muscle (it inhibits the Na/K ATPase pump resulting in accumulation of sodium in cells. This inactivates a sodium-calcium antiport pump which takes calcium to outside in exchange to sodium. Calcium increases contractility and therefore SV. The core of medical physiology (1) 3 rd edition Page 259

260 - Digitalis also decreases heart rate and gives ventricles extra time for filling. This increases the end diastolic volume and therefore the SV is increased (by Frank-Starling law described below). Calcium ions - SV is increased by calcium ions (positive inotropic effect) -Severe hypercalcemia is fatal. It stops the heart in systole. Preload & after load Preload - It is the load on a ventricle before contraction (or the degree of stretch before contraction). - It is equivalent to the end diastolic volume (EDV), which depends on venous return. Therefore, when the preload is increased, the SV is increased (direct relationship). The increase in SV occurs according to the Frank-starling Law (see below). After load - It is the resistance in arteries against ejection. - When increased, the stroke volume is decreased (inverse relationship). - After load is increased by: aortic stenosis, pulmonary stenosis, systemic hypertension, pulmonary hypertension or vasoconstriction. Frank-Starling Law - Described first by Frank and confirmed experimentally later by Starling. It states that: Within certain limits, the energy of contraction is directly proportional to the initial length of muscle fibers. - The length of cardiac muscle fibers depends on the EDV, which also depends on venous return. Therefore, higher venous return increases EDV, this increases contractility & so increases the SV. The core of medical physiology (1) 3 rd edition Page 260

261 THE VENOUS RETURN - It is the blood that returns back to the heart through veins. - It equals the cardiac output (= 5 L/min in a resting adult male. - It is affected by the following factors: Pressure gradient - Pressure in arteries is higher than vein, higher than right atrium. - Therefore, blood passes down the pressure gradient from arteries to veins to right atrium in the heart. Respiratory pump - Inspiration increases venous return (inspiration increases chest volume and therefore decreases intra-thoracic pressure; that s why venous return is increased). Expiration decreases venous return especially expiration against closed glottis (valsalva maneuvre) which is done during defecation, labor or lifting heavy weights. Muscle pump - Contraction of the lower limb muscles squeezes blood in the veins upwards towards the heart (the venous blood does not pass down during muscle contraction because of the one way valves in veins. Gravity - Standing decreases venous return due to gravity whereas lying down increases venous return. Blood volume - Bleeding decreases venous return by decreasing the total blood volume whereas fluid overload increases venous return. Venodilation & venoconstriction - Venodilation decreases venous return because it increases diameters of these capacitance vessels to store blood. The core of medical physiology (1) 3 rd edition Page 261

262 - Venoconstriction increases venous return (by adding some of the stored blood to the circulation). This is very important in shock. State of heart valves - Stenosis or regurgitation of any of the heart valves decreases the venous return and results in heart failure. Pericardial pressure - Pericardial effusion increases pressure within the pericardial sac and therefore decreases venous return. - It is caused by inflammation (pericarditis) due to viral or bacterial infection or due to hypothyroidism or connective tissue diseases. CONTROL OF ARTERIAL BLOOD PRESSURE Definitions Blood pressure - The pressure of blood on walls of blood vessels. - Remember that: hydrostatic pressure is the pressure of water (i.e. plasma) on walls of blood vessels. Systolic pressure - The maximum pressure in a vessel during systole of the heart. - Normal value is less than 120 mmhg in adults. Values of 120 mmhg or more and less than 140 have been regarded as normal; however, according to recent studies, these values indicate prehypertension state. Systolic blood pressure of 140 mmhg or more is hypertension. Diastolic pressure - The minimum pressure in a vessel during diastole of the heart. The core of medical physiology (1) 3 rd edition Page 262

263 - Normal value is less than 80 mmhg in adults. Values of 80 mmhg or more and less than 90 have been regarded as normal; however, according to recent studies, these values indicate pre-hypertension state. Diastolic blood pressure of 90 mmhg or more is hypertension. Pulse pressure - The difference between the systolic and the diastolic pressures. - Normal pulse pressure is less than 60 mmhg. - When the systolic pressure is increased and the diastolic is decreased, the pulse pressure becomes wide. - Causes of wide pulse pressure include: o Hyperthyroidism o Aortic regurgitation o High body temperature o Hard exercise o Severe anemia o Pregnancy o Arterio-venous fistula Mean arterial pressure - The mean pressure during the cardiac cycle. - It is calculated as follows: The mean arterial pressure= The diastolic + 1/3 pulse pressure - Its value is more near to the diastolic than the systolic because the diastolic phase takes longer time than the systolic in the cardiac cycle). - Example: If a blood pressure of a subject = 120/80 o The systolic = 120 mmhg o The diastolic = 80 mmhg The core of medical physiology (1) 3 rd edition Page 263

264 o The pulse pressure = = 40 mmhg o The mean arterial pressure = 80 + (1/3 x 40) = 93 mmhg Control of the arterial blood pressure - Blood pressure = Cardiac output Peripheral resistance. - Therefore the blood pressure is controlled by controlling the cardiac output and the peripheral resistance. - The cardiac output is controlled by controlling both the heart rate and the stroke volume (see above). It determines the systolic pressure (i.e. the increase in COP increases systolic pressure). - The peripheral resistance is determined by blood viscosity, length of arteries and radius of arteries as follows: PR = 8VL/ r 4 - Where V is the blood viscosity, L is the length of arteries and r is the radius of blood vessels. - The peripheral resistance determines the diastolic blood pressure. Viscosity of the blood - Depends on: o The packed cell volume (PCV) o Plasma proteins especially globulins and fibrinogen (because of the large size of their particles) o Body temperature (this is quite constant in the normal physiological conditions) Length of blood vessels - Constant in adults. Radius of blood vessels - The most important factor in determining the peripheral resistance. The core of medical physiology (1) 3 rd edition Page 264

265 - Inversely proportional with the peripheral resistance. For example: vasoconstriction decreases radius of arteries & increases the peripheral resistance and therefore increases the blood pressure whereas vasodilatation increases the radius & decreases the peripheral resistance and therefore decreases the blood pressure. Remember that: Blood pressure in children is less than that in adults. The systolic is less because the COP in children is less (child s heart is small= stroke volume is smaller= COP is lower; in spite of the faster heart rate). The diastolic is less because the length of arteries is less; therefore, peripheral resistance is less (in spite of other factors). The mechanisms that control the blood pressure Very rapid mechanism (act in seconds) Baroreceptors Chemoreceptors CNS ischemic response Less rapid mechanisms (act in minutes to hours) Hormonal vasoconstriction by o Renin- Angiotensin system o Antidiuretic hormone (ADH) o Catecholamines Stress relaxation and inverse stress relaxation Capillary fluid shift Long term mechanisms (act in days) Renin-Angiotensin-Aldosterone system The core of medical physiology (1) 3 rd edition Page 265

266 ADH Atrial natriuretic peptide (ANP) Thirst mechanism Other hormones that may affect the blood pressure Local regulation of blood pressure VERY RAPID MECHANISMS Baroreceptors - Stretch receptors found in high pressure areas of the circulation (aortic sinus in aortic arch and carotid sinus in carotid bifurcation). - They are stimulated by stretch caused by high blood pressure. - They send impulses through the vagus & glossopharyngeal nerves to the medulla oblongata. - The impulses reach the nucleus of tractus solitarius (NTS) and from there inhibitory impulses pass to the vaso-motor center (VMC) & cardiac center (CC) in the medulla causing reduction in sympathetic discharge from these centers to the heart and blood vessels. - Excitatory impulses pass to the cardio-inhibitory center in the medulla causing increased parasympathetic discharge from this center to the heart. - The decreased sympathetic & increased parasympathetic result in: o Reduction in heart rate & stroke volume (i.e. lower COP and therefore lower systolic blood pressure) o Vasodilatation (i.e. decreased peripheral resistance and therefore lower diastolic blood pressure) - Consequently the B.P is reduced back to normal within a second. The core of medical physiology (1) 3 rd edition Page 266

267 - The opposite occurs when there is reduction in B.P: hypotension= less stretch= less stimulation of baroreceptors= less inhibitory discharge to the medulla= more sympathetic and less parasympathetic= increased HR & SV= higher COP= Increased blood pressure back to normal within a second (systolic & diastolic). Important notes: When the blood pressure is normal, the baroreceptors send tonic discharge through the buffer nerves (9 and 10) causing continuous reduction in activity of the VMC and the CC. Denervation of the baroreceptors (cutting the buffer nerves) causes elevation in blood pressure. Baroreceptors adapt to new pressures (this is known as resetting). For example when the BP is chronically elevated, the baroreceptors increase the rate of their tonic discharge to correct the pressure; however, if the BP remains elevated, the rate of discharge will decrease gradually over time until it reaches the earlier rate. The resetting phenomenon is reversible. - There are other types of baroreceptors found at the venous side (low pressure areas). These include: o Type A atrial baroreceptors: discharge during systole o Type B atrial baroreceptors: discharge during diastole - Stimulation of these venous barorecptors results in reflex vasodilatation like the arterial baroreceptors; however, the heart rate increases. The core of medical physiology (1) 3 rd edition Page 267

268 Chemoreceptors - The peripheral chemoreceptors are found in the carotid body in carotid bifurcation and aortic body in aortic arch. - They are stimulated by hypoxia (low O 2 in tissues), hypercapnia (high CO 2 ) and acidosis (high H + ). These stimuli are associated with hypotension because of the low tissue perfusion. - They send excitatory impulses through the vagus and glossopharyngeal nerves to the respiratory center to increase respiration. - The impulses also stimulate the vasomotor and the cardiac centers (due to radiation of impulses in the medulla). - This increases the blood pressure by increasing sympathetic discharge from these centers to the heart and blood vessels causing increased heart rate, higher stroke volume and vasoconstriction. CNS ischemic response - Reduction of the blood supply to the brain (ischemia), is caused by hypotension. This results in accumulation of CO 2. - The vasomotor center is very sensitive to CO 2. It is stimulated to release its sympathetic discharge to the blood vessels. This increases the blood pressure and therefore improves the blood supply to the brain. - A high intracranial pressure (e.g. caused by a brain tumor) impairs cerebral circulation and results in brain ischemia. This induces similar CNS ischemic response resulting in elevation of the blood pressure to high levels (hypertension). - The high blood pressure stimulates the baroreceptors to inhibit the heart through the cardiac center and the cardioinhibitory center, but The core of medical physiology (1) 3 rd edition Page 268

269 they can not inhibit the vasomotor center which is stimulated by the CO 2 ; this results in bradycardia. - This sign (hypertension with bradycardia) is an important sign of raised intracranial pressure (known as Cushing's sign). LESS RAPID MECHANISMS Hormonal vasoconstriction ADH - Release of this nona-peptide hormone from the posterior pituitary gland is stimulated, among other stimuli, by hypotension. - It acts on V1 receptors in the blood vessels causing vasoconstriction. This elevates the blood pressure. - It also elevates the B.P. by acing on V2 receptors in the kidney; however, this action is grouped with the long term mechanisms. Catecholamines - Adrenaline and noradrenaline are released in response to hypotension (which is a form of stress). - They act on receptors in blood vessels causing vasoconstriction. This elevates the blood pressure. - Remember that: noradrenaline acts on alpha receptors better than beta whereas adrenaline acts on beta receptors better than alpha. - That s why noradrenaline increases the diastolic (by increasing the peripheral resistance) whereas adrenaline increases the systolic (by increasing the cardiac output). Renin-Angiotensin II - Renin enzyme is released by the Juxtaglomerular cells in the kidney. It is stimulated by renal ischemia, hyponatremia & sympathetic stimulation (all these are associated with hypotension). The core of medical physiology (1) 3 rd edition Page 269

270 - It acts on angiotensinogen (plasma protein from the liver) converting it to angiotensin I. - Angiotensin I is converted to angiotensin II by angiotensin converting enzyme (ACE) which is poduced by endothelial cells (especially of pulmonary capillaries). - Angiotensin II causes vasoconstriction. - It also activates the sympathetic to release renin, then renin converts angiotensinogen to angiotensin I and the cycle repeats itself (positive feedback mechanism). - Other actions of angiotensin II are long term effects (see below). Stress relaxation and inverse stress relaxation - The stress on walls of blood vessels, caused by high blood pressure, leads to relaxation of smooth muscles in the walls and reduction in the blood pressure in minutes (stress relaxation). - Conversely, reduction in the blood pressure leads to less stress on the walls of blood vessels and therefore constriction of the blood vessels leading to elevation in the blood pressure (inverse stress relaxation). Capillary fluid shift - Occurs due to hypotension because there is reduction in the hydrostatic pressure (which is responsible for filtration). - It becomes lower than the oncotic pressure in capillaries (which is responsible for absorption). - This shifts fluid from the interstitium to the intravascular space. The blood volume is increased and therefore the blood pressure is slightly increased. The core of medical physiology (1) 3 rd edition Page 270

271 LONG TERM MECHANISMS Renin-Angiotensin Aldosterone system - As mentioned above, angiotensin II rapidly elevates the blood pressure by causing vasoconstriction. - In addition it has other long term effects. These include stimulation of aldosterone, stimulation of ADH and stimulation of the thirst center. - There are many stimuli of aldosterone. However its stimulation by angiotensin II completes activation of the renin angiotensin aldosterone system. - Aldosterone Acts on the distal convoluted tubules and collecting ducts in kidney causing reabsorption of sodium and secretion of potassium. Water follows sodium to the intravascular space. - This increases blood volume & therefore the blood pressure. ADH - As mentioned above, in addition to vasoconstriction, ADH has another long term effect to elevate the blood pressure. It acts on V2 receptors in the collecting ducts of the kidney causing reabsorption of water to the intravascular space. - This increases blood volume & therefore the blood pressure. Thirst - Controlled by a thirst center in the hypothalamus. - It is stimulated by hypotension and other stimuli (hypovolemia, hyperosmolarity & angiotensin II). The subject drinks water in response to thirst. - This increases the blood volume & therefore the blood pressure. The core of medical physiology (1) 3 rd edition Page 271

272 Atrial natriuretic peptide (ANP) - Atrial natriuretic peptide is a hormone released by atria in response to stretch by hypervolemia (hypervolemia is associated with higher blood pressure). - ANP acts in the kidney to decrease sodium reabsorption in the proximal convoluted tubules and antagonizes aldosterone in the distal convoluted tubules and collecting ducts of the kidney. Sodium is lost in urine followed by water. - This decreases the blood volume & therefore the blood pressure. Other hormones that may affect the blood pressure: o Kinins: (vasodilators- decreases the B.P.) o Adrenomedullin & pro-adrenomedullin (vasodilators- decrease it) o VIP (vasodilator- decreases the B.P.) o Urotensin II (vasoconstrictor- increases the B.P.) LOCAL REGULATION - Aim of Local regulation of blood pressure: o To maintain adequate perfusion and therefore adequate supply of O 2 and nutrients to the tissues. o To adjust the perfusion to tissues according to their needs; which vary from time to time according to variation in activities. - Local regulation occurs by the following: 1- Autoregulation: - It is the intrinsic capacity of tissues to regulate their own blood flow. - Found in many tissues like skeletal muscles, cardiac muscle, brain, liver,... The core of medical physiology (1) 3 rd edition Page 272

273 - Can be explained by: The myogenic theory of autoregulation - High perfusion pressure results in local vasoconstriction (in organs) to prevent their rupture (according to Law of Laplace, see below) and to adjust blood flow to organs. This mechanism is not expected to occur in response to very low or very high perfusion pressures. Metabolic theory of autoregulation - Active tissues produce metabolites that can cause vasodilatation. When the blood flow decreases, they accumulate and when the blood flow increases, they are washed away. - Metabolites that can cause vasodilatation include: CO 2, H + and K +, ATP, ADP, adenosine, pyruvate, lactate - Localized vasoconstriction can be caused by serotonin and cold. 2- Substances secreted by the endothelium: Prostacyclin: - Cause vasodilatation & inhibits platelet aggregation - Prostacyclin is balanced by throboxane A2 (TXA2) which is released from platelets (TXA2 causes vasoconstriction and stimulates platelet aggregation). The balance is shifted towards prostacyclin by low dose aspirin; that s why low dose of aspirin is commonly prescribed to patients at risk of thrombosis (e.g. diabetic and hypertensive patients). Nitric oxide (NO): - It is the endothelial derived relaxation factor (EDRF). - It is synthesized from arginine by the enzyme NO synthase - It is an important vasodilator in many organs (e.g. causes erection in males); however, it has many other functions in other organs. The core of medical physiology (1) 3 rd edition Page 273

274 Endothelins - Polypeptides (21 aa) - They are potent vasoconstrictors - They have many other functions. IMPORTANT NOTES ABOUT BLOOD VESSELS Arteries and arterioles - The walls of large arteries contain high amount of elastic fibers whereas the walls of the arterioles contain less amount of elastic fibers, but more smooth muscle. - The arterioles are the major site of resistance to blood flow (resistance vessels). Capillaries - These are the major site of fluid exchange between plasma and interstitium (exchange vessels). - The junctions between endothelial cells in capillaries may be very tight (e.g. in brain capillaries and to a lesser extent in muscles); or fenestrated (e.g. in liver sinusoids and to a lesser extent in glomerular capillaries). - Blood capillaries have the highest surface area (surface area exceeds 6300 m 2 in adults) and the lowest velocity of blood flow. - In spite of the thin wall of capillaries, they do not rupture because of their small diameter. Similarly, arterioles constrict to resist rupture when the perfusion pressure is high (explained by Law of Laplace ). The core of medical physiology (1) 3 rd edition Page 274

275 - The law states that: the tension (T) in the wall of a cylinder is equal to the product of the transmural pressure (P) and the radius (r), divided by the wall thickness (w). Fig As mentioned above: T = Pr/w - The transmural pressure (P) = pressure inside the cylinder pressure in tissue which is negligible. Therefore (P) = the pressure inside the cylinder (= the distending pressure) - The wall thickness of capillaries (w) is negligible - Therefore the equation becomes: T = Pr P = T/r (in blood vessels) or P = 2T/r (in spheres) - From the above law, the smaller the radius of a blood vessel, the lower the tension that s needed to balance the distending pressure; that s why vessels with smaller radius resist rupture. - On the other hand, the pressure needed to inflate a sphere should be higher than the pressure inside (i.e. higher than P). Since P is inversely related to the radius, the smaller the radius, the higher the distending pressure needed for inflation. The core of medical physiology (1) 3 rd edition Page 275

276 Venules and veins - Their walls are relatively thin and easily distended. Therefore they can accommodate large volume of blood (capacitance vessels); for example they accommodate 50% of circulating blood at rest. - Venoconstriction occurring during hypotension (e.g. shock) adds large amount of this stored blood into the circulation. - The inner layer (intima) of the limb veins is folded into valves. These are absent from the veins in the abdomen, chest, head and neck. Lymphatics - The excess interstitial fluid is collected by diffusion into lymphatic capillaries. - These start in the interstitium of the whole body, joined progressively together and traverse lympn nodes to drain eventually in the right and left subclavian veins, at the neck. - Once within the lymphatics, the fluid is called lymph. The lymph is similar to interstitial fluid; however, it circulates lymphocytes and transports lipids (chylomicrons) absorbed in the small intestine. It also carries small amount of protein filtered from capillaries. - Lymphatic vessels contain valves, and there are no visible fenestrations in their walls. The pulse wave - Is a pressure wave that travels along the blood vessels and expands them on its way. The expansion is palpable as pulse. - In the arteries it is known as the arterial pulse. The pulse wave moves faster than the blood flow, especially with increased age (i.e. when the arteries lose their elastic fibers and become rigid). The core of medical physiology (1) 3 rd edition Page 276

277 The blood flow - The blood flow through a blood vessel = pressure/ resistance. - It is calculated directly by the Fick principle using special substances consumed by the organs to which the blood flow is being measured (revise measurement of the cardiac output). Examples include: or example: o N 2 O for cerebral blood flow (N 2 O = nitrous oxide) o PAH for renal blood flow (PAH= Para-amino-hippuric acid) o Oxygen for blood flow to the lung (i.e. the cardiac output) - The aorta has the highest velocity of blood flow, then the velocity decreases gradually to be lowest in the capillaries and then it increases slightly in veins. - The blood flow through straight blood vessels is laminar. However, there is certain critical velocity, above which the blood flow becomes turbulent. - This critical velocity may be exceeded at sites of constriction within a blood vessel, producing turbulence beyond the constriction, or in the heart due to rapid blood flow or closure of the valves. - Turbulent blood flow produces noise that s heard as bruit over arteries or a murmur over the heart whereas laminar blood flow is silent. CIRCULATION THROUGH SPECIAL ORGANS THE CORONARY CIRCULATION - The cardiac muscle is supplied by the right and left coronary arteries that originate from coronary sinuses at the root of the aorta, behind two cusps of the aortic valves. The core of medical physiology (1) 3 rd edition Page 277

278 - The venous blood is drained to the right atrium through the coronary sinus and anterior cardiac veins; however, small cardiac veins (e.g. thebesian veins) drain into other chambers, resulting in reduction of the PO2 in arterial blood (physiological shunt). - Coronary blood flow to the left ventricle occurs during diastole and to the atria and the right ventricle occurs during both systole and diastole. This is explained by the pressure gradient between the aorta and theses chambers during the cardiac cycle (see above). - The coronary blood flow = 250 ml/min (= 5% of the cardiac output). It is controlled by: - Metabolites (high CO 2, H +, lactate, K +, prostaglandins and adenosine): These are the primary dilators of the coronary artery. Among these metabolites adenosine is the most important dilator. - Sympathetic stimulation: Both alpha and beta 2 receptors are found in the coronary artery but the direct sympathetic effect is vasoconstriction through alpha receptors; however, the sympathetic increases contractility and therefore increases metabolites. Through metabolites it causes vasodilatation and increases the coronary blood flow (i.e. the indirect effect is more dominant). - Parasympathetic stimulation: causes dilatation of the coronaries. Factors affecting the coronary blood flow (CBF) include: - Tachycardia (decreases diastole and therefore decreases coronary blood flow CBF ). - Aortic stenosis (associated with severe compression of the coronary artery during systole of the left ventricle= decreases CBF). - Hypotension (= decreases pressure in aorta and therefore decreases CBF). The core of medical physiology (1) 3 rd edition Page 278

279 - Reduction in the coronary blood flow (ischemia) decreases oxygen supply to the cardiac muscle. This produces severe chest pain that s aggravated by exercise and relieved by rest (angina pectoris). - Prolonged or severe ischemia (due to complete obstruction of the coronary artery) results in necrosis and death of the cardiac muscle (Myocardial infarction). Here the pain is not relieved by rest. CEREBRAL CIRCULATION = 0.75 L/min (measured by the Fick principle using inhaled N 2 O). - In addition to the sympathetic and parasympathetic innervation, cerebral blood vessels are supplied by sensory nerves. These nerves carry pain sensation triggered by traction or injury of these vessels. - The brain is very sensitive to hypoxia; occlusion of its blood supply causes unconsciousness in about 10 seconds. - Chronic hypoxia produces intellectual deficits and affects the basal ganglia, the thalamus and the inferior colliculus; however, the vegetative structures in the brain stem are more resistant to hypoxia. SPLANCHNIC CIRCULATION = The liver receives 1.5 L/min of blood (0.5L /min by the hepatic artery and 1.0 L/min by the portal vein). - Other abdominal viscera receive about 1.0 L of blood per minute. - This indicates that the liver and viscera receive about 1.5 L of arterial blood per minute (= about 30% of the cardiac output). - However, the blood flow to the small intestine increases after a meal for up to 3 hours and therefore shifts some of the blood supply to the brain. That s why subjects become sleepy after a meal. The core of medical physiology (1) 3 rd edition Page 279

280 - The pressure in the portal vein has a clinical importance (= 10 mmhg). It is high in patients with portal hypertension (e.g. due to bilharziasis). CUTANEOUS CIRCULATION = less than 0.5 L/min but varies with environmental temperature. It is controlled by sympathetic neurons (no parasympathetic supply). - Skin blood vessels develop the following reactions: White reaction - Follows light skin trauma by a pointed object. The reaction is caused by reduction in capillary blood flow following contraction of the precapillary sphincter. Triple response - Follows firm skin trauma by a pointed object. It involves three changes in the skin: o Red reaction: (due to capillary dilatation by the pressure) o Local swelling (wheal): (due to increased capillary permeability) o Diffuse reddening (flare): (due to arteriolar dilatation) - The capillary changes appear to be due to local release of substance P. - The triple response is an example of axon reflex (in which afferent impulses travel antidromically through axons of sensory nerves). Reactive hyperemia - Increased blood flow to an area after a transient occlusion of its blood supply; due to vasodilatation caused by hypoxia and metabolites. The core of medical physiology (1) 3 rd edition Page 280

281 CARDIOVASCULAR RESPONSES TO EXERCISE - The cardiovascular responses to exercise differ according to the type and level of exercise and according to the age and degree of training. Most of the responses involve changes in the cardiovascular and reparatory systems. The following is a brief account about some of the cardiovascular responses: Increased heart rate due to: o Increased sympathetic stimulation (due to stress) o Withdrawal of the parasympathetic effect on the heart (more important than the increased sympathetic) o Circulating catecholamines (from adrenal medulla & sympathetic) o Proprioceptors (send excitatory impulses to the medullary centers) o Temperature (stimulates the SA node directly) o Bainbridge effect (due to increased venous return by the muscle pump & respiratory pump) o Stimulation of chemoreceptors (due to hypoxia and acidosis) o Stretch receptors in the lung (when the lung is inflated, impulses pass through the vagus to inhibit the cardio-inhibitory center) - The maximum heart rate (MHR) achieved during exercise decreases with age. - The easiest method to calculate it is by the formula: MHR = age However, there are many alternative formulas suggested by researchers (e.g. MHR= (0.67 x age)). - Trained athletes start with lower heart rate because their resting heart rate is low (they have physiological bradycardia). The core of medical physiology (1) 3 rd edition Page 281

282 Increased stroke volume due to: o Increased sympathetic stimulation (due to stress) o Circulating catecholamines (from adrenal medulla & sympathetic) o Temperature (stimulates the SA node directly) o Stimulation of chemoreceptors (due to hypoxia and acidosis) o Increased venous return = increases EDV (Frank-Starling s law) - Exercise with isotonic contractions produce marked increase in stroke volume whereas exercise with isometric contraction produces little change in it. Increased venous return due to: o Muscle pump o Respiratory pump (hyperventilation) o Venoconstriction (by the sympathetic and catecholamines) Increased cardiac output due to: o Increased HR & SV o Depends on degree of training and level of exercise o May reach more than 35L/min in athletes Increased or decreased peripheral resistance (PR) due to: o Compression of blood vessels during isometric contractions (= increased peripheral resistance PR ) o Dilatation of skeletal muscle arterioles during isotonic contractions (= decreased peripheral resistance). This dilatation occurs due to: - Sympathetic cholinergic discharge acting on M receptors - Circulating catecholamines acting on B 2 receptors - Metabolites - Remember that: the level of exercise determines the net effect on peripheral resistance. Hard exercise decreases PR. The core of medical physiology (1) 3 rd edition Page 282

283 Blood pressure changes: - Changes in systolic blood pressure are determined by the cardiac output whereas changes in the diastolic blood pressure are determined by the peripheral resistance. - Generally, isometric contraction increases both systolic and diastolic pressures whereas isotonic contraction increases the systolic and decreases the diastolic; however, these effects depend, to a large extent, on the level of exercise. - In strenuous exercise the systolic is increased, the diastolic is decreased and therefore the pulse pressure is increased. HEART FAILURE & SHOCK HEART FAILURE - Defined as failure of the heart to meet the metabolic demands of tissues. - Causes include: Severe anemia, severe hypertension, arrhythmia, myocardial infarction, valvular disease and thyrotoxicosis. - Heart failure can be classified as: o Left sided HF (LHF): failure of the left side of the heart o Right sided HF (RHF): failure of the right side of the heart o Congestive HF (CHF): failure of the left & right sides of the heart - Other terms may be used: for example high output heart failure Here the cardiac output is increased; however, the high COP is still not enough to meet the metabolic demands of tissues which are highly increased (e.g. in thyrotoxicosis). The core of medical physiology (1) 3 rd edition Page 283

284 Physiological mechanisms in heart failure = All the mechanisms in heart failure are stimulated by hypotension and tissue hypoxia. - These include activation of the renin-angiotensin-aldosteone system because of the low blood supply to the kidney. This results in retention of sodium and water and therefore contributes to edema formation (see control of blood pressure). - When the left ventricle fails to eject blood (LHF), blood accumulates in the lung causing pulmonary edema whereas when the right ventricle fails (RHF), blood accumulates in the venous side causing raised JVP, hepatomegaly, ascites and lower limb edema. - When the two ventricles fail (CHF), blood accumulates in the lung and the venous side; therefore, all symptoms and signs of LHF and RHF are found in CHF. Symptoms of heart failure include: - Due to blood accumulation in the lung & pulmonary edema: o Breathlessness: occurs in LHF & CHF o Cough: occurs in LHF & CHF o Sputum with blood: occurs in LHF & CHF - Due to blood accumulation in venous side: o LL swelling: occurs in RHF & CHF o Venous pulsations in the neck: occur in RHF & CHF - Due to low blood supply to muscles: o Fatigability & weakness: may occur in all types of HF - Other symptoms: o Palpitation: may occur in all types of HF o Cyanosis: may occur in all types of HF (especially LHF & CHF) The core of medical physiology (1) 3 rd edition Page 284

285 Signs of LHF include: o Third heart sound (galloping rhythm) o Signs of pulmonary edema (basal crepitations) Signs of RHF include: o Third heart sound (galloping rhythm) o Generalized edema o Engorged neck veins (raised JVP) o Hepatomegaly and sometimes splenomegaly o Ascites Signs of CHF include: o Signs of both LHF & RHF Signs that may give clue to the possible cause of HF include: o Displaced apex beat: Lt ventricular hypertrophy (hypertension) o Pale mucus membranes: Anemia (or vasoconstriction) o Murmur: Valvular lesion o Irregular pulse: Arrhythmia (atrial fibrillation) o Goiter (thyroid enlargement): Thyrotoxicosis Investigations: o To assess the heart: ECG, chest X ray and echocardiography. o For a possible cause: Hb and PCV, level of thyroid hormones in the plasma Treatment o Correction of the cause (e.g. blood transfusion for anemia) o Diuretics like Lasix (for the fluid overload) o Angiotensin converting enzyme inhibitors (ACEI) (to inhibit formation of angiotensin II and to decrease aldosterone) o Others (e.g. oxygen, morphine ) The core of medical physiology (1) 3 rd edition Page 285

286 SHOCK - Defined as state of the circulation in which there is inadequate tissue perfusion resulting in disturbance of functions. Types Hypovolemic shock (due to decreased blood volume) Distributive or low resistance shock (due to vasodilatation) Cardiogenic shock (due to cardiac lesion causing low COP) Obstructive shock (due to obstruction of blood flow in the chest) Symptoms o Irritability (due to low blood supply to the brain) o Thirst (due to hypovolemia) o Palpitation (due to increased contractility of the heart for compensation) Signs (Not in all types of shock) o Pallor and cold clammy skin (due to vasoconstriction) o Sweating (due to sympathetic activation) o Tachycardia (due to sympathetic activation) o Hypotension (due to hypovolemia, vasodilatation, cardiac lesion or kinking of the aorta ) o Low urine output (due to low renal blood flow and high release of ADH) o Hyperventilation (due to chemoreceptor stimulation by hypoxia or acidosis) Body responses to shock o Revise the mechanisms that control the blood pressure (very rapid, less rapid and long term mechanisms). The core of medical physiology (1) 3 rd edition Page 286

287 Complications of shock - Failure to treat shock leads to refractory or irreversible state. Here a positive feedback mechanism is initiated (low COP= low blood pressure= low venous return= low COP= low blood pressure and so on) which leads eventually to death. Hypovolemic shock - Subdivided according to the cause of hypovolemia into: o Hemorrhagic shock o Surgical shock o Traumatic shock o Burn shock o Shock of fluid loss (e.g. by vomiting or diarrhea) - The compensatory reactions to shock are rapid and long term (see control of blood pressure). - In hemorrhagic shock, plasma is restored in about 3 days whereas red blood cells are restored in 4-8 weeks. Distributive shock - Subdivided according to the cause of vasodilatation into: o Anaphylactic shock (caused by histamine released by allergic reactions) o Septic shock (caused by endotoxins released by bacteria) o Neurogenic shock (caused by vasovagal attacks caused by severe traumatic pain in certain sites; e,g. testicular trauma) - Due to the vasodilatation, the skin is usually warm (this differentiates hypovolemic shock, in which the skin is cold, from distributive shock (like septic shock), in which the skin is warm. The core of medical physiology (1) 3 rd edition Page 287

288 Cardiogenic shock - Caused by diseases of the heart which impair the cardiac output. - Examples include: o Myocardial infarction o Arrhythmias o Congestive heart failure - In addition to the symptoms and signs of shock, there are usually symptoms and signs of pulmonary congestion. Obstructive shock - Occurs due to obstruction of blood flow within the chest (kinking of the aorta or interruption of pulmonary blood flow). - Examples include: o Tension pneumothorax o Cardiac tamponade o Cardiac tumor o Pulmonary embolism The core of medical physiology (1) 3 rd edition Page 288

289 QUESTIONS FOR SELF ASSESSMENT-9 (BEST OF FIVE) 1. The cardiac muscle differs from skeletal muscle because it is: a. Striated muscle b. Supplied by the autonomic nervous system c. Inactive in the absence of external stimulation d. Tetanized after repeated stimulation e. Active in the absence of oxygen 2. The stroke volume is directly proportional to: a. Parasympathetic simulation b. The chronotropic effect of sympathetic stimulation c. Starling s forces d. The initial length of muscle fibers e. All of the above 3. During the cardiac cycle, closure of the aortic valve occurs at the: a. End of isometric contraction b. Beginning of rapid ejection phase c. Beginning of ventricular relaxation d. End of ventricular contraction e. End of rapid filling phase 4. Normal P wave in the ECG indicates: a. Increased size of atria b. Normal atrial contraction c. Ventricular depolarization d. Normal cardiac pacemaker e. Papillary muscle repolarization 5. Which of the following about the ECG is not true: a. Can detect the size of the heart b. Is useful in detecting reduction in the coronary blood flow c. It is recorded from limb leads and chest leads d. It can detect some electrolyte disturbances e. Is used for measurement of the cardiac output 6. Measurement of cardiac output using Fick principle depends on: a. Measurement of circulation time b. Frequent arterial blood sampling c. Use of a dye injected into an arm vein d. Calculation of blood flow using the formula (blood flow= Q x 60/Ct) e. None of the above 7. Left ventricular heart failure leads to: a. Increased pulmonary capillary hydrostatic pressure b. Engorged neck veins c. Bradycardia d. Increased myocardial contractility e. Ascites The core of medical physiology (1) 3 rd edition Page 289

290 8. Coronary blood flow: a. Is mainly regulated by sympathetic supply b. Increases due to beta blockers c. Is highest during systole because of myocardial activity d. Increases when myocardial metabolism increases e. Is regulated by myogenic autoregulation 9. If the radius of an artery is halved (divided by 2) its resistance will increase: a. 2 times b. 4 times c. 8 times d. 16 times e. 32 times 10. End diastolic volume may not increase in which of the following: a. An increase in preload b. Sympathetic stimulation c. Reduction in the ejection fraction d. An increase in venous return e. An increase in afterload 11. The pressure in the left ventricle: a. Varies between 0 am 120 mmhg b. Rises rapidly during ventricular filling c. Shows a maximum of 80 mmhg d. Falls rapidly during the initial phase of diastole e. Remains constant during the rapid ejection phase 12. Venous return: a. Is increased on standing b. Increases during inspiration c. Is decreased by venoconstriction d. When decreased, it activates bainbridge reflex e. When increased, it increases both heart rate & stroke volume 13. Which of the following is a vasodilator: a. Serotonin b. Endothelin c. Nitric oxide (NO) d. Thromboxane A2 e. Norepinephrine 14. When viscosity of blood is increased, which of the following is increased: a. Systolic blood pressure b. Diastolic blood pressure c. Central venous pressure d. Venous return e. PCV The core of medical physiology (1) 3 rd edition Page 290

291 15. Activity in the carotid sinus results in: a. Tachycardia b. Hyperventilation c. Increased peripheral resistance d. Edema e. Sweating 16. Lead II in the ECG is: a. Unipolar lead b. Normally characterized by absent Q wave c. Characterized by tall peaked T wave in hypokalemia d. Characterized by absent P wave in fast atrial fibrillation e. Not characterized by ST elevation in anterior myocardial infarction 17. The heart rate is increased by: a- Parasympathetic stimulation b- Beta blockers c- Cervical sympathectomy d- Denervation of the SA node 18. Concerning the ECG: a- P wave follows atrial systole b- ORS complex is due to ventricular repolarization c- ST segment represents conduction in all the conductive system d- the first heart sound follows the P wave e- the third heart sound occurs at the same time as the P wave 19. The cardiac muscle proper: a- Consumes protein as the main source of energy b- Depends on anaerobic metabolism for generation of energy c- Characterized by prepotential phase on its action potential d- Undergoes rhythmic contractions e- Is not protected from tetanus 20. The ECG is most important in detecting a major reduction in: a- Ventricular contractility b- Mean blood pressure c- Total peripheral resistance d- Cardiac output e- Coronary blood flow 21. Propagation of Action Potential through the heart is fastest in: a- SA node b- AV node c- Atrial muscle d- Purkinge fibres e- Ventricular muscle 22. The cardiac output: a. Is about 2 L/min at rest in adults b. Is always increased by increasing the heart rate The core of medical physiology (1) 3 rd edition Page 291

292 c. Is decreased by increasing the stroke volume d. Is not changed during exercise e. Is higher in males than females 23. If a blood pressure is 130/70, which of the following is not true: a. Systolic pressure equals 130 mmhg b. Diastolic pressure equals 70 mmhg c. Pulse pressure equals 60 mmhg d. Mean arterial pressure equals 120 mmhg e. The blood pressure is normal 24. The sino-atrial node (SA node): a. Is an un-myelinated neural structure b. Is found in the left atrium c. Is supplied by the sympathetic but not the parasympathetic d. Delays conduction from atria to ventricles e. Responsible for the normal cardiac rhythm 25. The stroke volume is decreased by: a. Stimulation of the parasympathetic b. Calcium ions c. Stimulation of the baroreceptors d. Exercise e. Digitalis 26. A drug that has a positive inotropic effect on the heart will: a. Increase the heart rate b. Increase the force of contraction c. Decrease the force of contraction d. Decrease the heart rate e. Increase the end diastolic volume 27. The peripheral resistance in adults is mainly determined by: a. Radius of arterioles b. Radius of great arteries c. Viscosity of the blood d. Length of blood vessels e. Radius of veins 28. Baroreceptors: a. Are located in the carotid and aortic bodies b. Their activity is increased on standing c. Result in tachycardia when stimulated d. Afferents from them terminate directly on the vasomotor centre e. Send tonic discharge in response to normal blood pressure 29. Hypovolemic shock is characterized by all the following except: a. Tachycardia b. Sweating c. Thirst d. Vasodilatation The core of medical physiology (1) 3 rd edition Page 292

293 e. Low urine output 30. Bradycardia may be produced by stimulation of a. 1 adrenergic receptors b. 2 adrenergic receptors c. adrenergic receptors d. Muscarinic receptors e. Nicotinic receptors 31. The stroke volume is proportional to: a. Parasympathetic simulation b. The chronotropic effect of sympathetic stimulation c. Starling s hypothesis d. The initial length of muscle fibers e. End systolic volume 32. The pacemaker prepotential: a. Is a slow depolarization due to opening of Ca ++ channels b. Is a slow inecrease in the RMP c. Maitained by opening of long acting Ca channels d. Is due to a decrease in K + efflux e. Occurs only in the SA node 33. The following is true regarding action potential of cardiac muscle: a. Increased extracellular K + causes immediate depolarization b. Repolaristion is due to Na + current c. Exrtacellular Na + affects the pacemaker potential d. Plateau phase of action potential is due to Ca ++ influx e. Repolarisation is due to delayed K + efflux 34. Clinical examination of a patient shows pale mucous membranes, a pulse rate of 110/min and blood pressure of 150/ 40 mmhg. Which of the following is a possible diagnosis: a. Heart failure b. Hypertension c. Aortic regurgitation d. Hypothyroidism e. High grade fever Question Answer b d c d e e a d d b a e Question Answer c b c d d d d e d e d e Question Answer c b a e d d d d d c The core of medical physiology (1) 3 rd edition Page 293

294 CHAPTER 7 THE RESPIRATORY SYSTEM STRUCTURE AND FUNCTION Divisions - The respiratory system is divided anatomically into: Upper respiratory tract (URT) - includes all structures outside the thoracic cavity (the chest). These are the nasal cavity, pharynx, larynx and upper part of the trachea. Lower respiratory tract (LRT) - includes all structures inside the thoracic cavity. These are the lower part of the trachea, bronchi, bronchioles, alveolar sacs (including alveolar ducts and alveoli). Fig 7.1: The respiratory system The core of medical physiology (1) 3 rd edition Page 294

295 - The URT is characterized by presence of hair (within the nose), ciliated epithelium, mucus secreting cells and rich blood supply. - Evaporation of water from surface of the respiratory mucosa moistens and equilibrates temperature of inspired air with that of the body; thus making the inspired air suitable for gas exchange in the distal parts of the lung. - The respiratory system is divided according to major function: Conducting zone: - For conduction of air to the lower zone. Includes the nasal cavity, pharynx, larynx, trachea, bronchi and bronchioles (up to the terminal bronchioles). Respiratory zone: - For gas exchange. Includes the respiratory bronchioles and alveolar sacs (alveolar ducts and alveoli). Fig 7.2: Physiological divisions of the respiratory system The core of medical physiology (1) 3 rd edition Page 295

296 Important anatomical points The tracheo-bronchial tree - Is formed by about 23 divisions. - The first 16 divisions (starting from the trachea to the terminal bronchioles) form the conducting zone whereas the other divisions (starting from the respiratory bronchioles to the alveoli) form the respiratory zone. - The trachea and bronchi have cartilage in their walls but little smooth muscle while the bronchioles have smooth muscle in their walls but no cartilage. - The cartilage supports walls of the trachea and large bronchi and prevents their collapse when the pressure inside them is decreased (as occurs during inspiration). - This support is lost in cases of tracheomalacia; that s why patients suffer from an inspiratory sound due to URT obstruction (stridor). The lungs - The lungs (the right and the left lungs) are found within the thoracic cavity, protected by the rib cage. - Each lung consists of parenchymal tissue supporting airways, blood vessels, nerves and lymphatics. - Each lung is divided, by horizontal and oblique fissures, into lobes. The right lung (consisting of 3 lobes) is larger than the left lung (consisting of 2 lobes due to presence of the heart). - The lungs provide a surface for gas exchange. - LRT diseases mainly affect the lungs. They include: inflammation of the lung (pneumonia), acute airway obstruction (asthma), chronic airway obstruction COPD (emphysema), lung fibrosis... The core of medical physiology (1) 3 rd edition Page 296

297 The Pleural cavity - Each lung is covered by a membrane that s attached tightly to its outer surface (the visceral pleura). The membrane continues to line the inner surface of the chest wall (the parietal pleura). - The potential space which is formed between the visceral and parietal pleurae is called the pleural cavity. - The pleural cavity contains a few millimeters of fluid that acts as a lubricant. It allows easy expansion of the lungs and resists separation of the two membranes, therefore normally, no cavity is actually present. Fig 7.3: The pleural cavity FUNCTIONS OF THE RESPIRATORY SYSTEM Provides oxygen to the tissues Eliminates carbon dioxide from the tissues Participates in regulation of ph of the blood The core of medical physiology (1) 3 rd edition Page 297

298 - These are the major functions of the respiratory system; however, participation of other systems is essential to perform these functions; especially the blood, cardiovascular system and the renal system. Other functions of the respiratory system: Participates in regulation of body temperature. Hyperventilation increases heat loss by evaporation from the mucus membranes. This is especially important in animals like dogs panting. Has some important metabolic functions. Theseinclude: - Conversion of angiotensin I to angiotensin II (by angiotensin converting enzyme (ACE) which is produced by the pulmonary endothelium). - Inactivation of certain vasoactive substances like bradykinin (also by ACE). - Breakdown of arachidonic acid metabolites like prostaglandins and leukotriens. - Synthesis of surfactant (see below). Has many important defense mechanisms: - Hairs within the nose for filtration of air (removes particles > 10 µm in diameter). - Mucus on the surface of respiratory epithelium for trapping of smaller particles (2-10 µm in diameter). - Cilia on cells for transporting the trapped particles upwards towards the nasopharynx to be swallowed or coughed out (= This is known as muco-ciliary clearance). - Cough or sneezing reflexes for ejection of unwanted substances through the mouth to the outside. The core of medical physiology (1) 3 rd edition Page 298

299 - IgA antibodies and complement proteins within the respiratory secretions for certain antigens. - Antiproteases (e.g. alpha 1-antitrypsin) for proteases released from dead bacteria or WBCs. - Alveolar macrophages for ingestion of bacteria, debris and foreign particles that reach the alveoli (usually less than 2 µm in diameter). Remember these clinical notes: ACE inhibitors are used for treatment of hypertension. They block the conversion of angiotensin 1 to angiotensin II; however, they also block the breakdown of bradykinin by the angiotensin converting enzyme. This results in many side effects caused by the bradykinin, including angioedema and irritating cough. For this reason, the angiotensin receptor blockers are very important for patients who suffer from these side effects. The receptor blockers block effects of angiotensin II without affecting the converting enzyme; therefore the enzyme inactivates bradykinin. Congenital or acquired deficiency of one or more of the above defense mechanisms results in certain respiratory problems, for example: deficiency of IgA antibodies causes repeated respiratory infections, deficiency of alpha 1-antitrypsin causes destruction of the lung tissue by proteases (as occurs in emphysema) and impaired muco-ciliary clearance due to immotile cilia causes repeated respiratory infections (as occurs in primary ciliary dyskinesia, also known as Kartagener's syndrome). The core of medical physiology (1) 3 rd edition Page 299

300 VENTILATION Definitions - Ventilation is the process of getting air into and out of the lungs during breathing. It is always adjusted to meet the metabolic demands of the body (i.e. to provide sufficient oxygen and to eliminate excess carbon dioxide). - Hyperventilation refers to ventilation in excess of the metabolic demands of the tissues. It usually results in hypocapnia (low Pco 2 ). - Hypoventilation refers to ventilation less than the metabolic demands of the tissues. It results in hypercapnia (high Pco 2 ). Mechanism of ventilation - Air moves into or out of the lungs due to pressure gradient (when the atmospheric pressure is higher than the intrapulmonary pressure it gets into the lungs (= inspiration); and when the atmospheric pressure is lower than the intrapulmonary pressure it gets out of the lungs (= expiration)). Fig 7.4: Ventilation The core of medical physiology (1) 3 rd edition Page 300

301 - According to Boyle s law: there is an inverse relationship between pressure of gases and volume. Therefore, there is an inverse relationship between pressure within the lungs and their size. - Inspiration results in inflation of the lungs and therefore reduction in intrapulmonary pressure (IPP) whereas expiration does the reverse. - The following table shows variations in IPP during respiration: Table 7.1: The intrapulmonary pressure Phase of respiration (with closed glottis) IPP End of normal inspiration -1 mmhg End of normal expiration +1 mmhg End of maximum inspiration -30 mmhg End of max expiration (valsalva maneuver) > +50 mmhg Remember that: The atmospheric pressure is 760 mmhg. Values of the IPP indicate difference from the atmospheric pressure. A value of -1 mmhg indicates a pressure less than the atmospheric by 1 (i.e. 759 mmhg) whereas +1 indicates a higher pressure (761 mmhg). Closure of the glottis at the upper part of the larynx isolates the respiratory system from the atmosphere. Therefore, there is no equilibration between IPP and atmospheric pressure. Opening of glottis allows equilibration of IPP with the atmospheric pressure. That s why the IPP at the end of all respiratory phases equals zero (i.e.=760 mmhg similar to the atmospheric pressure). Intrapleural pressure (IPLP) - The intra pleural pressure (IPLP) undergoes similar changes; however, opening and closure of the glottis do not change its values. - The following table shows variations in IPLP during respiration: The core of medical physiology (1) 3 rd edition Page 301

302 Table 7.2: The intrapleural pressure Phase of respiration IPLP End of normal inspiration -6 mmhg End of normal expiration -2.5 mmhg End of maximum inspiration -30 mmhg End of max expiration (valsalva maneuver) > +50 mmhg Remember that: The intra-pleural pressure is subatmospheric (-ve) during normal inspiration and expiration whereas the IPP is ve during inspiration and +ve during expiration. - Negativity of intra-pleural pressure is explained by the tendency of the lung and the chest wall to recoil into opposite directions (the lung tends to recoil inwards, due to its elastic properties, whereas the chest tends to recoil outwards, due to position of the ribs). - The point when recoil of the lung equals recoil of the chest is the end of normal expiration. Here the volume of air within the lungs equals the functional residual capacity (see below). - In the upright position, there is difference in intrapleural pressure between apex and base of the lung, because of gravity. The pressure at the apex is lower than that at the base. That s why there is higher tendency of bullae at the apex of an emphysemayous lung to rupture more than bullae at the base. Mechanism of Inspiration: Contraction of inspiratory muscles Expansion of the chest Reduction of intra-pleural pressure The core of medical physiology (1) 3 rd edition Page 302

303 Expansion of the lungs Reduction of intra-pulmonary pressure Air moves into the lungs - Inspiration is an active process because it involves contraction of inspiratory muscles. The inspiratory muscles can be grouped into: Inspiratory muscles working at rest (and during exercise): The diaphragm: - Responsible for about 75% of inspiration - Descends down during contraction (about 1.5 up to 7cm). This increases the vertical diameter of the chest - Supplied by the phrenic nerve (C4) - Consists of central tendon, costal fibers and crural fibers The external intercostals muscle - Contraction causes expansion of the chest by increasing the antero-posterior and transverse diameters of the chest Accessory inspiratory muscles working during forced inspiration only: Scalene Sternocleidomastoid Serratus anterior Trapezius Mechanism of Expiration: Relaxation of inspiratory muscles Increased intrapleural pressure Recoil of the lungs to the expiratory position Increased intra-alveolar pressure Air moves out of the lungs The core of medical physiology (1) 3 rd edition Page 303

304 - Expiration at rest is a passive process since it does not involve contraction of any expiratory muscle. - However forced expiration requires the action of the following expiratory muscles that decrease the size of the chest: Internal intercostals muscle Abdominal muscles Measurement of ventilation - Volumes of air that enter or leave the lungs can be measured by special devices (e.g. the Benedict Roth Spirometer). Fig 7.5: The Benedict Roth Spirometer The core of medical physiology (1) 3 rd edition Page 304

305 Volumes and capacities measured by the Spirometer: Tidal volume (TV) - Volume of air inspired or expired each breath. = 0.5L in adult males and females at rest. Inspiratory reserve volume (IRV) - Volume of air inspired by maximum inspiratory effort following tidal inspiration. = 3L in adult males and 1.9L in adult females. Inspiratory capacity (IC) - Volume of air inspired by maximum inspiratory effort following tidal expiration. = TV + IRV Expiratory reserve volume(erv) - Volume of air expired by maximum expiratory effort following tidal expiration. = 1L in adult males and 0.7L in adult females. Vital capacity (VC) - Volume of air expired by maximum expiration following maximum inspiration. (= IRV + TV + ERV or = IC + ERV). - Normal values: About 5L in adult males, 4L in adult females. - Like other lung volumes, it differs according to age, gender, body size (height or weight), position (higher during standing) and ethnic background (higher in Western population than African ones). - It is an important index of disease. For this reason it is usually measured to diagnose certain respiratory problems. - During measurement, the subject is asked to inspire air maximally and then to expire maximally into the mouth piece of the Spirometer. - When the subject is asked to expire forcefully and as quickly as possible, the measured volume is called forced vital capacity (FVC). - The FVC is an important parameter in chest medicine (see below). The core of medical physiology (1) 3 rd edition Page 305

306 The forced vital capacity (FVC) - Volume of air expired forcefully by maximum expiration following maximum inspiration. - Expiration normally takes about 4 s up to 6 s. Forced expiratory time that takes longer than 6 seconds indicates airway obstruction. - The volume of air expired during the first second of the FVC is called the forced expiratory volume in the first second (FEV 1 ). It equals more than 3 quarters of the FVC (i.e. more than 75%). - For example when the FVC is 5 L, the FEV 1 is about 4 L (i.e. FEV 1 /FVC ratio = 80%). - The values of the FEV 1 and the FVC can be measured by a vitalograph. The device provides FVC and FEV 1 values on a graph paper in the Y axis; whereas X axis represents time in seconds. Fig 7.6: The vitalograph - The FEV 1 /FVC ratio is usually measured to differentiate between obstructive and restrictive lung diseases. - Normal ratio is about 80% (see above). The core of medical physiology (1) 3 rd edition Page 306

307 - In obstructive lung diseases (in which FEV 1 is lower than normal) the ratio is less than 75%, e.g. asthma, emphysema and chronic bronchitis (see curve B in fig 7.7). - In restrictive lung diseases (in which both FEV1 and FVC are lower than normal) the ratio is normal or increased (up to 100%), e.g. lung fibrosis and lung collapse (see curve C in fig 7.7). - In combined problems (obstructive and restrictive problems), all the parameters are lower than normal (i.e. low FEV1, low FVC and low FEV1/FVC ratio), e.g. an asthmatic patient with lung fibrosis (see curve D in fig 7.7). Remember that: When the FEV 1 = 5 L and the FVC = 5 L; the FEV 1 /FVC ratio = 100%. This indicates that the expiratory time is only one second (i.e. wrong maneuver); however, the values indicate normal test. The use of the vitalograph is replaced by the digital spirometer which gives FEV1, FVC and the FEV1/FVC ratio directly. Fig 7.7: The vitalograph in different cases The core of medical physiology (1) 3 rd edition Page 307

308 Table 7.3: Spirometry in different cases Lung condition FEV1 FVC FEV1/FVC ratio Normal Normal Normal Normal Obstructive diseases Low Normal Low Restrictive diseases Low Low Normal Obstructive + Restrictive Low Low Low Volumes and capacities not measured by the Spirometer: Residual volume (RV) - Volume of air that remains in the lungs after maximum expiration. = 1.2 L in adult males and 1.1 L in adult females. - Higher volumes are found in obstructive lung diseases (due to difficulty in expiration) and lower volumes in restrictive lung diseases. - The residual volume has the following functions: o Allows easy expansion of the lungs o Allows continuous gas exchange throughout the respiratory cycle. o Prevents complete lung collapse Functional residual capacity (FRC) - Volume of air that remains in the lungs following tidal expiration. = ERV + RV Total lung capacity (TLC) - Volume of air accommodated by the lungs at the end of max. inspiration. = (IRV + TV + ERV + RV) or (IC + FRC) or (VC + RV) = 6L in adult males and 5L in adult females. - The RV & FRC are higher in: o Males compared to females The core of medical physiology (1) 3 rd edition Page 308

309 o Adults compared to children (i.e. increase with age) o Obstructive lung diseases (asthma, chronic bronchitis and emphysema) compared to restrictive (lung fibrosis). - The above volumes and capacities can be measured by the following methods; Body plethysmography, Helium Dilution Technique or Nitrogen Washout Technique. - Revise the last topic in this chapter (Lung function tests). Pulmonary ventilation (or respiratory minute volume) - The volume of air inspired or expired per minute =TV X RR (where TV= tidal volume & RR= respiratory rate) =500 X 12= (6L/min) at rest. Alveolar ventilation - The volume of air that ventilates the alveoli per minute = (TV-dead space volume) X RR = ( ) X 12= (4200 ml/min) or (4.2L/min) at rest. Fig 7.8: The spirogram The core of medical physiology (1) 3 rd edition Page 309

310 Dead space volume (DS) - Defined as volume of air that does not participate in gas exchange. - Includes two types: o Anatomical DS: volume of air that occupies the conducting zone. o Physiological DS: volume of air that occupies the conducting zone (anatomical DS) plus volume of air in the respiratory zone but not participating in gas exchange (e.g. air within the upper alveoli that receive low blood supply because of the gravity). - The anatomical DS is about 150 ml in an average adult male (or roughly it equals the weight of the body in pounds). - The physiological DS volume = the anatomical dead space volume + any additional alveolar air not participating in gas exchange. - Normally, the physiological is almost equal to the anatomical dead space. The difference being less than 5 ml of air. - The anatomical dead space volume can be measured by the single breath nitrogen test (see lung function tests). - The physiological dead space volume can be measured by the Bohr equation: V D /V T = P A CO 2 - P E CO 2 )/P A CO 2 Where: V D = Volume of dead space, V T = Tidal volume, P A CO 2 = Partial pressure of carbon dioxide in alveolar air and P E CO 2 = Partial pressure of carbon dioxide in expired air. - Normally P A CO 2 is the same as P a CO 2 (= Partial pressure of carbon dioxide in arterial blood). Therefore measurement requires an arterial blood sample to measure CO 2 in arterial blood and a gas analyzer to measure CO 2 in expired air. - Notice that CO 2 expired from the alveoli that contain DS air is zero (similar to the atmosphere) because there is no gas exchange. The core of medical physiology (1) 3 rd edition Page 310

311 ELASTIC PROPERTIES: SURFACTANT AND COMPLIANCE - The elastic properties of the lung are caused by: o Elastic fibers in the lung tissue o Surface tension of fluid in the alveoli (see below) - These act against inflation of the lung. - For ventilation to take place, it should overcome these two causes. However, the two causes are affected by many factors. These are discussed below: SURFACTANT A phospholipid produced by type II alveolar cells. Acts to reduce surface tension of fluid in the alveoli. This is achieved by covering the surface of water, separating it from air (because the surface tension occurs at the water/air interface). The surface tension is a physical property of liquids. It arises because the cohesive forces between water molecules attract each other, tending to contract their surface and eventually cause alveolar collapse. Reduction of the surface tension prevents: o Alveolar collapse o Development of pulmonary edema (due to negative interstitial pressure caused by the alveolar collapse) The presence of surface tension in the lung was first noticed when air and saline were compared during inflation of excised lungs. Inflating lungs with saline was found to be easier than inflating them with air. This is because there is no surface tension acting against inflation when saline was used. The core of medical physiology (1) 3 rd edition Page 311

312 Surfactant effects are mainly exerted on small alveoli; especially during expiration. This is because these small alveoli have higher tendency to collapse. The higher tendency of small alveoli to collapse can be explained by the law of Laplace: P = 2T/r Where: P= pressure inside the alveolus (= distending pressure), T= tension and r= radius of an alveolus. This indicates that the smaller the radius the higher the distending pressure needed to keep it patent. Production of surfactant starts late in pregnancy (after the 32 nd week of pregnancy). Therefore it is deficient in pre term babies. These babies develop cyanosis & difficulty in breathing at birth. A serious condition known as infant respiratory distress syndrome (IRDS) or (hyaline membrane disease); characterized by collapse of alveoli and retention of fluids in the interstitium and alveoli. Retention of fluid in the alveoli occurs because surfactant is needed for maturation of epithelial sodium channels (ENaC) responsible for absorption of sodium and water from the alveoli after birth. Failure of maturation of these channels due to deficiency of surfactant results in fluid retention. Treatment of IRDS requires, in addition to high oxygen supply and fluid balance, inhalation of phospholipid or synthetic surfactant. Surfactant production is increased by: Glucocorticoids (that s why pregnant women who develop premature labor contractions are given injections of hydrocortisone, to increase its production). The core of medical physiology (1) 3 rd edition Page 312

313 Surfactant production is decreased by: o Occlusion of the pulmonary artery o Occlusion of a main broncus o Chronic inhalation of (100%) oxygen o Cigarette smoking LUNG COMPLIANCE Compliance is defined as change in volume per unit change in pressure. Lung compliance is described as the distensibility or stretchibility of the lungs (i.e. the capacity of the lungs to expand or stretch). It differs from elasticity which is the resistance to that stretch (i.e. compliance = 1/elasticity). Therefore when elasticity is decreased, compliance is increased. It is measured in terms of change in volume per unit change in pressure (i.e. C = V/ P). Here a pressure volume curve is used for its measurement. For example the relaxation pressure curve. To obtain the relaxation pressure curve, a subject breathing through Spirometer is asked to inhale a given amount of air and then to relax his respiratory muscles while his mouth and nose are shut. During the process, the intrapulmonary pressure is measured by a device in his mouth. Then the amount of inhaled air is increased and the procedure is repeated until he takes max. inspiration, folled by max. expiration. The intrapulmonary pressure is plotted against volume as appears in the following figure. The core of medical physiology (1) 3 rd edition Page 313

314 Notice that the relaxation pressure equals zero at the end of quiet expiration (i.e. when the lung volume equals the functional residual capacity, the point of equilibrium between the inward recoil of the lungs and the outward recoil of the chest). Fig 7.9: The relaxation pressure curve The slope of the curve equals compliance. However, it differs in different lung volumes. For this reason the term specific lung compliance is sometimes used. It equals the value of the lung compliance divided by the lung volume Specific compliance = Lung compliance / Lung volume The compliance obtained in this way is known as static lung compliance. The core of medical physiology (1) 3 rd edition Page 314

315 It is important to notice that static lung compliance during inflation is slightly lower than static lung compliance during deflation. Therefore the relaxation pressure curves during inflation and deflation are not the same. This is known as hysteresis of the lung. When the change in lung volume is measured during breathing; the resistance within the airways affects the value of compliance; here the measured compliance is known as the dynamic lung compliance. Normal values: o Compliance of the lung (C L ) = 0.2 L/cm H 2 O o Compliance of the chest (C C ) = 0.2 L/cm H 2 O o Compliance of both (C L&C ) = 0.1 L/cm H 2 O - Notice that: 1/C L + 1/C C = 1/C L&C (like resistances connected in parallel). Factors that increase lung compliance: o Emphysema & old age (due to loss of elastic fibers in the lung) Factors that decrease lung compliance: o Lung fibrosis, pulmonary edema, high surface tension of fluid in alveoli (surfactant deficiency) and small lung size (children). Factors that decrease lchest compliance: o Stiffness of joints, obesity and deformity of the chest wall (e.g. kyphosis, scoliosis). Remember that: High lung compliance decreases work of breathing whereas low lung compliance increases work of breathing. Surfactant decreases work of breathing. The core of medical physiology (1) 3 rd edition Page 315

316 Bronchial tone - The smooth muscle in the bronchial wall is controlled by the autonomic nervous system. The sympathetic dilates it (e.g. during inspiration) and the parasympathetic constricts it (e.g. during expiration); however, there are multiple irritants, chemicals and hormones that may affect the normal tone of the bronchial tree; these include: Factors causing bronchoconstriction: o Irritants & chemicals: e.g. sulfur dioxide o Cool air o Exercise (possibly by the cool air during hyperventilation) o Substance P o Adenosine o Many inflammatory modulators & cytokines involved in the pathogenesis of asthma (e.g. leukotriens); that s why antileukotriens are added for treatment of asthma. Factors causing bronchodilation: o Catecholamines o VIP (vasoactive intestinal polypeptide) - There is circadian rhythm in bronchial tone throughout the day, with maximal constriction early in the morning. That s why asthmatic patients usually suffer from symptoms of airway obstruction early in the morning. The core of medical physiology (1) 3 rd edition Page 316

317 Pulmonary circulation - Each lung receives its blood supply from two sources: the pulmonary artery (which supplies the alveoli) and bronchial arteries (which supply the airways and the pleurae). - The pulmonary artery carries deoxygenated blood from the right ventricle. It forms an extensive network of capillaries that surround the alveoli to allow gas exchange. Oxygen is taken up into the blood while carbon dioxide diffuses into the alveoli. The oxygenated blood returns through pulmonary veins to the left atrium. - The bronchial arteries carry oxygenated blood from the aorta. They supply the lung parenchyma, airways and pleurae with oxygen and nutrients. They also equilibrate temperature of inspired air with that of the body. Deoxygenated blood is drained through bronchial veins to the azygos vein and therefore to the right atrium via the inferior vena cava; however, there are anastomoses between some bronchial capillaries and pulmonary capillaries. This allows some deoxygenated blood in bronchial capillaries to drain into the pulmonary capillaries and then into the pulmonary vein, resulting in the physiological shunt (mixture of oxygenated blood with some deoxygenated blood). - In addition, there is another source for the physiological shunt. It is from small cardiac veins (thebesian veins) that drain deoxygenated blood into the left side of the heart, which contains oxygenated blood. - The physiological shunt results in reduction of arterial PO 2 by 2 mmhg and reduction of arterial oxygen saturation by 0.5% compared to oxygenated blood coming from alveolar capillaries. The core of medical physiology (1) 3 rd edition Page 317

318 GAS EXCHANGE IN THE LUNGS - There are two sites of gas exchange in the body: o Between alveoli & pulmonary capillaries (in the lungs) o Between tissue cells & systemic capillaries (in the tissues). - Gas exchange in the lungs depends on the following factors: o Pressure gradient of the gas o Surface area of the respiratory membrane o Thickness of the respiratory membrane o Physical properties of the gas 1) Pressure gradient - Gases move passively from an area of high pressure to an area of low pressure. - The pressure of a single gas in a container containing mixture of gases is called its partial pressure. - The partial pressure of a gas is calculated by multiplying its fractional concentration times the total pressure of all gases. The following table explains calculation of partial pressures of gases in the atmosphere (dry air): Table 7.4: Calculation of partial pressures of gases Gas Percentage (%) Partial pressure Nitrogen x 760 = mmhg Oxygen x 760 = mmhg Carbon dioxide x 760 = 0.3 mmhg Inert gases x 760 = 7 mmhg Total mmhg The core of medical physiology (1) 3 rd edition Page 318

319 Partial pressure of oxygen (Po 2 ) o In dry air = 159 mmhg o In inspired air (after humidification in the airways) = 149 mmhg 20.98% x [760-47]; P H2O = 47 mmhg at body temperature o In alveolar air = 100 mmhg (due to rapid diffusion of oxygen into pulmonary capillaries & diffusion of CO 2 into alveoli) o In venous blood (coming to pulmonary capillaries) = 40 mmhg (Prior to gas exchange) o Po 2 in arterial blood (leaving pulmonary capillaries)= 100 mmhg (After the gas exchange; however, this value is decreased by the physiological shunt). Fig 7.10 The core of medical physiology (1) 3 rd edition Page 319

320 Partial pressure of carbon dioxide [Pco2 ] o In dry air = 0.3 mmhg o In inspired air = 0.29 mmhg (0.04% x [760-47] o In alveolar air = 40 mmhg (due to rapid diffusion of CO2 from pulmonary capillaries to alveoli) o In venous blood (coming to pulmonary capillaries) = 45 mmhg (Prior to gas exchange) o Pco 2 in arterial blood (leaving the pulmonary capillaries)= 40 mmhg (After the gas exchange) Fig 7.11 The core of medical physiology (1) 3 rd edition Page 320

321 2) Thickness - The respiratory membrane consists of the following layers (fig 7.11): o Fluid in the alveoli o Alveolar wall (basement membrane + epithelium) o Interstitial fluid o Capillary wall (basement membrane + endothelium) - Normal thickness = 0.5 micrometer - Gas exchange is inversely proportional to thickness of the respiratory membrane. For example when the thickness is decreased (as occurs during exercise), gas exchange is increased. - It is impaired when the thickness is increased (e.g. due to lung fibrosis or pulmonary edema). This causes hypoxemia (low oxygen in blood); however, thickness of the respiratory membrane is a less common cause of hypoxemia than ventilation: perfusion mismatching (see below). Fig 7.12; The The core of medical physiology (1) 3 rd edition Page 321

322 3) Surface Area - The available area for gas exchange is called the effective surface area. It indicates well ventilated alveoli in contact with well perfused capillaries. - Gas exchange is directly proportional to the effective surface area. - For example when the surface area is increased (as occurs during exercise), gas exchange is increased. - The effective surface area is increased during exercise because: o More alveoli are ventilated (due to increased ventilation) o More capillaries are perfused (due to increased perfusion) - Total surface area equals about 70 m 2 (normal range: m 2 ). 4) Diffusion Coefficient - Defined as the amount of gas that diffuses across the respiratory membrane per unit pressure difference per unit surface area per unit time. It depends on: o Solubility of the gas (direct relation) o Molecular weight of the gas (inverse relation) - Although molecular weight of CO 2 is larger than O 2, its diffusion coefficient is higher than O 2. This is due to the high solubility of CO2. Diffusion capacity of the respiratory membrane: - The volume of gas that crosses the respiratory membrane per unit partial pressure difference per unit time. It is affected by: o Thickness of the membrane (inverse relationship) o Surface area of the membrane (direct relationship) - It is measured by using carbon monoxide which is highly soluble in blood (unlike other gases it is diffusion limited ) - Normal diffusion capacity equals 25 ml/min/mmhg. The core of medical physiology (1) 3 rd edition Page 322

323 The Ventilation : Perfusion Ratio (V/Q ratio) - The ratio of alveolar ventilation to pulmonary blood flow (perfusion). - Alveolar ventilation is about 4 L/min whereas pulmonary blood flow is about 5 L/min; therefore V/Q ratio = 0.8 ( 1.0). - It is affected by: Gravity and lung diseases Effect of gravity on V/Q ratio: - In the upright position, the V/Q ratio differs in different parts of the lung due to the effect of gravity. At the apex - Blood flow (Q) is decreased and ventilation (V) is also decreased but to a lesser extent. Therefore the ratio is increased. - When perfusion is decreased to zero, the ratio is increased to infinity (V/Q =V/0 = Infinity). - Since ventilation > perfusion, the extra air wasted ventilation (or dead space ventilation). At the base - Blood flow (Q) is increased and ventilation (V) is also increased but to a lesser extent. Therefore the ratio is decreased. - Since ventilation < perfusion, the extra blood wasted perfusion (or shunt flow). Effect of lung diseases on V/Q ratio: - Many lung diseases are characterized by V/Q inequality. - These may result in either: wasted ventilation (e.g. pulmonary embolism) or wasted perfusion (e.g. Lung collapse); the ratio is changed accordingly. - Remember that, V/Q inequality is the most common cause of hypoxemia. The core of medical physiology (1) 3 rd edition Page 323

324 Effect of V/Q mismatching on PO2 and PCO2 of alveolar air If ventilation to an alveolus is reduced relative to its perfusion (i.e. less O 2 supply from environment and less CO 2 removal): o PO 2 in alveoli (PAO 2 ) decreases o PCO 2 in alveoli (PACO 2 ) increases - This normally occurs in some alveoli at the base of the lung. If perfusion to an alveolus is reduced relative to its ventilation (i.e. less carbon dioxide reaches the alveoli from blood): o PO 2 in alveoli (PAO 2 ) increases o PCO 2 in alveoli (PACO 2 ) decreases - This normally occurs in some alveoli at apex of the lung. - The lung apex is the most favorable site of infection for the tubercle bacilli (because of the high PAO 2 ). GAS TRANSPORT IN THE BLOOD TRANSPORT OF OXYGEN - Oxygen is transported in the blood in two forms: o Dissolved in plasma... 2% o Bound to hemoglobin % Dissolved oxygen: = Solubility of oxygen x PO 2 Solubility of oxygen = ml/100ml blood/mmhg Po 2 = 100 mmhg (in arterial blood) and 40 mmhg (in venous blood) - Therefore dissolved oxygen in 100 ml arterial blood= 100 x = 0.3 ml oxygen/ 100 ml blood - Dissolved oxygen in 100 ml venous blood= 40 x =0.12 ml oxygen/ 100 ml blood The core of medical physiology (1) 3 rd edition Page 324

325 Remember that PO 2 in arteries (PaO 2 ) is actually less than 100 mmhg (= 95 mmhg) because of the physiological shunt. Oxygen bound to hemoglobin: - Oxygen binds to hemoglobin in a rapid reversible oxygenation reaction (iron remains in the ferrous state) - The reaction takes less than 0.01 s. - Each gram of Hb can carry up to 1.34 ml oxygen (If 100% saturated; as in arteries). - Oxygen bound to Hb in arterial blood can be calculated as follows: o O 2 = [Hb] x 1.34 x (% saturation of Hb with oxygen) o [Hb] = 15 g/100 ml blood o There fore O2 = 15 x 1.34 x 100% = 20 ml O2 /100 ml blood - Oxygen bound to Hb in venous blood can be calculated as follows: o O 2 = [Hb] x 1.34 x (% saturation of Hb with oxygen) o [Hb] = 15 g/dl o Therefore O2 = 15 x 1.34 x 75% = 15 ml O2 /100 ml blood - The relation between Po2 & percent saturation of Hb with oxygen is explained by the oxygen hemoglobin dissociation curve: The Oxygen-Hemoglobin Dissociation Curve - Indicates direct relation between PO 2 and % saturation of Hb with oxygen. - Sigmoid shaped. (starts slowly, becomes steep in the middle and then reaches a maximum). - The sigmoid shape can be explained as follows: o Oxygen binds to the subunits of Hb successively (not all of them at the same time). The core of medical physiology (1) 3 rd edition Page 325

326 o The binding with the first subunit facilitates binding with the second subunit and this facilitates binding with the third subunit & so on. o The facilitation occurs due to changes in the configuration of Hb from the tense (T) form to the relaxed (R) form. - Therefore, binding: o Starts slowly: indicating low affinity of Hb to oxygen (occurs when oxygen is binding to the first subunits). o Becomes steep in the middle: indicating high affinity of Hb to oxygen (occurs when oxygen is binding to the other subunits). The affinity is increased up to 500 folds. o Reaches maximum at the end (indicating full saturation). Fig 7.13: The oxygen hemoglobin dissociation curve The core of medical physiology (1) 3 rd edition Page 326

327 Notes to remember from the curve: PO 2 of 40 mmhg gives oxygen saturation of 75% (as in veins) PO 2 of 95 mmhg gives oxygen saturation of 97% (as in arteries) PO 2 of 97 mmhg gives oxygen saturation of 97.5% (as in oxygenated blood in pulmonary capillaries). Less saturation in arteries (0.5%) is due to the physiological shunt. PO 2 of 26 mmhg gives oxygen saturation of 50%. This is known as the P 50. The P 50 is defined as the PO 2 when Hb is 50% saturated with O 2. It is used to describe the affinity of Hb to O 2 (e.g. high P 50 indicates low affinity of Hb to O 2 whereas low P 50 indicates the reverse. Affinity of hemoglobin to oxygen: - The affinity of Hb to oxygen is affected by certain factors. These factors can shift the curve to the right or to the left. - The P 50 gives information about affinity of hemoglobin to oxygen. Normal value = 26 mmhg; higher values indicate shift to the right (low affinity) & lower values indicate shift to the left (high affinity). Shift to the right: o Indicates lower affinity of Hb to oxygen (high P 50 ) o Indicates increased release of oxygen to tissues o Caused by: High carbon dioxide, High Hydrogen ions (low ph) High 2,3 DPG High temperature The core of medical physiology (1) 3 rd edition Page 327

328 - The 2-3 diphosphoglycerate (2,3 DPG) is a product of glycolysis. It is highly present in RBCs when metabolism is increased. It is also increased in exercise, high altitude and by some hormones like growth hormone, thyroid hormones and androgens. Its binding to the beta chain of Hb decreases the binding of Hb to oxygen). Shift to the left: o Indicates increased affinity of Hb to oxygen (low P 50 ) o Indicates decreased release of oxygen to tissues o Caused by: Low carbon dioxide, Low hydrogen ions, Low 2,3 DPG (e.g. due to acidosis or in stored blood) Low temperature Myoglobin Hemoglobin F Fig 7.14: Shifts of the oxygen-hemoglobin dissociation curve The core of medical physiology (1) 3 rd edition Page 328

329 Remember that: - Shift to the right occurs in tissues, where CO 2, H + & temperature are high whereas shift to the left occurs in the lung where these factors are decreased. - Hb F & Myoglobin have very high affinity to oxygen. They shift the curve to the left. - Hb F binds less avidly to 2,3 DPG; this increases its affinity to O2. - Anemia does not affect the shape of the curve. That s because PO 2 is normal and therefore the % saturation of Hb is normal. Bohr effect - The affinity of Hb to oxygen is decreased when the ph of the blood falls. - That s why increase in CO 2 content of the blood decreases the affinity of Hb to O 2 & causes shift of the curve to the right. TRANSPORT OF CARBON DIOXIDE - Carbon dioxide is transported in 3 forms: o As Bicarbonate (the main form of transport) o Bound to proteins (carbamino compounds) o Dissolved Dissolved CO 2 - The solubility of CO 2 is higher than O 2 (up to 20 times). - The dissolved CO 2 constitutes about 5% of total CO 2 in arterial blood and 6% of total CO 2 in venous blood. - Generally there is no reaction between CO 2 & water in the plasma (due to absence of carbonic anhydrase enzyme in the plasma). The core of medical physiology (1) 3 rd edition Page 329

330 Transport as Bicarbonate - This is the main form of CO 2 transport in the blood. - CO 2 diffuses inside RBCs and reacts with water in the presence of carbonic anhydrase enzyme to produce carbonic acid & then bicarbonate & hydrogen ion. - CO 2 + H 2 O = H 2 CO 3 = HCO 3 + H + - Hydrogen ions are buffered by hemoglobin. - About 70% of bicarbonate diffuses to the plasma in exchange to chloride (= Chloride shift). Fig 7.15: Chloride shift Remember that: - Due to diffusion of CO 2 into RBCs, the number of active osmotic particles in RBCs is increased (by either HCO - 3 or Cl - ) - So, in venous blood water enters RBCs by osmosis, increasing the size of RBCs. Then it passes out in the lung; when chloride leaves out and the RBCs return to their normal size in arteries. - That s why PCV of venous blood is higher than arterial blood by about 3%. The core of medical physiology (1) 3 rd edition Page 330

331 Bound to proteins - CO 2 forms carbamino-compounds by binding to proteins (plasma proteins in plasma and hemoglobin in RBCs). - About 11% of CO 2 in the blood is carried to the lungs as carbamino- CO 2. Haldane effect - Deoxy Hb in venous blood binds CO2 more readily than oxy Hb in arterial blood. - Therefore binding of oxygen to Hb in the lungs facilitates release of CO 2 from Hb; this is known as the Haldane effect. - For this reason, arteries (containing oxygenated blood) carry less carbon dioxide than veins (containing deoxygenated blood). Summary - CO 2 is transported in plasma as: o Dissolved o Carbamino-CO 2 o HCO 3 - CO 2 is transported RBCs as: o Dissolved o Carbamino Hb o HCO 3 - About 70% of the HCO 3 enters the venous blood in exchange to chloride (chloride shift). - PCV of venous blood is higher than arterial blood by about 3%. The core of medical physiology (1) 3 rd edition Page 331

332 CONTROL OF RESPIRATION - Can be studied as: Neural control and Chemical control Neural Control - Two types: o Involuntary control - By the respiratory center o Voluntary control - By the cerebral cortex The respiratory center - Collection of neurons in the medulla & pons - Arranged into 4 groups: o Dorsal group o Ventral group o Apneustic center o Pneumotaxic center The dorsal group o Found at the dorsal aspect of the medulla. o It contains inspiratory neurons (it is responsible for inspiration). o It is called the rhythmicity center because it can discharge impulses rhythmically. o The rhythmic discharge is initiated in the pre-botzinger complex in the medulla. The ventral group o Found in the ventral aspect of the medulla. o Contains expiratory neurons + some inspiratory neurons. o Inactive at rest (that s why expiration occurs passively). The core of medical physiology (1) 3 rd edition Page 332

333 o Inactivated when the dorsal group is stimulated & vice versa (reciprocal innervation). o Responsible for forced expiration. Fig 7.16: The respiratory center The Apneustic center o Found in the lower part of the pons. o Stimulates the dorsal group to increase depth of inspiration. o Inhibited by: The vagus and the pneumotaxic center. The Pneumotaxic center o Found in the upper part of the pons. o Its function is unknown, may be switching between inspiration & expiration. - Functions of the different groups of the respiratory center are studied in animals by performing sections at various levels in the brain stem. The core of medical physiology (1) 3 rd edition Page 333

334 Section 1 [below the medulla] o Results in death if the lesion is above C 4. That s because the descending impulses from the respiratory center fail to reach the phrenic nerve which supplies the diaphragm. Section 2 [between medulla & pons] o Results in gasping (shallow) respiration. That s because the apneustic center fails to increase depth of inspiration. Section 3 [mid pontine section, + cutting the vagal supply] o Results in apneustic breathing (deep inspiration). That s because the pneumotaxic center fails to inhibit the apneustic center. Section 4 [Above pons] o No effect on involuntary respiration; however, it impairs the voluntary control of respiration. Fig 7.17: Sections below and above the respiratory center The core of medical physiology (1) 3 rd edition Page 334

335 Factors affecting the respiratory center - The respiratory center is affected by impulses coming from: Higher centers Cerebral cortex Hypothalamus Limbic system Other brain stem centers Baroreceptors Chemoreceptors Lung stretch receptors Proprioceptors Other receptors Higher centers - The cerebral cortex: o For voluntary modification of respiration o E.g. voluntary hyperventilation or voluntary apnea - The hypothalamus (temperature center): o Stimulates heat loss by increasing respiration o E.g. panting in dogs - The limbic system: o Emotions may affect respiration (e.g. fear) - Other brain stem centers: o Stimulation or inhibition of the cardiac or the vasomotor centers in the medulla, results also in stimulation or inhibition of the respiratory center (impulses radiate between the centers). That s why hyperventilation is associated with tachycardia and hypoventilation is associated with bradycardia. The core of medical physiology (1) 3 rd edition Page 335

336 The Baroreceptors - Stretch receptors found in the aortic & the carotid sinuses; connected to the cardiac & vasomotor centers in the medulla by the cranial nerves 9 & 10; send inhibitory impulses to these centers when stimulated by stretch caused by high blood pressure. - The inhibitory impulses decrease the sympathetic discharge from these centers to the heart & blood vessels. This lowers the blood pressure by: o Decreasing the heart rate o Decreasing contractility o Vasodilatation - The inhibitory impulses also inhibit the respiratory center. For this reason, hypertension is associated with hypoventilation & hypotension is associated with hyperventilation but mainly due to activity of the chemoreceptors. The Chemoreceptors - See chemical control of respiration below. The Proprioceptors - Found in the joints, ligaments & tendons of muscles. - Stimulated by movement (even passive movement). - Send impulses directly to the respiratory center to increase respiration. The Lung stretch receptors - Stretch receptors. - Found in the smooth muscles of bronchioles. - Stimulated by stretch during inflation of the lung. - Send inhibitory impulses through the vagi to stop further inspiration. The core of medical physiology (1) 3 rd edition Page 336

337 - This protective reflex is called Hering Breuer inflation reflex. - It is not active in humans (except with very high tidal volume). - There is also Hering Breuer deflation reflex stimulated by deflation of the lung. - Here excitatory impulses are carried also through the vagi to restart inspiration. Other receptors (I) receptors: o Found in upper respiratory tract o Stimulated by irritants (dust, smoke,...) o Mediate coughing reflex, sneezing reflex... (J) receptors: o Found in juxtaposition to pulmonary capillaries o Stimulated when the capillaries become distended with blood o Function unknown, may be mediation of the sense of dyspnea Chemical Control - By chemoreceptors that detect chemical changes in blood or CSF - There are two types of chemoreceptors: o Peripheral chemoreceptors o Central chemoreceptors The peripheral chemoreceptors - Special receptors found in: Aortic bodies and Carotid bodies - Aortic bodies are found in aortic arch and carotid bodies are found in carotid bifurcation. - They are stimulated by: o Hypoxia (the main stimulus) The core of medical physiology (1) 3 rd edition Page 337

338 o Hypercapnia o Acidosis - They send excitatory impulses through the cranial nerves 9 & 10 to stimulate the respiratory center in the medulla. - This results in hyperventilation to correct the stimulus. - The blood supply per gram tissue to these structures is very high, e.g. the carotid bodies receive 2000 ml/100 gram tissue whereas 100 gram tissue in the kidneys receives 420 ml and in the brain receives 54ml. That s why they can detect minor changes in the chemical composition of the blood. The central chemoreceptors - Found on the anterolateral surface of the medulla; in contact with the CSF. Fig 7.18: The central chemoreceptors The core of medical physiology (1) 3 rd edition Page 338

339 - The central chemoreceptors are stimulated by: o High carbon dioxide (in blood and therefore in CSF) o High hydrogen ions (in the CSF not that in blood) - Hydrogen ions in the blood cannot cross the blood brain barrier BBB easily. Hydrogen ions in the CSF are formed from carbon dioxide as follows: Carbon dioxide crosses the BBB & reacts with water in the CSF to produce carbonic acid & then dissociates into bicarbonate & hydrogen ions. Then hydrogen ions in the CSF stimulate the central chemoreceptors. - In other words, carbon dioxide stimulates the central chemoreceptors directly (by CO 2 itself) and indirectly (by H + ). Remember that: In patients with chronic hypercapnia (e.g. patients with COPD), respiration is stimulated by hypoxia not hypercapnia (because the receptors become used to the high CO 2 ). Treatment with high pressure O 2 in these patients corrects hypoxia and stops respiration. That s why they should be treated with low pressure O 2 (e.g. 24% or 28%; not 80% or 100% O 2 ). HYPOXIA AND CYANOSIS Hypoxia Defined as oxygen deficiency at the level of tissues or low tissue oxygenation (Notice that hypoxemia is reduction of oxygen in the blood). Classified into 4 types: Hypoxic hypoxia Anemic hypoxia Stagnant hypoxia The core of medical physiology (1) 3 rd edition Page 339

340 Histotoxic hypoxia Hypoxic hypoxia Oxygen delivery to tissues is reduced because of low oxygenation of blood. This is caused by: High altitude, Hypoventilation due to: Lung diseases Respiratory center depression Paralysis of respiratory muscles Venoarterial shunts It is characterized by: Low PO 2 (in arterial blood) Low % saturation of Hb Low total oxygen content of the blood All these parameters are also low in venous blood. Oxygen therapy is useful in this type of hypoxia; however, when the cause of hypoxia is veoarterial shunt, oxygen therapy fails to increase oxygen content of the blood. This differentiates venoarterial shunt from other types of hypoxia. Anemic hypoxia Decreased oxygen carrying capacity of the blood as a result of: Decreased Hb (e.g. iron deficiency anemia). Abnormal Hb (e.g. methemoglobinaemia). Unavailable Hb (e.g. carbon monoxide poisoning). Characterized by: Normal PO 2 in arterial blood The core of medical physiology (1) 3 rd edition Page 340

341 Normal % saturation of Hb Low total oxygen content of the blood These parameters are lower than normal in venous blood. Oxygen therapy is slightly useful in this type of hypoxia because it only increases dissolved oxygen. Heavy smoking in a closed room may cause coma due to carbon monoxide poisoning. Treatment of carbon monoxide poisoning requires administration of oxygen within a container under high pressure hyperbaric oxygen. That s because the affinity of hemoglobin to CO is higher than oxygen by 250 times. Histotoxic hypoxia Inability of the tissues to take oxygen as a result of: Poisoning of the oxidative enzymes (cyanide poisoning) Long distance between blood & cells (edema) Characterized by: Normal PO 2 (in arterial blood) Normal % saturation of Hb Normal total oxygen content of the blood All these parameters are higher than normal in venous blood. Oxygen therapy is not useful in this type of hypoxia. Stagnant hypoxia Reduced blood flow to tissues as a result of: Obstruction of a supplying vessel (localized hypoxia) Heart failure (generalized hypoxia) Characterized by: Normal or low PO 2 (in arterial blood) The core of medical physiology (1) 3 rd edition Page 341

342 Normal or low % saturation of Hb Normal or low total oxygen of blood When heart failure is mild, these parameters are low in venous blood because of high uptake of oxygen in tissues; and then corrected in the lungs to return to normal. In moderate-severe heart failure, all these parameters are lower than normal in both venous and arterial blood; because the lungs fail to oxygenate blood back to normal. Oxygen therapy is useful in this type of hypoxia. CYANOSIS Bluish coloration of the skin & mucus membranes o Appears when the concentration of reduced hemoglobin is more than 5g/dL. For this reason it is rarely seen in anemia and commonly seen in polycythemia. Types of cyanosis: Peripheral o Appears at the tips of the fingers o Due to peripheral vasoconstriction in response to cold Central o Appears in the skin & mucus membranes o Due to causes of hypoxic hypoxia & stagnant hypoxia Cyanosis is extremely rare in anemic hypoxia (anemic patients may die when > 5g/dL of Hb become deoxygenated). It is also extremely rare in CO poisoning (also anemic hypoxia) because it gives reddish color. No cyanosis occurs in histotoxic hypoxia. Patients with methemoglobinemia may acquire a dark color that resembles cyanosis. The core of medical physiology (1) 3 rd edition Page 342

343 LUNG FUNCTION TESTS Importance of lung function tests - Depending on history and examination to diagnose a respiratory problem, without objective measurement of lung function, may result in wrong diagnosis. - This was confirmed by many studies that recommend the use of lung function tests as objective tools for: o Diagnosis of respiratory diseases o Follow up of respiratory problems o Assessment of fitness for anesthesia o Insurance purposes o Clinical research Types of lung function tests: o Tests of mechanical properties o Gas diffusion o Blood gas interpretation o Exercise testing Tests of mechanical properties o Lung volumes and capacities o Spirometry & the flow volume loops o The peak expiratory flow o Static compliance o Airway resistance o Respiratory muscle power - This is a brief account about some of the devices and techniques used in lung function tests: The core of medical physiology (1) 3 rd edition Page 343

344 MEASUREMENT OF LUNG VOLUMES AND CAPACITIES Benedict Roth spirometer - Measures the tidal volume, inspiratory reserve volume, expiratory reserve volume and the vital capacity (see above). The helium dilution technique - For measurement of many volumes and capacities especially total lung capacity, residual volume and functional residual capacity. - This method depends on the fact that helium does not diffuses through the respiratory membrane into the blood. - The subject is connected to a helium container at the end of: o Maximum expiration (when measuring the residual volume) o Tidal expiration (when measuring the functional residual capacity) o Maximum inspiration (when measuring the total lung capacity) - The subject breathes into a bag containing a known volume and concentration of Helium (V1 & C1). This changes the concentration of helium to C2 and expands the volume to V1 + the volume being measured in the lung. - Since C1 x V1= C2 x V2; V2 can be obtained by calculation. - V2 = V1 + the required volume in the lung. - Therefore the required volume can be obtained. Body plethysmography (or body box) - For measurement of all types of lung volumes and capacities including the total lung capacity, residual volume and functional residual capacity. - Depends on the equation of gases: P 1 V 1 = PV - The subject sits within an airtight box. He breathes through a mouthpiece that can be closed electrically (For example when it is The core of medical physiology (1) 3 rd edition Page 344

345 closed at the end of normal expiration, the functional residual capacity (FRC) can be measured). Then the subject inhales against the closed shutter; his chest volume is increased while the volume within the box is decreased. The pressure within the box can be measured by a device connected to the box. The pressure within the lung can be measured by a device within the mouth. - At first the change in volume within the box is calculated using the formula (P 1 V 1 = PV). P 1 is the pressure within the box (known), V 1 is the volume within the box (known), P is the new volume within the box after inspiration (known), and V is the new volume within the box after inspiration (unknown). The change in volume within the box = V1 V = X; this equals the change in volume within the lung. - Then the formula (P 1 V 1 = PV) is used again to calculate the lung volume before inspiration (the FRC). P1 is the intrapulmonary pressure before inspiration (known), V1 is the FRC (unknown), P is the new intrapulmonary pressure at the end of inspiration (known), and V is the new volume within the lung at the end of inspiration (= FRC + X). X is known from the previous step; therefore the formula is solved to obtain the FRC. Single breath nitrogen washout test - For measurement of the, residual volume, functional residual capacity, uneven ventilation, anatomical dead space and closing volume. - The subject takes full inspiration of pure oxygen (100% O 2 ), then he exhales slowly (not more than 0.5 L/S). - A nitrogen analyzer near his mouth detects nitrogen concentration in expired air. The core of medical physiology (1) 3 rd edition Page 345

346 - Four phases appear when plotting nitrogen% against lung volume as follows: Fig 7.19 Phase I = pure oxygen (from the dead space) Phase II = nitrogen + oxygen (mixture of dead space air + alveolar air) Phase III = plateau of nitrogen (alveolar air); flat in normal people & has increased slope in uneven ventilation Phase IV = rapid rise in [N2] from upper alveoli (following closure of the distal airways). - Dead space volume = volume of phase I + mid portion of phase II - Phase III terminates at the closing volume - The closing volume is the volume within the lung when the distal airways begin to close because of less intra-mural pressure. - The rise in the slope of phase IV and to some extent phase III is due to expiration of air in the upper portions of the lung which contain higher proportion of nitrogen (i.e. less diluted by the inspired oxygen). The core of medical physiology (1) 3 rd edition Page 346

347 Spirometry (by the vitalograph or the digital spirometer) - For measurement of the forced vital capacity (FVC), the forced expiratory volume in the first second (FEV 1 ) and the FEV 1 /FVC ratio (read the section of volumes and capacities above). - Other parameters and tests that can be measured by spirometry include: The forced expiratory volume 25-75% (FEF 25-75) - The forced expiratory flow at the middle of the FVC - Normally equals or exceeds 50% of the predicted FVC - Has good correlation with the FEV1 in obstructive lung diseases. - Has the advantage that it avoids the effort dependent first quarter of the FVC. - May diagnose mild airway obstruction while other spirometric parameters are normal. Bronchodilator studies - See reversibility below Bronchial Provocation Testing (challenge tests) - These tests measure the response of the airways to chemical substances known to cause broncho-constriction. - This determines the extent of airway hyper-responsiveness which is a characteristic of asthma. - They are used to support the diagnosis of asthma when the results of spirometry are not conclusive. - The subject inhales increasing concentrations of a provocative substance, followed each time by spirometry. - A 20% fall in FEV 1 is considered as a positive test. - Examples of provocative substances: histamine & methacholine. The core of medical physiology (1) 3 rd edition Page 347

348 - The provocative dose needed to decrease FEV1 by 20% is called PD20% - PD20% is lower in patients with bronchial hyper-responsiveness than normal individuals. - Other indirect provocative tests include exercise, adenosine and non isotonic saline. The spirometric flow volume loops - The flow volume loops are a plot of inspiratory and expiratory flow against volume. Flow is recorded on the Y-axis while volume is recorded on the X-axis. - When a subject completes his forced expiration during the FVC maneuver, he immediately takes a deep inspiration to obtain a loop as appears in the following figure: Fig 7.20: the flow volume loop The core of medical physiology (1) 3 rd edition Page 348

349 - The normal expiratory portion of the flow-volume curve is characterized by a rapid rise to the peak flow rate, followed by a nearly linear fall in flow as the patient exhales towards the residual volume. - Changes in the contour of the loop can aid in the diagnosis of obstructive and restrictive lung diseases. However, it is not the primary diagnostic tool of these disorders. The peak expiratory flow (by the Peak Flow Meter) - The PEF is the highest velocity of air flow achieved transiently during forced expiration from the total lung capacity (i.e. after max inspiration). - The device used (the peak flow meter) is small, portable & inexpensive device. It is manufactured in many designs: Wright peak flow meter, Mini Wright peak flow meter and other designs Fig 7.21: The peak flow meter The core of medical physiology (1) 3 rd edition Page 349

350 - For interpretation of PEF readings (and other lung function test parameters), it should be compared to predicted values (reference values) that vary according to age, sex and body size (height). - Normal value in an average adult male is about 600 L/min (or 10 L/s). Therefore a value of 300 L/min is low since it is 50% of expected. Values more than or equal 80% of expected are normal. - The PEF readings are used for: 1- Diagnosis of asthma (by variability and/or reversibility) Variability: - The PEF readings are normally variable. Lowest values are obtained early in the morning (see the bronchial tone). - Variability more than 20% indicates asthma. It is detected by measuring and recording the PEF twice daily (morning and evening) for two weeks. Variability= Highest PEF Lowest PEF/Highest PEF Fig 7.22: PEF variability The core of medical physiology (1) 3 rd edition Page 350

351 Reversibility: - The PEF is measured before and then 15 minutes after administration of salbutamol (bronchodilator). - Improvement of the PEF reading by more than 15% indicates reversible airways, which is an important characteristic of asthma. - The FEV 1 is used more than the PEF for detection of reversibility, because it is more reproducible. Here improvement of the FEV1 by more than 12% (or 200 ml) indicates reversibility. 2- Assessment of severity of asthma - Reduction of PEF to less than 50% of expected indicates acute severe asthma whereas reduction to less than 33% of expected indicates life threatening asthma. 3- Other uses of the PEF - The PEF is used to guide therapeutic decisions in asthmatic patients. It is also used to measure the degree of response to therapy (i.e. follow up). Lung compliance - Read about compliance above Airway resistance - The force needed to inflate the lungs is greater than that needed to overcome the elastic recoil alone. - The additional impedance is the airway resistance. - The airway resistance is defined as the pressure difference between the alveoli and the mouth per unit of air flow. It is generated from friction between air and mucosa. The core of medical physiology (1) 3 rd edition Page 351

352 - Air way resistance = Mouth pressure alveolar pressure/flow of air; (Alveolar pressure is measured by the body plethysmograph). - Airway resistance is higher when the airflow is turbulent than when it is laminar. It is also increased by many other factors, including the factors that increase the bronchial tone. Respiratory muscle power - Investigated by many tests to exclude respiratory muscle weakness. These include the following tests: Vital capacity - It is a useful screening test to exclude respiratory muscle weakness. When measured in an erect and then supine posture, the difference is within 5%. This is because the abdominal viscera in supine posture exert more loads on the respiratory muscles. - A difference more than 25% indicates respiratory muscle weakness. Maximum inspiratory pressure - Measured during maximum inspiratory effort against an occluded airway at RV or FRC. Normal value varies with age and sex. Values above 80 cm H 2 O excludes respiratory muscle weakness. Maximum expiratory pressure - Measures the power of expiratory muscles at TLC. - It is less useful in predicting the ability to breathe. Transdiaphragmatic pressure - Measures diaphragmatic function. - Estimated from difference between pleural and abdominal pressures (i.e. esophageal and gastric pressures). The core of medical physiology (1) 3 rd edition Page 352

353 - Balloon catheters are used for measurement during spontaneous breathing and during phrenic nerve stimulation. Gas Diffusion studies The transfer factor: - Measures the transfer of carbon monoxide (CO) across the respiratory membrane, from the alveoli to the RBCs. - It is measured by many techniques. However, the single breath technique is the best. Here the subject exhales maximally and then inspires the test gas (containing 0.3% CO, 10% Helium in addition to oxygen and nitrogen) to the total lung capacity. - After 10 s he exhales into a bag, after discarding the first 0.5 L of expired air. - The sample is analyzed for CO and Helium. The change in concentration of CO and Helium is used to calculate the transfer factor. - The transfer factor obtained by this method is a measure of the diffusing capacity of the lung for carbon monoxide (D LCO ). It is also known as (T LCO ), the transfer factor of the lung for CO. - It is affected by diseases that affect the thickness of the respiratory membrane and the V/Q ratio. - For example it is reduced in lung fibrosis, emphysema, pulmonary embolism - When the D LCO is corrected for differences in lung volume, it is known as the transfer coefficient (K CO ); (i.e. K CO = D LCO /alveolar volume). The core of medical physiology (1) 3 rd edition Page 353

354 Blood gas interpretation - In addition to data obtained by the tests that assess mechanical properties of the lung, diagnosis of respiratory problems may need blood gas interpretation. - This requires information about: o Blood oxygenation (obtained by arterial blood gas analysis ) o Oxygen saturation of hemoglobin (see below) o V/Q distribution (read about V/Q ratio above) o Acid base status (read volume 2) Pulse oximetry: - The pulse oximeter probes, placed on fingers or earlobes are used widely to assess oxygen saturation of Hb (SpO 2 ). - Light originating from the oximeter probe is absorbed by Hb at a degree proportional to its level of oxygenation. This is calculated by a processor to obtain the degree of saturation. - Normal readings are higher than 95%. Readings lower than 88% raises the suspicion of hypoxemia and indicates the need for arterial blood gas analysis (ABG). - There are certain conditions that give false estimation of the oxygen saturation when using the pulse oximeter. For example Carboxyhemoglobin and Methemoglobin give overestimation of O 2 saturation (higher readings) while fingernail polish and motion artifacts underestimate the O2 saturation (lower readings). The core of medical physiology (1) 3 rd edition Page 354

355 Exercise testing - The cardiopulmonary exercise test is used to assess dyspnea that s not explained by other lung function tests. It is also used to assess fitness for anesthesia, disability and response to therapy. - The test assesses the responses of the respiratory, cardiovascular and muscular systems to increasing workload offered by a bicycle ergometer or treadmill. Fig 7.23: Body plethysmography The core of medical physiology (1) 3 rd edition Page 355