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696 Cards in this Set
- Front
- Back
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what proportion of the body's water is intracellular and what proportion is extracellular?
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1/3 extracellular, 2/3 intracellular
Measured using deuterium oxide - heavy water |
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What % of body weight is protein, minERAL, FAT
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18% PROTEIN, 7% MINERAL, 15% FAT
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% BODY WEIGHT THAT IS WATER
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60%= 40% INTRACELLULAR+20% EXTRACELLULAR
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WHAT % OF EXTRACELLULAR FLUID IS IN THE VASCULAR SYSTEM?
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25% (PLASMA IS 5% OF BODY WEIGHT) AND 75% IS OUTSIDE THE BLOOD VESSELS
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What is a mole?
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Molecular weight of a substance in grams
1 mol= 6 x 10^23 |
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What is the molecular weight of a substance?
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More properly known as the "relative molecular mass" = ratio of the mass of one molecule of a substance to the mass of 1/12 of an atom of carbon 12 (by definition has molecular weight of 12)
unit is daltons This is used to measure the mass of proteins |
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What is an equivalent?
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The amount of substance that will react with or supply one mole of hydrogen ions (H+) in an acid–base reaction.
Calculated as (the weight of) 1 mol of ionised substance divided by it's valence 1 mol of NaCl divides into 1eq of Na and 1eq of Cl 1 mol of calcium = 0.5eq calcium ions |
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What is a gram equivalent?
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The amount of a substance that will react with one gram of hydrogen, or with eight grams of oxygen, or with 35.5 grams (1.25 oz) of chlorine, or displaces any of the three
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What is the normality (N) of a solution?
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The number of gram equivalents in 1L
1N solution of HCL contains 1g of H+ equivalents and 35.5g of Cl- equivalents = total of 36.5 gram equivalents |
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Why is the oxygen molecule polar?
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because the oxygen slightly pulls electrons away from the hydrogen
This allows water molecules to interract with each other via hydrogen bonding and disolve polar molecules, causes water to have a high temperature of vapourisation |
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Intracellular, intersitial and plasma volumes as & body weight
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intracellular 40% of body weight, interstitial 15% of body weight, plasma 5% body weight
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Anions and cations in plasma?
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Na, Cl, bicarb and protein (very little K)
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Anions and cations in interstitial fluid?
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Na, Cl, Bicarb (very little K)
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Anions and cations in intracellular fluid?
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K, phosphates, protein (little bicarb and Cl and Na)
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Define the pH of a solution?
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log10 1/[H+] = -log[H+]
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What is the pH of water at 25 degrees when H+ and OH= are present in equal numbers?
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7.0
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What is the pH in the plasma of healthy individuals
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7.35-7.45
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How much more H+ is there in a solution at pH 8
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1/10 (as it is a negative log scale)
This is the pH of pancreatic secretions |
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pH of gastric fluid
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3.0 = 10^4 x pH 7
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Define an acid
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Molecule that acts as an H+ donor in solution
A strong acid dissolves completely in solution and donates all of it's H+ e.g. HCL (same as a strong base of OH-) |
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Are most physiological acids strong or weak?
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Weak, they contribute relatively few H+ or take away relatively few H+ from solution
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What is a buffer?
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Substance that has the capacity to bind or release H+ in solution, thus keeping pH stable despite the addition of acid or base
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What is the isohydric principle?
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All buffer pairs in a homogenous solution are in equilibrium with all the H+
The Isohydric principle is the phenomenon whereby multiple acid/ base pairs in solution will be in equilibrium with one another, tied together by their common reagent: the hydrogen ion and hence, the pH of solution. Any condition that changes the balance of one of the buffer systems, also changes the balance of all the others because the buffer systems actually buffer one another by shifting hydrogen ions back and forth from one to the other. body fluids contain many buffer pairs, each of which competes for the same H+ ions phosphate and protein buffer systems: closed systems within the body bicarbonate buffer system: open system in communication with the external environment |
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What is the equilibrium constant Ka
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In the equation HA
HB <----> H+ + B- Ka = [H+][B-] / [HB] As in denotes how far to the right the equation goes in the steady state i.e. is a measure of a weak acid's ability to ionize Weak acids with more than one ionizable H+, H3PO4, for example, dissociate stepwise, one H+ at a time. Each step has a different Ka expression and a different Ka value. The Ka value decreases with each successive step the smaller the value of Ka, the weaker the acid is |
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What is the relationship between pH and pKa?
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pH
= pKa + log [base]/[acid] |
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When is the buffering ability of a weak acid most powerful?
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When the pH = the pKa
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What is diffusion?
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The process by which a substance in solution or gas expands by motion of it's particles. Particle is equally likely to go from low to high concentration or visa versa. Since there are more particles in areas of high concentration the net movement is from high to low concentration.
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What is Fick's law of diffusion?
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J=-DA dc/dx
j = net rate of diffusion D= diffusion coefficient dc/dx is the concentration gradient A is area Magnitude of diffusing tendency is proportional to concentration gradient and cross sectional area across which diffusion takes place and is inversely proportional to thickness of membrane. Net rate of diffusion = diffusion coefficient X area X concentration gradient. |
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What is osmosis and how do you measure osmotic pressure?
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When you introduce solute into water (solvient) you decrease the concentration of the water molecules. If you introduce a membrane permeable only to water with pure water on the other side the water molecules will diffuse into the solution where there is more solute. This is called osmosis.
Osmosis can be prevented if you apply pressure to the more concentrated solution. The pressure needed to prevent this movement is the osmotic pressure. |
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What is the formula for osmotic pressure?
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p=nRT/V
n= number of particles (depends on number not type of particles) R= gas constant T= absolute temperature R= gas constant i.e. proporional to number of particles per unit volume |
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Explain osmoles? (the unit for osmotic pressure)
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The molecular weight of a solute, in grams, divided by the number of ions or particles into which it dissociates in solution.
For example, a solution of 1 mol/L NaCl corresponds to an osmolarity of 2 osmol/L. The NaCl salt particle dissociates fully in water to become two separate particles: an Na+ ion and a Cl- ion. Therefore, each mole of NaCl becomes two osmoles in solution, one mole of Na+ and one mole of Cl-. Similarly, a solution of 1 mol/L CaCl2, gives a solution of 3 osmol/L (Ca2+ and 2 Cl-). |
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What is osmolarity vs osmolality?
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osmolarity= number of osmoles per litre of solution
osmolality = number of osmoles per kg of solvient Osmolality and osmolarity are measurements of the solute concentration of a solution. In practice, there is negligible difference between the absolute values of the different measurements. For this reason, both terms are often used interchangeably, even though they refer to different units of measurement |
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What is the normal osmolality of plasma?
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290mosm/L (270 of this comes from sodium and it's corresponding cations)
This is less than expected if you think about all of the dissolved molecules but the numerous ionic interactions reduce the number of particles free to have an osmotic effect |
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Define tonicity?
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describes the osmolality of a solution in relation to plasma e.g. hypo/hypertonic
Metabolism changes the tonicity of solutions e.g. 5% dextrose is initially isotonic but when the glucose is metabolised it leaves water and therefore the infusion behaves like an isotonic solutiom |
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What is nonionic diffusion?
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When a non-ionised form of a weak acid or base moves across a cell membrane then dissociates
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What is the donan-gibbs equation and what does it mean?
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describes the situation where there is an impermeable anion on one side of a semipermeable membrane. Thus in addition to concentration, there is also an electrical gradient at work.
It has 3 major concequences: 1. Because of charged proteins there are more osmotically active particles in cells than outside---> if not for Na/K/ATPase cells would blow up 2. Electrical gradient- magnitude determined by nernst equation The actual equation is [Kx]{Clx]=[Ky][Cly] |
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What is oncotic pressure?
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Oncotic pressure, or colloid osmotic pressure, is a form of osmotic pressure exerted by proteins in a blood vessel's plasma (blood/liquid) that usually tends to pull water into the circulatory system. It is the opposing force to hydrostatic pressure.
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What % body weight is plasma?
How is this measured? How is red cell volume measured? |
5% = 3500ml
Measured using Evans blue that binds to plasma protein Red cell volume measured using chromium 51 |
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How many mEq/kg sodium in the body?
Where is this? |
58mEq/kg - 90% extracellular.
Plasma sodium is a relatively accurate measure of osmalality |
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How many mEq/kg potassium in the body?
Where is this? |
45mEq/kg - 90% intracellular
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What is fick's law of diffusion?
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Magnitude of diffusing tendency is proportional to concentration gradient and cross sectional area across which diffusion takes place and is inversely proportional to thickness of membrane.
Net rate of diffusion = diffusion coefficient X area X concentration gradient. |
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What is the donnan effect?
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Where there is an ion on one side of the membrane which cannot diffuse through the membrane, the distribution of the other ions to which the membrane is permeable is affected in a predictable way.
In the presence of a non-diffusable ion the diffusible ions distribute themselves so that at equilibrium their concentration rations are equal. |
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Define filtration?
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Process by which fluid is forced through a membrane due to pressure differential across it. Depends on surface area and permeability.
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What is solvent drag?
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Solvent drag, also known as bulk transport, is a phenomenon primarily in renal physiology, but it also occurs in gastrointestinal physiology. It is when solutes in the ultrafiltrate are transported back from the renal tubule by the flow of water rather than specifically by ion pumps or other membrane transport proteins.
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What are the sources of hydrogen ions in the body?
2 endogenous and 4 extra |
(1) Amino acid metabolism
50meq/day (2) Carbon dioxide and carbonic acid 12500meq/day- Most CO2 is excreted by the lungs. (3) Lactic acid Anerobic glycolysis (4) Keto acids Acetoacetic acid and beta hydroxybutyric acid from DKA (5) Ingestion of acidifying salts Calcium chloride (6) Failure of the kidney to excrete acid |
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Describe how and how much acid amino acid metabolism generates?
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Amino acid metabolism yields NH4+ and HCO3-
NH4+ is incorporated into urea, HCO3- buffers protons Especially sulphur containing amino acids and phosphorylated amino acids which yield H3PO4 |
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What are the blood buffers?
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1. Bicarbonate (carbonic anhydrase)
2. Haemoglobin 3. Plasma proteins |
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Where are bicarbonate buffers present?
What inhibits these? |
Present in:
Red blood cells, Gastric parietal cells, Renal tubule cells Inhibited by: Cyanide, Azide, Sulphide, Sulphonamides |
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How does Hb buffering compare to plasma proteins? What state does the Hb have to be in?
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Six times the buffering capacity of plasma proteins Deoxygenated haemoglobin is a better buffer
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What are the interstitial fluid and intracellular fluid buffers?
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Interstitial fluid buffers: Bicarbonate
Intracellular fluid buffers: Phosphate Proteins |
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Describe respiratory acidosis and renal compensation for this?
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Rise in arterial pCO2 accompanied by fall in pH. Results from reduced ventilation and removal of CO2.
Retained CO2 equilibrates with carbonic acid and results in a rise in plasma hydrogen and bicarbonate. Renal tubular hydrogen ion secretion increases resulting in bicarbonate reabsorption and raised plasma bicarbonate (renal compensation) Causes: COPD, Hypoventilation |
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Describe respiratory alkalosis and the compensation for this?
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Fall in pCO2 accompanied by a rise in pH. Results from increased ventilation and removal of CO2. Reduced CO2 equilibrates with carbonic acid and results in a fall in plasma hydrogen and bicarbonate.
Renal tubular hydrogen ion secretion decreases resulting in bicarbonate loss and reduced plasma bicarbonate (renal compensation) Causes: Voluntary hyperventilation, Altititude |
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Describe metabolic acidosis and the compensation for this?
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Fall in pH accompanied by fall in pCO2. Addition of strong acid to the blood results in buffering and fall in buffer anion levels. Carbonic acid is formed and converted to water and CO2.
CO2.is removed by the lungs and respiratory compensation occurs due to increased respiratory rate stimulated by increased hydrogen ion concentration. Renal tubular cells excrete excess acid in exchange for sodium. Urinary buffers increase the amount of hydrogen ion that can be accommodated Causes: Diabetic ketoacidosis, Ingestion of acidifying salts |
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Describe metabolic alkalosis and the compensation for this?
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Rise in pH accompanied by fall in pCO2. Removal of acid/addition of alkali to the blood results in buffering and rise in buffer anion levels.
Hypoventilation elevates pCO2 and bicarbonate. If plasma bicarbonate exceeds 26-28meq/l, bicarbonate appears in the urine. Causes Prolonged vomiting, Ingestion of alkali |
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Describe the 2 types of hydrogen secretion in the kidney and how these occur?
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PCT and DCT:
Hydrogen ions enter luminal fluid via sodium/hydrogen exchanger. Hydrogen originates from the intracellular dissociation of carbonic acid. DCT and CD: Hydrogen secretion is independent of tubular sodium. Hydrogen is secreted by ATP driven proton pump. Pump activity increased by aldosterone. |
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How do urine buffers function in acid regulation?
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Amount of acid secreted is limited by minimum pH of 4.5. Presence of buffers remove free hydrogen ions permitting more acid to be secreted.
Buffers are bicarbonate, phosphate and ammonium |
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How does bicarbonate urinary buffering occur?
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␣␣␣␣␣␣␣
Most secreted hydrogen in the tubular fluid reacts with bicarbonate to form carbonic acid. Carbonic anhydrase is present in the brush border of the PCT and facilitates formation of water and carbon dioxide. Carbon dioxide diffuses into the tubular cells, and is rehydrated back to carbonic acid. Carbonic acid dissociates making hydrogen available for the sodium/hydrogen exchanger. This mechanism effectively reabsorbs (though indirectly) filtered bicarbonate as sodium bicarbonate. |
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How does phosphate urinary buffering occur?
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pK 6.8
Hydrogen reaching the DCT and CD reacts with dibasic phosphate (HPO42-) to form monobasic phosphate (H2PO4-) |
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How does ammonium urinary buffering occur?
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Tubular cells produce NH4+ via the formation of glutamate and alpha ketoglutarate.
Non-ionic diffusion NH4+ enters the PCT lumen and is reabsorbed in the thick ascending limb of the loop of Henle In tubular cells, NH4+ is in equilibrium with NH3 but since pK is 9.0, the ratio of NH3 to NH4+ is 1:100 NH3 is lipid soluble and is able to enter the CD where it combines with hydrogen and is excreted. In chronic acidosis NH4+ secretion is increased |
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What 4 factors affect renal acid secretion?
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Intracellular pCO2
Potassium concentration Carbonic anhydrase level Aldosterone |
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What is the range of urine pH
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pH of urine varies from 4.5 to 8
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What is the anion gap?
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The anion gap is the difference in the measured cations and the measured anions (negatively charged ions) in serum, plasma, or urine.
([Na+] + [K+]) − ([Cl−] + [HCO3−]) |
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What is the 'standard bicarbonate'
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parameter standard bicarbonate concentration (SBCe) is the bicarbonate concentration in the blood at a PaCO2 of 40 mmHg (5.33 kPa), full oxygen saturation and 36 °C
i.e. what the bicarbonate would be if any respiratory component was eliminated |
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What is the 'buffer base'?
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Total number of buffer anions that can accept hydrogen in the blood
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Define base excess?
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Base excess is defined as the amount of strong acid that must be added to each liter of fully oxygenated blood to return the pH to 7.40 at a temperature of 37°C and a pCO2 of 40 mmHg (5.3 kPa).
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What causes a high base excess?
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A high base excess, thus metabolic alkalosis, usually involves an excess of bicarbonate. It can be caused by:
1. Compensation for primary respiratory acidosis 2. Excessive loss of HCl in gastric juice by vomiting 3. Renal overproduction of bicarbonate, in either contraction alkalosis or Cushing's disease |
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What cases a low base excess (or base deficit)?
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A base deficit (a below-normal base excess), thus metabolic acidosis, usually involves either excretion of bicarbonate or neutralization of bicarbonate by excess organic acids.
1. Compensation for primary respiratory alkalosis 2. Diabetic ketoacidosis, in which high levels of acidic ketone bodies are produced 3. Lactic acidosis, due to anaerobic metabolism during heavy exercise or hypoxia 4. Chronic renal failure, preventing excretion of acid and resorption and production of bicarbonate 5. Diarrhea, in which large amounts of bicarbonate are excreted 6. Ingestion of poisons such as methanol, ethylene glycol, or excessive aspirin |
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Define plasma?
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The fluid portion of blood containing ions, inorganic molecules, organic molecules, clotting factors
Clots on standing. If whole blood is allowed to clot and the clot is removed the remaining fluid is serum. Serum contains more Serotonin due to the degradation of platelets during the clotting process |
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What is the molecular weight and concentration of albumin?
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69000
5g/dl |
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What is the molecular weight and concentration of fibrinogen?
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Fibrinogen 340000 400mg/dl
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What is the concentration of alpha 2 macroglobilin?
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300mg/dl
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What are some examples of plasma proteins?
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Alpha1 antiprotease Antothrombin III CRP Transferrin Angiotensinogen Clotting factors II, VII, IX, X SHBG
Thyroxine binding globulin |
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What are the 4 major functions of plasma proteins?
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(1) Osmotic regulation
Capillary walls relatively impermeable to plasma proteins, therefore they exert an osmotic force of 25mmHg that pulls water into the blood (2) Buffering 15% of buffering capacity Major anionic component of blood (3)Clotting (4)Transport/carriers |
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How many neutrophils per microlitre?
What percent does this translate to? |
3000-6000
50-70% |
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How many eosinophils per microlitre?
What percent does this translate to? |
150-300
1-4% |
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How many basophils per microlitre?
What percent does this translate to? |
0-100
0.4% |
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How many lymphocytes per microlitre?
What percent does this translate to? |
1500-4000
20-40% |
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How many monocytes per microlitre?
What percent does this translate to? |
300-600
2-8% |
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How many total white cells per microlitre?
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4000-11000
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What regulates white cell production?
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Colony stimulating factors and interleukins IL1-IL6 regulate cell production.
CSFs and cytokines are derived from activated T cells, macrophages, fibroblasts and endothelial cells. |
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What are the 3 types of granulocytes?
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basophils, eosinophils, neutrophils
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Where are basophils found?
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Functionally similar to mast cells
Circulate in blood None in tissues |
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How are eosinophils recruited?
What do they do? |
Phagocytose parasites
Recruited in late phase of type I hypersensitivity due to action of IL3, IL5. Abundant in mucosal surfaces of respiratory tract, lower urinary tract, GIT. Produce LTC4, PAF Also produce major basic protein and eosinophilic cationic protein that are toxic to epithelial cells |
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What do neutrophils do?
Half-life of neutrophils? How many produced each day? |
Seek, ingest and kill bacteria
Half life 6 hours 100 billion produced each day by bone marrow Phagocytosis |
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How long do monocytes circulate and persist?
What do they differentiate into? |
Enter blood from bone marrow
Circulate for 24 hours then become tissue macrophages Persist for about 3 months. Macrophages may differentiate into: Kuppfer cells, Pulmonary alveolar macrophages Microglia Osteoclasts |
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What is the function of monocytes?
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Antigen presentation to T cells
Phagocytosis: Activated macrophages migrate in response to chemotactic stimuli to engulf and kill bacteria. Also phagocytose bacteria opsonised by IgG or C3b Macrophages are also the predominant cell type in acute inflammation after they replace neutrophils (first 48 hours) They are also the most important cell type in chronic inflammation |
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What activates macrophages?
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Cytokines (especially gamma interferon) from T lymphocytes
Bacterial endotoxin Extracellular matrix proteins Other chemical mediators |
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What do activated macrophages secrete that causes
1. tissue injury 2. fibrosis |
1. Reactive oxygen metabolites
Proteases Neutrophil chemotactic factors Coagulation factors Arachidonic acid metabolites Nitric oxide 2. Growth factors Cytokines Angiogenesis factors Collagenases (remodeling function) |
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Where are mast cells found?
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Derived from bone marrow
Heavily granulated Mainly found along epithelial surfaces and near blood vessels |
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What are the mediators secreted by mast cells?
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Primary mediators (granule contents):
Histamine, adenosine Heparin Enzymes (proteases, acid hydrolases) Secondary mediators (synthesised, not stored): Leukotrienes B4, C4, D4. Prostaglandins D2. PAF. Cytokines TNF, IL1, IL2, IL4, IL5, IL6, GM- CSF. |
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What causes mast cell degranulation?
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Binding of IgE coated antigen to membrane Fc receptor
C5a C3a IL8 Drugs: Codeine, Morphine Physical stimuli |
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Where do lymphocytes originate? Where are they found?
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Lymphocyte precursors originate in bone marrow, then either populate thymus (T lymphocytes) or fetal liver/bone marrow (B lymphocytes) Most then migrate to lymph nodes, spleen and bone marrow 2% in peripheral blood at any one time Rest in lymphoid organs
Most processing occurs in fetal life though there is slow continuous production throughout adult life. |
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What % of lymphocytes are T-cells?
How do they work? What are CD3, CD4, CD8 |
60-70% of circulating lymphocytes
Each T cell is programmed to recognize a specific cell- bound antigen by means of an antigen-specific T cell receptor. TCRs linked to a cluster of polypeptide chains called CD3. CD4 and CD8 are co-receptors that enhance the signal produced when MHC bound antigen binds to the TCR. CD8 (30%) occurs on cytotoxic T cells and binds MHC-I CD4 (60%) occurs on helper T cells and binds MHC-II |
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What are CD4 cells and what do they do?
What are CD8 cells? What are memory cells? |
Helper (CD4) T Cells Regulate the immune system
Secrete cytokines to influence action of other cells Cytotoxic (CD8) T cells Secrete cytokines but primarily act as cytotoxic cells Memory cells are cells that have been exposed to antigen and are readily converted to effector cells by a later encounter with the same antigen. |
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How are b-cells activated?
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10-20% of circulating lymphocytes
Following antigenic stimulation B cells form plasma cells that secrete immunoglobulins B cells recognize antigen via a B cell receptor that is composed of IgM Naive B cells express membrane-bound antibodies, IgM & IgD, that function as antigen-specific receptors Ag-recognition plus Th cells & other stimuli induce clonal expansion & differentiation |
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What else is on the surface of b-cells?
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CD40
Essential for activation by T cells and subsequent secretion of antibody CD 21 Also binds Epstein Barr virus |
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How to T-cells help activate b-cells?
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B cell receptors (Ig BCR) may recognise foreign proteins, but may also bind foreign lipids, polysaccharides, nucleic acids & chemicals
T helper cells play a major role ‘helping’ B cells respond to protein antigens: T dependent antibody responses TCR only binds proteins, therefore B cell responses to other antigens, polysaccharides, lipids etc, do not involve T cell help: T independent antibody responses T cell help induces class switch and affinity maturation T independent antibody responses involve little or no class switching or affinity maturation Antibodies are largely low affinity IgM Minimal if any memory |
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Where do naive b-cells find foreign antigens?
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Naïve B cells recirculate and enter follicles in peripheral lymph nodes, spleen etc ‘seeking’ antigen
Unprocessed foreign antigen accumulates in follicles (specialised antigen presenting cells display ‘native’ antigens) B cells use IgM and IgD receptors in membrane to directly bind to the antigen in the follicles |
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What do activated b-cells do?
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Proliferation
→expansion of antigen-specific clone Low level IgM secretion →early phase of humoral response Increased expression of B7 costimulators →ability to activate Th cells Migrate from follicles →location to activate Th cells Express cytokine receptors →response to T cell ‘help’ IgM secretion is greatest when antigens are multivalent (eg polysaccharides) many bacteria have polysaccharide-rich capsules early IgM production is very important in immunity to these microbes IgM activates elimination mechanisms eg complement activation Protein antigens (few repeating epitopes) elicit poor IgM response Protein antigens require T cell ‘help’ to elicit efficient antibody production |
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How do t-cells help b-cells?
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CD40 ligand (CD40L), newly expressed on activated T cells, binds CD40 molecules, constitutively expressed on B cells
Engagement of CD40L - CD40 → B cell proliferation antibody synthesis & secretion initiates heavy chain class switching Activated effector T cells secrete cytokines Cytokines bind to cytokine receptors expressed on B cells Cytokines determine outcome of class switching: class of antibody produced by class switched B cell is determined by the cytokine(s) (eg IFN-g / IL-4 / TGF-b) that the T cells secrete |
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How is antibody production shut down?
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B cell responses are inhibited when sufficient IgG has been produced
IgG-antigen complexes simultaneously bind Ig receptors and FcgR on B cell membrane FcgR signal inhibits B cell activation Inhibition shuts off antibody production |
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What are natural killer cells?
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10-15% of circulating lymphocytes
No TCR or cell surface immunoglobulins but have CD16 and CD56 Large with abundant granules Innate ability to lyse tumour cells, virus infected cell and some normal cells without prior sensitization. Specific ability to lyse IgG coated target cells Able to recognize self via MHC 1 receptor |
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What id the structure of plateleys?
How are they formed? What is their lifespan? |
2-4 micrometres diameter
Granulated 300,000/microlitre Half life 4 days Formed from pinching off portions of cytoplasm from megakaryocytes in bone marrow Production regulated by CSFs and thrombopoetin 60-70% in blood, rest in spleen (splenectomy causes a thrombocytosis) |
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What are the contents of platelet:
1. cytoplasm 2. dense granules 3. alpha granules |
1. Cytoplasm:
Actin and myosin, Mitochondria, Lysosomes, Glycogen, VWF, Fibrin, stabilizing factor 2. Dense granules: Serotonin Histamine, ADP, Calcium, Adrenaline 3. Alpha granules: Clotting factors PDGF (also produced by macrophages and endothelial cells) TGF Fibrinogen Fibronectin Platelets synthesise Thromboxane A2 |
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What are the steps in platelet adhesion?
What are the 3 things that activate platelets? |
Endothelial injury exposes thrombogenic extracellular matrix that allows platelets to adhere Platelets adhere via vWF that binds Gp1b and also adhere directly to collagen and laminin
Adhesion is a passive process Platelets are activated by: Binding to collagen ADP ' Thrombin |
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What are the 3 steps of platelet activation?
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1. adhesion
2. secretion + exposure of phospholipid complex 3. aggrigation and contraction |
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Describe secretion (the second step in platelet activation)?
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Once activated, platelets change shape by forming pseudopodia and discharge their granules.
Calcium and ADP release is especially important for stimulation of aggregation Phospholipid complex is then expressed on the surface that provides nucleation site for intrinsic pathway. |
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Describe platelet aggregation and contraction?
What activates this? |
Aggregation stimulated by ADP and calcium
PAF (secreted by neutrophils and monocytes) stimulates the platelet to produce thromboxane A2 from arachidonic acid. Thromboxane A2 and thrombin stimulate further calcium influx Fibrinogen is an important cofactor that binds platelets via GpIIb-IIIa and later forms a fibrin mesh Platelet aggregate then contracts creating an irreversibly fused mass of platelets. |
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What is the structure, production and lifespan of red cells?
How many red cells and Hb in circulation? |
7.5um diameter biconcave disc
4.8-5.4million/microlitre Survival 120 days Manufactured in bone marrow Each contains 29pg of haemoglobin 3X1013 in circulation 900g haemoglobin |
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What is the molecular structure of haemoglobin?
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Globular protein with molecular weight of 64,450 2 pairs of polypeptide subunits
A2B2=adult haemoglobin A A2D2=haemoglobin A2 A2G2=fetal Each subunit has a heme moeity. Heme is an iron containing porphyrin derivative |
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What is the molecular weight of haemoglobin?
How much haemoglobin in the average person? |
64,450
Average haemoglobin 16g/dl men, 14g/dl women 900g 0.3g destroyed and synthesised every hour |
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What regulates the production of red cells?
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Erythropoetin
CSFs IL1, 3, 6. |
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How is haemoglobin catabolised?
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Globin spilt off
Heme converted to biliverdin by heme oxygenase Biliverdin converted to bilirubin |
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What does the affinity of haemoglobin depend on?
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pH (lower at acidic)
Temperature 2,3 diphosphoglycerate Hydrogen and 2,3 DPG compete for oxygen binding sites |
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What is methaemoglobin?
How is it converted back to haemoglobin? |
Formed when ferrous iron Fe2+ is converted to ferric iron Fe3+ by drugs or oxidising agents
Dark Converted back to haemoglobin by NADH- methaemoglobin reductase |
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What is carboxyhaemoglobin?
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Formed when haemoglobin reacts with carbon monoxide, for which it has a greater affinity.
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Give 2 examples of genetic conditions with abnormal haemoglobin?
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Haemoglobinopathies -abnormal polypeptide chains
Thallassaemias -normal structure, produced in decreased amounts. |
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Where are ABO antigens found?
(agglutinogens) |
Red cell membranes
Other tissues: Salivary glands Saliva Pancreas Liver Kidney Lungs Testes Semen Similar antigens are found on intestinal bacteria |
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What are abo antibodies?
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Antibody is formed in response to non-self antigen that is present on bacterial surfaces and possibly in food Antibodies against red cell antigens are agglutinins
Blood group A have A antigens and develop anti-B antibody Blood group B have B antigens and develop anti-A antibody Blood group AB do not develop agglutinins Blood group O develop anti-A and anti-B |
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How common is it to be d-antigen positive?
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85%
85% are D antigen positive Antibodies do not develop without exposure to D cells Rhesus incompatibility may result in haemolytic disease of the newborn |
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Frequency of each blood group
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0 45%
a 41% b 10% ab 4% |
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What is the neuronal resting membrane potential and what sustains this?
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Resting membrane potential ␣70mV. This is maintained by Na/K pump.
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How is the neuronal action potential generated?
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Stimulus may be electrical, chemical or mechanical.
Gradual 15mV depolarization until threshold. At firing level there is rapid depolarization to +35mV (overshoots) due to opening of voltage-gated sodium channels. Sodium channels then become inactivated before returning to resting state. Inactivation leads to repolarisation and this is aided by voltage gated potassium channels. After-hyperpolarisation (overshoots) due to opening of voltage gated potassium channels and slow return of these channels to their closed state. |
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What is the absolute refractory period for neurones?
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From firing time to one third completion of repolarisation.
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What is the
1) relative refractory period 2) absolute refractory period of neurons |
Absolute: From firing time to one third completion of repolarisation.
Relative: From one third completion of repolarisation to start of hyperpolarisation. |
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Describe how the action potential propagates and why it moves forwards instead of backwards?
What is a current sink? |
Nerve cell membrane is polarized at rest with positive charges lined up along the outside of the cell.
During the AP, polarity is briefly reversed. Positive charges ahead and behind flow into the area of depolarization (current sink). By drawing positive charges this makes the surrounding membrane approach firing level. The area behind the AP is refractory therefore the AP moves forward |
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What are the 4 different type A fibres in the Erlanger and Gasser classification?
What is the size and speed of propagation for each of these |
A alpha: Proprioception, somatic motor
15um, 100m/s A beta: Touch, pressure 10um, 50m/s A gamma: Motor to muscle spindles 5um, 25m/s A delta: Pain, temperature 3um, 20m/s |
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What is the size, type, diameter velocity of type B neuronal fibres?
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B
Preganglionic autonomic 1um 1m/s |
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What is the size, type, diameter velocity of type C neuronal fibres?
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C (unmyelinated)
Pain, temp, itch, reflexes, postganglionic sympathetic 1um 1m/s |
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Describe the structure of a muscle fibre?
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Each muscle fibre is a single cell surrounded by sarcolemma. Fibre made up of myofibrils. Myofibrils made up of filaments Filaments made up of contractile proteins.
Thin filaments are composed of actin ( forms 2 chains in a long double helix), tropomyosin and troponin. Thick filaments are composed of myosin (2 globular heads and a long tail). |
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What defines a sarcomere?
What forms the A and I bands? Where are t-tubules? go draw/look at a picture |
Caused by arrangement of thick and thin filaments. Area between two Z lines is a sarcomere.
Thick filaments form the A band. Thin filaments form the I band. T tubules enter between A and I. Each T tubule has a cistern on either side. M lines are at the centers of the A bands. |
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Describe/write out the events involved in excitation/contraction coupling
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1. Discharge of motor neuron
2. Release of transmitter at motor end plate 3. Binding of acetylcholine to nicotinic acetylcholine receptors. 4. Increased Na/K conductance in end plate membrane. 5. Generation of EPP. 5. Generation of AP in muscle fibres. 6. Inward spread of AP via T tubules 7. Calcium released from terminal cisterns of SR that diffuses to thick and thin filaments. 8. Calcium binds troponin C, weakening troponin I bindings, causing tropomyosin to move laterally, exposing actin/myosin binding sites. 9. Myosin head binds actin chain. 10. ATP enters ATP binding site and is hydrolysed, causing a power stroke that shortens the sarcomere by 10nm. Calcium pumped back into the SR by a calcium magnesium pump that requires ATP. Release of calcium from troponin C. Cessation of interaction between actin and myosin |
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What are type 1 muscle fibres?
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Red muscles - maintain posture
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What are type 2 muscle fibres?
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White muscles - fine movements
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What is phosphocreatine?
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Energy rich phosphate compound used to supply energy for short periods.
Hydrolysed to creatine and phosphate with release of ATP. |
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When are lipids used to power muscle?
When are carbs used to power muscle? What is that cycle called? |
At rest and during light exercise muscles utilize FFAs.
More intense exercise requires carbohydrates Glucose is metabolized by the citric acid cycle to CO2 and H2O. Glucose may come from blood stream or from breakdown of glycogen stores |
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When is lactate produced by muscle?
What is oxygen debt? |
If oxygen is insufficient, pyruvate is reduced to lactate. After exercise is finished, extra oxygen is required to remove lactate, replenish ATP and phosphorycreatine stores
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Describe cardiac muscle structure?
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Characterized by intercalated discs and gap junctions. Intercalated discs have very low resistance and thus cardiac muscle is termed a syncytium.
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What is the range of the cardiac muscle action potential?
How long does this last? |
-90mV to +20mV
200ms duration |
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What are the 5 phases of the cardiac cycle?
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Phase 0:
Depolarisation Opening of voltage gated sodium channels resulting in rapid sodium influx Phase 1: Initial rapid repolarisation Closure of voltage gated sodium channels Plateau Phase 2: Slow, prolonged opening of voltage gated calcium channels resulting in calcium influx Sodium also flows through these channels There is reduced permeability to potassium during this phase Phase 3: Late rapid repolarisation Closure of voltage gated calcium channels Potassium efflux through various potassium channels (inward rectifying, delayed rectifying and transient outward potassium channels) Phase 4: Baseline |
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Give 5 structural features of smooth muscle?
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No cross striations
Irregular actin/myosin chains No troponin Poorly differentiated SR Few mitochondria |
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Describe the activation of smooth muscle?
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Calcium binds calmodulin and activates MLCK
MLCK catalyses phosphorylation and allows ATPase activation Dephophoylation of MLCK leads to relaxation |
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What is a synapse?
How many per neuron? Size of synaptic cleft? |
Junction where the axon of one cell terminates on the dendrites, soma (cell body) or axon of another neuron (or muscle or gland cell)
Each neuron divides to form 200 synaptic endings Synaptic cleft - 20-40nm |
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What are the 3 types of synaptic vesicles?
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Small, clear - Ach, glycine, GABA, glutamate
Small, dense core - catacholamines Large, dense core -neuropeptides. |
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What is the difference between where small clear and dense core vesicles discharge?
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Vesicles manufactured in cell body.
Small clear vesicles are continually recycled in the presynaptic nerve terminal and only discharge into the cleft active zones, which contain rows of calcium channels (large, dense vesicles discharge all over the terminal) |
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What triggers synaptic fusion and discharge?
What proteins assist with this? |
AP reaches pre-synaptic terminal
Opens voltage gated calcium channels Calcium influx Fusion with the synaptic membrane and exocytosis is aided by several proteins including synaptobrevin and syntaxin Calcium removed by calcium/sodium antiport Synaptic delay = 0.5ms |
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What is the major factor in terminating neurotransmitter action?
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Major factor in terminating the action of the transmitters.
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Major transmitter types
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Acetylcholine
Amines (dopamine, noradrenaline, adrenaline, serotonin, histamine) Amino acids (glutamate, aspartate, glycine, GABA) Polypeptides (substance P, vasopressin, oxytocin) Purines (adenosine) Gases (NO) Lipids (anandamide) |
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How is acetylcholine made and broken down?
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Active uptake of choline into cholinergic neurons. Choline acetyltransferase catalyses combination of acetyl CoA with choline.
Ach then taken up by vesicles. Ach hydrolysed to choline and acetate in cleft by acetylcholinesterase. Receptors - muscarinic, nicotinic (binding of Ach with the nicotinic receptor causes sodium influx) |
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How is noradrenaline made and destroyed?
What is the rate-limiting step? |
Noradrenaline most sympathetic post ganglionic endings
Phenylalanine>Tyrosine (phenylalanine hydroxylase)>dopa (tyrosine hydroxylase is subject to feedback inhibition and is the rate limiting step)>dopamine (dopamine decarboxylase). Dopamine then enters vesicles. Dopamine>noradrenaline (dopamine beta hydroxylase) Removed from cleft by binding to presynaptic receptors, reuptake, or catabolism (oxidation and methylation by MAO and COMT catachol O methyl transferase) |
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Where is serotonin found and how is it made?
How is it's action terminated? How many serotonin receptors are out there? |
Mainly found in platelets and GIT and brain
Formed by hydroxylation and decoarboxylation of tryptophan Active reuptake from cleft 7 receptors 5HT1-7 plus subtypes |
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What is the mechanism of gaba a and gaba b receptors?
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Major inhibitory mediator in the brain
GABAa receptors increase chloride influx. GABAb receptors increase potassium efflux and block influx of calcium. |
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Give 2 examples of endogenous opioids?
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Met-enkephalin and leu-encephalin = opioid peptides which bind opioid receptors
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What effects does activation of mu opioid receptors have?
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activation increase potassium conductance ␣ analgesia, respiratory depression, constipation, euphoria, sedation, meiosis
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What effects does activation of kappa opioid receptors have?
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closes calcium channels
analgesia, diuresis, sedation , meiosis, dysphoria |
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What effects does activation of delta opioid receptors have?
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closes calcium channels -analgesia only
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What is an EPSP?
What are the 2 ways in which they summate? |
Produced by depolarization of the post synaptic membrane. Excitatory neurotransmitter opens sodium and calcium channels in a localized area of the post synaptic membrane.
EPSPs summate (spacial = more than one knob, temporal = repeated EPSPs in the same knob) EPSPs are not all-or-nothing but proportional to the afferent stimulus Constant interplay between EPSPs and IPSPs. When 10-15mV depolarization attained, propagation spike occurs |
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What is an IPSP?
How much depolarisation needs to be attained for a propagation spike to occur? |
Produced by hyperpolarisation of the post synaptic membrane. Inhibitory neurotransmitter opens chloride channels localized area of the post synaptic membrane. IPSPs summate (spacial = more than one knob, temporal = repeated IPSPs in the same knob) IPSPs can also be produced through closure of sodium/calcium channels or opening of potassium channels that cause movement of potassium out of the cell.
Constant interplay between EPSPs and IPSPs. When 10-15mV depolarization attained, propagation spike occurs |
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What are the indirect ways a synapse can be inhibited (assumind direct is IPSP)?
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Post-synaptic refractory period
After-hyperpolarisation Reciprocal innervation in spinal cord (EPSP to agonist, IPSP to antagonist muscles) |
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How does pre-synaptic inhibition occur?
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Increased chloride conductance which decreases the size of the AP and therefore reduces calcium entry and the amount of neurotransmitter released.
Voltage gated potassium channels open causing potassium efflux and decreased calcium influx. Direct inhibition of transmitter release (GABA does all of this) |
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Describe activation of the neuromuscular junction in skeletal muscle?
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One nerve fibre per endplate
AP increases permeability to calcium This triggers exocytosis Ach diffuses to nicotinic Ach receptors Binding of Ach causes sodium influx This results in depolarizing potential (EPP) and muscle action potential Ach removed by acetylcholinesterase. |
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How does the activation of smooth muscle and cardiac muscle differ from skeletal muscle?
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No muscle endplates
Afferent nerve have varicosities and run along the membranes of muscle cells. Synaptic discharge causes an excitatory or inhibitory junction potential instead of EPSP/IPSP |
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What is the path out of the spinal cord of preganglionic sympathetic nerves?
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Axons of sympathetic preganglionic neurons leave spinal cord via ventral roots and white rami communicantes to the paravertebral sympathetic ganglion chain.
Some postganglionic axons re-enter via the grey rami communicantes. |
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Where are the parasympathetic nerves found peripherally?
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Cranial : oculomotor, facial, glossopharyngeal, vagus Sacral : sacral spinal nerves.
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Which ANS nerves are cholinergic?
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Cholinergic :
All preganglionic neurons + parasympathetic post ganglionic neurons, sympathetic post ganglionic neurons to sweat glands, sympathetic post ganglionic neurons to skeletal muscle casuing dilatation: anabolic effects |
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Which ANS neurons use noradrenaline?
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Sympathetic post ganglionic except those to sweat glands
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What are the components of a reflex arc?
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ense organ
Afferent neuron (enters cord via dorsal roots or cranial nerves) One or more synapses Efferent neuron (leaves the cord via ventral roots or cranial nerves) Effector |
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What is the bell-magendie law?
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Spinal cord dorsal roots are sensory Spinal cord ventral roots are motor
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What are the components of a stretch reflex?
What neurotransmitter is used? |
Sense organ (muscle spindle)
Afferent neuron (same as efferent nerve supply) One synapses (neurotransmitter is glutamate) Efferent neuron Effector (muscle) Reciprocal innervation of muscle antagonist |
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What senses the inverse stretch reflex?
How does this work? |
Stretch can increase to a maximum, but once this point is reached, the muscle relaxes
Sense organ (golgi apparatus) Afferent neuron (same as efferent nerve supply) One synapses (neurotransmitter is glutamate) Efferent neuron Effector (muscle) |
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What is clonus and what is it caused by?
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Regular rhuthmic contraction of a muscle that is subjected to sudden maintained stretch.
Caused by increased gamma efferent discharge in response to hyperactive muscle spindles |
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Give an example of a polysynaptic reflex?
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Withdrawal reflex
Polysynaptic reflexes branch in a complex fashion Number of synapses is variable Reverberating circuits are common |
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What is the result of the withdrawal reflex?
What is the neurotransmitter used? |
Effector (ipsilateral flexion and extension plus crossed extensor response)
glutamate |
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What is carried in the anteriolateral tracts of the spinal cord?
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Lateral spinothalamic (pain, temperature) Ventral spinothalamic (crude touch, pressure)
Pain Temperature Crude touch, itch, tickle Tracts to cerebellum for muscular coordination |
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What is the path of nerve fibres that are to travel with the lateral or ventral spinothalamic tract?
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Fibres entering the cord form the
dorsolateral tract that runs at the tip of the posterior horn and ascends or descends for 1 or 2 segments before synapsing. Fibres then decussate to enter the anterolateral tract (anterior to the denticulate ligament) 90% then synapse with the brainstem reticular formation |
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What are the 2 parts of the dorsal columns and what do they contain?
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Fibres from lower body carried medially in the gracile tract, upper body laterally in the cuneate tract
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Where do the dorsal columns travel?
Where do they decussate? How many synapses before the cortex? |
Both tracts synapse in the medulla (gracile and cuneate nuclei) then decussate to form the medial lemniscus, pass to the thalamus, synapse again then pass to the cortex
Light (discriminative) touch Vibration Proprioception (position sense) Bladder and rectum fullness |
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What are the sensory organs for pain and what fibres does pain travel in?
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Naked nerve endings
Found in most areas of the body Respond to multiple stimuli including chemical, heat, electrical, mechanical Afferent fibres: A delta -20m/s (fast, sharp pain) C (unmyelinated) - 1m/s (slow, dull pain) |
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Where do A delta and C fibres synapse?
What are the neurotransmitters for signal modulation? |
A delta - lamina I and IV of the dorsal horn C (unmyelinated) - lamina I and II of the dorsal horn Considerable plasticity results in the dorsal horn cells acting as a gate where impulses can be modified by presynaptic inhibition
Transmitters include glutamate and substance P Some axons end in the spinal cord Most ascend in the lateral spinothalamic tract and ascend to the thalamus, reticular system and cortex |
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Describe the visual pathways from the optic nerve to the visual cortex?
Go draw/write this out |
Optic nerve
Nasal hemiretina fibres decussate in the optic chiasm -Ipsilateral temporal fibres and contralateral nasal fibres in optic tract Lateral geniculate body of thalamus -Upper half of retina projects to medial side -Lower half of retina projects to lateral side Geniculocalcarine tract passes to occipital cortex (Brodman's area 17) Medial fibres pass to the superior lip of the calcarine fissure Lateral fibres pass to the inferior lip of the calcarine fissure Macular fibres separate from other fibres and project more posteriorly |
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What kind of visual problems do the following lesions cause?
Optic nerve Optic tract Optic chiasm Occipital lesions |
Optic nerve - monocular blindness
Optic tract - homonymous hemianopia Optic chiasm - bitemporal hemianopia Occipital lesions - macular sparing common |
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What does the 'near response' accommodation involve?
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1. Accommodation due to contraction of ciliary body 2. Convergence of the visual axes due to contraction of medial rectus
3. Pupillary constriction Involve cortical and subcortical pathways via the edinger- westphal nucleus, ciliary ganglion and ciliary body |
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What is the pathway of the Pupillary light reflex/consensual light reflex?
How many synapses? |
First order neurons bypass the lateral geniculate body and project to the superior colliculus of the midbrain via the optic nerve
Second order neurons project to ipsilateral and contralateral Edinger-Westphal nucleus Third order neurons project to ciliary ganglion of oculomotor nerve Fourth order neuron project via short ciliary nerves to the pupillary sphincter |
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What is the normal body temperature?
What is the circadian fluctuation? |
Balance between heat loss and heat production determines body temperature.
Constant body temperature is essential to the normal functioning of enzymatic and other body processes. Normal oral body temperature 36.3-37.1oC Oral temperature is 0.5oC lower than core temperature Circadian fluctuation 0.5oC |
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What are the processes of heat production?
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Muscular exercise
Assimilation of food Processes contributing to metabolic rate Cold triggers: ncrease heat production: 1. Shivering 2. Hunger 3. Increased voluntary activity 4. Increased secretion of catecholamines Decreased heat loss 1. Cutaneous vasoconstriction 2. Reducing body surface area |
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What are the four mechanisms of heat loss and how many % do they account for?
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Radiation and conduction 70%
Vapourisation of sweat 27% 1g of water removes 0.6kcal of heat. In humid environments sweat production can reach 1600ml/hr Respiration 2% Urine and faeces 1% |
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Describe radiation and conduction heat loss?
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Radiation:
Transfer of heat by infrared electromagnetic radiation from one object to another at different temperature with which it is not in contact. Conduction: Heat exchange between objects or substances in contact. Temperature of the skin largely determines the degree to which heat is lost or gained Convection: Movement of molecules away from the area of contact |
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What are some mechanisms activated by heat which increase heat loss?
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Increase heat loss
Cutaneous vasodilation Sweating Increased respiration Decreased heat production Anorexia Apathy and inertia |
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What are temperature receptors?
What temperatures do these respond to and what fibres do they use? |
Temperature sense organs are naked nerve endings.
Cold receptors respond from 10-38o and utilise Adelta and C fibres Warm receptors respond from 30-45o and utilise C fibres |
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Where do temperature pathways go in the brain?
What are the thresholds for shivering and sweating? |
Afferents project via the lateral spinothalamic tract to the postcentral gyrus
Hypothalamus receives afferents mainly from cold receptors in the skin, spinal cord, and hypothalamus itself. Temperature thresholds exist for the main regulating responses: Shivering -35.5o Sweating - 37o |
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How many times do the lungs divide between the trachea and the aleoli.
How many divisions in the conducting vs respiratory zone? |
Between the trachea and the alveoli the airways divide 23 times.
First 16 divisions form the conducting zone Bronchi, bronchioles, terminal bronchioles. Last 7 divisions Respiratory bronchioles Alveolar ducts Alveoli Portion of lung distal to the terminal bronchus is the acinus |
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What are the properties of the trachea and bronchi?
What epithelium lines them? What receptors do they contain? |
Cartilaginous walls (trachea and bronchi only) Relatively little smooth muscle
Lined by ciliated epithelium (cilia are present as far as the respiratory bronchioles) Numerous mucous and serous glands (trachea and bronchi only). Abundant muscarinic receptors and beta2 adrenoceptors. |
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What are type 1 alveolar cells?
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Flat. Large cytoplasmic extensions. Primary lining cells.
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What are type 2 alveolar cells?
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Thick.
Numerous lamellar inclusion bodies. Secrete surfactant. |
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Define dead space?
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Gas that occupies the respiratory system that is not available for gas exchange with the pulmonary capillary bed
anatomical: volume of the conducting airways physiological: anatomical + alveolar dead space anatomical and physiological are equal in healthy individuals |
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What is the volume of alveolar ventilation and dead space?
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Alveolar ventilation = 350ml
Dead space = 150ml |
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What is fowler's method to measure anatomical dead space?
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Measures the volume of the conducting airways down to the level where the rapid dilution of inspired gas occurs with gas already in the lung.
Analysis of single breath nitrogen curves. Commence at mid inspiration. Deep breath of pure oxygen. Nitrogen content of expired gas is constantly measured. Phase 1 = dead space gas with no nitrogen Phase 2 = dead space mixed with alveolar gas Phase 3 = alveolar gas Phase 4 = portion between closing volume and residual volume where airways in lower dependent parts of the lungs begin to close due to the lesser transmural pressure in these areas. Gas in the upper lungs is richer in nitrogen because the upper alveoli are more distended at the start of inspiration. |
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What is Bohr's method of measuring physiological dead space?
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Measures the volume of the lung that does not eliminate carbon dioxide, which is a measure of function It assumes that all expired carbon dioxide comes from the alveolar gas and none from the dead space.
Therefore dead space can be calculated from the partial pressure of carbon dioxide in expired air, end alveolar partial pressure of carbon dioxide and tidal volume VD/VT = (PACO2 -PECO2)/PACO2 |
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What is the alveolar gas equation and what does this measure?
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Measures the relationship between alveolar oxygen partial pressure and alveolar carbon dioxide partial pressure
pAO2 =FIO2 -(pACO2/R) R = respiratory exchange ration -ratio of CO2 production to O2 consumption |
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What are the regional differences in ventilation between the upper and lower zones of the lung?
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Lower regions of the lung ventilate more than the upper zones.
Intrapleural pressure is less negative at base than at the apex (- 2.5cm water vs -10cm water) this is due to the weight of the lung. Base of lung has small resting volume and expands well on inspiration. Apex has a large resting volume and a small change in volume on inspiration. |
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What is the pO2 of inspired vs alveolar air?
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pO2 of inspired air = 150mmHg
pO2 of alveolar air = 100mmHg (due to alveolar replenishment and removal into capillaries) |
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What are the pCO2 and pO2 at the apex and base of the lung?
What is the result of this V/Q mismatch? |
pO2 and pCO2 are determined by ratio of ventilation to blood flow.
Ventilation perfusion ratio reduces from apex to base due to regional differences in ventilation and blood flow. pO2 changes by over 40mmHg from apex to base (132 at apex, 89 at base) pCO2 changes by 14mmHg from apex to base (28 at apex, 42 at base) These difference result in alveolar-arterial oxygen difference because the best perfused region of the lung is the most poorly oxygenated therefore overall pO2 will never reach alveolar pO2. |
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What is the end-expiratory volume?
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Volume of gas present in alveoli at end of expiration
220ml |
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What is the alveolar volume?
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350ml
Alveolar volume is a small proportion of FRC therefore oxygen and carbon dioxide content of alveoli remain remarkably constant |
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What governs gas diffusion along alveolar capillary membrane?
How quickly is CO2 absorbed relative to O2 |
Fick's law
Diffusion of oxygen is generally complete by the time the red cell has passed one third along the capillary. Diffusion of carbon dioxide is 20 times faster as it is 20 times more soluble than oxygen. Uptake of oxygen also involves reaction of oxygen with haemoglobin but this is extremely rapid. |
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What is the alveolocapillary membrane composed of?
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Pulmonary epithelium
Capillary endothelium Fused basement membranes. |
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Describe flow vs diffusion limted gas uptake and give examples?
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Flow limited gas uptake: Rapid equilibrium by diffusion, therefore rate of diffusion is determined by blood flow.
Nitrous oxide reaches equilibrium in 0.1s -far less than the 0.75s it takes for blood to traverse the pulmonary capillaries. Uptake is purely limited by blood flow and is independent of diffusion properties. Diffusion limited gas uptake: Equilibrium is not achieved and is not limited by flow of blood. Carbon monoxide is taken up by haemoglobin therefore partial pressure in plasma remains low and there is no opportunity to equilibrate. Uptake of carbon dioxide is also diffusion limited. |
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What are the determinants of the diffusion capacity of the lung?
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Diffusing capacity of a gas is proportional to the surface area of the alveolocapillary membrane, a diffusion constant and the difference in partial pressure and inversely proportional to its thickness
These are the only factors important for diffusion limited gases such as carbon monoxide, therefore carbon monoxide is the gas of choice for measuring diffusing capacity |
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What is the DLCO?
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Measure of the diffusion capacity of the lung using CO2 as this is a diffusion-limited gas
DL CO = VCO/PA CO Diffusing capacity of carbon dioxide = amount of carbon dioxide entering the blood divided by the partial pressure of carbon dioxide in the alveoli DL CO = 25ml/min/mmHg |
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What decreases DLCO?
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Increased membrane thickness
Fibrosis Decreased membrane surface area Emphysema |
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What is the normal pulmonary blood pressure?
|
Pressure = 24/9, mean pressure 15mmHg.
Flow is pulsatile |
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What is the volume of blood in the pulmonary vessels?
What are the 2 ways in which blood flow bypasses gas exchange? (physiological) |
Volume of blood in pulmonary vessels is 1000ml, 100ml of which is in the capillaries. Lung is obliged to accept whole blood volume.
Entire circulation passes from left ventricle to right atrium and right ventricle with 2 exceptions: 1. Anastomoses between bronchial capillaries and pulmonary capillaries and veins therefore bypassing the right ventricle. 2. Blood flow direct from coronary arteries to chambers of the left side of the heart. |
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Smooth muscle in the wall of large--> small pulmonary blood vessels?
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Pulmonary artery 30% as thick as the wall of the aorta.
Smaller arteries have very little smooth muscle. Some post capillary vessels have some smooth muscle. Pulmonary capillary networks are large with multiple anastomoses |
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What is the pulmonary vascular resistance compared to systemic vascular resistance?
Why does this fall when blood pressure rises and rise when the lung distends? |
Pulmonary vasculature has one tenth the resistance of the systemic circulation
Resistance falls as blood pressure rises due to: Recruitment of capillaries. Distension of capillaries. Pulmonary vascular resistance is also influenced by lung volume Capillaries are resistant to stretch by increasing lung volume and hence vascular resistance rises at large lung volumes |
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Describe the perfusion of the
1. apex 2. mid-ling 3. base |
Pressure in capillaries at apex are close to atmospheric pressure in alveoli, therefore pulmonary artery pressure is only just sufficient to maintain perfusion. If perfusion pressure decreases or alveolar pressure increases, the capillaries may collapse and the affected alveoli will become part of the physiological dead space.
In the middle portions of the lungs pulmonary artery and capillary pressure exceeds alveolar pressure but pulmonary veins are collapsed. In the lower portion of the lungs, blood falls into the pulmonary veins and alveolar pressure is lower than all parts of the vasculature - waterfall effect. |
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Descrive V/Q ratio at the base and apex?
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Blood flow is also greatest at the base and the relative change from apex to base is greater than ventilation, so Ventilation/perfusion ratio is low at the base and high at the apex.
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What is the fick principle?
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Oxygen consumption per minute is equal to the amount of oxygen taken up by the lungs
Q = VO2 / (CaO2 - CvO2) Flow equals the amount of oxygen taken up by the lung divided by the arterial minus the venous partial pressure of oxygen |
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What is hypoxic pulmonary vasoconstriction and at what threshold does it become significant?
|
Contraction of smooth muscle in arteriole walls in response to alveolar hypoxia. Blood is then shunted away from the area of hypoxia.
Marked vasoconstriction occurs below 70mmHg. Hypoxia results in opening of smooth muscle potassium channels, causing a potassium efflux and depolarization of the cell to cause contraction. Very important mechanism for newborn infant |
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What are vascoconstricting hormones in the lung?
|
Circulating adrenaline and noradrenaline
Angiotensin II Vasopressin/ADH Endothelins |
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What are the vasodilating hormones in the lung?
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Kinins
Serotonin Histamine Prostaglandins Prostacyclin (and thromboxane A2) ANP |
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What happens to pulmonary blood volume when you lie/stand?
|
Pulmonary blood volume increases by 400ml when lying and this volume is discharged into the general circulation on standing.
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What are the metabolic/endocrine functions of the lung?
|
Production of surfactant
Production and release into blood -Prostaglandins -Histamine -Kallikrein Activated in the lungs (ACE is located in capillary endothelial cells) -Angiotensin I > angiotensin II Partially removed/inactivated from the blood -Prostaglandins -Bradykinin -Adenine nucleotides -Serotonin -Noradrenaline -Acetylcholine |
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What happens to particles in the lung that are:
1. > 10micrometers 2. 2-10 micrometers 3. <2 micrometers |
1. Hairs remove particles greater than 10 micrometres Remaining particles settle on mucus membranes, particularly near the tonsils and adenoids
2. Particles 2-10 micrometres fall onto the walls of the bronchi as airflow slows and are then removed by ciliary action at a rate of 16mm/min 3. Particles less than 2 micrometres reach the alveoli and are ingested by macrophages |
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What antibodies do the lungs secrete?
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IgA
Epithelia of paranasal sinuses contain NO which is bacteriostatic. |
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Describe the mechanics of inspiration?
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Active process
Most important muscle of inspiration is the diaphragm. Contraction of inspiratory muscles increases intrathoracic volume. Intrapleural pressure at base of lungs reduces from -2.5mmHg to - 6mmHg. Negative pressure causes airflow into the lungs. |
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Describe the mechanics of expiration?
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Passive process at rest.
Lung recoil pulls chest back to expiratory position. Airway pressure becomes positive and air flows out of the lungs. |
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What are the inspiratory muscles?
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Diaphragm
-Accounts for 75% of change in intrathoracic volume during quiet respiration. -Moves 1.5-7cm during respiration. External intercostal muscles -Elevate the lower ribs and increase the anteroposterior diameter of the chest. Scalene anterior, medius, posterior Sternocleidomastoid |
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What are the expiratory muscles?
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Internal intercostals
Rectus abdominis Internal oblique External oblique |
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Describe lung volume during inspiration vs expiration?
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Hysteresis: Lung volume at any given pressure during expiration is larger than in inspiration
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What is lung compliance?
|
Change in lung volume vs change in airway pressure
Stretchability of the lungs that is a function of the recoil of the lungs and recoil of the chest Slope of the pressure volume curve Compliance in humans = 200ml/cm water -this increases at higher volumes. |
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What is lung compliance in humans and what factors modify this?
|
Compliance in humans = 200ml/cm water
This increases at higher volumes. Compliance is reduced by: Fibrosis Oedema Atelectasis Compliance is increased by: Emphysema Asthma Ageing |
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What is the relaxation volume of the lungs?
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The point at which the recoil of the chest and the recoil of the lungs balance
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Define surface tension?
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The force acting across an imaginary line 1cm long in a liquid surface
Surface tension arises because attractive forces between adjacent molecules of liquid are much stronger than between liquid and gas therefore the liquid surface becomes as small as possible. Surface tension would tend to collapse alveoli if surfactant was not present due to the Law of Laplace. Surface tension is low at small lung volumes due to the production of surfactant by type 2 pneumocytes. |
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What are the roles of surfactant?
|
Roles:
1. Increased compliance and reduced work of breathing 2. Increased alveolar stability Small alveoli would normally have a tendency to collapse due to and for their volume to transfer to neighbouring alveoli - this is reduced by surfactant. 3. Surface tension tends to suck fluid into the alveolar spaces from the capillaries ␣ this is reduced by surfactant. |
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What is the composition of surfactant?
|
Dipalmitoylphosphatidylcholine 62% Phosphatidylglycine 5%
Other phospholipids 10% Neutral lipids 13% Proteins 8% Carbohydrate 2% |
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How is surface tension related to the amount of surfactant available?
|
Surface tension is inversely proportional to concentration of surfactant - as alveoli enlarge during inspiration, concentration falls and surface tension increases.
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What is the airways resistance?
|
The pressure within the mouth and the alveoli divided by the flow rate
Most airways resistance occurs in the first 7 generations. (small airways should theoretically offer more resistance but they are much more numerous) |
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|
What are the components of work of breathing?
|
Non-elastic work
Viscous resistance (moving inelastic tissues) 7% Airway resistance 28% Elastic work 65% |
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How much dissolved oxygen in 100ml of blood?
what does this depend on? |
Each 100ml contains 0.3ml of dissolved oxygen in solution. (for each mmHg of pO2 there is 0.003ml of oxygen per 100ml of blood) .
Henry's law states that the amount of oxygen dissolved in the blood is proportional to the partial pressure of oxygen. |
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Describe the binding of haemoglobin to oxygen?
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Each of the four atoms of ferrous iron can bind one oxygen molecule. Reaction is oxygenation (not oxidation) therefore the iron remains in the ferrous state. Rapid reaction takes 0.01s.
Affinity for oxygen is determined by the quaternary structure of haemoglobin -when haemoglobin binds oxygen the 2 beta chains move closer together and the haem moeties form a relaxed state which favours further oxygen uptake. Each gram of haemoglobin contains 1.34ml of oxygen or 20.1ml per 100mls of blood. At rest, a total of 250ml of oxygen per minute is delivered to the tissues. |
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What are the physiological advantages of the Hb/oxygen dissociation curve?
|
Flat upper portion means that a moderate fall in pO2 has little effect on saturation. A large partial pressure gradient is maintained along the length of the pulmonary capillary.
Steep lower portion means that tissues can extract large quantities of oxygen over a small decrease in pO2. |
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|
What is 2,3 DPG?
|
Product of glycolysis that binds to beta chains of deoxyhaemoglobin. Half life of 6 hours. Acidosis decreases concentration.
Thyroid hormones, growth hormones, androgens, anaemia and exercise increase concentration. |
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What shifts the oxygen/hb dissociation curve to the right? i.e. lets go of more oxygen
|
Decreased pH, increased temperature and increased 2,3 DPG cause a shift in the curve to the right.
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What are the axes on the O2/Hb dissociation curve?
|
horizontal: PO2
vertical: % saturation therefore if shift to right, for same PO2 less saturation |
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What is the bohr effect?
|
more acidotic--> less affinity for O2
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What is myoglobin?
How many oxygen molecules does it bind? |
Iron-containing pigment found in skeletal muscle. Resembles haemoglobin but binds one rather than four molecules of oxygen.
Rectangular hyperbolar dissociation curve rather than sigmoidal which sits to the left of the haemoglobin dissociation curve Myoglobin takes oxygen from haemoglobin in blood and releases oxygen at low pO2 in exercising muscles. |
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How much CO2 is dissolved in blood?
Is it more or less soluble then oxygen? |
Solubility of carbon dioxide is 20 times that of oxygen. 5% of carbon dioxide in arterial blood is dissolved, 10% in venous blood.
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What is the main state of CO2 in arterial blood?
What is chloride shift? |
Carbon dioxide diffusing into red cells is rapidly hydrated to H2CO3 because of the presence of carbonic anhydrase.
H2CO3 dissociates to H+ and HCO3-. H+ is buffered primarily by haemoglobin. HCO3- enters the plasma in exchange for chloride (chloride shift). 90% of carbon dioxide in arterial blood is bicarbonate |
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What are carbamino compounds?
|
Carbon dioxide in red cells reacts with the amino groups of proteins, particularly haemoglobin to from carbamino compounds. 5% of carbon dioxide in arterial blood is carbamino compounds
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What is the haldane effect and why is it useful?
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deoxygenated haemoglobin binds more hydrogen than oxyhaemoglobin (because it is less acid and therefore accepts protons) and forms carbamino compounds more readily, therefore venous blood can carry more carbon dioxide than arterial blood.
The haldane effect facilitates uptake of carbon dioxide from the tissues and its release in the lungs. |
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|
What are the three centres in the brainstem which control respiration?
|
1. Medullary respiratory centre
-Dorsal group Mainly controls inspiration. Controls intrinsic rhythmic pattern of respiration. Receive afferents from the airways and the carotid and aortic bodies. -Ventral group Mainly controls expiration. 2. Apneustic centre Lower pons Impulses have an excitatory effect on the medullary centre to prolong inspiration. Damage to this area results in prolonged inspiratory gasps and transient expiratory effort. 3. Pneumotaxic centre Dorsolateral pons Regulates inspiratory volume and rate. Damage to this area results in slow respiration with increased tidal volume. |
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What involvement does the cortex have in respiration?
What tract does this go by? What are the limits to hyper/hypoventillation? |
Voluntary control is possible within limits - able to half pCO2 by hyperventilation. Voluntary hypoventilation more closely controlled. Break point determined by pCO2 therefore prior hyperventilation can increase ability to breath hold.
Cerebral cortex sends impulses to respiratory motor neurons via the corticospinal tracts. |
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What do the medullary chemoreceptors sense and why is this efficient?
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Located separate from the dorsal and ventral respiratory neurons on the ventral surface of the medulla.
Monitor H+ concentration of CSF. CO2 readily penetrates blood brain barrier whereas H+ and HCO3- penetrate slowly. CO2 promptly hydrated to H2CO3, which dissociates to H+ and HCO3. CSF has a much lower buffering capacity and as a result change in pH for a given change in pCO2 is greater. Change in pH also occurs more quickly. |
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Where can peripheral chemoreceptors be found?
What stimulates these? |
Carotid bodies most important in humans - located at bifurcation of carotid artery. 2 or more aortic bodies in arch of aorta.
Receptors stimulated by a rise in pCO2, H+ or a fall in pO2 -they are most sensitive to pO2 and are the most important regulator in hypoxia. Sensitivity to arterial pO2 begins at 500mmHg though relatively little response occurs until below 100mmHg. Blood flow per gram of tissue is enormous - 2000ml/100g of tissue. They have a high metabolic rate but arterial and venous oxygen difference is very small. |
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What are the type 1 and type 2 cells that control respiration?
What is their function? |
Type I (glomus) cells closely associated with afferent nerves. Resemble adrenal chromaffin cells and have dense core granules containing catecholamines. Hypoxia causes opening of oxygen sensitive potassium channels that results in potassium efflux and depolarization. Depolarisation results in calcium influx which triggers action potentials.
Cells excited by hypoxia and transmit to afferent nerve via dopamine receptors. Afferent fibres ascend via glossopharyngeal and vagal nerves. Type II cells Surround type I cells, function unclear. |
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What is the ventillatory response to hypoxia?
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In normal individuals increased efferent output does not result in increased respiratory rate due to Hypoxia causes a relative decrease in hydrogen concentration of arterial blood that results in decreased stimulation of medullary chemoreceptors and inhibition of respiration. Any increase in ventilation that does occur results in reduced pCO2 and negative feedback via medullary chemoreceptors. Hypoxia results in increased sensitivity of medullary chemoreceptors.
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What is the function of pulmonary stretch receptors?
|
Located within smooth muscle of the airways. Hering-breuer reflex - increased respiratory time therefore slowing of respiratory frequency. Probably not important in humans
Pulmonary stretch receptors present in the smooth muscle of the airways respond to excessive stretching of the lung during large inspirations. Once activated, they send action potentials through large myelinated fibers of the vagus nerve to the inspiratory area in the medulla and pneumotaxic center of the pons. In response, the inspiratory area is inhibited directly and the apneustic center is inhibited from activating the inspiratory area. This inhibits inspiration, allowing expiration to occur |
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What are the irritant receptors in the lungs?
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Located between airway epithelial cells. Stimulated by noxious gas, smoke, dust, cold air. Stimulate bronchoconstriction and increased respiratory rate.
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What are the j-receptors in the lungs?
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Located in alveolar walls (juxta capillary) Stimulation results in rapid shallow breathing.
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Name 5 types of receptors in the airways?
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1. Nose and upper airway
Respond to mechanical and chemical stimulation. May result in coughing, sneezing, bronchoconstriction and laryngeal spasm. 2. Joint and muscle receptors Impulses from moving limbs may stimulate ventilation. 3. Gamma system Muscle spindles in muscles of respiration 4. Arterial baroreceptors Increase in blood pressure can cause reflex hypoventilation through stimulation of aortic and carotid sinus baroreceptors. 5. Pain and temperature |
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What are the 4 components of the respirartory response to exercise?
|
1. Increased oxygen extraction
pO2 of blood flowing into the pulmonary capillaries is reduced, thereby increasing the alveolar-capillary gradient. 2. Increased pulmonary blood flow Blood flow increases from 5.5l/min to 20-35l/min causing recruitment and distension of capillaries. Increased ventilation 3. Abrupt increase in ventilation with the onset of exercise - initially tidal volume increases, then rate (mechanisms responsible for increase in ventilation are unclear). Ventilation increases more than cardiac output 4. Increased oxygen carriage Total oxygen entering the blood increases from 250ml/min to 4000ml/min. Shift of the oxygen dissociation curve to the right pH, pCO2 and pO2 remain constant during moderate exercise, then oxygen dissociation curve is shifted to the right, aiding oxygen offload at the tissues. |
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What are the immeadiate effects of high altitude?
|
At 10,000ft, alveolar pO2 is 60mmHg.
1. Hypoxic stimulation of peripheral chemoreceptors Leads to hyperventilation and resultant respiratory alkalosis Initial response is small as the alkalosis tends to override the effect of hypoxia 2. Initial right shift of the oxygen dissociation curve Due to increased 2,3 DPG. 3. Later left shift of the oxygen dissociation curve Occurs at higher altitudes Due to respiratory alkalosis Aids oxygen loading. 4. CSF pH is returned towards normal Movement of bicarbonate out of CSF pH of blood is returned towards normal by excretion of bicarbonate by kidney. 5. Hyperventilation continues. Gradual desensitization to the effects of hypoxia. Increased erythropoetin results in increased red cell mass. Mitochondria increase in number. Maximum breathing capacity increases because the air is less dense. |
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What is acute mountain sickness?
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Develops 8-24 hours after arriving at altitude and lasts for 4-8 days.
Characterised by headache, irritability, insomnia, breathlessness, nausea and vomiting. Caused by hypoxaemia and alkalosis Pulmonary oedema may also occur if there is high physical activity - this is due to hypoxic vasoconstriction and pulmonary hypertension Symptoms reduced by acetazolamide (reduces alkalosis) and glucocorticoids (reduces oedema). Nifedipine is also effective. |
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What is chronic mountain sickness?
|
Develops in long-term resisdents Characterised by polycytemia, fatigue, reduced exercise tolerance, severe hypoxaemia
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Describe the mechanism of carbon monoxide toxicity?
|
Affinity of haemoglobin for carbon monoxide is >200 times that of oxygen therefore the oxygen carrying capacity of the blood is markedly reduced.
The oxygen dissociation curve also shifts to the left resulting in reduced ability to give up oxygen to the tissues. |
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What is absorption atelectasis?
|
A kind of oxygen toxicity.
If an airway is blocked by mucous...Breathing 100% oxygen increases arterial pO2 but causes a small rise in venous pO2. The sum of the partial pressures in mixed venous blood remains small due to the lack of dissolved nitrogen. Due to the large partial pressure difference, gas diffuses into the blood and the alveolus collapses. |
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What is Oxygen toxicity?
|
Toxicity can occur if 80-100% oxygen is administered for greater than 8 hours.
Results from the production of superoxide and hydrogen peroxide. In infants may result in bronchopulmonary dysplasia and retinopathy of prematurity. |
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What is the nephron composed of?
How many in humans? |
The nephron is composed of the renal tubule and the glomerulus.
1.3 million in humans. |
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What is the diameter of a nephron?
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200um diameter
Formed by the invagination of a tuft of capillaries by the dilated blind end of the nephron (Bowman's capsule). Capillaries supplied by an afferent and efferent arteriole. |
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What separates the blood and the filtrate in the bowman's capsule
|
1. Capillary endothelium
Fenestrated with pores 70-90nm diameter 2. Mesangial cells Between basal lamina and endothelium Functions: Contractile Secretion of substances Uptake of immune complexes 3. Basal lamina Continuous: no pores or gaps 4. Specialised epithelium Composed of podocytes with numerous pseudopodia that form filtration slits along the capillary wall Filtration slits 25nm wide and closed by thin membrane |
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What is the size of the molecules that are filtered in the nephron?
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Glomerular membrane permits free filtration of neutral substances up to 4nm.
Excludes neutral substances above 8nm. |
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How long and what is the diameter of the proximal tubule?
What makes up the wall of the proximal tubule? |
15mm long
55um diameter Wall composed of single layer of cells united by apical tight junctions. Luminal surface of cells covered in microvilli First convoluted part of proximal tubule is the pars convoluta. This drains into the straight pars recta which forms the first part of the loop of Henle |
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What is the structure of the loop of henle?
What is the difference between cortical and juxtamedullary nephrons in the loop of henle? |
Composed of thin descending limb (2-14mm long) and thick ascending limb (12mm long).
Cortical nephrons with glomeruli in the outer cortex have short loops. Juxtamedullary nephrons have long loops extending down into the medullary pyramids - 15% of nephrons in humans are like this. Cells of thick limb are cuboid with numerous mitochondria. |
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What are the three components of the juxtaglomerular apparatus?
|
1. Juxtaglomerular cells
Located in the walls of the afferent arteriole Secrete renin 2. Macula densa Modified tubular epithelium 3. Lacis cells |
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What is the structure of the distal tubule?
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5mm long
Few microvilli Tubules coalesce to form collecting ducts |
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What is the structure of collecting ducts?
|
20mm long
Pass through the renal cortex to the medulla and empty into the renal pelvis Contain p-cells and I-cells |
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What do principal cells in the collecting ducts do?
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Principal (P) cells
Tall Few organelles Sodium reabsorption ADH induced water reabsorption |
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What do I cells in the collecting ducts do?
|
Intercalated (I) cells
Also found in distal tubules. More microvilli, cytoplasmic vesicles and mitochondria Acid secretion Bicarbonate transport Collecting duct cells also secrete prostaglandins |
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How much renal blood flow is there?
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25% of cardiac output - 1.2 l/m
99% reabsorbed |
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What is the structure of renal blood vessels?
|
1. Afferent arterioles are branches of interlobular arteries
2. Each divides into multiple capillary branches to form the tuft of vessels inside the glomerulus 3. Capillaries then coalesce to form the efferent arteriole 4. Efferent arteriole forms the peritubular capillaries and vasa recta 5. Vasa recta follow the loops of Henle - Descending vasa recta have non-fenestrated epithelium -Ascending vasa recta have a fenestrated endothelium |
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What is the difference between descending and ascending vasa recta?
|
- Descending vasa recta have non-fenestrated epithelium
-Ascending vasa recta have a fenestrated endothelium |
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How do you measure renal blood flow?
|
Renal plasma flow can be measured using para aminohippuric acid. PAH is filtered and secreted into tubular fluid such that 90% is removed from blood in a single circulation.
Therefore renal plasma flow can be measured by infusing PAH and determining its urine and plasma concentrations. |
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What is the blood pressure in each type of renal vessel?
|
Glomerular capillary pressure is approximately 40% of mean arterial pressure
There is a 1-3mmHg drop across the capillary The efferent arteriole drops pressure from 38mmHg to 8mmHg Peritubular capillaries have a pressure of 8mmHg |
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What is the blood flow to the renal cortex, outer medulla and inner medulla?
|
Cortex blood flow 5ml/g/min
Outer medualla 2.5ml.g/min Inner medulla 0.6ml/g/min Cortex has a low oxygen extraction ratio compared to the medulla therefore the medulla is vulnerable to hypoxia |
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|
What are the three types of renal autoregulation that are controlled locally?
|
1. Tubuloglomerular feedback
Decreased macula densa sodium causes dilation of afferent arterioles and production of renin by the juxtaglomerular cells 2. Glomerulotubular feedback 3. Myogenic autoregulation Afferent arteriole stretch produces a direct contractile response of the arteriole to maintain constant pressure |
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3 ways in which the nervous system regulates renal blood supply/filtration
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1. Stimulation of alpha1 receptors results in renal vasoconstriction - renal blood flow is therefore decreased during exercise.
2. Stimulation of beta1 adrenoceptors on juxtaglomerular cells results in increased renin release. 3. Noradrenaline also causes increased sodium uptake by renal tubular cells |
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Name 4 renal vasoconstrictors and state where they work?
|
1. Noradrenaline
Vasoconstriction Interlobular arteries and afferent arterioles 2. Angiotensin II Vasoconstriction Efferent arterioles greater than afferent arterioles 3. Endothelin |
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|
Name four renal vasodilators and state how they work?
|
1. Dopamine
Vasodilation and natriuresis. 2. Prostaglandins Vasodilation within cortex Vasoconstriction within medulla 3.NO 4. Bradykinin |
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|
What % of plasma flow is GFR?
|
GFR represents 20% of renal plasma flow
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How is GFR measured?
|
GFR can be measured using a substance that is freely filtered through the glomeruli and neither secreted or reabsorbed. Clearance of the substance equals urinary flow, multiplied by the concentration of the substance in the urine and divided by the plasma concentration of the substance.
Clearance=(urine flow X urine concentration)/plasma concentration Inulin is commonly used. Other important properties include: Not metabolized Not stored Not toxic Easy to measure. Creatinine clearance can be used but can be inaccurate as creatinine is secreted and reabsorbed. Normal value 125ml/min 180l/day |
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What causes mesangial cells to contract?
What effect does this have? |
Mesangial cells have a contractile function and can regulate capillary blood flow
Contraction caused by: Endothelins Angiotensin II Vasopressin Noradrenaline PAF PDGF Thromboxane A2 PGF2 Leukotrienes C and D Histamine Relaxation caused by: ANP Dopamine PGE2 cAMP |
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Are glomerular capillaries more permeable to anions or cations?
|
Proteins in the capillary wall are negatively charged therefore anionic substances are filtered poorly and cationic substances better than neutral substances.
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Why is glomerular pressure higher than other capillary beds?
|
Glomerular pressure is higher than other capillary beds due to short afferent capillaries and high efferent arteriolar pressure.
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What % of sodium is reabsorbed?
|
99.4% reabsorbed
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What are the sodium transporters in the proximal tubule?
|
Sodium/glucose co-transporter
Sodium/phosphate co-transporter Sodium/amino acid co-transporter Sodium/lactate co-transporter Sodium/hydrogen exchanger |
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|
What is the sodium transporter in the thick ascending limb?
|
Sodium/potassium/2 chloride cotransporter (note that due to the action of the sodium/potassium/chloride cotransporter and sodium potassium ATPase, there is accumulation of potassium in the cell.
Potassium diffuses out of the cell down its concentration gradient in exchange for magnesium or calcium) Sodium/hydrogen exchanger |
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What is the sodium transporter in the distal tubule?
|
Sodium/chloride co-transporter
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What is the sodium transporter in the collecting duct?
|
Sodium channel (sodium exchanged for potassium or hydrogen)
Sodium is the most abundant cation in the ECF and accounts for over 90% of the osmotically active solute in the plasma and interstitial fluid It is therefore important to be able to closely control sodium excretion. |
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How does tubuloglomerular feedback work?
|
Macula densa cells in the ascending limb and DCT control GFR ␣ as flow in the DCT rises, GFR falls.
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|
How does glomerulotubular balance work?
|
Increase in GFR results in increased solute reabsorption, especially sodium.
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|
How does aldosterone work?
|
Aldosterone causes increased CD reabsorption of sodium in association with secretion of potassium and hydrogen. Act on P cells in CD on CD that contain epithelial sodium channels.
Also increases the number of sodium/potassium ATPase molecules in the basal membrane. Small action in bladder. |
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How does ANP work?
|
Causes increased P cell cGMP which inhibits sodium uptake from lumen
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How does angiotensin II work?
|
Increases reabsorption of sodium and bicarbonate by an action on the PCT.
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How does PGE2 work in the kidney?
|
Increases P cell intracellular calcium that inhibits sodium uptake from lumen. Endothelin and IL1 cause increased PGE2
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How is sodium secretion related to acid secretion in the kidney?
|
Sodium excretion is increased by drugs that decrease renal acid secretion via inhibition of carbonic anhydrase
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|
How is glucose handled by the kidney?
|
Re-absorbed with sodium in PCT by secondary active transport Glucose and sodium bind to SGLT 2 in the luminal membrane Glucose is carried into the cell as sodium moves down its electrical and concentration gradient
Glucose then combines with GLUT 2 to be transported into the interstitial fluid Transport mechanism becomes saturated above 200mg/dl (10mmol/dl). This represents the transport maximum. This is below the predicted amount due to splay Splay describes deviation from the ideal curve and occurs as individual cells have slightly different saturatable levels |
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How is water handled in the proximal tubule?
|
Water moves passively out of the tubule along osmotic gradients set up by active transport of solutes Movement is facilitated by the presence of water channels in the apical membranes
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How is water processed in the loop of henle?
|
Descending limb of the loop is permeable to water but the ascending limb is impermeable.
Sodium, potassium and chloride are co-transported out of the ascending limb therefore the fluid in the descending limb becomes progressively hypertonic as water moves into the hypertonic interstitium. In the ascending limb tubular fluid becomes more dilute until it is hypotonic to plasma due to movement of sodium, potassium and chloride out of the lumen. |
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|
How is water processed in the distal tubule?
|
The distal tubule is effectively a continuation of the ascending loop and is relatively impermeable to water.
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How is water processed in the collecting duct?
|
Permeability to water depends on the action of ADH. ADH causes rapid insertion of aquaporin-2 water channels into the luminal membrane of principal cells.
Urine osmalarity may reach 1400mosm/l (5 times that of plasma) with 99.7% of water reabsorbed. In the absence of ADH the CD is relatively impermeable to water and osmalarity may reach 30mosm/l. About 2% of water is reabsorbed if no ADH is present. |
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|
What is the countercurrent mechanism?
|
A countercurrent mechanism is one in which the inflow runs parallel to the outflow for some or all of it's lenth
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How does the countercurrent mechanism work in the kidney?
|
The countercurrent mechanism depends on the maintenance of a gradient of increasing osmolality along the medullary pyramids by the Loop of Henle (countercurrent multipliers) and the vasa recta (countercurrent exchangers)
The operation of each loop as a countercurrent multiplier depends on the ability of the thick ascending limb to actively transport sodium, potassium and chloride and the ability of the thin descending limb to passively transmit water. The vasa recta maintain osmotic gradient in the medullary pyramids because solutes (sodium, chloride and urea) diffuse out of the vessels conducting blood towards the cortex and into vessels conducting blood towards the medulla. Conversely, water diffuses out of the descending vessels into the ascending vessels. The blood supply to the medulla is very poor, therefore limiting washout of solutes |
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|
How does urea work in the kidney?
|
Urea contributes 25% to the establishment of the osmotic gradient in the medullary pyramids and to the ability to form concentrated urine in the CD.
Urea passively moves out of the PCT but the rest of the tubular epithelium is relatively impermeable. Therefore urea becomes progressively concentrated until in the inner medullary portion of the CD urea moves into the interstitium facilitated by ADH, adding to hyperosmolarity |
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How is potassium handled in the proximal tubule?
|
65% of filtered potassium is actively reabsorbed in the PCT
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|
How is potassium handled in the loop of henle?
|
25% is reabsorbed in the thick ascending limb of the loop of Henle
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How is potassium handled in the DCT/CD?
|
Potassium secretion is mostly passive through potassium channels in P cells of the DCT and CD. Although this diffusion is passive, the intracellular concentration gradient is generated by sodium/potassium ATPase.
There is also some active secretion by I cells of the collecting duct Potassium competes with hydrogen for secretion and potassium secretion is reduced when hydrogen secretion increases. Similarly, when total body potassium is high, hydrogen secretion is inhibited. Potassium secretion is also decreased when there is reduced sodium in the tubular fluid. |
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Where does most regulation of potassium excretion occur?
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Most regulation of potassium secretion occurs in the DCT
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What four factors regulate potassium excretion?
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1. Extracellular potassium concentration
Increased extracellular potassium stimulates the sodium/potassium ATPase to increase tubular epithelial cell intracellular potassium 2. Hyperkalaemia causes aldosterone release: Aldosterone Increases secretion of potassium and increases the number of sodium/potassium ATPase molecules 3. Distal tubular flow: The greater the flow through the distal tubule the less the concentration gradient driving transport from the epithelial cell to the tubular fluid 4. Blood pH Acidosis results in competition for potassium with hydrogen ions |
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At what volume does the first urge to void occur? At what volume do you really need to go?
|
First urge to void occurs at 150ml.
Marked fullness at 400ml. |
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Describe the physiology of bladder emptying?
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Spinal reflex facilitated and inhibited by higher centers. Urine enters the bladder without producing much increase in intravesical pressure.
During micturition the detrusor contracts and the perineal muscles and external urethral sphincter contracts. Stretch receptors in the bladder wall initiate reflex contraction via pelvic nerve (S2,3,4) afferents. Reflex is integrated in the sacral portion of the spinal cord. Voiding mediated via efferent parasympathetic fibres. |
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What is the normal range for body osmolarity?
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Total body osmolality is proportional to total body sodium and potassium and inversely proportional to total body water.
Normal range 280-295mosm/l |
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What are the factors that control/protect total body tonicity?
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ADH and thirst.
When the osmotic pressure of the plasma rises, osmoreceptors in the anterior pituitary stimulate the posterior pituitary to release ADH ADH also released in response to decreased circulating volume |
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What are the factors that maintain blood volume?
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Volume of the ECF is determined by total amount of osmotically active solute. Sodium and chloride are the most abundant solutes. Changes in chloride occur secondary to changes in sodium therefore sodium balance is the major influence on ECF volume.
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What are the factors that maintain blood volume?
for each of the 5 factors describe how it works |
1. Low pressure receptors
Reduced stretch of low pressure receptors causes afferent arteriolar vasoconstriction 2. Pressure natriuresis Reduced blood pressure results in reduced GFR therefore less sodium is filtered. 3. ADH and thirst. ADH (vasopressin)- volume control Simple volume control also occurs via ADH and volume stimuli override osmotic stimuli. 4. Angiotensin II Stimulates thirst Stimulates ADH secretion. Causes vasoconstriction Stimulates aldosterone secretion Increases tubular reabsorption of sodium. 5. ANP Causes natriuresis and diuresis |
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How and where is renin synthesised and what is it's half-life?
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Protease enzyme synthesized from preprorenin and prorenin. Prorenin also produced by ovaries but there is very little conversion of prorenin to renin in the circulation.
Renin made by juxtaglomerular cells located in the media of afferent arterioles as they enter the glomerulus. Half life 80 minutes. |
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How does renin act?
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acts on angiotensinogen to form angiotensin I.
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What are 5 factors which control renin secretion?
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1. Angiotensin II feedback Afferent arteriolar pressure decrease results in increased renin secretion.
2. Sodium reabsorption across the macula densa - decreased absorption causes increased renin secretion. 3. Stimulation of beta 1 adrenoceptors by circulating catecholamines result in increased renin release. 4. Increased sympathetic activity via renal nerves. 5. Prostaglandins (especially prostacyclin) stimulate renin secretion. |
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Where is angiotensinogen synthesised and what increases circulating levels?
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Synthesised in the liver. Circulating level is increased by glucocorticoids, thyroid hormones, oestrogens, cytokines and angiotensin II.
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Where is angiotensin I synthesized and what is it's half-life?
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Angiotensin I is the precursor of angiotensin II and has no function.
Rapidly metabolized by red cells and other tissues and also trapped in vascular beds. Angiotensin III has 40% pressor activity but 100% of the aldosterone-stimulating activity. Half life 1-2 minutes. |
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What are the 8 actions of angiotensin II
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1. Vasoconstriction
Acts directly on vascular smooth muscle to produce arteriolar constriction, raising systolic and diastolic blood pressure. 8 times more potent than noradrenaline. 2. Secretion of aldosterone Acts on the adrenal cortex to cause increased secretion of aldosterone. 3. Release of noradrenaline Direct action on post-ganglionic neurons to cause release of noradrenaline. 4. Contraction of mesangial cells Resulting in decreased GFR 5. Increased sodium reabsorption Direct action on renal tubules 6. Decreases the sensitivity of the baroreflex 7. Increases secretion of ADH 8. Causes thirst. |
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What is ACE and where is it found?
|
Carboxypeptidase that acts on angiotensin I to form angiotensin II and inactivates bradykinin.
Located on endothelial cells - most conversion occurs in the lung but can occur elsewhere |
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Where is erythropoetin produced?
|
85% produced by interstitial cells in the peritubular capillary bed of the kidneys.
15% produced by perivenous hepatocytes in liver. Hepatic production is not sufficient to compensate and anaemia will develop in renal production ceases. |
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Where and how quickly is EPO inactivated?
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Half life 5 hours.
Principally inactivated by liver. |
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How does EPO act?
|
Increases the number of committed stem cells in the bone marrow that are converted to erythrocytes. Without the presence of erythropoetin stem cells undergo apoptosis.
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How does hypoxia stimulate red blood cell production?
|
Hypoxia stimulates erythropoetin secretion.
Facilitated by beta-adrenergic stimulation. |
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Where is vitamin D3 produced?
How is it transported in the plasma? What 2 changes does it undergo to make calcitriol? |
Vitamin D3 (cholecalciferol) is produced in the skin by the action of sunlight on 7 dehydrocholesterol. Small amount absorbed from the gut.
Vitamin D3 is transported in plasma bound to vitamin D binding protein. In the liver, vitamin D3 is converted to 25-hydroxycalciferol (calcidiol). In the cells of the proximal tubules of the kidney, 25- hydroxycalciferol is converted to 1,25-dihydroxycholecalciferol (calcitriol). 24,25-dihydroxycholecalciferol is also formed. |
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What are the kinins?
What are they made from? |
Bradykinin and lysylbradykinin.
Derived from HMW kininogen and LMW kininogen respectively by the action of plasma kallikrein and tissue kallikrein. Kallikrein is activated by factor XII and catalysed by plasmin. Bradykinin and lysylbradykinin are metabolized to active fragments by kininase I. Inactivated by kininase II (ACE). Primarily limited to tissues although also found in circulating blood. Act via bradykinin receptors. |
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Where is tissue kallikrein found?
|
Tissue kallikrein is found in many tissues including glandular tissue, pancreas, prostate, intestine and kidney.
|
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What does bradykinin do?
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Contraction of visceral smooth muscle.
Relaxation of vascular smooth muscle Increased capillary permeability Attract leucocytes |
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What is the structure of cardiac muscle?
|
Characterized by intercalated discs and gap junctions. Intercalated discs have very low resistance and thus cardiac muscle is termed a syncytium.
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What is the magnitude and duration of the cardiac action potential?
|
-90mV to +20mV
200ms duration |
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What are the 5 phases of the cardiac muscle depolarisation/repol cycle?
|
0. Depolarisation
Opening of voltage gated sodium channels resulting in rapid sodium influx 1. Initial rapid repolarisation Closure of voltage gated sodium channels 2. Plateau Slow, prolonged opening of voltage gated calcium channels resulting in calcium influx Sodium also flows through these channels There is reduced permeability to potassium during this phase 3. Late rapid repolarisation Closure of voltage gated calcium channels Potassium efflux through various potassium channels (inward rectifying, delayed rectifying and transient outward potassium channels) 4. Baseline |
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Where is the sinoatrial node located?
Why is it an important cardiac pacemaker? |
Located at junction of SVC and right atrium.
Discharges most rapidly therefore is the cardiac pacemaker. Contains pacemaker cells. |
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What causes the action potential at the sinoatrial node?
Why is there no rapid depolarisation spike? What is the conduction rate? |
AP largely due to calcium influx - little sodium influx therefore no rapid depolarisation spike.
Conduction rate 0.05m/s |
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What are the three internodal atrial pathways?
|
3 bundles of fibres connect to the AVN and bundle of His...
1. anterior internodal tract of Bachman 2. middle internodal tract of Wenckbach 3. posterior internodal tract of Thorel. |
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What is the conduction rate of the internodal atrial pathways?
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Conduction rate 1m/s
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Where is the AV node located? Why is it the only conduction pathway?
What is the action potential like at the AV node? What is the AV nodal delay? |
Located in the right posterior portion of interatrial septum. Only conducting pathway between atria and ventricles. Fibrous muscle ring separates atria and ventricles.
AP largely due to calcium influx - little sodium influx therefore no rapid depolarisation spike. AV nodal delay 0.1ms Conduction rate 0.05m/s |
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What are the 2 branches of the bundle of His?
What is the conduction rate here? |
LBB (divides into anterior fascicle and posterior fascicle)
RBB Conduction rate 1m/s |
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What is the conduction rate of the bundle of His?
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Fibres supply all parts of ventricular myocardium. Conduction rate 4m/s
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What is the resting membrane potential in the bundle of His?
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Resting membrane potential -60mV
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How do pacemaker potentials work?
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1. Reduction in potassium efflux following the previous impulse initiates depolarisation.
2. Transient calcium channels open to produce the prepotential. 3. Long-lasting calcium channels open to produce the AP. 4. Repolarisation caused by opening of potassium channels and potassium efflux from the pacemaker cell. |
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What is the mechanism of sinus arrhythmia?
|
During inspiration, impulses in vagi from stretch receptors in lungs inhibit the cardioinhibitory area in the medulla oblongata.
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What happens when conduction rate is blocked at the AV node?
|
AV node and any other portion of heart can become a pacemaker.
If conduction is blocked at the AV node an idioventricular rate of 45bpm will develop. |
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What is a physical way of terminating artia arrhythmias?
|
Oculocardiac reflex or carotid sinus massage causes vagal discharge.
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Describe atrial fibrillation and atrial flutter?
|
1. Atrial flutter - ectopic focus causes atrial rate of 200-350bpm. Almost always associated with 2;1 or greater block.
2. Atrial fibrillation -multiple reentry rhythms cause atrial rate of 300- 500bpm. Beats in irregular and disorganised fashion. |
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What are the three major changes in cell function that ccur with a myocardial infarction?
|
1 Abnormally rapid repolarisation - due to accelerated opening of potassium channels -occurs almost immediately, lasts a few minutes
2 Decline in resting membrane potential - due to loss of intracellular potassium - starts after a few minutes 3 Slow repolarisation of fibres |
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What are the 5 phases of the cardiac cycle?
|
Phase 1
Atrial systole Additional blood propelled into ventricles (70% of ventricular filling is passive). Phase 2 Isovolumetric contraction of ventricles -lasts about 0.05s - until pressures exceed aortic/pulmonary artery pressures and the aortic and pulmonary valves open. AV valves bulge, causing rise in atrial pressure. Phase 3 Ventricular ejection - rapid initially then slows. Peak left ventricular pressure 120mmHg. Peak right ventricular pressure 25mmHg. 70-90ml ejected (end diastolic ventricular volume 130ml - therefore 50ml left) ejection fraction 65% Early diastole Ventricular pressure drop rapidly - protodiastole lasts 0.04s. Eventually momentum of propelled blood overcome and aortic and pulmonary valves close. Phase 4 Isometric relaxation. Isometric relaxation ends when ventricular pressure falls below atrial pressure and the AV valves open permitting the ventricles to fill. Phase 5 Late diastole Ventricular filling. Blood passively fills atria and ventricles. Filling is rapid initially. Rate of filling declines as chambers fill and cusps of AV valves drift closed. |
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What side does ... begin on
a. atrial systole b. ventricular ejection c. aortic or pulm valve closes |
Right atrial systole before left. Left ventricular systole before right.
Right ventricular ejection begins before right. Left (aortic valve) closes before right in inspiration. |
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How do systole and diastole vary with rate?
|
Duration of diastole variable in relation to heart rate (much more so than systole)
Rate 65 - systole=0.3s, diastole=0.62s Rate 200 - systole=0.16s, diastole=0.14s |
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Why is the length of diastole important?
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1 Most ventricular filling occurs in diastole -therefore filling may be compromised at high rates.
2. Coronary blood flow to subendocardial left ventricle - only occurs in diastole. |
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Describe the a-wave during the JVP and describe this in pathological states?
|
Atrial pressure rises during atrial systole (a wave - cannon wave if AV valve is closed due to complete heart block)
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Describe the c-wave during the JVP and describe this in pathological states?
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Atrial pressure continues to rise during isovolumetric ventricular contraction when the AV valves bulge into the atria. (c wave - giant in tricuspid insufficiency)
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What does contraction of the ventricles do to the jvp?
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Contraction of the ventricles pulls down on the AV valves causing falling pressure. (significant effect on atrial filling - effectively sucks blood into the atria)
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Describe the v-wave during the JVP?
|
Pressure rises again during early diastole as the AV valves open. (v wave)
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What causes the 1st and 2nd heart sounds?
|
First: Vibration of closure of AV valves at start of systole
Second: Vibration of closure of aortic and pulmonary valves at end of systole |
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What causes the third and fourth (pathological) heart sounds?
|
Third: Rapid ventricular filling - heard 1/3 through diastole
Fourth: pathological Immediately before first- due to ventricular filling when atrial pressure is high. |
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What determines cardiac output?
|
Cardiac output is a function of stroke volume and rate. Stroke volume is a function of preload and afterload
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What is the cardiac output at a stroke volume 70ml and a rate of 72
What is the cardiac index? |
Stroke volume = 70ml
70ml X 72bpm=5L/m=cardiac output. Cardiac index=cardiac output per square metre of body surface area=3.2L |
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What are the 5 methods of measuring cardiac output?
|
1 Electromagnetic flow meter placed on ascending aorta. Experimental animals only.
2 Fick method: Fick principle 'The amount of substance taken up by an organ/whole body per unit time is equal by the arterial level-the venous level x the blood flow" Therefore if the amount of oxygen taken up by the body is known and the amount of oxygen in the aorta and pulmonary artery is known, the blood flow can be derived. 3 Indicator dilution technique: Known amount of substance injected then measured at regular intervals from artery. Output is equal to the amount of substance injected divided by average concentration. 4 Thermodilution Cold saline of known temperature injected into right atrium, temperature measured in pulmonary artery. Temperature difference is proportional to output. 5 Dopplar echocardiography |
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What is the starling principle?
|
'the energy of contraction is proportional to the initial length of the cardiac muscle fibre'
As muscle is stretched, the developing tension increases to a maximum and then declines as stretch becomes more extreme. The length of muscle fibres (ie the extent of preload) is proportional to the end-diastolic volume. |
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What is the frank-starling curve?
What happens to the curve if contractility is increased or decreased? |
Relationship between stroke volume and end-diastolic volume is the Frank-starling curve.
The curve shifts downward and to the right as contractility is decreased and shifts to the left if contractility is increased. If maximum contractility is exceeded, the curve forms a descending limb |
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What increases cardiac contractility?
|
Circulating catecholamines
Digitalis and other inotropes Sympathetic/parasympathetic regulation |
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What decreases cardiac contractility?
|
Pharmacological depressants
Hypoxia Hypercapnia Acidosis Loss of myocardium Sympathetic/parasympathetic regulation |
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What is heterometric and homometric regulation?
|
Heterometric regulation: Regulation of cardiac output as a result of changes in muscle fibre length.
Homometric regulation: Regulation of cardiac output as a result of changes in contractility. |
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What is preload?
|
The degree the myocardium is stretched before it contracts i.e. EDV
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What increases preload?
|
Stronger atrial contractions
Increased blood volume Increased venous tone Increased muscular pumping of venous blood Increased negative intrathoracic pressure |
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What decreases preload?
|
Standing
Increased pericardial pressure Decreased ventricular compliance- infarction, infiltration |
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What is afterload?
|
The resistance against which blood is expelled
= total peripheral resistance |
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What is the equation for flow?
|
Flow=pressure/resistance
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Describe laminar flow in a vessel?
|
Parabolic distribution of velocity - infinitely thin layer next to vessel wall does not move, greatest velocity in centre of the stream.
This applies up to a critical velocity, above which flow is turbulent. |
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What increases the turbulence of flow in a vessel?
What law governs this? |
Reynolds number=probability of turbulence
p=density D=diameter V=velocity n=viscosity Re=pDV/n |
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What factors influence the viscosity of blood?
How much more viscous is blood and plasma than water? |
Plasma is 1.8 times more viscous than water, whole blood is 3-4 times more viscous. Viscosity depends on the haematocrit (percentage of blood volume occupied by red cells).
The clinical effect of viscosity differs from that derived from the Poiseuille- Hagen formula below. In large vessels, haematocrit increases viscosity. In arterioles, capillaries and venules the effect is less due to the nature of flow in these vessels. |
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What is the formula for the velocity of blood in vessels?
|
Important to differentiate between velocity (displacement per unit time) and flow (volume per unit time)
Velocity V=Flow (Q) / cross sectional area (A) |
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What is the critical closing pressure of a vessel?
|
Critical closing pressure -the pressure within a vessel lumen at which blood flow ceases.
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What is the Poiseuille-Hagen Formula?
|
Poiseuille-Hagen Formula R=8nL/pye r4
R=resistance r=radius "Flow varies directly and resistance inversely with the fourth power of the radius" |
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|
What is the law of Laplace?
|
␣the tension on the wall of a cylinder or sphere (T) is equal to the product of the transmural pressure (P) and the radius (r ) divided by the wall thickness (W)
T=Pr/W OR P=T/r (for spherical structure this is 2T/r) W can be ignored in thin walled structures. (transmural pressure = pressure inside minus pressure outside ␣ since tissue pressure inside the body is negligible, p = pressure inside the viscus.) The smaller the diameter of the vessel, the smaller the tension on the wall necessary to balance the distending pressure. Similarly in the heart a dilated ventricle must generate greater tension to produce a given pressure therefore the work of the heart is greater. |
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What is the difference between arterial flow and aortic flow?
|
Aorta flow is phasic, ranging from 120m/s in systole to negative value in diastole. (average is 40m/s)
Arterial flow becomes progressively continuous due to elastic recoil of the vessel walls (Windkessel Effect) though pulsatile flow is necessary for optimal organ function. |
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How to calculate the pulse pressure and the mean arterial pressure?
|
Pulse pressure - difference between systolic and diastolic pressure
Mean pressure (approximation)- diastolic pressure plus one third of the pulse pressure. |
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|
What is the effect of gravity on blood pressure?
|
Effect of gravity=0.77mmHg/cm from heart.
(if heart=100, head=60, feet=180) |
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What are the main sites of peripheral resistance?
|
small arteries and arterioles
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What % of blood is in capillaries at any one time?
|
5%
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Describe the starling forces that act on capillaries?
|
Rate of filtration at any point along a capillary depends on hydrostatic pressure gradient and osmotic pressure gradient. Net flow varies between capillary beds.
Capillary hydrostatic pressure 30mmHg at arterial end, 10mmHg at venous end Plasma colloid osmotic pressure 28mmHg Interstitial fluid pressure -3mmHg Interstitial fluid colloid osmotic pressure 8mmHg Net outward force at arterial end = (30+3+8)-28=13 Net inward force at venous end = 28-(10+3+8)=7 Pulse pressure 5mmHg arterial end, zero at venous end. Transit time 1-2 seconds. |
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What is the normal range in venous pressure?
|
A large amount of blood can be added to veins before there is a significant rise in venous pressure
Aided by contraction of muscles, negative intrathoracic pressure during inspiration. Venular pressure 12-18mmHg, 5mmHg in great veins of thorax. Flow velocity - 10m/s |
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What is normal right atrial pressure?
|
Normal right atrial pressure is 0mmHg but can vary between -5 and 30mmHg
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|
What regulates venous return to the heart?
|
Right atrial pressure
Mean systemic filling pressure (pressure forcing venous blood towards the heart) Resistance to blood flow in the peripheral vessels |
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|
What is blood flow autoregulation?
|
Describes the ability of tissues to regulate their own blood supply
Most vascular beds have the intrinsic capacity to compensate for moderate changes in perfusion pressure by changes in vascular resistance so that blood flow remains relatively constant. |
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|
What are the myogenic and metabolic theories of autoregulation?
|
Myogenic theory of autoregulation - intrinsic response of smooth muscle to stretch.
Heart, circulation and cardiovascular homeostasis Metabolic theory of autoregulation - vasodilator substances accumulate in active tissues. |
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|
What are the local factors that contribute to blood vessel autoregulation?
|
Chemical factors:
Adenosine- Released in response to hypoxia Carbon dioxide Potassium Lactate Histamine Substances released by endothelium Nitric oxide |
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|
Describe nitric oxide
-what stimulates its production -role as vasodilator |
-Derived from arginine, activates guanylyl cyclase to produce cGMP which mediates smooth muscle relaxation.
Release stimulation by -Arterial wall sheer stress -Bradykinin -ATP -Parasympathetic nerves Causes dilation of upstream vessels in response to local vasodilation Half life 6 seconds |
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|
How do adrenaline and noradrenaline at as vasoconstrictors?
|
Produced by adrenal medulla
Both increase the force and rate of cardiac contraction Noradrenaline produces vasoconstriction in most if not all organs via alpha1 receptors Adrenaline dilates blood vessels in skeletal muscle and liver via beta2 receptors. |
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|
What is the action of angiotensin II as a vasoconstrictor?
|
Angiotensin II has a generalised vasoconstrictor action. Increases aldosterone secretion and therefore increases the reabsorption of sodium and water.
|
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|
What 6 factors influence renin secretion in the kidney?
|
1. Angiotensin II feedback
2. Afferent arteriolar pressure decrease results in increased renin secretion. 3. Sodium reabsorption across the macula densa decreased absorption causes increased renin secretion. 4. Stimulation of beta 1 adrenoceptors by circulating catecholamines result in increased renin release. 5. Increased sympathetic activity via renal nerves. 6. Prostaglandins (especially prostacyclin) stimulate renin secretion. |
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|
What are the 6 systems affected by endothelins?
|
Act in a paracrine fashion and bind to specific receptors. Released in response to endothelial injury
1. Haemodynamic actions Contracts vascular smooth muscle - initial depressor response followed by sustained pressor response. 2. Cardiac effects Positive inotropic and chronotropic effects. Vasoconstriction of coronary arteries. 3. Neuroendocrine effects Increase levels of ANP, renin, aldosterone, catecholamines. Modulates synaptic transmission. 4. Renal effects Increase renal vascular resistance Decreases glomerular blood flow. Increase sodium reabsorption through haemodynamic actions, decrease sodium absorption by inhibiting sodium potassium ATPase. 5. Respiratory effects Produces bronchoconstriction 6. GIT effects Enhances gluconeogenesis Regulates gastrointestinal blood flow |
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|
Describe the creation and breakdown of bradykinins?
|
Bradykinin and lysylbradykinin. Derived from HMW kininogen and LMW kininogen respectively by the action of plasma kallikrein and tissue kallikrein. Tissue kallekrein is found in many tissues including glandular tissue, pancreas, prostate, intestine and kidney. Kallikrein is activated by factor XII and catalysed by plasmin.
Bradykinin and lysylbradykinin are metabolized to active fragments by kininase I. Inactivated by kininase II (ACE). Primarily limited to tissues although also found in circulating blood. Act via bradykinin receptors. |
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|
What actions do bradykinins have?
|
Contraction of visceral smooth muscle.
Relaxation of vascular smooth muscle Increased capillary permeability Attract leucocytes |
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|
What is the action of ANP?
|
Secreted by the heart in response to atrial stretch. Antagonises the action of other vasoconstrictors and lowers blood pressure by causing sodium loss.
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|
What are the 3 areas in which baroreceptors are found?
|
Carotid sinus (just above bifurcation of common carotid)
Aortic arch Stretch receptors in walls of heart and blood vessels. |
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|
What is the signalling pathway of baroreceptors?
|
Stimulated by distension of the structure causing increased rate of discharge. Afferents pass via glossopharyngeal and vagus nerves to the medulla.
Afferents end on the nucleus of the tractus solitarius resulting in glutamate transmission. Project to the RVLM and stimulates GABA inhibitory neurons. |
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|
Where are low pressure receptors found
|
atria and pulmonary artery
|
|
|
What does stimulation of low pressure receptors do?
|
Effective in control of sudden volume change
Stretch causes: Reflex dilatation of afferent arterioles in the kidney Decreased vasopressin/ADH secretion by the hypothalamus Release of ANP Tachycardia (direct effect) Tachycardia (Bainbridge reflex) |
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|
Do chemoreceptors have a role in BP control?
|
Play a secondary role in BP control - more active in respiratory control
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|
Where are the cell bodies for the PNS and SNS vasomotor neurons in the medulla?
What is the path that sympathetic and parasympethetic neurons take? |
Neurons project directly to sympathetic preganglionic neurons in the intermediolateral gray column of the spinal cord.
Cell bodies are in the rostral vento lateral medulla (RVLM) Vagal neurons arise from the dorsal motor nucleus of the vagus and the nucleus ambiguous. |
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|
What factors directly stimulate the vasomotor centre in the medulla?
What are indirect excitatory and inhibitory inputs? |
1. Direct stimulation:
Carbon dioxide Hypoxia 2. Excitatory inputs From cortex via hypothalamus From pain pathways and muscles From carotid and aortic chemoreceptors 3. Inhibitory inputs From cortex via hypothalamus From lungs From carotid and aortic baroceptors |
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|
Do vasoconstrictor fibres have tonic activity?
|
Vasoconstrictor fibres have some tonic activity - sympathectomy therefore causes vasodilation.
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|
What are the 2 major ANS outputs to the heart?
What happens when you block cholineric output? |
eart, circulation and cardiovascular homeostasis
Noradrenergic sympathetic nerves: Inotropic and chronotropic action. Cholinergic vagal nerve: Negative inotropic and chronotropic action Cholinergic fibres have tonic activity (vagal tone) - division of the vagus causes tachycardia |
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|
Describe the valsalva response?
|
1. Blood pressure rises at the onset of strain due to increase intrathoracic pressure adding to the aortic pressure.
2. Increased intrathoracic pressure causes reduced venous return and cardiac output. 3. This causes tachycardia and increased peripheral vascular resistance. 4. At cessation, intrathoracic pressure returns to normal but peripheral vessels are constricted, causing hypertension, This stimulates baroreceptors and blood pressure is returned to normal by vasodilation and bradycardia. |
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|
Describe the anatomy of the circle of willis?
Is there much anastomotic flow from one carotid to another? |
2 internal carotids, 2 vertebral arteries. Vertebral arteries unite to form the basilar artery.
Basilar artery and internal carotid arteries unite to form the circle of Willis below the hypothalamus. Very little anastomotic flow from one carotid to the other. |
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|
Describe what makes cerebral capillaries different from other vessels?
|
Capillaries are fenestrated but there are tight junctions between endothelial cells that limit passage of substances through the junctions.
Brain capillaries are surrounded by end feet of astrocytes that are applied to the basal lamina of the capillary but do not cover the entire wall. |
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|
What is the average cerebral blood flow and what % of cardiac output is this?
|
Average cerebral blood flow = 54ml/100g/min = 756ml/min=13%
Blood flow varies between different parts of the brain and flow increase when a particular area of the brain is utilised. |
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|
What is the Kety method?
|
Kety method - utilises the Fick principle to measure difference in concentration of nitrous oxide between arterial and venous blood.
|
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|
What is cerebral vascular resistance?
|
cerebral perfusion pressure/cerebral blood flow
|
|
|
What local and systemic factors control cerebral autoregulation?
|
Prominent in the brain and maintains a normal cerebral blood flow at arterial pressures between 65 and 140mmHg.
Local factors: Oxygen, hydrogen and carbon dioxide are particularly important Nervous system control: Strong sympathetic innervation but questionable effect as local factors seem much more important |
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|
What is the monroe-kelly doctorine?
How does this lead to the cushing reflex? |
volume of blood, csf and brain within the cranium must remain constant
When intracranial pressure rises, cerebral blood flow is reduced and resultant ischaemia causes a rise in systemic BP. There is also vagal stimulation to cause bradycardia - Cushing reflex |
|
|
How does CNS ischaemia lead to hypertension?
|
Hypotension below 60mmHg stimulates intense sympathetic vasoconstriction
|
|
|
What forms the blood-brain barrier?
|
Tight junctions between capillary endothelial cells and choroid plexus epithelial cells act as a barrier.
|
|
|
What penetrates the blood brain barrier easily?
|
Water, carbon dioxide, oxygen and lipid soluble substances penetrate with ease.
Free hydrogen and bicarbonate penetrate poorly. |
|
|
How does glucose penetrate the BBB?
|
Slow passive penetration. Active transport by glucose transporter GLUT1
|
|
|
What is the potassium level in the BBB?
|
Cotransporter that keeps brain potassium low.
|
|
|
How do Choline, nucleic acid precursors, amino acids penetrate the BBB?
|
active transport
|
|
|
Where do the Circumventricular organs lie?
|
outside the BBB
|
|
|
What are the Circumventricular organs? (4)
|
1. Posterior pituitary
Oxytocin and ADH secreted directly into circulation. 2. Area postrema Acts as a chemoreceptor trigger zone to control vomiting 3. Organum vascularum of the lamina terminalis (OVLT) Osmoreceptors to control ADH secretion. May control fever via action of IL1 4. Subfornical organ |
|
|
What are the functions of the blood-brain barrier?
|
Maintains constant environment for neurons - minor variation of ion concentration can have profound effect.
Protection from endogenous and exogenous toxins Prevention of the escape of neurotransmitters into the circulation. |
|
|
What % of total body O2 does the brain consume
|
20% of total body resting oxygen consumption.
Brain extremely sensitive to hypoxia - unconsciousness in <10 seconds. |
|
|
What is the main source of energy for the brain?
|
Glucose is the main energy source of the brain - RQ is 0.95-0.99 in resting individuals.
Available glycogen is small and is used in 2 minutes if blood supply is occluded. Is there much glycogen available? |
|
|
What is the volume and production of CSF?
How many times a day is it turned over? |
Volume 150ml.
Production 550ml/day - therefore turnover 3.7 times/day. |
|
|
Where is CSF produced?
|
50-70% formed in choroid plexus, remainder formed around blood vessels and along ventricular walls.
|
|
|
What is the path of CSF flow?
|
CSF flows through foramina of Magendie and Luschka. Absorbed through arachnoid villi into veins, primarily the cerebral venous sinuses.
Meninges and CSF protect the brain. Brain is supported within the arachnoid by blood vessels, nerve roots and multiple fine fibrous arachnoid trabeculae. |
|
|
Is brain ECF different from CSF?
|
same
|
|
|
Normal pH of CSF?
|
7.33
|
|
|
Electrolyte composition of CSF?
|
Sodium
147 150 Potassium 2.9 Magnesium 2.2 Calcium 2.3 Chloride 113 (99) Bicarbonate 25 24 pCO2 50 39 pH 7.33 7.4 Osmalality 289 289 Protein 20 6000 Glucose 64 100 |
|
|
Describe the anatomy of the coronary arteries?
|
2 coronary arteries arise from the sinuses behind the 2 cusps of the aortic valve at the route of the aorta. Eddy currents keep the valve leaflets away from the artery lumen.
|
|
|
Which coronary artery carries more blood?
|
Right coronary has greater flow in 50% of individuals. Left greater in 20%, equal in 30%.
|
|
|
How does cardiac venous blood return to the heart?
|
Most venous blood returns to the heart through the coronary sinus and anterior cardiac veins which drain into the right atrium. Other vessels which empty directly into the heart chambers include:
1. Arterioluminal vessels - small arteries that drain directly into the chambers. 2. Arteriosinusoidal vessels - sinusoidal capillary-like vessels that connect arterioles to the chambers. 3. Thebesian vessels - connect capillaries to the chambers. |
|
|
At what point in the cardiac cycle does coronary flow occur?
|
Vessels are compressed when the heart muscle contracts.
Flow occurs to the subendocardial left ventricle only in diastole. Flow in diastole greater than in systole, though less pronounced in the right ventricle Diastole shortens as heart rate increases. |
|
|
How to increase coronary oxygen consumption?
|
Heart muscle extracts 70-80% of oxygen from blood - consumption can only be increased by increasing flow.
|
|
|
How do coronary vessels autoregulate?
|
Coronary circulation shows considerable autoregulation.
Chemical factors include hypoxia and adenosine - heart muscle demonstrates reactive hyperaemia in a similar way to skin. Neural factors indirectly maintain coronary perfusion - noradrenergic stimulation causes a (predictable vasoconstriction), but this is dominated by local increase in work, increased production of chemical factors and local vasodilation. |
|
|
How is body heat loss regulated in the skin?
|
Regulation of heat loss is controlled by varying the blood flow through the skin.
|
|
|
What is the 'triple' response?
|
Normal response to unsustained firm pressure on the skin
1. Red reaction - capillary dilation as a result of mechanical pressure. 2. Wheal - local swelling and diffuse mottling around the injury due to increased capillary permeability and local oedema as a result of local histamine release. 3. Flare - redness spreading out from the site of the injury - due to arteriolar dilation as a result of antidromic conduction in which impulses initiated in sensory nerves are relayed down other branches of the same nerve. |
|
|
What is reactive hyperaemia?
|
'Increase in blood flow in a region where blood flow is re-established after a period of occlusion'. Due to local release of NO is response to hypoxia.
|
|
|
By how much does uterine blood flow increase during pregnancy?
|
Uterine blood flow increases 20 fold during pregnancy. More oxygen is extracted from the uterine blood during the latter part of pregnancy.
|
|
|
What is the physiology of the placental circulation?
|
Villi of foetal umbilical arteries and veins project into the large blood sinus or lake that forms the maternal portion of the placenta. Diffusion of oxygen and carbon dioxide is inefficient compared with the lung due to thicker cellular layers covering the villi.
Oxygen exchange is aided by foetal haemoglobin, which binds oxygen more avidly due to less avid binding of 2,3 DPG. |
|
|
What is the physiology of the foetal circulation?
|
55% of foetal cardiac output passes through the placenta. Umbilical vein blood 80% saturated - pO2 30mmHg Ductus venosus diverts some of the blood direct to the IVC, rest mixes with the portal blood.
Most blood entering the heart is directed through the foramen ovale into the left heart. Most of the blood from the superior vena cava enters the right ventricle and the pulmonary artery. High pulmonary artery pressure results in most blood passing through the ductus arteriosus to the aorta. Umbilical artery blood is 60% saturated. |
|
|
What are the changes to the foetal circulation at birth?
|
Placental circulation ceases.
Peripheral resistance rises. Pressure in aorta rises to exceed pulmonary artery pressure. Hypoxia stimulates gasp that causes lung expansion and reduced pulmonary artery pressure. Foramen ovale closes and ductus arteriosus constricts. |
|
|
Define shick
|
systemiic hypoperfusion due to reduction in cardiac output or in effective circulating volume resulting in hypotension, impaired tissue perfusion and cellular hypoxia
|
|
|
What are the acute compensatory responses to hypocolaemic shock?
|
Baroreceptor reflexes
CNS ischaemic response Reverse stress-relaxation of the circulatory system Formation of angiotensin Formation of vasopressin |
|
|
What are the long term compensations for hypocolaemia?
|
Mobilisation of tissue fluid and influx of pre-formed albumin.
Absorption of fluid from GIT Conservation of salt and water Increased thirst Stimulation of erythropoetin |
|
|
What is distributive shock
|
Blood volume is normal but the capacity of the circulation is increased
|
|
|
What is the mechanism of septic shock?
|
Caused by gram-negative bacilli that produce endotoxins. Endotoxins are bacterial wall lipopolysaccharides (LPS).
LPS binds and activates leucocytes and endothelial cells causing release of mediators. At low doses, IL1, TNF, IL6 and IL8 predominate. At high doses NO and PAF become significant and endothelial injury may result. LPS also directly activates complement. These factors result in: Diminished myocardial contractility. Systemic vasodilation. Widespread endothelial injury and leucocyte activation. Activation of clotting cascade. |
|
|
What are the 3 stages of shock?
|
1. Non-progressive
Reflex compensatory mechanisms are activated and perfusion of vital organs is maintained. Full recovery occurs without intervention 2. Progressive Characterised by tissue hypoperfusion and acidosis. Reduced coronary blood flow leads to cardiac depression (positive feedback mechanism) Vasomotor failure due to poor perfusion of the vasomotor center Sludging of blood Increased capillary permeability Release of toxins by ischaemic tissues Generalised cellular dysfunction 3. Irreversible (refractory): Cellular and tissue injury such that even if perfusion is restored death will follow. Hypoxia eventually results in irreversible cellular injury |
|
|
What is the antigravity compensation mechanism?
|
Standing causes a drop in blood pressure in the aortic arch and carotid sinus.
Heart rate increases to maintain cardiac output. Prompt increase in circulating levels of renin and aldosterone Arteriolar constriction and increased circulating blood volume causes blood pressure to return to normal. Prolonged standing results in increasing interstitial fluid in the lower extremities, relied by the action of the muscle pump. |
|
|
What is resting blood flow to muscle?
|
Resting blood flow - 2-4ml/100g/min.
|
|
|
What happens to blood flow as muscle contracts?
|
Above 70% muscle tension blood flow ceases but increases 30 fold between contractions.
Oxygen consumption increases 100 fold. |
|
|
What are local factors that control blood flow to muscles?
|
Reduced pO2 resulting in local adenosine release Increased pCO2 Increased potassium Increased temperature (these factors also cause a shift of the oxygen dissociation curve to the right so that more oxygen is given up in the tissues)
|
|
|
How does the nervous system control muscle blood flow?
|
reduction in tonic activity of vasoconstrictor fibres may occur prior to exercise in addition to stimulation by sympathetic vasodilator fibres.
|
|
|
Describe the systemic effects of isometric vs isotonic contraction?
|
1. Isotonic contraction (contraction without difference in muscle tension)
Centrally mediated reduction in vagal tone and increased sympathetic output in anticipation of work. At commencement of work local blood flow is reduced. Peripheral resistance falls. Systolic blood pressure rises moderately, diastolic pressure unchanged or falls. Stroke volume and heart rate rise sharply as a result of autonomic change and central stimulatory effect of increased carbon dioxide. Venous return increases markedly and blood is mobilized from splanchnic and other reservoirs. After completion of exercise blood pressure normalizes more quickly than heart rate. 2. Isometric contraction (contraction without difference in muscle length). Centrally mediated reduction in vagal tone and increased sympathetic output in anticipation of work. At commencement of work local blood flow is reduced. Peripheral resistance rises. Blood pressure rises sharply. Stroke volume remains constant. |
|
|
What are the results of muscle training?
|
Increased stroke volume
Reduced heart rate Increased maximal oxygen consumption Increased numbers of mitochondria and enzymes in muscle cells. Increased number of capillaries causing better distribution of blood flow. |
|
|
Where is ANP produced and inactivated?
|
Produced by atrial muscle and stored in granules.
ANP release stimulated by atrial stretch induced by increased atrial pressure. Inactivation: Short half-life, metabolized in blood. |
|
|
What are the actions of ANP?
|
Mechanism unclear - natriuresis may be due to relaxation of mesangial cells in the glomerulus and increased GFR, or may relate to increased tubular reabsorption of sodium.
Additional actions are broadly opposite to angiotensin II |
|
|
What % of adrenal gland is medulla and what % of cells secrete adrenaline?
|
30% of the mass of the adrenal gland 90% of cells secrete adrenaline Functions as a sympathetic ganglion, supplied by pre-ganglionic fibres from the splanchnic nerve
|
|
|
What does the adrenal medulla produce and how are these strored?
|
Adrenaline Noradrenaline Dopamine
Stored in granules with ATP |
|
|
What is the mechanism if mediator release by the adrenal medulla?
|
Secretion initiated by Acetylcholine release from pre-ganglionic neurons
Acetylcholine causes cation channels to open, calcium to enter and trigger exocytosis |
|
|
What is the mechanism of dopamine and catecholamine breakdown in the blood and what are they broken down to?
What is their half-life? |
95% of dopamine and 70% of adrenaline and noradrenaline are conjugated to sulfate in the plasma
Catecholamines are methoxylated and oxidized to vanillylmandelic acid n(VMA) Half life 2 minutes |
|
|
What % of the adrenal gland is cortex?
What does it produce? |
70% of the mass of the adrenal gland Numerous steroids are produced but few in physiological quantities All steroids are derived from cholesterol
Most steroids have mixed glucocorticoids (effects on glucose and protein) and mineralocorticoid (effects on sodium and potassium excretion) actions but are defined by their dominant action Cortisol has equal glucocorticoids and mineralocorticoid action |
|
|
What are the zones of the adrenal cortex and what do they produce?
|
1. Zona glomerulosa (outer layer)
15% Secretes aldosterone and corticosterone Formation of new cells occurs adjacent to the capsule and is able to regenerate all cortical zones 2. Zona fasciculata 50% Secretes cortisol, sex hormones and corticosterone 3. Zona reticularis 7% Secretes cortisol, sex hormones and corticosterone |
|
|
What is corticosterone bound to in the blood and what is the point of this binding?
|
Bound to corticosteroid binding globulin and albumin Bound cortisol and corticosterone functions as a blood resevoir
Free cortisol and corticosterone provide physiological function and feedback control |
|
|
What is the half life of corticosterone in the blood?
Where is it metabolised? |
Half life 100 minutes
Metabolized by liver to active and inactive metabolites and excreted in the urine |
|
|
Is aldosterone bound to anything in the blood?
What is the half life? What metabolises aldosterone? |
Minimal protein binding
Half life 20 minutes Metabolized by liver and kidney |
|
|
Where are ACTH and CRF produced and what is the pattern of production?
|
Produced by the anterior pituitary
Basal secretion follows a diurnal circadian rhythm Diurnal rhythm controlled by CRF from hypothalamus Feedback control from free cortisol and corticosterone act on both anterior pituitary and hypothalamus Response to stress, emotion and trauma mediated by CRF from the hypothalamus |
|
|
How does ACTH act and what is it's half-life?
|
Binds to adrenocortical receptors and results in increased formation of pregnenolone derivatives
Half life 10 minutes |
|
|
How does angiotensin II act on adrenal cortex?
|
Binds to receptors in the zona glomerulosa and results in increased formation of aldosterone
ACTH: Provides a transient response only Glucocorticoids treatment does not suppress mineralocorticoid release |
|
|
How do steroids act at a cellular level?
|
Steroid enters the cell as a free molecule Binds to intracellular receptor that is bound to stabilising heat shock protein Heat shock protein is released and the steroid-receptor complex enters the nucleus and bind to glucocorticoid response element on the DNA This causes regulation of transcription and production of appropriate protein
|
|
|
What are the metabolic effects of glucose?
|
Intermediary metabolism:
Protein catabolism Gluconeogenesis and decreased peripheral glucose utilisation Ketogenesis Permissive action effects: Required for glucagon and catecholamines to exert their effects |
|
|
What are the blood effects of glucocorticoids?
|
Increased sequestration of eosinophils Increased circulating neutrophils, platelets and red blood cells
Reduced lymphocytes |
|
|
What are the actions of mineralocorticoids?
|
Increased reabsorption of sodium from urine, sweat, saliva and gastric juice resulting in retention of sodium in the ECF
Aldosterone causes increased renal tubular reabsorption of sodium in association with secretion of potassium and hydrogen. Act on P cells in CD on CD that contain epithelial sodium channels. Also increases the number of sodium/potassium ATPase molecules in the basal membrane. Small action in bladder. |
|
|
What is the average daily iodine intake?
In what form is it absorbed? |
Ingested iodine converted to iodide and absorbed. Average daily intake 500ug.
|
|
|
What proportion of iodine intake is taken up by thyroid daily?
How much of this drifts into ECF? How much is made into hormones on a daily basis? |
120ug/day (approximately 1⁄4 of daily intake) is taken up by thyroid.
120ug/day (approximately 1⁄4 of daily intake) is taken up by thyroid. 40ug/day diffuses from thyroid to ECF. Thyroid secretes 80ug/day as iodine in T3 and T4. |
|
|
Where are T3 and T4 metabolised
How much iodine re-enters the circulation daily and how much is excreted? How much iodineenters urine per day? |
T3 and T4 are metabolized by liver. 60ug/day re-enters ECF from liver, 20ug/day excreted in bile. Overall, 480ug/day enters urine.
|
|
|
How is iodine concentrated in the thyroid?
|
Iodide is concentrated in thyroid by secondary active transport with sodium.
Sodium and iodide are co- transported then sodium is pumped into the interstitium by sodium/potassium ATPase. |
|
|
What are the steps in thyroid hormoone synethesis?
How is it stored before it is released? |
1. Thyroid peroxidase oxidizes iodide to iodine and binds it to tyrosine to form monoiodotyrosine (MIT). 2. MIT is iodinated to form DIT.
3. 2 DIT molecules are condensed to form tetraiodothyronine (T4) 4. 1 MIT and 1 DIT form triiodothyronine - a small amount forms RT3. 5. All of the above are bound to thyroglobulin until secreted. |
|
|
What % MIT, DIT, T4 and T3 does a normal thyroid contain?
|
23% MIT
33% DIT 35% T4 7% T3 |
|
|
How much T3 and T4 does the normal thyroid secrete daily?
How much more powerful is T3? |
80ug T4
4ug T3 (T3 is 3-4 times more potent that T4) 2ug RT3 MIT and DIT are not secreted. |
|
|
What is the mechanism of release of thyroid hormone?
What enzyme breaks down MIT and DIT? |
Thyroid cells ingest colloid and produce reabsorption of lacunae.
Peptide bonds between iodinated residues and thyroglobulin are broken and T4, T3, MIT and DIT are released into cytoplasm. MIT and DIT are de-iodinated by iodotyrosine deiodinase and iodine liberated is recirculated back into the thyroid |
|
|
What is the purpose of bound vs free thyroid hormone?
|
Free thyroid hormones in plasma are physiologically active.
There is an equilibrium between free active form and bound inactive form. The function of bound hormone is to provide a large pool of readily available free hormone and promotes uniform tissue distribution. |
|
|
What is the concentration of bound and free T4 in plasma?
What % of T4 is protein bound? |
Plasma bound T4 - 8ug/dl
Free T4 - 0.002ug (2ng)/dl 99.98% of T4 is protein bound, 99.8% of T3. |
|
|
What are the three protins that bind thyroid hormone?
|
1. Albumin
3500mg/dl - very large capacity low binding affinity Half life 13 days Binds 13% of T4 and 53% of T3 2. Transthyretin 15mg/dl - small capacity Moderate affinity Half life 2 days Binds 20% of T4, 1% of T3 3. Thyroxine binding globulin 2mg/dl - very low capacity Very high affinity Half life 5 days Binds 67% of T4 and 46% of T3 |
|
|
Describe the capacity, affinity and % binding of thyroid hormone to albumin?
|
1. Albumin
3500mg/dl - very large capacity low binding affinity Half life 13 days Binds 13% of T4 and 53% of T3 |
|
|
Describe the capacity, affinity and % binding of thyroid hormone to Transthyretin?
|
2. Transthyretin 15mg/dl - small capacity
Moderate affinity Half life 2 days Binds 20% of T4, 1% of T3 |
|
|
Describe the capacity, affinity and % binding of thyroid hormone tothyroxine binding globulin?
|
3. Thyroxine binding globulin
2mg/dl - very low capacity Very high affinity Half life 5 days Binds 67% of T4 and 46% of T3 |
|
|
What kind of in concentration of binding proteins affect concentration of free T4 and free T3?
|
Sudden changes
|
|
|
What increases TBG levels?
|
oestrogens and pregnancy
|
|
|
What reduced TBG levels?
|
Glucocorticoids Androgens Danazol
|
|
|
What substances change the binding of T3 and T4 to TBG?
|
Salicylates
Phenytoin 5-fluoruoacil |
|
|
How and where is TSH produced?
|
Pulsatile secretion by anterior pituitary peaks at night.
|
|
|
What is the half life of TSH and where is it broken down?
|
Half life 60 minutes. D
egraded by kidneys and liver. |
|
|
What inhibits TSH and TRH
|
TSH secretion inhibited by freeT4 and free T3. (and stress) Free T4 and free T3 also inhibit TRH.
TSH secretion increased by TRH. |
|
|
What is the action of TSH?
|
Stimulates thyroid function resulting in iodide trapping, increased blood flow and cell hypertrophy. Prolonged stimulation results in goiter.
|
|
|
What is the mechanism of thyroid hormone action?
|
Thyroid hormones bind to receptor. T4 is converted to T3 T3-receptor complex then binds with DNA and controls enzymes that regulate cell function.
|
|
|
How is thyroid hormone related to catecholamines?
|
Actions of thyroid hormones and catecholamines are intimately related -their actions are similar and thyroid hormones increase the number and affinity of adrenergic receptors in heart and probably other tissues.
|
|
|
Where does thyroid hormone increase oxygen consumption?
|
Most tissues except adult brain, testes, uterus, LN, spleen,
anterior pituitary. |
|
|
What is the effect of thyroid hormone on metabolic rate?
|
Increases it. If food intake is not increased there in weight loss and likely nutritional deficiency. Large increases result in increased body temperature
|
|
|
What does thyroid hormone do for carb and cholesterol metabolism?
|
Increased rate of absorption of carbohydrates, causing rapid glucose rise which may exceed the renal threshold.
Increased LDL receptors in liver results in increased hepatic removal of cholesterol. |
|
|
What are the bone effects of thyroid hormone?
|
Essential for normal bone growth including epiphyseal
plate closure. |
|
|
What are the CNS effects of thyroid hormone?
|
Irritability
Restlessness Increased responsiveness to catecholamines. Shortened reflex time. Thyroid deficiency during development results in mental retardation, motor rigidity and deafness. |
|
|
What are the cardiovascular effects of thyroid hormone?
|
Increase the number and affinity of beta-adrenergic receptors therefore increasing the sensitivity to catecholamines.
Affect the type of myosin in cardiac muscle resulting in increased speed of contraction. |
|
|
What are the skeletal effects of thyroid hormone?
|
Muscle weakness, cramps and stiffness ␣ probably due to protein catabolism rather than direct muscle effect.
|
|
|
What % of the pancreas do islet cells comprise?
|
Islet cells compose 2% of pancreas and number 1-2 million.
|
|
|
What are the 4 types of islet cells and what do they secrete?
|
1. Alpha cells
20% Secrete glucagon 2. Beta cells 60-75% Secrete insulin 3. Delta cells Secrete somatostatin 4. F cells Secrete pancreatic polypeptide |
|
|
What is the structure of insulin and how is it processed prior to release?
|
Polypeptide containing 2 chains (A and B) of amino acids linked by disulfide bridges.
Synthesised as part of preproinsulin. Removal of a peptide leader sequence forms proinsulin. Connecting peptide is removed in the granules prior to release. |
|
|
What is the half-life of insulin and how is i broken down?
|
Half life 5 minutes.
Binds to insulin receptors and is internalized. Destroyed by insulin protease. 80% is degraded in liver and kidney. |
|
|
What is the mechanism of glucose/mannose/fructose stimulating insulin release?
|
Glucose, mannose, fructose Glucose enters B cells via GLUT 2 transporters.
Glucose is then metabolized by glucokinase generating ATP that closes ATP sensitive potassium channels. Depolarisation results in opening of voltage sensitive calcium channels and intracellular calcium triggers insulin release. |
|
|
What intestinal hormones trigger insulin reease?
|
Gastrin
Secretin CCK Glucagon GIP |
|
|
What Protein and fat derivatives trigger insulin reease?
|
Amino acids (leucine, arginine)
Beta keto acids |
|
|
How does acetylcholine trigger insulin release?
|
via M4 receptors and right vagus nerve
Causes activation of phospholipase C, release of IP3 and subsequent calcium release from endoplasmic reticulum. |
|
|
What effect do beta agonists have on insulin release?
|
alpha agonists cause inhibition
and this tends to be the dominant effect unless there an beta antagonist is present Causes increased cAMP |
|
|
Why do glucagon and theophilline trigger insulin release?
|
increase cAMP
|
|
|
How do sulphonylureas trigger insulin release?
|
Cause membrane depolarization of B
cells and calcium influx. |
|
|
What are the inhibitors of insulin release?
|
1. Somatostatin
2. Glucose metabolism preventors 2-deoxyglucose Mannoheptulose 3. Autonomic nervous system -Alpha adrenergic agonists -Beta antagonists -Galanin --->Polypeptide found in some of the autonomic nerve innervating the islets --->Causes opening of potassium channels 4. Hypokalaemia and potassium depleters -Thiazide diuretics 5. Phenytoin 6. Alloxan 7. Microtubule inhibitors 8. Insulin |
|
|
What does insulin binding the the membrane receptor cause?
What happens with exposure to continued insulin? |
Insulin binds with an insulin transmembrane receptor that binds and stimulates a protein tyrosine kinase. Exposure to increased insulin down regulates receptor concentration and affinity.
|
|
|
What is the net effect of insulin?
|
Insulin has a hypoglycaemic action but it has many other effects on amino acid and electrolyte transport, enzymes and growth. The net effect is storage of carbohydrate, protein and fat.
|
|
|
What is the rapid action of insulin
|
Increased transport of glucose, amino acids and potassium into insulin sensitive cells.
|
|
|
What does insulin do within minutes?
|
Stimulation of protein synthesis Inhibition of protein degradation Activation of glycolytic enzymes and glycogen synthase Inhibition of phophorylase and gluconeogenic enzymes
|
|
|
What does insulin do after hours?
|
Increase in mRNAs for lipogenic and other enzymes.
|
|
|
What is the effect of insulin on the liver?
|
Decreased glucose output due to decreased gluconeogenesis and increased glycogen synthesis. Increased protein synthesis Increased lipid synthesis Decreased ketogenesis
|
|
|
What is the effect of insulin on fat?
|
Increased glucose entry Increased fatty acid synthesis Increased triglyceride deposition Activation of lipoprotein lipase Increased potassium uptake
|
|
|
What is the effect of insulin on muscle?
|
Increased glucose entry Increased glycogen synthesis Increased amino acid uptake Increased protein synthesis Decreased protein catabolism Decreased release of gluconeogenic amino acids Increased ketone uptake Increased potassium uptake
|
|
|
Where is glut 1 found?
|
brain, red cells, placenta, many other organs
|
|
|
Where is glut 2 found?
|
B cells, liver, intestine, kidney ␣ transport glucose out of the cell
|
|
|
Where is glut 4 found?
|
adipose tissue and muscle A pool of GLUT4 transporters is maintained in the cytoplasm of insulin sensitive cells and when these cells are exposed to insulin the transporters move to the cell membrane.
|
|
|
Where and how does glucose movie via secondary active transport?
|
intestine and kidney
Utilise sodium dependent glucose transporters - SGLT1 and SGLT2. |
|
|
Where is glucagon found and what is if formed from?
What else does this form? |
Polypeptide produced by A cell of pancreatic islets and upper gastrointestinal tract. Formed from a precursor molecule named preproglucagon that is found in A cell and in L cells of the lower gastrointestinal tract and brain
In A cells preproglucagon forms: Glucagons Major proglucagon fragment Glicentin-related polypeptide In L cells preproglucagon forms: Glicentin Glucagon-like polypeptides Oxyntomodulin Glicentin-related polypeptide |
|
|
Where is glucagon degraded?
Why are blood levels low? What happens in cirrhosis? |
Half life 5-10 minutes
Actions Degraded by many tissues, especially liver. Secreted into the portal vein therefore peripheral blood levels are low. Degradation is reduced in cirrhosis |
|
|
What stimulates glucagon release?
|
1. Protein and fat derivatives
-Amino acids (leucine, arginine) 2. Intestinal hormones -Gastrin -CCK 3. Cortisol 4. Exercise 5. Infection 6. Autonomic nervous system 7. Acetylcholine -M4 receptors and right vagus nerve -Causes activation of phospholipase C, release of IP3 and subsequent calcium release from endoplasmic reticulum. Beta adrenergic agonists (beta response is dominant in contrast to effect on B cells) Causes increased cAMP 8. cAMP and agents that increase cAMP Theophylline |
|
|
What reduces glucagon release?
|
1. Glucose, mannose, fructose
2. Intestinal hormones -Somatostatin -Secretin 3. Protein and fat derivatives - Free fatty acids - Ketones 4. Autonomic nervous system -Alpha adrenergic agonists 5. Phenytoin 6. Insulin 7. GABA -Release is stimulated by hyperglycaemia, acts locally on A cells to cause hyperpolarisation and reduced glucagons release. |
|
|
How does GABA reduce glucagon release?
|
Release is stimulated by hyperglycaemia, acts locally on A cells to cause hyperpolarisation and reduced glucagons release.
|
|
|
What is the mechanism of glucagon action?
|
Binds with transmembrane receptor protein that stimulates a GTP-binding signal transducer protein (G protein) that in turn generates an intracellular second messenger. Second messengers include cAMP, calcium and phosphoinositides.
|
|
|
What are the actions of glucagon?
|
Glycogenolysis (liver but not muscle) Gluconeogenesis Lipolysis Ketogenesis
Secretion of growth hormone, insulin and pancreatic somatostatin. |
|
|
Where is somatostatin produced and what stimulates it?
|
Produced by D cells of pancreatic islets.
Stimulation: Glucose, amino acids, CCK Inhibition of the secretion of insulin, glucagons and pancreatic polypeptide. |
|
|
Where is pancreatic polypeptide produced and what stimulates it?
|
Produced by F cells of pancreatic islets.
Secretion under autonomic (cholinergic) control. Stimulation: Hypoglycaemia Fasting Protein meal (though not individual amino acids) Inhibition: Glucose Somatostatin |
|
|
What is the action of pancreatic polypeptide?
|
Unclear - slows absorption of food and may control peaks and troughs.
|
|
|
What does exercise do to glucose levels?
|
Increased entry of glucose into muscle.
Increased insulin sensitivity |
|
|
What does thyroid hormone do to glucose levels?
|
Increase the absorption of glucose from the gastrointestinal tract.
Accelerated degradation of insulin Potentiates the effects of catecholamines |
|
|
What do adrenal glucocorticoids do to glucose levels?
|
Elevate blood glucose and cause diabetic type glucose tolerance curve.
Glucocorticoids have direct actions on carbohydrate, protein and fat metabolism but are also necessary for glucagons to exert its gluconeogenic effect during fasting. Direct effects include: 1. Increased gluconeogenesis and glucose release 2. Decreased peripheral glucose utilisation Increase protein catabolism leading to increased amino acids 3. Increased hepatic uptake, deamination and transamination of amino acids 4. Decreased hepatic lipogenesis, increased FFA formation, increased ketone formation |
|
|
What does growth hormone do to glucose levels?
|
Increases hepatic glucose output.
Decreases insulin binding uptake into tissues. (?affects receptor numbers) Mobilises FFAs from dipose tissue therefore favours ketogenesis. |
|
|
What do catecholamines do to glucose levels?
|
Activation of phosphorylase in liver resulting in glycogenolysis and increased glucose output.
Lactate produced by muscles is oxidized in liver to pyruvate and converted to glycogen. Adrenaline decreases peripheral utilization of glucose. Noradrenaline and adrenaline liberate FFAs. |
|
|
How much calcium in a young adult and where is it?
What is the turnover in children vs adults? |
Actions
1100g (27.5mol) of calcium in young adult 99% in skeleton (100% turnover per year in infants, 18% per year in adults) |
|
|
How much plasma calcium is ionised and complexes?
How much is bound to albumin and globulin? |
Plasma calcium
Total 2.5mmol/l Ionised 1.18mmol/l Complexed with bicarbonate, citrate: 0.16mmol/l Bound to albumin 0.92mmol/l Bound to globulin 0.24mmol/l |
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|
What does the degree of calcium - protein binding depend on?
|
Degree of binding depends on amount of plasma protein and pH - plasma proteins are more ionized at high pH and are able to bind more calcium therefore causing reduced ionized calcium.
|
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|
Describe calcium processing in the gut?
|
If dietary intake equals 1000mg (25mmol) per day: 15mmol is absorbed by active transport (plus a small amount of passive diffusion) in a process regulated by 1,25 dihydroxycholecalciferol
12.5mmol is secreted into gut 22.5mmol is excreted in faeces The 15mmol that is absorbed enters the ECF that contains 35mmol. |
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|
Describe calcium processing in the kidney?
|
250mmol is filtered per day but 247.5mmol (98%) is reabsorbed.
60% is reabsorbed in the proximal tubule, remainder in ascending loop and DCT. |
|
|
Describe the calcium equilibrium between ECF and bone?
|
500mmol per day moves between ECF and rapid exchange pool in bone.
7.5mmol/day is involved in slow interchange with bone in the process of constant resorption and deposition. |
|
|
What are the physiological actions of calcium?
|
500mmol per day moves between ECF and rapid exchange pool in bone.
7.5mmol/day is involved in slow interchange with bone in the process of constant resorption and deposition. |
|
|
How much phosphate in the body and where is this mainly found?
|
800g (25.8mol) of phosphate in young adult 90% in skeleton
|
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|
What is the concentration of phosphorous in plasma and what fraction is organic vs organic
|
Total 12 mg/dl
2/3 of this in found in organic compounds 1/3 is inorganic phosphate. |
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|
Where is inorganic phosphate absorbed?
How much is reabsorbed in the kidney and where does this occur? |
Inorganic phosphate is absorbed in the duodenum and small intestine by active transport and passive diffusion. Absorption is increased by 1,25 dihydroxycholecalciferol
3mg/day recirculates with bone. Inorganic phosphate in blood is filtered and 90% reabsorbed. Reabsorption occurs in the PCT and is inhibited by PTH. |
|
|
Where is vitamin D3 produced?
|
Vitamin D3 (cholecalciferol) is produced in the skin by the action of sunlight on 7 dehydrocholesterol. Small amount absorbed from the gut.
|
|
|
Describe vitamin D processing in the liver and kidney?
|
Vitamin D3 is transported in plasma bound to vitamin D binding protein.
In the liver, vitamin D3 is converted to 25-hydroxycalciferol (calcidiol). In the cells of the proximal tubules of the kidney, 25- hydroxycalciferol is converted to 1,25-dihydroxycholecalciferol (calcitriol). 24,25-dihydroxycholecalciferol is also formed. |
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|
Is vitamin D closely regulated?
|
no
|
|
|
What are the stimulators of vitamin D production?
|
Hypocalcaemia
Hypophosphataemia PTH Calcitonin Prolactin Growth hormone |
|
|
What are the inhibitors of vitamin D production?
|
Hyperthyroidism
Metabolic acidosis |
|
|
What are the molecular actions of vitamin D?
|
Binds with steroid receptor, resulting in production of mRNA and the formation of calbindin-D proteins in intestine, kidneys and brain. This results in increased calcium transport.
|
|
|
What are the ways in which vitamin D increases cellular calcium?
|
Increased calcium absorption from gastrointestinal tract
Increased calcium reabsorption in kidneys. Increased numbers of osteoclasts resulting in mobilising of bone stores of calcium. |
|
|
Where and how is parathyroid hormone produced?
|
Polypeptide produced by chief cells of parathyroid gland.
Synthesised as preproPTH and converted to proPTH prior to packaging in secretory granules as PTH. |
|
|
What is the half-life of PTH and what metabolises it?
|
Half life 10 minutes. Rapidly cleaved by Kuppfer cells in liver and cleared by kidney.
|
|
|
What stimulates PTH?
What inhibits PTH? |
Phosphate
Calcium Magnesium 1,25-dihydroxycholecalciferol |
|
|
What is the mechanism of PTH?
|
3 different PTH receptors. Either result in increased cAMP via Gs, or increased intracellular calcium via PLC, PIP2 and IP3
|
|
|
How does PTH increase plasma calcium? (5 ways)
|
1. Acts directly on bone to increase bone resorption and mobilise calcium.
2. Increases reabsorption of calcium in DCT 3. Increases the formation of 1,25-dihydroxycholecalciferol Stimulates osteoblasts and osteoclasts 4. Increases phosphate excretion in urine due to decreased reabsorption in proximal tubules. |
|
|
Which cells secrete calcitonin and when is it secreted?
|
Polypeptide produced by parafollicular cells of the thyroid.
Not secreted until plasma calcium reaches 9.5mg/dl |
|
|
What is the half-life of calcitonin?
|
Half life less than 10 minutes
|
|
|
What are the stimulators of calcitonin?
|
Calcium
Beta adrenergic agonists Dopamine Oestrogens Gastrin CCK Glucagon Secretin |
|
|
What does calcitonin do?
|
Mechanism Receptors found in bone and kidney.
Inhibits bone resorption Increase calcium secretion in urine Despite its physiological actions calcitonin is non-essential. It may play a role in bone development, bone loss in pregnancy or management of post prandial hyperglycaemia |
|
|
How do glucocorticoids control plasma calcium?
|
Lower plasma calcium by inhibiting osteoclasts.
Over long periods of time osteoporosis results due to decreased osteoblast activity and increased osteoclast activity. Decreased absorption of calcium from the intestine Increased renal excretion of calcium |
|
|
How does growth hormone control calcium metabolism?
|
Increased calcium excretion in urine Increased calcium absorption (this usually outweighs increased losses)
|
|
|
How does thyroid hormone control calcium metabolism
|
Hypercalcaemia
Hypercalciuria Osteoporosis |
|
|
How does insulin control calcium metabolism?
|
Increase bone formation
|
|
|
Where is the Myenteric (auterback's plexus and what does it do?)
|
Between outer longitudinal and middle circular layers
Mostly motor function Contains sensory and motor neurons Connected to CNS via sympathetic and parasympathetic fibres Can function autonomously |
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|
Where is the submucous (Meissner's) plexus and what does it do?
|
Between middle circular layer and the mucosa Mostly concerned with intestinal secretion
Contains sensory and motor neurons Connected to CNS via sympathetic and parasympathetic fibres Can function autonomously |
|
|
What are the neurotransmitters of the enteric nervous system?
|
Acetylcholine
Noradrenaline Serotonin GABA ATP Nitric oxide Peptides (also act in a paracrine or endocrine fashion): CCK Neuropeptide Y Somatostatin Substance P TRH VIP (plus others) |
|
|
What is peristalsis and how does it work?
|
Reflex response (contraction behind the stimulus, relaxation in front) initiated by stretch of the gut wall
Local stretch releases serotonin that activates neurons in the myenteric plexus. Neurons release acetylcholine and substance P causing smooth muscle contraction and NO/VIP causing relaxation ahead of the stimulus |
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|
Where is gastric produced (3 places)?
What is macro and microheterogenaity? |
1. G cells in lateral walls of glands of gastric antrum mucosa
-Neural crest origin (APUD cells -amine precursor uptake and decarboxylation) 2. TG cells in stomach and small intestine 3. Pancreas -Questionable role although gastrinomas form here Macroheterogeneity and microheterogeneity Secreted in several similar forms with some differences in activity |
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|
Where is gastrin metabolised and what is it's half-life?
|
Kidney and small intestine
Half life 2-15 minutes |
|
|
What 3 factors stimulate gastrin secretion?
|
1. Luminal factors
-Distension -Amino acids and polypeptides Act directly on G cells 2. Neural control -Vagal discharge (GIP is the transmitter) 3. Endocrine control -Calcium -Adrenaline |
|
|
What factors inhibit gastrin secretion?
|
Luminal factors
-Acid -Somatostatin Endocrine control -Secretin -GIP -VIP -Glucagon -Calcitonin |
|
|
What is the mechanism gastrin?
|
Binds with gastrin/CCK receptor to cause histamine release and direct stimulation of parietal cells
|
|
|
What does gastrin do?
|
1. Gastric acid secretion
2. Pepsin secretion 3. Growth of stomach and small intestine mucosa 4. Increases gastric motility 5. Contraction of lower oesophageal sphincter 6. Stimulates insulin secretion (only in high doses after a protein meal) |
|
|
Where is Cholecystokinin-pancreozymin (CCK) produced?
|
I cells of the mucosa of upper small intestine (also found in nerves in distal ileum,brain and other parts of the body)
Macroheterogeneity and microheterogeneity: Secreted in several similar forms with some differences in activity |
|
|
What stimulates the secretion of Cholecystokinin-pancreozymin (CCK)?
|
Amino acids and polypeptides
Long chain fatty acids |
|
|
What are the actions of Cholecystokinin-pancreozymin (CCK) ?
|
Contraction of the gallbladder Secretion of pancreatic juice rich in enzymes Augments the action of secretin Inhibits gastric emptying Increases secretion of enterokinase Enhances motility of the gut Augments contraction of the pyloric sphincter Stimulates glucagon secretion Stimulates insulin secretion
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|
|
What produces secretin?
What substances are similar in structure to secretin? |
S cells deep in the glands of the mucosa of the
upper small intestine Similar structure to glucagons, VIP, GIP |
|
|
Half-life of secretin?
|
Half life 5 minutes
|
|
|
What stimulates secretin?
|
Amino acids and polypeptides
Acid (good example of negative feedback) |
|
|
What are the actions of secretin?
|
Increases secretion of bicarbonate by the pancreas and biliary tract
Augments the action of CCK Decreases gastric acid secretion Causes contraction of the pyloric sphincter Stimulates insulin secretion |
|
|
What produces GIP?
|
K cells of the mucosa of the duodenum and jejunum
|
|
|
What stimualtes GIP production?
|
Glucose and fat Acid (good example of negative feedback)
|
|
|
What are the actions of GIP?
|
Stimulates insulin secretion Inhibits gastric secretion and motility
|
|
|
For the parotid gland:
1. Is histology mucous or serious? 2. Is secretion water or viscous? 3. What % of the 1500ml per day does it comprise? |
Serous
Water 20% |
|
|
For the Submandibular gland:
1. Is histology mucous or serious? 2. Is secretion water or viscous? 3. What % of the 1500ml per day does it comprise? |
Mixed
Viscous 70% |
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|
For the Sublingual gland:
1. Is histology mucous or serious? 2. Is secretion water or viscous? 3. What % of the 1500ml per day does it comprise? |
Mucous
Viscous 5% |
|
|
What electrolytes do the salivary ducts absorb and secrete?
How does aldosterone influence this? |
Sodium, potassium, chloride, bicarbonate Roughly equate to plasma
Ducts reabsorb sodium and chloride and secrete potassium and bicarbonate at low flow rates Aldosterone increase potassium and reduces potassium concentration |
|
|
What are the contents of saliva?
|
1. Electrolytes
2. Enzymes -Lingual lipase -Salivary alpha amylase 3. IgA 4. Lysozyme -Attacks bacterial walls 5. Lactoferrin Binds iron Bacteriostatic 6. Proteins Protect enamel Bind tannins 6. Mucins -Lubricating glycoproteins |
|
|
Function of saliva?
|
Facilitates swallowing
Keeps mouth and lips moist Solvent for molecules that stimulate taste Keeps mouth clean Antibacterial action |
|
|
Control of saliva?
|
Parasympathetic stimulation results in profuse watery saliva
Local release of VIP (as a co-transmitter) causes vasodilation Sympathetic stimulation causes vasoconstriction and small amounts of submandibular secretion rich in organic constituents Food in the mouth stimulates reflex secretion Reflex is easily conditioned |
|
|
What is the reflex response to swallowing?
|
Triggered by afferent impulses from trigeminal, glossopharyngeal and vagus nerves Integrated in the nucleus of the tractus solitarius and nucleus ambiguous
Efferent fibres pass to the pharynx and tongue via the trigeminal, facial and hypoglossal nerves 600 swallows per day, 200 while eating and drinking |
|
|
How many ml of gastric secretion per day?
|
2500
Contents: Sodium Potassium Magnesium Hydrogen Chloride Phosphate Sulphate Pepsins Lipase Mucus -Secreted by mucous cells in body and fundus -Contains bicarbonate and mucins -Forms a flexible gel that coats the mucosa Intrinsic factor |
|
|
What is the pH of the stomach?
|
1
|
|
|
What does gastric mucous contain and what makes this?
|
-Secreted by mucous cells in body and fundus -Contains bicarbonate and mucins
-Forms a flexible gel that coats the mucosa |
|
|
What cells produce gastric acid?
|
Produced by gastric body parietal cells
|
|
|
What 3 things stimulate gastric acid?
|
1.Histamine via H2 receptors (cAMP messenger)
2. Acetylcholine via M3 receptors (calcium messenger) 3. Gastrin via enterochromaffin-like cells (calcium messenger) |
|
|
What inhibits gastric acid?
|
Prostaglandins (cAMP messenger)
|
|
|
How is acid produced in the stomach?
|
H+/K+ ATPase pumps hydrogen ions against their concentration gradient
H+ is derived from carbonic acid formed by the hydration of carbon dioxide, catalysed by carbonic anhydrase Bicarbonate is exchanged for chloride causing a postprandial alkaline tide |
|
|
What are the three points of regulation of gastric acid secretion?
|
1. Cephalic (one third-half of acid response)
Food in the mouth Sight, smell and thought of food 2. Gastric Food in the stomach (local reflex arc) 3. Intestinal Fats, carbohydrates and acid in the duodenum inhibit gastric secretion |
|
|
What do parietal cells manufacture?
|
Acid (kills bacteria) and intrinsic factor
|
|
|
Describe B12 absorption?
|
1. B12 initially binds to haptocorrin produced by salivary glands and gastrointestinal mucosa
2. Pancreatic proteases modify haptocorrin to a product with less affinity, so B12 is transferred to intrinsic factor 3. Intrinsic factor/B12 complex binds to receptor in terminal ileum 4. Absorbed by endocytosis 5. Transferred to transcobalamin II |
|
|
What produces pepsinogen?
|
chief cells
|
|
|
What produces gastrin?
|
antral mucosal cells
|
|
|
How does the exocrine pancreas secrete things?
|
Acinar cells contain zymogen granules that discharge from the apex of the cell by exocytosis into the lumen of the pancreatic duct.
The pancreatic duct joins the common bile duct to enter the duodenum. |
|
|
What are the digestive enzymes found in the pancreas?
|
1. Trypsin
Activated by enteropeptidase on the brush border as the pancreatic juice enters the duodenum Cleaves proteins and polypeptides 2. Chymotrypsins and chymotrypsinogens Activated by trypsin Cleaves proteins and polypeptides 3. Carboxyypeptidase A and B Activated by trypsin Cleaves proteins and polypeptides 4. Elastase Activated by trypsin Cleaves elastin 5. Pancreatic lipase Cleaves triglycerides 6. Cholesteryl ester hydrolase Cleaves cholesteryl esters 7. Pancreatic alpha amylase Cleaves starch 8. Ribonuclease Cleaves RNA 9. Deoxyribonuclease Cleaves DNA 10. Phospholipase A2 Cleaves phospholipids |
|
|
What are the anions secreted by the pancreas?
|
Bicarbonate (113meq/l vs 23meq/l in plasma) Chloride Sulphate
|
|
|
What is the pH of pancreatic secretions and how much is secreted daily?
|
pH=8, 1500ml secreted per day
|
|
|
What is the pH of secretions after pancreatic secretions mixed with gastric?
|
Bile+intestinal juice+pancreatic juice raise gastric pH to 6-7.
|
|
|
How does secretin act on pancreatic secretions?
|
Acts on pancreatic ducts to cause copious secretion of pancreatic juice rich in bicarbonate but poor in enzymes.
|
|
|
How does CCK act on pancreatic secretions?
|
Acts on acinar cells to cause release of zymogen granules.
|
|
|
How does acetylcholine act on pancreatic secretions?
|
Release via the vagus nerve also causes a small amount of enzyme release
|
|
|
Function of the liver?
|
1. Formation and secretion of bile
2. Nutrient and vitamin metabolism -Glucose and other sugars -Amino acids -Lipids ---Fatty acids ---Cholesterol ---Lipoproteins -Fat-soluble vitamins -Water-soluble vitamins 3. Inactivation of various substances -Toxins -Steroids -Other hormones 4. Synthesis of plasma proteins -Acute phase proteins -Albumin -Clotting factors -Hormone-binding proteins 5. Immunity Kuppfer cells |
|
|
What % of bile is water?
|
Water 97%
Bile salts 0.7% Bile pigments (bilirubin, biliverdin) 0.2% Cholesterol 0.06% Inorganic salts 0.7% Fatty acids 0.15% Lecithin 0.1% Fat 0.1% |
|
|
How does the gallbladder concentrate bile?
|
The gallbladder concentrates the bile by removal of water (89% versus 97%)
|
|
|
What are bile salts composed of?
How many g per day? |
Sodium and potassium salts of bile acids conjugated to glycine or taurine
Synthesised from cholesterol 0.2-0.4g/day (to replace that lost in faeces) |
|
|
What is the total bile salt pool?
|
0.2-0.4g/day (to replace that lost in faeces)
Total bile salt pool 3.5g |
|
|
What are the bile salts and relative percentages of each?
|
Cholic acid 50%
Chenodeoxycholic acid 30% Deoxycholic acid 15% Lithocholic acid 5% |
|
|
What are the functions of bile?
|
Emulsification of fat (in conjunction with phospholipids and monoglycerides)
Formation of micelles |
|
|
How do micelles work to emulsify fat?
|
Bile salts are amphipathic ␣ they have hydrophilic surfaces facing out and hydrophobic surfaces facing in
Lipids collect in the micelles -cholesterol in the center, phospholipids and monoglycerides lined up with the bile salts Micelles keep the lipids in solution and transport them to the brush border |
|
|
What % of fat appears in faeces when no bile is secreted?
|
If no bile is excreted, 50% of fat appears in faeces
|
|
|
What % of bile salts are reabsorbed and where?
What happens to those that are not reabsorbed? |
95% of bile salts are reabsorbed by sodium dependent secondary active transport
Absorption is from the small intestine, most from the terminal ileum 5% enter the colon and form secondary bile acids |
|
|
Where are bile acids converted to bile salts?
|
Primary bile acids are converted to secondary bile acids by bacteria in the colon
|
|
|
What happens to secondary bile acids in the colon?
|
-Cholic acid is converted to deoxycholic acid
-Chenodeoxycholic acid is converted to lithocolic acid -Deoxycholic acid is reabsorbed -Most lithocholic acid is excreted in stool Reabsorbed bile salts are transported back to the liver and re-excreted in bile |
|
|
How is bilirubin formed?
How is it processed? |
1.Most bilirubin formed from the breakdown of haemoglobin
2. Bilirubin bound to albumin 3. Dissociates in the liver to enter hepatocytes 4. Binds to cytoplasmic proteins 5. Conjugated to glucuronic acid by UDP glucuronyltranferase 6. Conjugated bilirubin actively transported into bile canaliculi 7. Small amount of conjugated bilirubin enters blood 8. Converted to urobilinogens in the colon 9. Some bile pigments and urobilinogens reabsorbed |
|
|
What is the major carbohydrate digestive enzyme in the mouth?
|
Salivary alpha amylase
Optimal pH 6.7, inhibited by stomach acid |
|
|
What are the 2 carbohydrate digestive enzymes in the small intestine?
|
1. Pancreatic alpha amylase
(plus salivary amylase) 2. Oligosaccharidases (lactase, sucrase, maltase, dextrinase) located in the brush border digest products of amylase digestion to glucose, fructose and galactose |
|
|
How are glucose and galactose absorbed in the small intestine?
|
Most glucose and galactose is absorbed before the terminal ileum by secondary active transport Sodium dependent glucose transporter (SGLT 1 and 2) transports glucose into the enterocyte (sodium passes down its concentration gradient then is actively transported out of the cell)
GLUT2 transports glucose out of the enterocyte into the interstitium and hence the capillaries |
|
|
What is the maximum rate of glucose absorption?
|
Maximum rate of glucose absorption is 120g/h
|
|
|
How is fructose absorbed from the GIT?
|
Transported by facilitated diffusion into the enterocyte by GLUT5 and out of the enterocyte by GLUT2
|
|
|
What digests proteins in the stomach?
What is the optimal pH for this? |
Pepsinogen 1 and 2
Secreted by stomach converted to pepsins by hydrochloric acid Optimal pH 1.6-3.2, therefore action terminated in duodenum and jejunum (pH 6.5) Gelatinase |
|
|
What digests proteins in the small intestine?
|
Pancreatic proteolytic enzymes:
Trypsin Chymotrypsin Elastase Carboxypeptidase Mucosal proteolytic enzymes: Enteropeptidase Aminopeptidase Carboxypeptidase Endopeptidase Dipeptidase Intracellular peptidases: Some di and tri peptides are actively transported into the cell then hydrolysed |
|
|
Compare the rate of protein absorption throughout the small intestine?
|
Rapid absorption in duodenum and jejunum, slow in ileum Infants also absorb IgA in the lower intestine
|
|
|
How are amino acids absorbed in the small intestine?
|
At least 7 different transport systems
5 are secondary active transport mechanisms involving sodium Two involve chloride Three are independent of sodium |
|
|
How are di and tripeptides absorbed in the small intestine?
|
Active transport with hydrogen
|
|
|
How are lipids digested in the mouth?
|
Lingual lipase:
Secreted by Ebners gland on the dorsum of the tongue Active in the stomach Digests up to 30% of dietary triglyceride |
|
|
How are lipids digested in the stomach?
|
Gastric lipase
Little importance |
|
|
How are fats digested in the small intestine?
|
Fats are emulsified by bile slats, lecithin and monoglycerides
Fatty acids, monoglycerides, cholesterol and bile salts spontaneously interact to form micelles that move down their concentration gradient to the brush border of the enterocyte |
|
|
What are the 3 active lipases in the small intestine?
|
1. Pancreatic lipase: Secreted as an inactive form and activated by trypsin
Hydrolyses triglycerides to fatty acids and monoglycerides 2. Pancreatic co-lipase Secreted as an inactive form and activated by trypsin Binds to lipase 3. Bile salt activated lipase 4% of total lipase Catalyses the hydrolysis of cholesterol esters, esters of fat-soluble vitamins, phospholipids and triglycerides |
|
|
How is fat absorbed in the small intestine?
|
Most absorption is in the upper parts of the small intestine.
Passive (some evidence of carriers) transport into the enterocyte Fatty acids with less than 10-12 carbon atoms enter the portal blood and are transported as free fatty acids. Fatty acids with more than 12 carbons are re-esterified to TG and form chylomicrons |
|
|
Water input into the small intestine?
|
Ingested 2000ml
Saliva 1500ml Stomach 2500ml Bile 500ml Pancreas 1500ml Intestine 1000ml Total 9000ml Water moves in or out of the intestine down its concentration gradient |
|
|
Water reabsorption in the small intestine?
|
Jejunum 5500ml
Ileum 2000ml Colon 1300ml Total 8800ml Water moves in or out of the intestine down its concentration gradient |
|
|
How is sodium processed in the small intesting and colon?
|
Mostly passive diffusion down concentration gradient Active transport is important for co-transport of glucose and amino acids
Basolateral membranes contain Na/K/2Cl transporters and chloride is then secreted into the lumen of the intestine Basolateral membranes of enterocytes also contain sodium potassium ATPase. Increases in intracellular potassium result in diffusion down its concentration gradient into the lumen. Aldosterone increases the action of this enzyme |
|
|
How is iron absorbed by the small intestine?
|
More readily absorbed in the ferrous state (Fe2+)
Gastric acid dissolves iron and permits it to form complexes with vitamin C and other substances that convert it to its ferrous form Most iron absorbed in the upper small intestine Haem and non-haem iron are both absorbed by different transport proteins Some ferrous iron in the cytoplasm of enterocytes is converted to ferric iron and bound to apoferritin to form ferritin. This ferritin stays in the enterocytes until it migrates to tips of villi and is lost in stool Most of the rest of the iron is actively transported across the basolateral membrane, oxidized to its ferric form, and bound to apotransferrin to form transferrin |
|
|
What enhances iron absorption in the small intestine?
|
Vitamin C
Citric acid Amino acids Sugars |
|
|
What inhibits iron absorption in the small intestine?
|
Tea
Carbonates Oxalates Phosphates |
|
|
Normal transferrin saturation?
|
Transferrin normally 35% saturated
|
|
|
What is metabolism?
|
the amount of energy liberated per unit of time
|
|
|
What is the respiratory quotient?
|
The ratio of the steady state of the volume of carbon dioxide to the volume of oxygen consumed per unit time
|
|
|
What is the respiratory quotient of carb, fat, protein
|
Carbohydrate 1.0
Fat 0.7 (extra oxygen is required for the formation of water) Protein 0.82 (average value) The approximate amounts of carbohydrate, fat and protein consumed at any one time can be calculated from the RQ and urinary nitrogen excretion |
|
|
What is the respiratory quotient of brain?
|
RQ brain 0.97-0.99
|
|
|
What factors affect metabolic rate?
|
Height, weight, surface area
Gender and age Growth, reproduction, lactation, emotional state Circulating levels of thyroid hormones Circulating levels of catecholamines Muscular exertion (increases 10-20 times) Sleep (decreases 10%) Body and environmental temperature (metabolic rate rises 14% for each degree rise in body temperature) Recent ingestion of food (the specific dynamic action (SDA) of a food is the obligatory energy expenditure that occurs during its assimilation into the body) Starvation (decreases 40%) |
|
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How do you measure the basal metabolic rate?
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Standardized metabolic rate in order to minimize variation
Determined at rest in a thermoneutral room, 12 hours after last meal BMR of average male 2000kcal/day |
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What % of ingested gluose becomes glycogen?
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5% converted to glycogen in the liver
30-40% converted into fat 55-65% metabolized |
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What are the body's carbohydrate reserves?
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2500kcal total (112000kcal (45 times more) in fat and protein)
400g muscle glycogen 100g liver glycogen 20g extracellular glucose |
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What organs use most of the glucose at rest?
What about during exercise? |
Brain utilises 70-80% of glucose at rest, red blood cells utilise most of the rest (resting muscle utilises fatty acids)
During exercise, glycogenolysis and increased muscle uptake of glucose supplies extra energy |
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Describe the intracellular metabolism of glucose?
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Glucose phosphorylated to G6P inside cells (hexokinase, glucokinase)
G6P then polymerized to glycogen or catabolised via the Embden Meyerhof pathway or hexose monophosphate shunt to pyruvate Pyruvate is converted to acteyl CoA then to ATP, carbon dioxide and water via the citric acid cycle. Citric acid cycle only functions in aerobic conditions In anaerobic conditions, pyruvate is converted to lactate which is converted back when oxygen becomes available Interconversions between carbohydrate, protein and fat occur via this pathway though conversion from fat to carbohydrate is limited |
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What are the essential amino acids?
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Phenylalanine
Arginine Leucine Methionine Valine Histidine Isoleucine Lysine Threonine |
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What are amino acids used for in the body?
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Absorbed amino acids and amino acids derived from body protein form an amino acid pool that supplies most of the needs of the body
Amino acids are essential for Formation of body protein Formation of hormones, catecholamines, histamine, serotonin, melatonin, purine and pyramidines Formation of urinary sulphates Interconversions occur between amino acids and the products of carbohydrate and fat metabolism and involve transfer, removal or addition of amino groups Oxidative deamination of amino acids forms keto acids and ammonia Ammonia is converted to urea |
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What is creatine made from and what is it used for?
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Creatine is synthesised from methionine, glycine and arginine.
In skeletal muscle creatine is phosphorylated to phosphorylcreatine which is an important store of ATP Phosphorylcreatine is either utilised as an energy source or converted to creatinine. Rate of excretion is relatively constant |
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What is uric acid formed by?
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Breakdown of purines Direct synthesis from 5-PRPP and glutamine Uric acid filtered, 98% reabsorbed 80% of urinary uric acid is secreted
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Describe the body's nitrogen balance?
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Amount of nitrogen in the urine equals the amount of nitrogen in the diet
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What are the biologically important lipids?
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Fatty acids
Triglycerides Phospholipids Sterols |
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What are fatty acids broken down into?
How much ATP is generated? |
Fatty acids are broken down to acetylCoA that enters the citric acid cycle and yields ATP, carbon dioxide and water.
1 mol of fatty acid generates 44 ATPs versus 38 produced by carbohydrate |
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How do you synthesize fatty acids?
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Fatty acids are a major source of energy for many tissues, especially the heart
Fatty acids can be synthesized from acetylCoA in many tissues. In fat depots, fatty acids are combined with glycerol to form triglyceride. |
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Which 2 lipases control the supply of free fatty acids?
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Endothelial derived lipoprotein lipase Intracellular hormone-sensitive lipase
Activity increased by: Catecholamines Growth hormone Glucocorticoids Thyroid hormones. Activity decreased by: Insulin Prostaglandin E |
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What are the common ketone bodies?
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Acetoacetate is formed from acetyl CoA in the liver, then converted to beta hydroxybutyrate and acetone These compounds are metabolized with difficulty in the liver therefore diffuse into the circulation
Tissues other than the liver metabolise acetoacetate to carbon dioxide and water via the citric acid cycle. If acetylCoA accumulates (due to decreased supply of products of glucose metabolism) and keto acids accumulate. |
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What are the 2 types of cells in lipids
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Lipids in cells are of 2 types
Structural lipids Neutral fat. Neutral fat is mobilized in starvation but structural lipid is preserved |
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What does brown fat contain?
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Brown fat makes up a small proportion (more abundant in infants) located between the scapulae and at the nape of the neck.
Brown fat cells contain many mitochondria and are responsible for ATP and heat production. |
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What are fats bound to in plasma?
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Free fatty acids are bound to albumin.
Cholesterol, TG and phospholipids are bound to lipoprotein complexes that increase the solubility of the lipids. Lipoproteins consist of a hydrophobic core of TG and cholesterol esters surrounded by phospholipids and apoproteins |
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Where are chylomicrons found and what do they do?
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Formed in the intestinal mucosa during absorption of products of fat digestion
Large lipoprotein complexes that enter the blood via lymphatics. Cleared from the blood by endothelial lipoprotein lipase (activated by apolipoprotein C-II) Lipoprotein lipase catalyses breakdown of TG to FFA and glycerol that then reenter adipose cells and are re-esterified or circulate in the blood bound to albumin Chylomicron remnants are internalized by liver cells and degraded. |
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VLDL
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Synthesised by the liver
Transports TG formed from fatty acids and carbohydrates in the liver to extra hepatic tissues. Their TG is removed by endothelial lipoprotein lipase and they become IDL |
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IDL
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IDL, formed by removal of TG from VLDL, give up their phospholipids and pick up cholesterol esters from HDL Lecitin-cholesterol acetyltransferase helps this process.
Some IDL is taken up by liver. The rest of IDL loses more TG and protein and becomes LDL. |
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LDL
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LDL is formed from IDL and supplies cholesterol to the tissues. Cholesterol is an essential component of cell membranes and steroid hormones. LDL is recognised by its APO B100 component, binds to a receptor and is endocytosed.
The LDL receptor is recycled and the endosome fuses with the lysosome where cholesterol is formed. |
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HDL
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Cholesterol leaves as well as enters cells and is taken up by HDL HDL is synthesized in the liver and other tissues. HDL transports cholesterol to the liver where it is excreted in bile.
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Cholesterol metabolism?
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Cholesterol is a precursor of steroid hormones and a component of cell membranes. Cholesterol absorbed from the intestine is incorporated into chylomicrons.
Chylomicron remnants bring cholesterol to the liver, where more cholesterol is synthesized. Some cholesterol is excreted in bile as a free form and incorporated into bile acids. Most cholesterol is incorporated into VLDL Cholesterol provides negative feedback by inhibiting further synthesis via inhibition of HMG CoA reductase. It also stimulates esterification of excess cholesterol. Plasma cholesterol is reduced by thyroid hormones and oestrogens. Plasma cholesterol is increased by diet and diabetes. |
