Medsci 205 Lecture Notes PDF

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Lecture 1: Body Fluid Compartments and Water TransportDescribe the relationship between cells, tissues, organs and organ systemsCells: are the basic unit of a living organisms, they undergo differentiation and are assigned specialised roles.Tissues: are a group of cells with specialised roles (muscl...

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Lecture 1: Body Fluid Compartments and Water Transport Describe the relationship between cells, tissues, organs and organ systems Cells: are the basic unit of a living organisms, they undergo differentiation and are assigned specialised roles. Tissues: are a group of cells with specialised roles (muscles, connective, nerve and epithelial). Functional Unit: composed of fur types of tissue. Organs: are made up of tissue which carries out a particular function. Organ System: are several organs which work together to perform a particular role such as the gastrointestinal tract, urinary system, nerve system and etc. Describe the location and composition of the various fluid compartment in the body Total Body Water – 60% of body weight in men and 55% body weight in women. Intracellular compartment fluid consists of 60% of the total body water. Extracellular compartment fluid consists of 40% of the total body fluid. Interstitial fluid consists of 75% of the ECF. Plasma consists of 20% of ECG. Transcellular fluid consist of 5% of ECF. Transcellular fluid – in the synovial fluid, joint fluid and plural fluid. Define homeostasis and explain how it relates to extracellular fluid Homeostasis is an organisms process of maintaining a stable environment suitable for sustaining life.

Negative feedback loop deceases the initial stimuli effect, reverses a change in the controlled condition. Positive feedback loop increases the stimuli effect, reinforces the change in the controlled condition – in pregnancy.

Gain = correction/error

To gain an understanding of how changes in the composition of interstitial fluid can influence cell volume Although the ICF and ECF have different compositions, the number of osmotically active particles in the ECF and ICF are almost the same. If the fluid has to move there must be a change in osmolarity and that is the key thing to know about this section. Main Electrolytes In Humans: -

Sodium (Na+), Chloride (Cl-), Potassium (K+) Magnesium (Mg+2), Calcium (Ca+2), Hydrogen Phosphate (HPO42-) Hydrogen Carbonate (HCO3−) Protein free plasma: means that the plasma has proteins and fluid/water, and water usually makes up 93% and protein is 3%. The more accurate way of looking at sodium in the body is by looking at protein free plasma which is sodium dissolved in the water component of plasma rather than plasma + protein + water. Total osmolarity of the solution intercellular and extracellular ranges from 280mM to 300mM. The difference in ICF/ECF solutes are responsible for:

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Setting the membrane potential Generating electrical activity Muscle contraction Nutrient uptake via secondary active transport Generation of intracellular signalling cascades More sodium outside and less sodium inside, that is the gradient that allows us to have action potentials, cardiac potentials and nutrient uptake and etc. Water moves via: passive movement generally dependent on solutes, bulk movement through aquariums, transcellular pathways and paracellular pathways. One of the most important functions of Na/K ion pump is the control of cell volume. Bings 2 potassium into the cell and 3 sodium out of the cell, while using 1 ATP, this creates a high concentration of potassium in the cell and a high concentration of sodium outside the cell. Osmosis is net diffusion of water (across a semi-permeable membrane) from a region of high water concentration to one that has a lower water concentration Isotonic solution = no change in cell volume. Hypotonic solution = cause cell swelling and eventually cell lysis. Hypertonic solution = causes cell shrinkage (crenation).

After adding 1.5L of 145mM NaCl in H2O to ECF: -

Saline, isotonic solution Adds to the ECC, ECC expands, no net change in osmolarity as osmolarity of solution is the same as that of ECF an ICF, no net movement of H2O.

After adding 1.5L of pure H2O to ECF: -

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No electrolytes Goes into ECF, ECF expands and while it expands it also dilutes osmolarity of ECF which means over a period of time there will be movement of solutes and water between the ECF and ICF. Over a period of time there will be movement of solutes and solvents.

After adding 217.5mM of pure NaCl to ECF: -

Adding salt to ECC, there is an increase in solutes in ECC Osmolarity changes in ECF and water then drags from ICF to ECF, there is shrinkage of the ICF compartment.

Lecture 2: Water and electrolyte absorption and secretion in the gastrointestinal tract (GI) To review the macro- and micro-structure of different regions of the GI tract and its surface epithelia Surface of small intestine is amplified (folded) at 3 levels – key for small intestine is absorption, provide acidic environment in first part of the GI tract and absorb all the nutrients. -

Folds of Kecking – large numbers of folds Microvilli and crypts of Lieberkühn – to provide mucous for effective absorption - Sub microscopic microvilli Surface of Large intestine is amplified (folded) at 3 levels

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Semilunar folds – less absorptive region Crypts, but no villi Microvilli Small Intestine Large Intestine Length (m) 6 2.4 Area of apical plasma membrane (m2) 200 25 Folds Yes Yes Villi Yes No Crypts or glands Microvilli

Yes Yes

Yes Yes

Nutrient absorption

Yes

No

Active Na absorption

Yes

Yes

Active K+ secretion

No

Yes

+

Key purpose is to show that the main function of the small intestine is to absorb nutrients and the large intestine is to absorb fluid and have some secretory function.

The amount of fluid showing up to the upper GI tract is roughly 8.5L. About 6.5L is reabsorbed, so only 2L is presented to the large intestine of which about 90% of it is reabsorbed (1.9L), and 100mL is being lost as faecal fluid. What if there is a problem with absorption, it will lead to diarrhoea, more fluid being lost. If there is a problem in the colon where absorption is not effective– diarrhoea. So either less absorption or less secretion will increase fluid loss from the body. We are absorbing almost everything in the small intestine, the key purpose of the large intestine is secretion of hydrogen ions and bicarbonate ions but mostly reabsorb sodium chloride and water. If there is less absorption or more secretion then it results in more fluid loss – diarrhoea. Absorption of non-electrolyte nutrients occurs mainly in small intestine, whereas both the small and large intestine absorb water and electrolytes (Na+, Cl- etc) The small intestine absorbs net amounts of water, Na +, Cl- and K+ and secretes HCO3-, whereas the large intestine absorbs net amounts of water, Na+, Cl- and secretes both K+ and HCO3To review and extend your understanding of osmosis, water permeability and the movement of water across epithelial tissues Lumen of GI tract is where the food is presented. Basal membrane is in touch with the extracellular compartment. In the basolateral membrane are the Na+/K- ATPases, they remove 3Na+ and bring 2K- in. High concentration of K- in the ICC and high concentration of Na+ in the ECF (54mM). Maintain a low concentration of Na+ inside the cell which then drives the electrochemical gradient of sodium in the lumen into the cell whilst also bringing along other proteins, glucose as co-transporter. If you gave a drug to someone that blocks the Na/K ATPases, sodium is not being pushed out of cell, buildup of Na+, electrochemical gradient not very effective as you can’t bring glucose or proteins in. Build-up of sodium within the cell and breakdown of the electrochemical gradient.

Transepithelial movement of water and solutes: -

Either absorptive or secretory Transcellular (going across basolateral membrane and apical membrane) or paracellular (through junctions between the two cells) Transcellular, must move across 2 membranes in series. Transcellular: solutes, across at least one membrane is active

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Paracellular: movement passive via tight junctions

Absorption of water: -

Entirely by osmosis Coupled to solute movement Occurs vis transcellular or paracellular routes Paracellular predominates mode of absorption Primarily in the jejunum driven by glucose, Na+ or urea which is a solute that moves across the membrane ‘Solvent drag’ responsible for considerable Na+ and urea absorption in jejunum Any problem in the jejunum we might not absorb water which means the water goes to large intestine and out ending up with diarrhoea

To understand the processes of electrolyte absorption and secretion NA/GLUCOSE OR COTRANNSPORTER

NA/AMINO

ACID

Facilitated by Na/K ATPases, there’s deficiency of Na drives from outside (lumen) into cell and brings glucose or amino acid. SPECIFIC NA CHANNELS Usually in jejunum or early part of small intestine and they are specific NHE3 channels, and they exchange Na with the H ions, exchange 1Na with 1H ion and that is a way of getting Na into the cell. NA-H AND CL-HCO3 EXCHANGERS NaCl is salt, if Na moves into the cell which is a positive ion and cl is its companion t will come into the cell, Na is exchanged in means of H and Cl is exchanged in means of HCO3 and H and HCO go together very well to form H2CO3 (bicarbonate acid) which dissociates into H20 and CO2. EPITHELIL NA+ CHANNELS In the colon/large intestine. PASSIVE CL ABSORPTION: As Na moves into the cell it attracts Cl through moving through the passive Cl channels. Cl moving through paracellular pathways through the tight junction.

CL-HCO3 EXCHANGER & PARACELL NA-H AND CL-HCO3 EXCANGER: These are the ways the body actively absorbs Cl.

PASSIVE K+ ABSORBTION & PASSIVE K+ SECRETION This is done through the Na/K ATPases and the K from the ECF gets passively drawn/secreted into the lumen.

ACTIVE K+ SECRETION & ABSORBTION BK channels – actively secreting potassium and also have K/H exchangers.

ACTIVE SECRETION OF CHLORIDE 1)

Na/K ATPases: taking 3 bringing 2K+ into the cell, of Na within the cell.

Na+ out of cell and always a deficiency

2)

Potassium Channels: of K+ within the cell.

regulating

3)

NKCC1 Channels: Taking bringing Na and Cl into the 1Na+ and 2Cli- into the cell.

K+ into the cell and cell. Brings 1K+,

4)

Cystic Fibrosis Transmembrane Receptor: Cl gets moved out of cell by CFTR. Channel inserted as per need to secrete Cl into the lumen. This is regulated by cyclic AMP (cAMP), works as a second messenger and is driven by calcium.

amount

Over-regulation of cAMP, CFTR open, flow of Cl- out of cell, negative charge in lumen, Na+ also flows out of cell to balance charge, NaCl flows outside cell taking along with it water, results in secretory diarrhoea. The thing about this type of diarrhoea is that the composition of it is the same number of osmotically active particles as ECF, which means the amount of ECF is shrinking but the composition of it is not changing, osmolality of ECF is not changing, which means ICF is intact, ECF is decreasing, plasma goes down which means blood goes down which means bp goes down.    

The small intestine is a net absorber of Na, Cl, K and a net secretor of bicarbonates. The human colon carries out a net absorption of water, Na, Cl, with few exceptions, but it carries net secretion of K and bicarbonate. Fluid movement is always coupled with active solute movement. Solute movement may be coupled to fluid movement by solvent drag, a phenomenon in which the dissolved solute is swept along by bulk movement of the solvent (i.e. water). To consider how nutrient malabsorption (e.g. in lactose intolerant or celiac individuals) can lead to osmotic diarrhoea

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Small intestine origin – voluminous, absorption of nutrients. Large intestine origin – small volume diarrhoea, absorption of water and secretion problem.

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Osmotic diarrhoea results from disturbances of absorption Secretory diarrhoea results from disturbances in secretion Lack of absorption or lack of enzymes (in lactose intolerance) or coeliac disease which is an autoimmune reaction to gluten which damages epithelial cells leading to nutrient malabsorption Examples include pancreatic disease, large intakes of sugar, alcohol, fructose, lactose intolerance, coeliac disease Creates a large osmotic pressure/load n the lumen which leads to fluid loss. To understand how water secretion is driven and how over stimulation of secretion can produce diarrhoea.

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Increase in active secretion E. coli r cholera toxin, other bacterial endotoxins activate cAMP which upregulates CFTR, increased Cl secretion, increased NaCl secretion, increased fluid loss Does not effect Na/Glucose transporters or Na/Amino acid transporters which are target areas for treatment of secretory diarrhoea Isotonic solution saline comprises of large amount of glucose which facilitates the movement of Na. Since losing Na, Cl and fluid. Oral rehydration therapy glucose which allows facilitated diffusion through that and also has bicarbonate as when you lose water via diarrhoea you become acidic and bicarbonate compensates that. Lecture 3: Acid Base Physiology Define Acids and Bases and pH regulation A base is an ion or molecule that can accept an H+ , for example HCO3 is a base as it can combine with H+ to form H2CO3. An acid is an ion or molecule that can donate an H+. The term alkali and base are used synonymously, an alkali is a molecule formed by the combination of one or more of the alkaline metals with a basic ion such as hydroxyl (OH-). The term alkalosis refers to excess removal of H+ from the bod fluids on contrast to acidosis which refers to the excess addition of H+ in the body. The normal pH of arterial blood is 7.4, can say we are alkaline, have a lot more bicarbonate in our body PH regulation refers to the processes in maintaining an optimal pH within the body for cellular processes to occur. Processes involved in the regulation of pH There are 3 processes/mechanisms involved in the regulation of pH. The chemical acid-base buffer systems of the body fluids which immediately combine with the acid or base to prevent excessive changes in H+ concentration, it is quick and fast. The respiratory centre which regulates the removal of CO2 and therefore H2CO3 from the extracellular fluid, this takes a few minutes and occurs after the acid-base buffer. The kidneys which can excrete either acid or alkaline urine, thereby readjusting the extracellular fluid H+ concentration toward normal during acidosis or alkalosis, this takes a few hours/days to kick in.

Regulation of pH by Bicarbonate and Phosphate Buffers

Reaction very slow but is accelerated by the enzyme carbonic anhydrase. Bicarbonate acid is an unstable compound, and it dissociates into H+ an HCO3- (acidic buffer), NaHCO3 dissociates into Na+ and HCO3- (basic buffer).

If you have more H+ ions, more acidic environment, it combines with HCO3- which dissociates into H2O and CO2. H2O gets released into the system and CO2 is breathed out.

NaOH combines with H2CO3 to form less harmful salt and water. Bicarbonate buffers are weak as their pKa of 6.1 is not close to the optimum pH of 7.4.

The phosphate buffer system has a pKa of 6.8 which is close to the normal pH of 7.4, this means it is a very strong buffer as it can actively sort out the changes in the pH. Phosphate buffers are especially important in the tubular fluids of the kidney (renal tubule). Strong acid and strong base get converted to inert (unreactive) compounds.

Regulation of pH by Respiratory and Renal System Increased H+ concentration due to holding breath, CO2 levels will also increase, more carbonic acid (H2CO3) produced, more acid in the body, this triggers for increased ventilation. Ventilation curve – small increase in CO2 there is a marked increase in ventilation.

Kidneys: -

Buffers and respiration are quick and fast, prevent damage, kidneys take longer Reabsorption of HCO3- (bicarbonate ion) as we are alkaline (7.4) Secretion of H+ ions Production of new HCO3- ions

Secretion of H+: Way of reabsorbing Bicarbonates (HCO3-) -

Na/K ATPase channel removes 3Na+ from the tubular cell while inserting 2K+ into the cell In the tubular lumen there are Na/H exchanger channels which take 1Na+ into the cell while sending 1H+ out of the cell In the tubular lumen HCO3- exists and it readily combines with H+ ions to produce H2CO3 (carbonic acid) as it is a weak acid it readily dissociates to form CO2 and H2O CO2 diffuses back into the cell and combines with H2O in the presence of carbonic anhydrase to form H2CO3 and H2CO3 readily dissociates into HCO3and H+ ions.

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Active secretion of H+: only occurs when in acidosis, too much H+ ions / acid in body -

Active secretion of H+ ions by the means of H+ active channels charged by ATP (H/Cl exchanger channel) H+ ion is removed from the cell into the renal interstitial fluid CO2 diffuses from renal interstitial fluid into the tubular cell In tubular cell CO2 combines with H2O in the presence of carbonic anhydrase to form H2CO3 H2CO3 readily dissociates into HCO3- and H+ H+ ions get removed via an active transport channel in the tubular lumen

Addition of new HCO3- (Bicarbonate ions): way of producing new HCO3-

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If we are very acidic not only do we have to secrete H+ ions we also need to have new forms of bicarbonate so that we can combine it with HCO3-, in order to produce CO2 and H2O, CO2 can be breathed out Na/K ATPase there is always deficiency of Na+ within the cell, Na/H exchanger channel in the tubular lumen – phosphate buffer Na+ moves into the cell in exchange for a H+ ion, H+ was produced via the CO2 entering the cell from interstitial fluid H+ combines with NaHPO4- to make NaH2PO4 in the renal tubule.

Alternate way of producing bicarbonate (HCO3-) ions is through glutamine which is a biproduct of amino acids Glutamine dissociates into 2HCO3- and 2NH4+ Ammonium (NH4+) gets exchanged via the Na/NH4 exchangers Ammonium ion then combines with Cl- in the lumen and gets release as NH4CLl.

Brief overview on common Acid Base disturbances Regulation of Renal Tubular H+/HCO3- and Respiratory System Table

Acid Base Disturbances Table

Lecture 4: Kidneys – The Stuff of Philosophy GFR- what is it? GFR = Glomerular filtration rate, rate at which things get filtered In the glomerulus. Normal GFR is 125ml per minute. Small changes in filtration rat can effect how well things get secreted or absorbed within in terms of molecules in the blood. 1.Filtration of substances from the capillaries into the bowman’s capsule. 2.Reabsorption back into the capillaries. 3.Secretion back into the tubular fluid & 4.Effectively that forms urine.

Afferent arteriole takes blood into the glomerulus and efferent takes blood out. Blood leaks from the vascular space in the glomerulus into Bowmans capsule. Effectively the diameter of the blood vessel going in compared the diameter of the blood vessel ging out is what defines GFR. GFR is modulated by modulating the diameter of either the afferent or efferent arteriole. Arteriole Afferent Afferent Efferent Efferent

Diameter Increased Decreased Increased Decreased

Filtration Increased Decreased Decreased Increased

How is GFR modulated? Tubular Glomerular Feedback: Intrinsic Mechanism -

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Have some degree of GFR which flows into the Bowmans capsule, goes through the loop of Henle, the distal tubule and at some point the distal tubule comes back and interacts with the afferent arteriole Tubule gives feedback to the glomerulus and can effect GFR Mediators are nitric oxide, ang...