2012 lecture 4 Body Fluids, Compartments, Na, K

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Chapter 2 in Marshall, Clinical Biochemistry :

Chapter 2 in Marshall, Clinical Biochemistry Body Fluid and Compartments 1

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Concentrations: the basic units Molarity : number of moles/litre solution 1 mol/L NaOH solution MW of NaOH is 40g/mol To make a 1 mol/L solution of NaOH: dissolve 40 g of NaOH in 1 L of water Molality -number of moles of solute per kg solvent (water) In the case of substances that can dissociate: Osmolarity -number of moles of particles/ litre solution Osmolality -number of moles of particles/ kg of water Number of mOsm determined by # of particles in solution If molecule ionizes, each ion contributes to osmolarity 1 mmol glucose in 1L = 1 mOsm/L 1 mmol CaCl 2 in 1 L = 3 mOsm/L Osmolarity vs Osmolality For a simple solution, there is no significant difference For plasma there is a significant difference Osmolality is the more appropriate term 90% Water 10% Solid Osmolarity Osmolality Plasma 2

Body Fluid and Compartments:

All body fluids are aqueous Transport of nutrients and removal of waste Chemical reactions of the body are conducted in water based buffer Compartments exist to perform specialized functions Volume, constituents and concentration must be maintained to support life. All factors are interconnected. Multiple regulatory systems. Body Fluid and Compartments 3

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Body Water Compartments Intracellular Compartment-2/3 of TBW(total body weight) Extracellular compartment -1/3 Major divisions Plasma – ¼ about 8-10 % of TBW Interstitial – ¾ Minor Division Transcellular- separated by a layer of epithelium CSF, intraocular, pleural, peritoneal, synovial fluid, digestive secretions Under pathological conditions (pleural effusions, ascites) this can represent a large portion of extracellular fluid 4

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Na is the major extracellular cation ECF [135 – 145 mmol /L], ICF [4 – 10 mmol /L] Input and output balanced (need to be balanced) K is the major intracellular cation ECF [3.5 – 5.5 mmol /L], ICF [ ~ 110 mmol /L] 2% of total K is located in ECF. ECF [K] is poor indicator of body K status. 95% ICF ECF [K] tightly regulated – effect on membrane excitability 5

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6

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7 Relationships between body fluid compartments and the barriers that separate them

Why do different compartments have different concentrations of ions?:

8 Why do different compartments have different concentrations of ions? Semi-permeable membranes separate the various compartments Intracellular/interstitial and interstitial/plasma Water moves freely between the compartments Small molecules (Na +, K + , Cl - ) move across membranes but large molecules (protein - ) do not.

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9 Solutions separated by semi-permeable membranes If solutes can move freely – ionic equilibrium will be established If non-movable solutes are present (protein) the distribution of movable solutes will be unequal so that two rules are satisfied Product of ion concentrations must be equal (Gibbs-Donnan Eq’m) Electrical neutrality must be maintained

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Interesting animation that explains Gibbs- Donnan equilibrium http://www.youtube.com/watch?v=uqr7FZ8oiyo 10

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Key concepts Osmosis The movement of water across a semipermeable membrane from a solution with low solute concentration to a solution with high solute concentration. (movement of water) Osmotic pressure The force necessary to exactly oppose osmosis of a solvent into a solution with high particle concentration Gibbs-Donnan equilibrium Higher concentration of negatively charged macromolecules (proteins) in one compartment causes an asymmetric distribution of diffusable ions between compartments separated by semipermeable membrane Osmotic pressure due Gibbs-Donnan equilibrium is known as oncotic pressure. 11

Interstitial/Plasma Compartments:

Interstitial/Plasma Compartments Capillaries are permeable to water, small ions and molecules but are less permeable to proteins and larger particles [Protein] in interstitial fluid = 10 g/L [Protein] in plasma = 70 g/L Higher concentration of negatively charged proteins in plasma causes an asymmetric distribution of diffusable extracellular ions between plasma and interstitial fluid. Albumin accounts for 65% of oncotic pressure in plasma 12

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13 Hydrostatic pressure vs Oncontic pressure

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Fluid movement in and out of the vascular system At the arterial end of the capillary bed hydrostatic pressure is high, but oncotic pressure is relatively low. Water moves from the vascular space to the intersitial space. (protein stay) Filtered fluid returns to the capillary at more distal portions of capillary where hydraulic pressure is lower and oncotic pressure higher because of prior movement of fluid out of capillary. 10% of fluid is normally returned to circulation by the lymphatics Disruption of this balance often leads to Edema Edema: an increase in interstitial fluid volume Resulting from increased capillary hydraulic pressure (heart failure) (to much water pushing out) Decreased plasma oncotic pressure (hypoalbuminemia - starvation, nephrotic syndrome, liver failure) ( cant pull water back ) 14

Intracellular/ Interstitial Compartments:

15 Intracellular/ Interstitial Compartments Plasma membranes are impermeable to ions (some leakage) The plasma membranes that separate these compartments contain energy dependent pumps that create concentration gradients for ions. Na/K ATPase pumps transport Na out of the cell and K into the cell Na/H antiporter pumps H + out of the cell in exchange for Na.

How Does your Body regulate Water and Electrolytes WATER:

How Does your Body regulate Water and Electrolytes WATER About 40 L of water Daily water loss is 2-3 L from the body majority from urine, other sources include sweat, stool and respiration water is taken in to replace lost fluids body regulates intake and release to maintain osmolality and volume of plasma l 16

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17 Water Balance

Changes in Water Content:

Changes in Water Content Changes in body water (loss or gain of pure water) will result in changes in osmolality (think Na concentration) Osmoregulators: hypothalamus responds to increase osmolarity activating two types of protective responses Thirst sensors respond to increase in osmotic pressure resulting in water intake and lowering osmolarity Antidiuretic hormone (ADH) (also called Vasopressin ) causes increased permeability of collecting ducts in the kidney to water. Changes Na concentration are responded to by changes in water intake and reabsorption. 18

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19

Sodium:

Sodium 20

Sodium Balance:

Sodium Balance The human body contains 4000 mmol Na 95% extracellular and 5% intracellular 25,000 mmol filtered by kidneys each day Vast majority reabsorbed 1,000 mmol secreted into gut and reabsorbed Daily intake of sodium is 100-300mmol/day Daily losses should match intake = 100 mmol/day Plasma concentration is 135-145 mmol/L 21

Sodium and Extracellular Fluid Volume:

Sodium and Extracellular Fluid Volume Na is confined almost exclusively to ECF Dietary intake is variable Na balance regulated by the kidney Large amounts of Na filtered through the glomerulus. Most is reabsorbed. Fine tuning of Na balance controlled by Renin – Angiotensin – Aldosterone system Natriuretic peptides Remember the role of ADH 22

Sodium reabsorption:

Sodium reabsorption Sodium is reabsorbed almost completely (~ 95%), esp. in proximal tubule. Fine tuning in the distal tubules (ADH and other hormones play a role here) 23

Hormonal Regulation of Water and Electrolytes:

Hormonal Regulation of Water and Electrolytes Volume Regulators day to day water status governed by osm body can override signal of osmoreceptors if necessary to preserve normal plasma volume volume regulators are relatively insensitive but more potent ADH: increased production when osmolality increases (1%), or blood volume decreases (5-10%) Renin-angiotensin-aldosterone system decrease in renal blood flow or sodium reaching the distal tubule results in the release of Renin Renin catalyzes production of angiotensin II (AGII), a potent vasoconstrictor. AGII potent stimulus to aldosterone (sodium retention), thirst behaviour and ADH Natriuretic peptide (NP): increased production caused by an increase in stretch of atrial myocardium (stretch receptors) NP decreases Na reabsorption, inhibits aldosterone decreased plasma volume and total body sodium 24

ADH:

ADH Produced by posterior pituitary and is increased when osmolarity rises Decreases renal water loss Increases thirst Simple tests to ascertain ADH status : measure plasma & urine osmolarity urine > plasma suggests ADH is active 25

Renin-angiotensin system:

Renin-angiotensin system Renin -> angiotensin -> aldosterone Activated by reduced Intravascular Volume (decreased renal blood flow) Na depletion Causes renal Na retention (and K loss) Changes in plasma volume result in changes in Na reabsorption WATER FOLLOWS SODIUM Simple test to ascertain Renin-angiotensin system status : measure urine Na if urine < 10 mmol/L suggests Renin-angiotensin system active 26

Natriuretic Peptides:

Natriuretic Peptides Increase in stretch receptors in the atrium and ventricles of the heart (Increase in plasma volume) causes increase in production of natriuretic peptides NPs cause loss of Na through the kidneys ‘natriuresis’ Changes in volume result in changes in Na loss WATER FOLLOWS SODIUM 27

Simplified Cycle of Na and Water Balance:

Simplified Cycle of Na and Water Balance 28 START HERE Water Renal Blood Flow Renin-Angiotensin System Aldosterone Natriuretic Peptides [Na] Osmolality Cardiac Stretch Osmolality Receptors in Pituitary 1 2 3 ADH

Hypovolemia and Sodium Concentration:

Hypovolemia and Sodium Concentration Definition: Hypovolemia is a decrease in effective arterial blood volume. Hypovolemia alters serum sodium concentration through three mechanisms: 1. Increase of aldosterone levels by RAA axis activation because of reduced kidney perfusion 2. Increase of ADH levels by sympathetic nervous system activation 3. Changes in NP levels due to changes in cardiac stretch Hypovolemia can be accompanied by increased, decreased or normal serum sodium concentration 29

Some Causes of Hypovolemia:

Some Causes of Hypovolemia Dehydration of any cause Edematous states (cirrhosis, nephrotic syndrome, etc) Reduced Cardiac Output – Heart Failure Primary hypoaldosteronism ( Αddison’s disease) Severe peripheral vasodilation 30

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31 Response to Hypovolemia

Definition of Hypernatremia:

Definition of Hypernatremia Hypernatremia is the increase of plasma sodium concentration above 150 mmol / L Hypernatremia doesn’t mean increase in whole body sodium. Hypernatremia represents relative water deficit in relation to sodium in the plasma. This can result from water loss or sodium retention. 32

Causes of Hypernatremia (pathophysiologic classification):

Causes of Hypernatremia (pathophysiologic classification) 1. Excessive sodium intake (usually through hypertonic NaCl or bicarbonate solutions) 2. Reduced water intake (psychogenic hypodipsia, etc) 3. Increased reabsorption of sodium in kidney (hyperaldosteronism) 4. Increased water losses (dehydration of any cause) 33

Definition of Hyponatremia:

Definition of Hyponatremia Hyponatremia is the decrease of plasma sodium concentration below 135 mmol /L. Plasma sodium represents the balance between water intake and water excretion. Hyponatremia doesn’t mean depletion of whole body sodium. Thus, hyponatremia can be associated with normal, increased or decreased total body sodium. 34

Causes of Hyponatremia (pathophysiologic classification):

Causes of Hyponatremia ( pathophysiologic classification) Increased water intake: water intoxication, intake of hypotonic fluids. Pathologic water retention: Edematous hypovolemia, Decreased intake of sodium (salt free diet, rare) Increased sodium losses (relative to water): a. renal losses ( hypoaldosteronism) b. skin losses 35

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Based on clinical examination BP (postural drop) Skin turgor Mucus membranes Urine output Fontanelle in newborns 36

Potassium:

Potassium 37

Disorders of Potassium:

Disorders of Potassium Potassium reference range - 3.5 to 5.0 mmol/L Values < 3.0 or > 6.0 are potentially dangerous Cardiac conduction defects Abnormal neuromuscular excitability Clinical Problems are common Many are iatrogenic and avoidable 38

In clinical situations we measure plasma Potassium concentrations:

In clinical situations we measure plasma Potassium concentrations Plasma Potassium does not reflect body Potassium Small proportion of total Potassium in plasma Total body Potassium determined by total cell mass Exchange ICF - ECF significantly affects Plasma K Acidosis Insulin/glucose therapy 39

Relationship of Potassium to Hydrogen Ions:

Relationship of Potassium to Hydrogen Ions K+ and H+ exchange across cell membrane Both bind to negatively charged proteins (eg Hb) Changes in pH cause shifts in the equilibrium Systemic acidosis - potassium moves out of cells -> hyperkalemia alkalosis - potassium moves into cells -> hypokalemia Acute same results but different mechanism involves renal excretion 40

Causes of Hyperkalemia:

Causes of Hyperkalemia Artifactual Delay in sample analysis Hemolysis Drug therapy Excess intake Renal Acute Renal Failure Chronic Renal Failure Acidosis (intracellular exchange) Mineralocorticoid Dysfunction (Aldosterone increases renal excretion of K) Adrenocortical failure Mineralocorticoid resistance - Cell Death 41

Treatment of Hyperkalaemia:

Treatment of Hyperkalaemia Correct acidosis if this is cause Stop unnecessary supplements / intake Give Glucose & insulin Drives potassium into cells Ion exchange resins Gastrointestinal tract potassium binding Dialysis short and long-term 42

Causes of Potassium Depletion:

Causes of Potassium Depletion Low intake Increased urine loss diuretics tubular dysfunction mineralocorticoid excess Gastrointestinal losses vomiting diarrhea / laxatives fistula Hypokalemia without depletion alkalosis insulin / glucose therapy. 43

Detection of Potassium Depletion:

Detection of Potassium Depletion History: diarrhea, vomiting, drugs (diuretics, digoxin) symptoms of lethargy / weakness cardiac arrhythmias Electrolytes investigation: hypokalemia 44

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