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TUMS

Azin Nowrouzi, PhD

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Principal functions of water• Universal solvent and suspending medium• Helps to regulate body temperature• Participates in hydrolysis reactions

– It is a medium where most cell’s metabolic reactions take place

• Lubricates organs• Provides cellular turgidity• Helps to maintain body homeostasis

– Ionization of water and its acid-base reactions important for the functions of proteins and nucleic acids

• The shapes of proteins and nucleic acids and structure of biological membranes are a consequence of their interaction with water.

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Permeability properties

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Solution Equilibrium

5Molar distributions

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Donnan’s Equilibrium

a. According to Donnan’s equilibrium, the product of diffusible electrolytes in both compartments will be equal.[K+]L x [Cl-]L = [K+]R x [Cl-]R

9 x 4 = 6 x 6

b. The electrical neutrality in each compartment is maintained (the number of anions should equal the number of cations)In left: K+ = R- + Cl- 9 = 5 + 4In right: K+ = Cl- 6 = 6

c. Total number of each type of ion is the same before and after equilibriumK+ = 9 + 6 = 15Cl- = 4 + 6 = 10

d. When there is nondiffusible anion in one side of a semipermeable membrane, the diffusible cations are more and diffusible anions are less, in that side.

Left Right

(5) K+

(5) Pr -

(10) K+

(10) Cl-

Before equilibrium

After equilibrium

Left Right

(9) K+

(5) Pr -

(4) Cl-

(6) K+

(6) Cl-

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Osmosis = diffusion of water across a semipermeable membrane (like a cell membrane) from an area of low solute concentration to an area of high solute concentration.

Osmosis &Osmotic pressure

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Cell membrane is a selectively Cell membrane is a selectively permeable membrane permeable membrane

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Osmotically effective solutes

• The major extracellular solute is Na and its associated anions.

• The major intracellular solute is K and its associated anions.

• These solutes are relatively restricted to their compartments

Solutes that are relatively restricted to one particular body fluid compartment are able to exert an osmotic force for water movement from other compartments.

Such solutes are called osmotically effective, or simply effective solutes.

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Noneffective solutes

• Some solutes, notably urea pass freely across cell membranes and do not exert a force for water movement between the two major body fluid compartments.

• Ethanol, methanol and ethylene glycol are also noneffective solutes.

• Such noneffective solutes contribute to body osmolality but not to tonicity.

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Osmolarity, Osmolality

Osmolarity: Number of particles dissolved in 1 L water = osm/L H2O

– 1 osmol = 6x1023 solute molecules per liter – example: 150 mM NaCl = 300 mosmol solute (150

mMNa+ + 150 mM Cl-)– It is not an SI unit

Volume depends on factors like temperature, thus osmolality is used: Number of particle in 1kg of water

= osm/kg H2OFor Glucose: molality = osmolalityFor NaCl: osmolality = molality x 2

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Osmolality & osmolarity measurement

• Osmolality can be measured using an osmometer. Osmometers are useful for determining the concentration of dissolved salts or sugars in blood or urine samples.

• Osmolarity = 2 x [Na+] + [urea] + [glucose]

(Concentrations are in mmol/L)• Difference between the two is osmolar gap. It

occurs when abnormal species are present in plasma (such as poisons)

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In medicine

Relative to blood plasma, a solution can be:

• Isosmolal: Equal osmolality• Hyposmolal: Lower

osmolality• Hyperosmolal: Higher

osmolality

Freezing point osmometer(cryoscope)

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U-Tube Osmometer

direction of net water movement?

semipermeable membrane (only permeable to water)

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Tonicity

Tonicity is a unitless concept that can be expressed only in reference to a physiologic system:

• A hypertonic solution is one that would shrink cells.

• A hypotonic one would cause them to swell.• In an isotonic solution cells are not affected.

• Loss of free water → The fluid becomes too concentrated (increased osmolarity) → Hypertonic

• Gain in free water → The fluid becomes too dilute → It is called Hypotonic

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Mean concentrations of the more important solutes in cell compartments

Fluid Na+ K+ Ca2+ Mg2+ Cl- Amino

acids

Glucose

mg%

Extracellular 142 4 5 3 103 5 90

Intracellular 10 140 1 58 4 40 0-20

All concentrations except those of glucose are in milliequivalents per liter.

• The osmolality of ECF is in the range of 282-290 mOsm/kg of water (282-295 mmmol/Kg of water).

• Intracellular fluid osmolality is the same (about 282-290 mOsm/kg water).– Water freely permeates across cell membranes.– Major extracellular and intracellular effective solutes do not. – Any loss or gain of water in the ECF will affect the water

concentration in the ICF.

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ECF osmolality

Major contributors to ECF osmolality:• Sodium • Chloride • Bicarbonate• Glucose• Urea

Osmotically noneffective solutes, such as urea, contribute to body osmolality but not to tonicity.

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• Liquid inside cells (Intracellular fluid) - 40 % • Extracellular fluids - 15 % • Liquid making the plasma of blood - 5 %

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Total body water

50%-60% BW

Intracellular fluid

35%-40% BW

Extracellular fluid

15%-20% BW

Blood plasma (intravascular fluid)

4%-5% BW

Interstitial fluid

(extravascular)

11%-15%BW

Lymph

Transcellular fluid:

Cerebrospinal fluid

Intraocular fluid

Synovial fluid

Pericardial fluid

Pleural fluid

Peritoneal fluid

BW = Body Weight

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Measurement of volumes of the fluid compartments by

an indirect dilution technique

Compartment Substance used

Total 3H2O (radioactive water), antipyrine

Extracellular Thiosulfate, inulin

Blood plasma Evans blue

Compartment V (ml) = Substance concentration in compartment (mg/ml)Quantity of substance introduced (mg)

Interstitial fluid = Extracellular fluid – Plasma volume

Intracellular fluid = Total body water – Extracellular fluid volume

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How does total body water vary?

Age Infants: Body water ~75%-80% of BW.

Elderly people: Water only 40%-50% of BW.

The percentage decreases with age.

Sex Women usually have less body water than men because the greater proportion of adipose tissue in women contains lesser amounts of water than other tissue types.

Weight Obese people have less body water because of and abundance of adipose tissue. Total body water content is inversely related to body fat content.

Environmental temperature, Physiological state, Food quality and quantity

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How much water can we lose?Infants compared to adults

• In adults: Percent body water is high compared to the skin surface – Adults are not very prone to

dehydration.

• Infants are at high risk of dehydration when febrile or lose fluids due to vomiting or diarrhea.– It is critical to administer

fluids to a febrile infant to maintain body homeostasis.

• Body can lose nearly all fat and over half of its protein and live.

But• 10 -15% loss of water will

result in death.• Loss of water through

skin is increased 13% for each degree rise in centigrade in body temperature.

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Sources of body water

1. Drinking water2. In food3. Metabolic water from nutrient oxidaton

– Glucose + 6O2 6CO2 + 6H2O– 1g carbohydreate = 0.6ml water– Alanine + 3O2 2.5 CO2 + CO(NH2)2 + 2.5

H2O– 1g protein releases 0.4ml water– Palmitic acid + 23O2 16CO2 + 16H2O– 1g fat generates 1.1ml water

– About 1000 kcal is equivalent to intake of 125ml of water

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Water losses• Urine

– Ambient temperature– Digestible dry matter

intake– N intake, metabolism and

excretion

• Feces– Water intake– Dry matter intake– Fiber content of food

• Insensible loss through evaporation– Ambient temperature

• Physiological state– Lactation– Pregnancy

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Water balance

Fluid intake = fluid outputHydration Positive water balance

When body water intake exceeds water input

Dehydration Negative water balance

When water output exceeds intake

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Water and salt disturbances1. Depletion

– Water depletion (Dehydration or hypovolemia)• Inadequate water intake • Excessive loss

– Sodium depletion (Hyponatremia)• Inadequate oral intake• Inadequate parenteral input• Excessive sodium loss (isotonic loss for example in plasma,

hypotonic loss (in sweat or urine)

2. Excess– Water excess (overhydration or hypervolemia)

• Impaired excretion• Excessive intake (psychiatric disorders, organic brain disease for

example trauma and following surgery)

– Sodium excess (Hypernatremia)• Increased intake• Decreased excretion (renal disease, primary adrenal disease,

secondary hyperaldosteronism).

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Dehydration or hypovolemia(Water loss)

• Causes: – Decreased intake (lack of water, psychogenic refusal to drink) – Increased output (vomiting, diarrhea, loss of blood, drainage from

burns, diabetes mellitus, diuretic use, lack of ADH due to diabetes insipidus.

• Symptoms: loss of weight, rise in body temperature, increase in heart rate and cardiac output, decrease in blood pressure, sunken eyeballs.

• Response: – Decrease in salivary secretion and drying of the mouth and pharynx

thirst– Increased osmolality and low blood volume and pressure release

of ADH from posterior pituitory, increased reabsorption of water in kidney tubules

– Aldosterone secretion from adrenal gland

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Overhydration or hypervolemia(Water gain)

• Causes: – Excessive IV administration of fluids, psychogenic

drinking episodes, decreased urinary output because of renal failure, congestive heart failure

• Symptoms: Decrease in body temperature, increased blood pressure, edema, weight gain.

• Response: – Decreased osmolarity of fluids in the hypothalamus

inhibition of thirst, decreased release of ADH and decreased aldosterone secretion increased urinary output

30Water intoxication=consumption of too much water too quickly

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Hyponatremia (sodium deficit) Hypernatremia (Sodium excess)

• Normal [Na+] in blood plasma = 150mEq/L• Excess of water [Na+] below 120 mEq/L

lethargy, coma, or death.Sodium loss: Decreased ECF volume

Aldosterone secretion Renal sodium reabsorption decreased Na+ excretion.

• [Na+] affects plasma & ECF osmolarity• [Na+] affects blood pressure & ECF

volume

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Too little aldosterone:

Addison’s disease

Hyperaldosteronism: 1- Primary (due to tumors of adrenal cortex)

2- Secondary: liver disease, heart failure, pregnancy, nephrosis…

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The hormones interact when blood loss or dehydration occurs to maintain

intravascular volume

Factors that stimulate renin release:

a. Decreased blood pressure

b. Salt depletionc. Prostaglandinsd. Beta-adrenergic drugs

Inhibitors of renin release:a. Increased blood pressureb. Salt intakec. Prostaglandin inhibitorsd. Beta-adrenergic

antagonistse. Angiotensin II

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Salt & water Disturbance

ECS ICS Osm Examples

1 Isosmotic loss

vomiting, diarrhea, diuretic therapy, blood loss, burn, drainage of ascites

2 Water deficit ICSECS sweating, hyperventilation, osmotic diuresis, chronic renal disease, diabetes insipidus

3 Salt deficit ECSICS

vomiting, diarrhea, sweating, adrenal insufficiency, hypokalemia, CNS lesion, salt-losing nephritis.

4 Isosmotic excess

Heart failure, nephrosis, acute glomerulonephritis, decompensated cirrhosis

5 Water excess

ECSICS

Water drinking, excessive ADH secretion, intensive gastric lavage, infusion of glucose solution.

6 Salt excess ICSECS

Infusion of hypertonic saline, adrenal hyperactivity, steroid therapy, drinking sea water, CNS lesions

1, 2, and 3 result in hypovolemia

3 and 5 lead to intracellular edema (including cerebral swelling)

4, 5, and 6 result in extracellular edema (for example, pulmonary edema)

Disturbances in salt and water balance:

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Clinical conditions regarding Na+

• Hyponatremia– Plasma [Na+] may be normal (if isotonic

loss), high (if hypotonic loss), low (vasopressin secretion secondary to hypovolemia causes water retention).

– Cause:I. Depletion of sodium (hypovolemic hyponatremia)

II. Water excess (euvolemic hyponatremia)

III. Combined water and sodium excess (hypervolemic hyponatremia)

• Hypernatremia

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Water and sodium regulation1. Through the action of osmoreceptors in the hypothalamus,

and baroreceptors (stretch receptors) in atria.– Antidiuretic Hormone (ADH) (vasopressin)

• Increases the water permeability of the distal tubule and collecting duct, thus increasing the concentration of urine.

– Atrial Natriuretic Peptide (ANP) • Released when atrial pressure is increased e.g. in heart failure or fluid

overload. It promotes loss of sodium and chloride ions and water chiefly by increasing GFR.

2. NaCl content of body determines the size of extracellular fluid.– Renin

• Increases the production of angiotensin II• Released when there is a fall in intravascular volume e.g. haemorrhage

and dehydration – Aldosterone

• Promotes sodium ion and water reabsorption in the distal tubule and collecting duct where Na+ is exchanged for potassium (K+) and hydrogen ions by a specific cellular pump

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Role of the Kidney

• GFR = Volume of filtrate formed by all the nephrons of both kidneys each minute.– In adult female GFR = 110 ml/min– In male, GFR = 125 ml/min

• Thus a volume of 7.5 L/h, or 180 L/day is formed.– ~99% of the filtrate is reabsorbed from renal tubules and

returned to the bloodstream.– ~1% is excreted in urine

• Urine volume is regulated according to the needs of the body.

• Most solutes are reabsorbed completely or almost completely according to the needs of the body.

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Renal handling of different substances

Substance Kg/day

filtered

Kg/day

excreted

Percentage reabsorbed

Water 180.00 1.8 99%

Glucose 0.180 0.180 100%

Sodium 0.630 0.0032 99.5%

Urea 0.056 0.028 50%

• Substances that are actively transported from peritubular capillaries to the tubule lumen:Hydrogen, potassium, penicillin, poisons, drugs, metabolic toxins, chemicals that are not normally present in the body.

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Nephron segment

• Proximal tubule– Glucose & Na+

• Loop of Henle– H2O, Na+, K+ & Cl-

• Distal tubule– Na+ & H2O

• Collecting duct– H2O, Na+ & urea– Hormone regulated

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Regulation of Urine Concentration by the kidneys

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Countercurrent multiplier exchange

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Diabetic Hyperosmolar state

• In diabetics with serum glucose ~ 700 mg/dL, the hyperosmolar state caused efflux of cellular water osmotic dilution of serum sodium. (For each 100 mg/dL increase in serum glucose, there is 1.6 mEq/L decrease in the serum [Na+]).

• Transport of glucose into cells happens along with concurrent potassium transport into cells insulin resistance causes high serum potassium.

• Pattern:• Low serum sodium and high serum potassium

(same as hypoaldosteronism), • High glucose levels.

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Drugs affecting water absorption in kidney tubules: Diuretics & Antidiuretics

• Diuretic drugs:• Act on nephronic

tubules • Increase the excretion

of salt (NaCl, NaHCO3) and water.

used in heart failure management

BP control reduction of edema correction of base-acid

balance (pH)

• Antidiuretic drugs: • Decrease the

secretion of salt and water.

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Free Water Passing Through Membrane Pores

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Cellular Mechanisms of Water Transport

• The precise pathways whereby water crosses membranes has only recently been discovered.

• A family of membrane proteins has now been described, termed aquaporins.

• To date three members of this family have been described in mammals and are termed CHIP28, WCH-CD and MIP26 and display about 45% homology.

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Water channel molecules• CHIP28 (channel forming integral protein) was the first

known water channel molecule.

– A 28 kDa protein, and within the kidney is found exclusively in the proximal tubule.

– CHIP28 protein is present in many tissues including lung, small intestine, and red blood cells, and therefore plays an important role in water transport in different organs

• WCH-CD (water channel of the collecting duct) – Found exclusively in the collecting duct, on the luminal surface

of the tubule, and is sensitive to ADH (whereas CHIP28 is not).

• MIP26 (major intrinsic protein of the mammalian lens) has not been detected in renal tissue.

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Formation of Water Pores: Mechanism of Vasopressin Action

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Potassium inside the kidney