Fluid balance & Transport

across membranes
• Body is formed by solids and fluids.
• Fluid part is more than two third of the whole body.
• Water forms most of the fluid part of the body.
• In humans, the TBW varies from 45% to 75% of body weight.
• In females, water is less because of more amount of adipose tissue.
• In thin persons, water content is more than that in obese persons.
• In elderly, water content is decreased due to increase in adipose
tissue.
• TBW in an average human weighing about 70 kg is about 42 L
COMPOSITION OF BODY FLUIDS

• Body fluids contain water and solids.

• Solids are organic and inorganic substances
Organic substances
• Organic substances are glucose, amino acids and other proteins, fatty
acids and other lipids, hormones and enzymes
Inorganic substances
• Inorganic substances present in body fluids are sodium, potassium,
calcium, magnesium, chloride, bicarbonate, phosphate and sulfate.
• ECF contains large quantity of Na+, Cl-, HCO3-, glucose, fatty acids
and oxygen.
• ICF contains large quantities of K+, Mg2+, phosphates, sulfates and
proteins.
• The pH of ECF is 7.4.
• The pH of ICF is 7.0.
• Maintenance of constant volume & stable composition important for
homeostasis
• Abnormalities in control systems that maintain above causes many
clinical symptoms
• There is continuous exchange of fluids & solutes with the external
environment as well as different body compartments
• Fluid intake varies considerably & must be balanced by equal output
from body to prevent body volumes to increase or decrease
Water intake
• Ingestion : about 1000ml/day
• End product of carbohydrate oxidation: 200ml/day
• Total intake about 1200ml/day but ingested water varies considerably
Water loss

• Evaporation through respiration & diffusion about 700ml/day

(insensible water loss)
• Above independent of sweating
• Loss through sweat: variable but about 100ml/day
• Through faeces: about 100ml
• Loss through kidneys: most important and accounts for remaining loss
• Kidney most important regulator of water & electrolyte levels in body
• Loss varies from 0.5 l a day for a dehydrated person to 2 l daily.
• Electrolyte loss also varies considerably
body fluid compartments
• Two compartments
Extracellular fluid: mainly divided into plasma & interstitial fluid
Intracellular fluid
Also trans cellular fluid
• An adult human being has about 42 liters fluids but varies with age
Intracellular fluid compartment
• Fluid inside cells
• About 28 liters
• Consists of different constituents but concetration’s are almost similar
from cell to cell and in different animals
Major Compartments of Body Fluid

• 1. Intracellular fluid (ICF) - 40 % (2/3) TBW (in the adult)

• 2. Extracellular fluid (ECF) - 20 % (1/3) TBW
• a. interstitial fluid (ISF) - compartment between the cells (15 %)
• b. intravascular fluid (IVF)
• in addition to the ISF and IVF, special secretions (cerebrospinal fluid,
intraocular fluid, and gastrointestinal secretions) form a small
proportion (1 % to 2 % of body weight) of the extracellular fluid called
transcellular fluid
Extracellular fluid compartment
• All the fluid outside cells
• Is 20% body weight ---14 liters
• Interstitial fluid: is the fluid in the interstitial space between cells and is
about 11 litres
• Plasma: the non cellular part of blood
• There is continuous exchange of substances between plasma & interstitial
fluids through capillary pores
• The pores are permeable to most solutes except for proteins
• Due to above continuous mixing, composition is almost the same except
for proteins
• MAJOR IONS
Extracellular fluid: sodium, calcium, chloride & bicarbonate
Intracellular fluid: potassium, magnesium, phosphates , proteins &
other organic anions
Non electrolytes in plasma include cholesterol, phospholipids,
neutral fats, glucose , urea, lactic acid , uric acid, creatinine, bilirubin
& bile salts
 Differences between extracellular fluid (ECF)
and intracellular fluid (ICF)
• ECF ICF
• Sodium 142 mEq/L 14 mEq/L
• Calcium 5 mEq/L 1 mEq/L
• Potassium 4 mEq/L 140 mEq/L
• Magnesium 3 mEq/L 28 mEq/L
• Chloride 103 mEq/L 4 mEq/L
• Bicarbonate 28 mEq/L 10 mEq/L
• Proteins 2 g/dL 16 g/dL
Major electrolytes and their distribution

• Sodium (Na+) - chief cation of the ECF

• Potassium (K+) - the chief cation of the ICF
• Calcium (Ca++)
• Magnesium (Mg++)
• Chloride (Cl-) - chief anion of the ECF
• Bicarbonate (HCO3- ) - chief anion of the ECF
• Phosphate (HPO42--) - chief anion of the ICF
Major electrolytes and their distribution - 2
• Sodium plays a major role in controlling total body fluid volume;
potassium is important in controlling the volume of the cell
• The law of electrical neutrality states that the sum of negative charges
must be equal to the sum of positive charges (measured in
milliequivalents) in any particular compartment
Major electrolytes and their distribution - 3
• Ionic composition of the ISF and IVF is very similar.
• Only difference being proteins since only a few proteins leak out of
capillary membrane
• As such, ISF contains very little protein as compared with the IVF.
• The protein in plasma plays a significant role in maintaining the
volume of the IVF.
• Conc’n of cations more in plasma than interstitial fluid(proteins have
net –ve charge hence binding cations such as sodium & potassium
• Anions more in interstitial fluid due to the same above however, ionic
conc’n considered equal in plasma & interstitial fluids
Composition of extracellular fluids and intracellular fluids
Ions extracellular fluid Interstitial fluid
(mOsm/l) ( mOsmol/l )

• Na+ 142 139

• k+ 4.2 4
• Ca++ 1.3 1.2
• Mg++ 0.8 0.7
• Cl- 108 108
• HCO3- 24 28.3
• HPO4- 2 2
• Glucose 5.6 5.6
• Protein 1.2 0.2
• Urea 4 4
Major electrolytes and their distribution
Transport across membranes
• All cells are surrounded by a
plasma membrane.
• Cell membranes are
composed of a lipid bilayer
with globular proteins
embedded in the bilayer.
• On the external surface,
carbohydrate groups join with
lipids to form glycolipids, and
with proteins to form
glycoproteins. These function
as cell identity markers.

21
Transport across membranes
• Cell membrane consists a lipid bilayer containing large numbers of
protein molecules in the lipid, many of which penetrate all the way
through the membrane
• Lipid bilayer constitutes a barrier against movement of water and
water-soluble substances between the ECF and ICF
• Lipid soluble substances can penetrate through this lipid bilayer by
diffusion
• All cells are surrounded by a plasma
membrane.
• Cell membranes are composed of a lipid
bilayer with globular proteins
embedded in the bilayer.
• On the external surface, carbohydrate
groups join with lipids to form
glycolipids, and with proteins to form
glycoproteins. These function as cell
identity markers.

23
• protein molecules in the membrane have different
properties for transporting substances.
• They interrupt the continuity of lipid bilayer,
constituting an alternative pathway through the cell
membrane.
• Most of these penetrating proteins function as
transport proteins.
• Different proteins function differently.
• Some have watery spaces all the way through the molecule
and allow free movement of water as well as selected ions or
molecules and are called channel proteins.
• Others, called carrier proteins, bind with molecules or ions
that are to be transported; conformational changes in the
protein molecules then move the substances through the
interstices of the protein to the other side of the membrane.
 Fluid Mosaic Model
Glycoprotein Extracellular fluid
• In 1972, S. Singer and G. Nicolson proposed the Fluid Mosaic Model of membrane
structure
Glycolipid
Carbohydrate

Cholesterol
Transmembrane
proteins
Peripheral Cytoplasm
protein
Filaments of
cytoskeleton

26
• Both the channel proteins and the carrier proteins are
usually highly selective in the types of molecules or
ions that are allowed to cross the membrane.
“Diffusion” Versus “Active Transport.
• Transport through the cell membrane, either through lipid bilayer or
through proteins, occurs either by diffusion or active transport.
• Although there are many variations of these basic mechanisms,
diffusion means random molecular movement of substances
molecule by molecule, either through intermolecular spaces in the
membrane or in combination with a carrier protein.
• Energy causing diffusion is the energy of the normal kinetic motion of
matter.
• Active transport means movement of ions or other substances across
the membrane in combination with a carrier protein in such a way
that the carrier protein causes the substance to move against an
energy gradient, such as from a low-concentration state to a high-
concentration state.
• Movement requires an additional source of energy besides kinetic
energy.
Diffusion
• All molecules and ions in the body fluids, including water molecules
and dissolved substances, are in constant motion, each particle
moving its own separate way.
• Motion of these particles is what physicists call “heat”—the greater
the motion, the higher the temperature—
• The motion never ceases under any condition except at absolute zero
temperature.
• When moving molecule, A, approaches a stationary molecule, B, the
electrostatic and other nuclear forces of molecule A repel molecule B,
transferring some of the energy of motion of molecule A to molecule
B
• Consequently, molecule B gains kinetic energy of motion, while
molecule A slows down, losing some of its kinetic energy.
• Thus, a single molecule in a solution bounces among the other
molecules first in one direction, then another, then another, and so
forth, randomly bouncing thousands of times each second.
• This continual movement of molecules among one another in liquids
or in gases is called diffusion.
• Ions diffuse in the same manner as whole molecules, and even
suspended colloid particles diffuse in a similar manner, except that
the colloids diffuse far less rapidly than molecular substances because
of their large size.
Diffusion
• The net movement of a substance from an area of higher concentration to an area of lower
concentration - down a concentration gradient
• Caused by the constant random motion of all atoms and molecules
• Movement of individual atoms & molecules is random, but each substance moves down its own
concentration gradient.
Random movement leads to net
Lump movement down a concentration
of sugar gradient

Water
No net movement at equilibrium
34
Diffusion Through the Cell Membrane
• divided into 2
• simple diffusion and facilitated diffusion.
• Simple diffusion means that kinetic movement of molecules or ions
occurs through a membrane opening or through intermolecular
spaces without any interaction with carrier proteins in the
membrane.
• Diffusion rate determined by amount of substance available, the
velocity of kinetic motion, and the number and sizes of openings in
the membrane through which the molecules or ions can move.
• Facilitated diffusion requires interaction of a carrier protein.
• Carrier protein aids passage of the molecules or ions through the
membrane by binding chemically with them and shuttling them
through the membrane in this form.
• Simple diffusion can occur through the cell membrane by two
pathways:
• (1) through the interstices of the lipid bilayer if the diffusing
substance is lipid soluble, and
• (2) through watery channels that penetrate all the way through some
of the large transport proteins,
Diffusion Across a Membrane
• The membrane has pores large enough for the molecules to
pass through.
• Random movement of the molecules will cause some to pass
through the pores; this will happen more often on the side
with more molecules. The dye diffuses from where it is more
concentrated to where it is less concentrated
• This leads to a dynamic equilibrium: The solute molecules
continue to cross the membrane, but at equal rates in both
directions.
38
Diffusion Across a Membrane
• Two different solutes are separated by a membrane that is permeable to both
• Each solute diffuses down its own concentration gradient.
• There will be a net diffusion of the purple molecules toward the left, even though the total solute
concentration was initially greater on the left side

Net diffusion Net diffusion Equilibrium

Net diffusion Net diffusion Equilibrium

39
FACTORS AFFECTING RATE OF DIFFUSION

• Rate of diffusion of substances through the cell membrane is affected by

the following factors:
• 1. Permeability of the Cell Membrane
• Rate of diffusion is directly proportional to the permeability of cell
membrane.
• Since the cell membrane is selectively permeable, only limited number of
substances can diffuse through the membrane.
• 2. Temperature
• Rate of diffusion is directly proportional to the body temperature. Increase
in temperature increases the rate of diffusion. This is because of the
thermal motion of molecules during increased temperature
• 3. Concentration Gradient or Electrical Gradient of the Substance across
the Cell Membrane
• Rate of diffusion is directly proportional to the concentration gradient or
electrical gradient of the diffusing substances across the cell membrane.
• However, facilitated diffusion has some limitation beyond certain level of
concentration gradient.
• 4. Solubility of the Substance
• Diffusion rate is directly proportional to the solubility of substances,
particularly the lipid-soluble substances.
• Since oxygen is highly soluble in lipids, it diffuses very rapidly through the
lipid layer
• 5. Thickness of the Cell Membrane
• Rate of diffusion is inversely proportional to the thickness of the cell
membrane.
• If the cell membrane is thick, diffusion of the substances is very slow.
• 6. Size of the Molecules
• Rate of diffusion is inversely proportional to the size of the molecules.
• Thus, the substances with smaller molecules diffuse rapidly than the
substances with larger molecules.
• 7. Size of the Ions
• Generally, rate of diffusion is inversely proportional to the size of the
ions.
• Smaller ions can pass through the membrane more easily than larger
ions with the same charge. However, it is not applicable always. For
instance, Na+ ions are smaller in size than K+ ions. Still, Na+ ions
cannot pass through the membrane as K+ ions because Na+ ions have
a tendency to gather water molecules around them thus making it
difficult for Na+ ions to diffuse through the membrane.
• 8. Charge of the Ions
• Rate of diffusion is inversely proportional to the charge of the ions.
• The greater the charge of the ions, lesser the rate of diffusion.
The Permeability of the Lipid Bilayer
• Permeability Factors
• Lipid solubility
• Size
• Charge
• Presence of channels and transporters
• Hydrophobic molecules are lipid soluble and can pass through the
membrane rapidly
• Polar molecules do not cross the membrane rapidly
• Transport proteins allow passage of hydrophilic substances across the
membrane
45
Diffusion of Lipid-Soluble Substances Through the Lipid
Bilayer.
• most important factor determining how rapidly a substance diffuses
through the lipid bilayer is the lipid solubility of the substance
• Oxygen, nitrogen, CO2 have high lipid solubility and dissolves rapidly
through bilayer
• Diffusion rate through bilayer proportional to lipid solubility hence
large amounts of O2 can be delivered to the interior of the cell almost
as though the cell membrane did not exist
Diffusion of Water and Other Lipid-Insoluble Molecules
Through Protein Channels
• water readily passes through channels in protein molecules that
penetrate all the way through the membrane.
• It moves very rapidly through the cell membrane
• Eg, water that diffuses in each direction through the red cell
membrane per second is about 100 times as great as the volume of
the red cell itself.
• Other hydrophilic molecules can pass through the protein pore
channels in same way as water if they are small enough.
• As they become larger, their penetration decreases
• off rapidly.
• Eg, Diameter of urea molecule only about 20% greater than that of
water, yet penetration through the cell membrane pores is about
1000 times less
• Even so, given the astonishing rate of water penetration, this amount
of urea penetration still allows rapid transport of urea through the
membrane within minutes.
Diffusion Through Protein Channels,
and “Gating” of These Channels
• These channels are tubular pathways all the way from the
extracellular to the intracellular fluid
• Therefore, substances can move by simple diffusion directly along
these channels from one side of the membrane to the other.
• The protein channels are distinguished by 2 characteristics:
• (1) Are often selectively permeable to certain substances,
• (2) many of the channels can be opened or closed by gates.
Selective Permeability of Protein Channels
• Many of protein channels very selective for transport of one or more
specific ions or molecules.
• Results from the characteristics of the channel itself, such as diameter,
shape, and nature of electrical charges and chemical bonds along its inside
surfaces.
• Eg, The sodium channel, is 0.3 by 0.5 nanometer in diameter, with the inner
surfaces being strongly -vely
• These –ve charges pull the Na ions into these channels
• Once in the channel, they diffuse in either direction according to the usual
laws of diffusion.
• Thus, the Na channel is specifically selective for passage of Na ions
Gating of Protein Channels

• Gating of protein channels provides a means of controlling ion

permeability of the channels.
• Some of the gates are actual gate like extensions of the transport
protein molecule, which can close the opening of the channel or can
be lifted away from the opening by a conformational change in the
shape of the protein molecule itself.
• The opening and closing of gates are controlled in two principal ways
 Voltage gating
• Here, molecular conformation of the gate or of its chemical bonds
responds to the electrical potential across the cell membrane.
• For instance, in when there is an activation gate and an inactivation gate.
• At potential of -90mv, the activation gate is closed with inactivation gate
open
• As voltage increases from -90 upwards, the activation gate opens
allowing diffusion of Na ions
• As the voltage reaches 0 the inactivation gate closes stopping any further
diffusion of Na
Voltage-Gated Sodium Channels
Chemical (ligand) gating
• Some protein channel gates are opened by the binding of a chemical
substance (a ligand) with the protein; this causes a conformational or
chemical bonding change in the protein molecule that opens or closes
the gate.
• Called chemical gating or ligand gating.
• Most important is the effect of acetylcholine on the so-called
acetylcholine channel.
Ion channel
Facilitated Diffusion
• Acetylcholine opens the gate of this channel, providing a negatively
charged pore allowing uncharged molecules or small positive ions to pass
through.
• Gate very important for the transmission of nerve signals from one nerve
cell to another and from nerve cells to muscle cells to cause muscle
contraction
• substance diffuses through the membrane using a specific carrier protein
to help.
• The carrier facilitates diffusion of the substance to the other side.
• In simple diffusion it is through an open channel and increases
proportionately with the concentration of the diffusing substance
• In facilitated diffusion the rate of diffusion approaches a maximum,
called Vmax, as the concentration of the diffusing substance
increases.
• As the concentration of the diffusing substance increases, the rate of
simple diffusion continues to increase proportionately,
• In case of facilitated diffusion, the rate of diffusion cannot rise greater
than the Vmax level.
• The molecule to be transported enters the pore and becomes bound.
• Then, in a fraction of a second, a conformational or chemical change
occurs in the carrier protein, so that the pore now opens to the
opposite side of the membrane.
• Because the binding force of the receptor is weak, the thermal
motion of the attached molecule causes it to break away and to be
released on the opposite side of
Carrier proteins

Animation: How Facilitated Diffusion Works

• Transport rate can never be greater than the rate at which the carrier
protein molecule can undergo change back and forth between its two
states.
• NB: Mechanism allows the transported molecule to move—that is, to
“diffuse”—in either direction through the membrane
• Examples of facilitated diffusion are transport of glucose and most of
the amino acids.
• For glucose, the carrier molecule is identified with a mwgt of 45,000
• Can also transport other monosaccharides with structures similar to
that of glucose such as galactose.
• Also, insulin can increase the rate of facilitated diffusion of glucose as
much as 10-fold to 20-fold.
• This is the principal mechanism by which insulin controls glucose use
in body
Effect of Concentration Difference on Net Diffusion
Through a Membrane
• Rate at which a substance diffuses into a cell is proportional to the
conc’n of substance outside
• Rate at which substance diffuse outward is proportional to the
conc’n inside the membrane.
• Thus, the rate of net diffusion into the cell is proportional to conc’n
the outside minus the conc’n on the inside, or:
• Net diffusion μ (Co - Ci)
• in which Co is conc’n outside and Ci is conc’n inside
Osmosis & osmotic pressure
• Movement of water from region of high water( or low solute) conc’n
to region of low water( or high solute) conc’n
• Wherever there is increase in solute conc’n either in extracellular fluid
or in the cells, water will move rapidly from the opposite side through
the cell membrane till a state of equilibrium is established
• Rate of this diffusion known as rate of osmosis
• Water conc’n depends on solute particles irrespective of
composition
• Total number of solutes measured in osmoles
• 1 osmoles is equivalent to 6.02 x 10(23) particles
• For a pdt dissociating into two, it will have twice osmoles
• 80% osmolality of interstitial fluids is due to Na+ & cl-
whereas for intracellular is due to K+ & other solutes
• Total osmolality for each compartment about 280mosm/l
• Osmotic pressure directly proportional to osmotically active particles
• True whether solute large(e.g. albumin: mwgt 70000) or small (e.g.
glucose: mwgt 180)
• Sodium chloride has twice osmotic pressure of albumin.
• Osmotic pressure = CRT where C is solute conc’n, R the ideal gas
constant & T the absolute temperature in degrees kelvin.
• Normally, osmolality of a 1mOsm/l is 19.3mmHg
• Osmolality of body fluids about 280mOsm/l
• Plasma osmolality slightly higher than in other compartments due to
presence of plasma proteins
“Active Transport” of Substances Through Membranes
• When a cell membrane moves molecules or ions “uphill” against a
concentration gradient (or “uphill” against an electrical or pressure
gradient), the process is called active transport.
• Some of the substances actively transported through at least some
cell membranes include Na⁺, K⁺, Ca ⁺⁺ ions, iron ions, H⁺, several
different sugars, and most of the amino acids.
Primary Active Transport and secondary Active
Transport
• Active transport is divided into 2 types : 1° active transport & 2°
active transport.
• In 1° active transport , energy derived from breakdown of ATP.
• In 2° active transport, energy derived secondarily from energy that
has been stored in the form of ionic conc’n differences of 2°
molecular or ionic substances between the 2 sides of a cell
membrane, created originally by 1° active transport.
• In both cases , transport depends on carrier proteins that penetrate
through the cell membrane, as is true for facilitated diffusion.
• However, in active transport, the carrier protein
functions differently from the carrier in facilitated
diffusion because it is capable of imparting energy to
the transported substance to move it against the
electrochemical gradient.
• Following are some examples of primary active
transport and secondary active transport, with more
detailed explanations of their principles of function.
“Active Transport” of Substances Through Membranes
• Primary Active Transport and Secondary Active Transport
• In primary active transport, the energy is derived directly from
breakdown of ATP
• In secondary active transport, the energy is derived secondarily from
energy that has been stored in the form of ionic concentration
differences of secondary molecular or ionic substances between the
two sides of a cell membrane, created originally by primary active
transport
• both instances, transport depends on carrier proteins that penetrate
through the cell membrane, as is true for facilitated diffusion
• in active transport, the carrier protein functions differently from the
carrier in facilitated diffusion because it uses energy to transport
substance against the electrochemical gradient
Primary Active Transport

• Sodium-Potassium Pump
• For transport of sodium, potassium, calcium, hydrogen, chloride, and a few
other ions.
• complex of 2 globular proteins: an a subunit, with a mwght of about
100,000, and a b subunit, with a mwgt of about 55,000.
• A subunit has 3 specific features important important for the functioning of
the pump:
• has 3 receptor sites for binding Na ions on side protruding to the inside of
cell.
• 2 receptor sites for K ions on the outside.
• The inside portion of this protein near the Na binding sites has ATPase
activity.
• When 2 K ions bind on the outside, of the carrier protein and 3 Na
ions on the inside, the ATPase function of protein becomes activated.
• This then cleaves one ATP, to ADP and liberating a high-energy
phosphate bond of energy.
• The energy causes conformational change in the protein carrier
molecule, extruding the 3 Na ions to the outside and the 2 K ions to
the inside.
Importance of the Na+-K+ Pump for Controlling Cell Volume.

• Most important functions of the pump is to control volume of each

cell.
• Without the pump, most cells would swell until they burst.
• The mechanism for controlling the volume is as follows:
• Inside the cell are large numbers of proteins and other organic
molecules that cannot escape from the cell.
• Most are –tively charged hence attract large numbers of Na, K and
other positive ions as well.
• All these then cause osmosis of water to the interior of the cell.
Unless this is checked, the
• Unless checked, cell would swell until it bursts.
• The Na+-K+ pump prevents this
• Pumps 3 Na+ ions to the outside of the cell for every two K+ ions pumped to the
interior.
• Also, membrane is far less permeable to Na than to K hence once Na ions are on
the outside, they have a strong tendency to stay there.
• This results in net loss of ions out of the cell, initiating osmosis of water out of cell
• If a cell begins to swell for any reason, this automatically activates the Na+-K+
pump, moving still more ions to the exterior and carrying water with them.
• Thus, the pump performs a continual surveillance role in maintaining normal cell
volume.
Electrogenic Nature of the Na+-K+ Pump

• Pump moves more +ve ions out of cell leaving inside more electo-ve
• Thus electrogenic causing inside of cell to be more negative

Primary Active Transport of Calcium Ions

• Calcium pump
• On cell membrane and pumps Ca out of cell
• On cell organelles pumping Ca into organelles such as sarcoplasmic
reticulum and endoplasmic reticulum
• Has ATPase activity hence utilizes energy
Primary Active Transport of Hydrogen Ions

• Occurs in 2 places in body: in the gastric glands of the stomach, and

in late distal tubules and cortical collecting ducts of kidneys.
• Called proton pump in gastric glands and pumps H ions into stomach
• In kidneys involved in active secretion of H ions into renal tubules
Secondary Active Transport— Co-Transport and Counter-
Transport
• When Na ions transported out of cells by 1ry active transport, a large
concentration gradient of Na ions across cell membrane develops
• ↑conc’n outside the cell and very ↓ conc’n inside.
• Excess Na outside the cell membrane is always attempting to diffuse
to the interior.
• Under appropriate conditions, this diffusion energy of sodium can
pull other substances along with the sodium through the cell
membrane.
• This phenomenon is called co-transport; it is oneform of secondary
active transport.
• For Na to pull another substance along with it, a coupling mechanism
is required.
• Achieved by means of another carrier protein in the cell membrane.
• The carrier serves as an attachment point for both the Na and the
substance to be co-transported.
• Once both are attached, the energy gradient of the Na ion causes
both the Na ion and the other substance to be transported together
to the interior of the cell.
• In counter-transport, Na ions again attempt to diffuse into the
cell because of their large concentration gradient.
• This time, the substance to be transported is on the inside of the
cell and must be transported to the outside.
• The Na ion binds to the carrier protein to the outside of the
membrane, while the substance to be counter-transported binds
to the interior projection of the carrier protein.
• Once both have bound, a conformational change occurs, and
energy released by the Na moving to the interior causes the
other substance to move to the exterior.
Co-Transport of Glucose and Amino Acids Along with Sodium
Ions

• Glucose and many amino acids are transported into most

cells against large concentration gradients
• Mechanism of this co-transport
• The transport carrier protein has two binding sites on its
exterior side, one for Na and one for glucose.
• The conc’n of Na is very high on the outside and very low
inside
• This provides energy for the transport.
• A special property of the transport protein is that a conformational
change to allow Na movement to the interior will not occur until a
glucose molecule also attaches.
• When they both become attached, the conformational change takes
place automatically, and the sodium and glucose are transported to
the inside of the cell at the same time.
• Hence, this is a sodium-glucose co-transport mechanism.
• Sodium co-transport of the amino acids occurs in the same way
except that it uses a different set of transport proteins.
Sodium Counter-Transport of Calcium and Hydrogen Ions

• In counter-transport mechanisms the transport is in a direction

opposite to the primary ion
• are Na-Ca counter-transport and Na-H counter-transport.
• Na-Ca counter-transport occurs through almost all cell membranes,
with Na ions moving to the interior and Ca ions to the exterior
• Both bound to the same transport protein in a countertransport
mode.
• This is in addition to 1ry active transport of Ca occuring in some cell
• Sodium-hydrogen counter-transport occurs in several tissues.
• Especially important in the proximal tubules of the kidneys
• Na ions move from the lumen of the tubule to the interior of the
tubular cell, while H Are counter transported into the tubule lumen.
• As a mechanism for concentrating hydrogen ions, it is not nearly as
powerful as the primary active transport of H ions that occurs in the
more distal renal tubules, but it can transport extremely large
numbers of hydrogen ions, thus making it a key to hydrogen ion
control in the body fluids
SPECIAL TYPES OF ACTIVE TRANSPORT

• In addition active transport systems, there are some special

categories of active transport called vesicular transport. They are
• 1. Endocytosis
• 2. Exocytosis
• 3. Transcytosis.
ENDOCYTOSIS

• It is a mechanism by which the macromolecules enter the cell.

• Macromolecules (substances with larger molecules) cannot pass
through the cell membrane either by active or by passive transport
mechanism.
• Are transported into the cell by endocytosis
• 3 types
• 1. Pinocytosis
• 2. Phagocytosis
• 3. Receptor-mediated endocytosis
• 1. Pinocytosis
• Is a process by which macromolecules like bacteria and antigens are taken
into the cells. Also known as cell drinking
• Stages
• i. Macromolecules (in the form of droplets of fluid) bind to the outer
surface of the cell membrane
• ii. Now, the cell membrane evaginates around the droplets
• iii. Droplets are engulfed by the membrane
• iv. Engulfed droplets are converted into vesicles and vacuoles, which are
called endosomes
• v. Endosome travels into the interior of the cell
• vi. Primary lysosome in the cytoplasm fuses with endosome and
forms secondary lysosome
• vii. Hydrolytic enzymes present in the secondary lysosome are
activated resulting in digestion and degradation of the endosomal
contents.
Phagocytosis

• Is a process by which particles larger than the macromolecules are

engulfed into the cells. Also called cell eating.
• Larger bacteria, larger antigens and other larger foreign bodies are
taken inside the cell by means of phagocytosis.
• Mostly by white blood cells
Mechanism of phagocytosis
• i. When bacteria or foreign body enters the body, first the phagocytic
cell sends cytoplasmic extension (pseudopodium) around bacteria or
foreign body
• ii. The particles are engulfed and then converted into endosome like
vacuole. – known as a phagosome
• iii. Phagosome travels into the interior of cell
• iv. Primary lysosome fuses with this phagosome and forms secondary
lysosome
• v. Hydrolytic enzymes present in the secondary lysosome are
activated resulting in digestion and degradation of the phagosomal
contents
Receptor-mediated Endocytosis

• Is the transport of macromolecules with the help of a receptor protein.

• Surface of cell membrane has some pits which contain a receptor protein
called clathrin- known as called receptor-coated pit.
• Mechanism of receptor-mediated endocytosis
• i. Receptor-mediated endocytosis is induced by substances like ligands
• Ligand molecules approach the cell and bind to receptors in the coated pits
and form ligand-receptor complex
• iii. Ligand-receptor complex gets aggregated in the coated pits.
• Then, the pit is detached from cell membrane and becomes the coated
vesicle. This coated vesicle forms the endosome
• Endosome travels into the interior of the cell.
• Primary lysosome in the cytoplasm fuses with endosome and forms
secondary lysosome
• v. Hydrolytic enzymes in secondary lysosome are activated resulting in
release of ligands into the cytoplasm
• vi. Receptor may move to a new pit of the cell membrane
EXOCYTOSIS

• Is a process by which the substances are expelled from the cell.

• The substances are extruded from cell without passing through the
cell membrane.
• This is the reverse of endocytosis.
CHANNELOPATHIES OR ION CHANNEL DISEASES

• Are caused by mutations in genes that encode the ion channels.

• 1. Sodium Channel Diseases
• Dysfunction of sodium channels leads to muscle spasm and Liddle’s
syndrome (dysfunction of sodium channels in kidney resulting in
increased osmotic pressure in the blood and hypertension).
• 2. Potassium Channel Diseases
• Potassium channel dysfunction causes disorders of heart, inherited
deafness and epileptic seizures in newborn.
• 3. Chloride Channel Diseases
• Dysfunction of chloride channels results in formation of renal stones
and cystic fibrosis.
• Cystic fibrosis is a generalized disorder affecting the functions of many
organs such as lungs (due to excessive mucus), exocrine glands like
pancreas, biliary system and immune system.
Major electrolytes and their distribution - 2
• Sodium plays a major role in controlling total body fluid volume;
potassium is important in controlling the volume of the cell
• The law of electrical neutrality states that the sum of negative charges
must be equal to the sum of positive charges (measured in
milliequivalents) in any particular compartment
Major electrolytes and their distribution - 3
• Ionic composition of the ISF and IVF is very similar.
• The main difference is that ISF contains very little protein as
compared with the IVF. The protein in plasma plays a significant role
in maintaining the volume of the IVF.
MOVEMENT OF BODY FLUIDS AND
ELECTROLYTES
• there is a continual intake and output within the body as a whole, and
between the various compartments
• the composition and volume of the fluid is relativelly stable, a states
called dynamic equilibrum or homeostasis.
Movement of Solutes Between Body Fluid
Compartments
• Several factors affect how readily a solute diffuses across capillary and
cell membranes
• 1. membrane permeability refers to the size of the membrane pores.
• 2. concentration and electric gradients interact to influence the
movement of electrolytes termed the electrochemical potential.
• 3. Electrical potential
Movement of Solutes Between Body Fluid
Compartments - 2
• 4. pressure gradients - hydrostatic pressure gradient increases the
rate of diffusion of solutes through the capillary membrane
• - active transport systems - NaK-activated - ATPase system (sodium-
potassium pump) located in cell membranes (3 Na+ ions out of the
cell in exchange for two K+)
Movement of Water Between Body Fluid
Compartments
• Controlled by 2 forces:
• -1. hydrostatic pressure
• -2. osmotic pressure

• Osmotic pressure refers to the drawing force for water exerted by soluted
particles.
• Osmosis is the process of the net diffusion of water caused by a concentration
gradient.
• Net diffusion of water occurs from an area of low solute concentration (dilute
solution) to one of high solute concentration (concentrated solution) .
Movement of Water Between the Plasma and
Interstitial Fluid
• - Na+ does not play an important role in the movement of
water between the plasma and interstital fluid
compartments
• - the distribution is determined by
• The hydrostatic pressure of the capillary blood produced,
mainly by the pumping action of the heart
• The colloid osmotic pressure produced primarily by
serum albumin
• The accumulation of excess fluid in the interstitial spaces
= edema
Factors favor edema formation:

• ↑ in capillary hydrostatic pressure (↑ Pc)

• ↓ in plasma oncotic pressure
• ↑ capillary permeability (Kf) resulting in an ↑ in interstitial fluid
colloid osmotic pressure
• . lymphatic obstruction (↑ interstitial oncotic pressure)
Pathogenesis of edema formation
• ↑ gradient of hydrostatic pressures (Pc – Pi)
• Heart failure; venous insufficiency

• gradient of oncotic pressures

Regulation of fluid exchange & osmotic
equilibrium
• Balance between fluids in plasma & interstitial fluid determined by
balance of hydrostatic & colloid osmotic pressure across capillary
membrane.
• Balance between ECF & intracellular fluid is by osmotic pressure of
solutes such as sodium, chloride and other electrolytes
• Cell membrane highly permeable to water but not the solutes hence
water moves rapidly either way hence fluids remains relatively
isotonic between ECF and intracellular fluid.
Osmosis & osmotic pressure
• Movement of water from region of high water( or low solute) conc’n
to region of low water( or high solute) conc’n
• Wherever there is increase in solute conc’n either in extracellular fluid
or in the cells, water will move rapidly from the opposite side through
the cell membrane till a state of equilibrium is established
• Rate of this diffusion known as rate of osmosis
• Water conc’n depends on solute particles irrespective of composition
• Total number of solutes measured in osmoles
• 1 osmoles is equivalent to 6.02 x 10(23) particles
• For a pdt dissociating into two, it will have twice osmoles
• 80% osmolality of interstitial fluids is due to Na+ & cl- whereas for
intracellular is due to K+ & other solutes
• Total osmolality for each compartment about 280mosm/l
• Osmotic pressure directly proportional to osmotically active particles
• True whether solute large(e.g. albumin: mwgt 70000) or small (e.g.
glucose: mwgt 180)
• Sodium chloride has twice osmotic pressure of albumin.
• Osmotic pressure = CRT where C is solute conc’n, R the ideal gas constant &
T the absolute temperature in degrees kelvin.
• Normally, osmolality of a 1mOsm/l is 19.3mmHg
• Osmolality of body fluids about 280mOsm/l
• Plasma osmolality slightly higher than in other compartments due to
presence of plasma proteins
Isotonic/hypotonic/hypertonic fluids
• During fluid replacement, important to know whether fluid isotonic,
hypertonic or hypotonic
• Hypotonic:
Lower solute conc’n
Water diffuse into cells diluting intracellular fluid till both have same
osmolality
Examples are saline solutions of < 0.9% conc’n
• Isotonic
Same osmolality as cells
No change in fluid movements
Important clinically
0.9% Saline solution and 5% glucose infusions
• Hypertonic
Has a higher conc’n of solutes
Water moves from cells into ECF till equilibrium reached
edema
• Presence of excess fluids in body tissues
• Mostly ECF but can also occur intracellular
• Intracellular edema may be caused by
Depression of metabolic systems in tissues
Lack of adequate nutrients in cells
Both above may lead to failure of cell membrane ionic pumps which pump
out any sodium ions leaking into cells
Leads to increased osmolality in cells hence water entering with resultant
edema
Can increase by 2-3 times and is mostly a prelude to death
Extracellular edema
• two types-:
Leakage of fluids from plasma into interstitial fluid through capillary
membrane
Failure of lymphatic system to return interstitium to blood
Most common clinically is due to excessive capillary filtration
Common causes
1. Increased capillary pressure due to
a) Excessive retention of sodium & water due to
I. acute kidney failure or
II. increased mineralocorticoids
b) High venous pressure due to
I. Heart failure
II. Venous obstruction
III. Failure of venous pumps due to
Muscle paralysis
Immobilization of some body parts
Failure of venous valves
c) Decreases arteriolar resistance due to
I. Increased body heat
II. Insufficiency of sympathetic nervous system
III. Vasodilator drugs
2) Decreased plasma proteins caused by -:
a) Loss of proteins in urine (nephrotic syndrome
b) Loss of protein through denuded skin as in burns & wounds
c) Failure to produce proteins as in -:
I. Liver disease as in cirrhosis
II. Serious protein malnutrition
3) Increased capillary permeability due to
a) Immune rxns
b) Toxins
c) Bacterial infections
d) Vitamin deficiency especially vit C
e) PROLONGED ISCHAEMIA
f) BURNS
4) Blockage of lymph return as in
a) Cancer
b) Infections e.g. with filarial nematodes
c) Surgery
d) Congenital absence or abnormality of lymphatic vessels
Types of iv fluids
1. Crystalloid: balanced salt electrolyte solution; forms a true solution
capable of passing thru’ semipermeable membranes. May be isotonic,
hypertonic or hypotonic.
 includes-: Normal saline(0.9% NaCl), lactated ringer’s,
hypertonic solutions considered plasma expanders as they act to
increase the circulatory volume via movement of intracellular and
interstitial water into intravascular space tonic saline(3,5, & 7.5%)
ringer’s solution.
2. Colloid: high molecular wgt solutions, draw fluid into intravascular
compartment via oncotic pressure(pressure exerted by plasma proteins
not capable of passing thru’ membranes on capillary walls). Plasma
expanders are composed of macromolecules and are retained in the
plasma.
Includes-: albumin, dextran, plasma, etc.
3. Free water solutions: provide water that is not bound by
macromolecules hence free to pass thru’ membranes
Includes-: D5W( dextrose 5% in water), D10W, D20W, D50W
4) Blood products: whole blood, packed RBC’s platelets, albumin and
essentially all colloids
• Iv fluids provide-:
• fluids
• Electrolytes
• Nutrition
• Most common uses are-:
I. Actively expand intravascular volume in hypovolemic states
II. Correct electrolyte imbalances
III. Maintain basal hydration
Normal saline

• Isotonic saline
• 154 mEq/l Na+, 154mEq/l Cl-, 308mOsm/l
• Cheapest and most commonly used resuscitative crystalloid
• High Cl- above normal which may not be readily excreted by kidneys
• May cause hyperchloremic acidosis
• May be administered with blood pdts
• No calories or free water
• Restores NaCl deficit
Lactated ringer’s
• Isotonic
• 273mOsm/l
• 130mEq/l Na+, 109mEq/l Cl-, 28mEq/l lactate and 4mEq/l K+
• Lactate used instead of bicarbonate used since more stable in IVF
during storage.
• Lactate converted to bicarbonate in liver
• Minimal effects on body fluid composition
• Resembles electrolyte of normal serum
Dextrose in normal saline
• Hypertonic
• 406mOsm/l
• 170 calories/l from dextrose
• Free water for insensible loss
• Some Na+ to promote renal function and excretion
Hypertonic saline( 3% NaCl)
• 1026 mOsm/L & 513mEq/L Na+.
• Increases plasma osmolality thereby acting as plasma expander
• Risk of hypernatremia hence careful neuro-monitoring and vascular
system.
• Fluid loss may be either water deficit or combined water & electrolyte
deficit
• Pure water deficit reflected by hypernatremia, increased plasma
osmolality, concentrated urine in low volume
• Treatment involves replacement of enough water to restore plasma to
normal
• Fluid deficit must be corrected in addition to giving maintenance
fluids for ongoing obligatory losses.
• Combined water & electrolyte loss associated with GIT losses, diuretic
therapy, burns etc.