Plasma Membrane

Structure and Function

1
Fluid Mosaic Model

Hydrophobic region
of protein

Hydrophobic region of protein

 SURFACE MEMBRANE

MEMBRANE COMPONENTS

Phospholipids
Proteins (integral and peripheral)
Cholestorol
Carbohydrates (glycose)
Membrane-Associated Proteins
 membrane proteins are classified as either integral
or peripheral
 The Fluidity of Membranes
Phospholipids can move laterally within the bilayer

Lateral movement Flip-flop

(~107 times per second) (~ once per month)

(a) Movement of phospholipids

Figure 7.5 A
Movement of membrane phospholipids
1. Rotation about long axis
2. Lateral exchanges
1x107 times/sec.
moves several m/sec
3. Flip-flop – rare
<1 time/wk to 1
time/few hrs
“flippases”
 Phospholipids
 Polar heads are hydrohilic « water
loving»
 Nonpolar tails are hydrohobic « water
fearing
 The cell membrane is made of 2 layers
of phospholipids called the lipid bilayer

Membrane-Associated Proteins
integral proteins are amphipathic proteins that are firmly
bound to the membrane, and can only be released from the
membrane by detergents
•some integral proteins are
transmembrane proteins, extending
completely across the membrane
•hydrophobic -helices are common in
the membrane spanning domains of
transmembrane proteins
•some wind back-and-forth across the
membrane
Membrane-Associated Proteins
 peripheral proteins
are not embedded in
the membrane
 usually bound
ionically or by
hydrogen bonds to a
hydrophilic portion of
an integral protein
Membrane-Associated Proteins
 the protein profile of one membrane side typically differs
from that of the other side
 many more proteins are on the cytoplasmic side of the plasma
membrane, as revealed by freeze-fracturing plasma membranes
 the types of processing that a protein receives differs depending
on the target side, or if it is integral
 Fluid Mosaic Model
predicts:

A. Membranes are fluid: lipids & proteins

move in the plane of the bilayer

B. Proteins and lipids are asymmetrically

distributed in the bilayers
 Transport Membrane Mechanisms
Types:
PASSIVE ACTIVE
- it does not need delivery - free energy from ATP is
of a free energy. needed and must be
delivered
 Simple Diffusion Na-Kpump,
Facilitated Diffusion  Ca-pump,
Osmosis  H-pump,
Filtration  exo/ endo-cytosis
 phagocytosis -
WHAT IS DIFFUSION ?

Diffusion is a process of migration of solute molecules

from a region of higher concentration to a region of lower
concentration and is brought by random molecular motion.

Movement from one side of membrane to another side.

Diffusion is a time dependent process.

Movement is based on kinetic energy(speed), charge,

and mass of molecule

14
 DIFFUSION
It is defined as a process of mass transfer of
individual molecules of a substance brought about by
random molecular motion and associated with a
driving force such as a concentration gradient.

15
16
 Consider the diffusant originally dissolved in the left
hand compartment of the cell , solvent alone is placed on the
right hand side of the barrier, the solute diffuses through the
central barrier from solution to solvent side.

17
 FICK´S I LAW
The amount “M” of material flowing through a unit cr
oss section “S” of a barrier in unit time “t” is known as the flux
“J”

dM
J
S .dt
The flux, in turn, is proportional to the concentration
gradient, dc/dx:
dc
J  D
dx
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 Diffusion coefficient/ diffusivity
No. of atoms dn dc
crossing area A   DA Cross-sectional area
per unit time dt dx Concentration gradient

Matter transport is down the concentration gradient

Flow direction
A

As a first approximation assumed D ≠ f(t)

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J  atoms / area / time  concentration gradient

dc
J
dx
dc
J  D
dx
1 dn dc
J  D
A dt dx

dn dc Fick’s first law

  DA
dt dx
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 Facilitated Diffusion
is a passive transport mechanism of bigger
molecules (e.g.aminoacids),along a
concentration gradient, when substance
binds to a protein carrier
the carrier is protein placed within the
membrane and undergoes a process of
conformation (is a change of its chemistry)
after binding of molecule and conformation,
the carrier shifts (turns around ) and finally
releases substance on an opposite site of a
cell membrane
Facilitated Diffusion
Types of Transports Proteins
Chanel proteins are embeddee in the cell
membrane in the membrane & have a pore
for materials to cross
Carrier proteins can change shape to move
material from one one side of the
membrane to the other

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Facilitated Diffusion
Molecules will randomly move throgh the pores in
channel proteins

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Facilitated Diffusion
Some Carrier proteins do
not extend through the
membrane.
They bond and drag
molecules through the
lipid bilayer and release
them on the opposite side.

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Figure 7.19
Passive transport Active transport

Diffusion Facilitated diffusion ATP

Osmosis
The diffusion of
water across a
differentially
permeable
membrane due to
concentration
differences
 Osmosis
is kind of passive transport through the
semipermeable cell membrane, when only water
moves from a space with lower concentration
(lower osmotic pressure) to a space with higher
concentration (higher osmotic pressure), till to
equilibrium.Total volume of solution in both
compartments will change.
Simply –water wants to dilute more concentrated
solution (Van Hoff´s Law)
normal osmolarity 300 mOsm/l- isotonic
solution with blood plasma (e.g. 0.9 % NaCl, or
5% of glucose) Below 0.9%- hypotonic solution
Above 0.9% - hypertonic solution
example: Osmotic fragility of RBC ( see
practicals )
 Filtration
is a passive transport of water and small particles
from a space with higher hydrostatic pressure to a
space with lower one
the power that drives Filtration is Pressure gradient
of a hydrostatic pressure (not a concentration
gradient ! )
examples: filtration and resorption in capillary loop
or in kidneys
ACTIVE MEMBRANE TRANSPORTS
 transport of molecules among cells against the
concentration, or electric gradients,

a delivery of free energy from ATP is crucial.

Classification: Primary active transport through the

selectíve ions channels. Pumps : Na +- K+ pump (in all
cells), Ca 2+- pump (in muscle cells), H+- proton pump (in
cells of stomach producing HCl)
Secondary active transport
when a substance (e.g. glucose) binds on ion (Na+),
then this complex (Na+ glucose) is carried through the
membrane actively (the glucose-Na+ contransport),
exo-/endo, phagocytosis
Na+-K+ pump (Na+- K+ ATPase)
Exocytosis, Endocytosis
(Phagocytosis)
ACTIVE membrane transports.:
Exocytosis and Endocytosis.

 Exocytosis - “cell vomiting“ is a release of

larger molecules by the protrusion of a cellular
membrane, under delivery of energy and Ca 2+
ions
Endocytosis –“cell eating“ is an uptake of
molecules by a cellular membrane, e.g.
ingestion of bacteria by leukocytes
(phagocytosis). It needs a delivery of energy,
too.
Resting membrane potential (RMP)
It is an electric potential difference measured
between (+) charged cell exterior and (–)
charged cell interior. Its value is negative and
equals to a Sum of Equilibrium Potentials of
all 3 ions (K+, Na+, Cl-).
is a result of membrane semipermeability i.e.
different leakage of cell membrane for 3 main
ions (K+, Na+, Cl-).
permeability of cell membrane for ions at rest
is:
K+ : Na+ : Cl- = 1 : 0.04 : 0.45
K+ : Na+ : Cl- = 100 : 4 : 45 (%)
Value of RMP for nerve cells is: -70 mV,
sceletal muscle:– 90 mV, heart muscle:-
80mV, smooth muscle: -50 mV (non-stabile)
 Equilibrium Potential (EP) is a value of
electrical voltage that just stops the passive
diffusion of ions (K+ ,Na+ ,Cl -) along their
concentration gradients
Cell Inside (-) charged Cell Outside(+) cha.
(because PROTEINS inside) (because Na + outside)
 Goldman´s Equation
Sumation of all Equilibrium potentials (for K, Na,
Cl ) results in a real value of Resting Membrane
Potential ( e.g. V m = -70 mV for neuronal cells)
Goldmann counted it for all 3 ions (their concentrations outside and
inside) + the permeabilities of membrane for 3 ions
 Nernst formula
Each ion has its own Equilibrium Potential (mV) which
can be counted: (Nernst counted it only for K+ )
.

for comming
and attention
 FICKS SECOND LAW
An equation for mass transport that emphasizes the
change in concentration with time at a definite location
rather than the mass diffusing across a unit area of barrier in
unit time is known as Fick’s second law
c J

t x

Differentiating the first law expression with respect to

x one obtains

J  2c
 D 2
x x
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 substituting Dc/dt From the above equation

c  2c
D 2
t x

Its represents diffusion only in x direction

c   2c  2c  2c 
 D 2  2  2 
t  x y z 

Its represents diffusion in three dimensions

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 STEADY STATE

The solution in the receptor compartment is constantly

removed and replaced with fresh solvent to keep the
concentration at low level . This is know as “ SINK
CONDITION ” . The left compartment is source and right
compartment is sink.
The diffusant concentration In the left compartment
falls and rises in the right compartment until equilibrium is
attained , based on the rate of removal of diffusant from the
sink and nature of barrier .

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 When the system has been in existence a sufficient
time, the concentration of diffusant in the solution at the left
and right compartments becomes constant , but obviously
not same .
Then within each compartment the rate of change of
concentration dc/dt will be zero and by second law.
dc d 2c
D 2 0
dt dx

Concentration will not be constant but rather is likely

to vary slightly with time, and then dc/dt is not exactly zero.
The conditions are referred to as a “QUASI STATIONARY
STATE” and little error is introduced by assuming steady
state under these conditions. 41
 Diffusion through membranes
Steady Diffusion Across a Thin Film and Diffusional
Resistance

• steady Diffusion across a thin film of thickness “h”,

•the concentration of both sides cd&cr kept constant,
•Diffusion occurs in the direction the higher concentration(Cd) to lower
concentration(Cr) the concentration of both sides cd&cr kept constant,
• after sufficient time steady state is achieved and the concentrations are constant at all
points,
•At steady state (dc/dt=0), ficks second law becomes
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 Permeability
after sufficient time steady state is achieved and the concentrations are
constant at all points
at steady state (dc/dt=0), ficks second law becomes

 2e
D 2 0
z
Integrating above equation twice using the conditions that at z=0,c=Cd and at
z=h, C=Cr yields the fallowing equation

D
J  (c1  c2 )
h
The term h/D is called deffusional resistance “R” the flux equation can be
written as
c1  c2
J
R
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 If a diaphragm separates the two compartments of a diffusion
cell, the first law of fick’s may be written as
dM  c1  c2 
J  D 
Sdt  h 

Where,
S=cross sectional area
H=thickness
c1 ,c2= concentration on the left and right sides of the
membrane
(c1-c2)/h within the diaphragm must be assumed to be
constant for quasi-stationary state to exist.
The concentrations c1,c2 can be replaced by partition
coefficient multiplied by the concentration Cd on the donor
side or Cr on receiver side. 44
 c1 c2
K 
cd cr

dM DSK (cd  cr )

dt h

DK
P (cm / sec)
h
If sink condition in the receptor compartment Cr  0
dM DSKcd
  PSCd
dt h
P=permeability coefficient
P is obtained from slope of a linear plot permeant (M) vs. t.

M  PSCd t 45
Pr o c e d u r e s a nd a ppa r a t u s
a s s e s ing d r u g d if f u s io n

46
SIMPLE DIFFUSION CELL
The diffusion chambrer constructed in a simple way

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DIFFUSION CELL FOR PERMEATION THROUGH
STRIPPED SKIN LAYERS:

It is developed by wurster et al. to study the diffusion

through stratum corneum of various permeants , including
gases, liquids and gels.
A-glass stopper

B-glass chamber

C-aluminum collar

D-mambrane & sample holder

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 BIOLOGIC DIFFUSION
Gastrointestinal absorption of drugs
Drug pass through living membranes according to two
main classes of transport
1) passive transfer
It involves a simple diffusion driven by differences in
drug concentration on the two sides of the membrane.
2)carrier mediated
This is 2types
a)active transport (requires energy)
b)facilitated diffusion(does not depend on energy )
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pH-partition Hypothesis

Biologic membranes are predominantly lipophlic, and

drugs penetrated theses barriers mainly in their molecular,
undissociated form.

drugs are absorbed from the gastrointestinal tract by

passive diffusion depending on the fraction of undissociated
drug at pH of the intestines.

pH-partition principle has been tested in a large

number of in vitro and in vivo studies, and it is only partly
applicable in real biologic systems.
50
Transport of a drug by diffusion across a membrane such as the gastrointestinal mucosa
is governed by Ficks law

dM Dm SK
  (c g  c p )
dt h

Gut compartment has high conc. and a large volume compared to Cp, Cg becomes
constant and Cp relatively small. Equation becomes

dM Dm SKC g
 
dt h

Where,
M= amount. Of drug in gut compartment at time ‘t’
Dm=diffusivity in intestinal membrane
S= area of the membrane
K= partition coefficient
h= membrane thickness
Cg=conc. of drug in intestinal compartment
Cp=conc. of drug in plasma compartment
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 the left hand side converted in to concentration units, C(mass/unit volume) x
V(volume). On the right hand side of the diffusion constant, membrane area , partition
coefficient, and membrane thickness are combined to yield a permeability coefficient. These
changes leads to the pair of equations

dc g
V  Pg C g 1
dt

dc p
V  Pp C g 2
dt
Cg , Pg are the concentration And permeability coefficient for drug
passage from intestine to plasma for reverse passage of drug from plasma to
intestine
Cg and V are constants

dC g / dt Pg

dC p / dt Pp
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Modification PH -partition Hypothesis

PH partition principle is only approximate ,

assuming drugs that absorbed through intestinal
mucosa , in nondissociated form alone.
For Small , ionic and nonionic following
complicating factors must be considered
1. Metabolism of drugs in the gastrointestinal membrane
2. Absorption in micellar form
3. Enterohepatic circulatory effects

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 Applications

• Release of drugs from dosage forms diffusion controlled

like sustained and controlled release products.

• Molecular weight of polymers can be estimated from

diffusion process.

• The transport of drugs from gastrointestinal tract, skin

can be predicted from principal of diffusion.
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• Processes such as dialysis, micro filtration, ultra
filtration, hemodialysis, osmosis use the principal of
diffusion.

• Diffusion of drugs into tissues and excretion through

kidney can be estimated through diffusion studies.

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 • An electrogenic pump is a transport protein
that generates voltage across a membrane
• The sodium-potassium pump is the major
electrogenic pump of animal cells
The main electrogenic pump of plants, fungi, and
bacteria is a proton pump
Electrogenic pumps help store energy that can be
used for cellular work

© 2011 Pearson Education, Inc.

 Two combined forces, collectively called the
electrochemical gradient, drive the diffusion
of ions across a membrane
 A chemical force (the ion’s concentration
gradient)
 An electrical force (the effect of the membrane
potential on the ion’s movement)

© 2011 Pearson Education, Inc.

Figure 7.20

ATP   EXTRACELLULAR
FLUID
  H 

Proton pump H
H 

H
  H

CYTOPLASM   H
Cotransport: Coupled Transport
by a Membrane Protein
Cotransport occurs when active transport of a
solute indirectly drives transport of other
solutes
Plants commonly use the gradient of hydrogen
ions generated by proton pumps to drive active
transport of nutrients into the cell

© 2011 Pearson Education, Inc.

Figure 7.21

ATP
H
  H

Proton pump H
H

  H

H  H

H
Sucrose-H Diffusion of H
cotransporter

Sucrose  
Sucrose
 References
‘SINKO .J PATRICK’ , “Martin’s physical pharmacy and
pharmaceutical sciences” , 5th edition , pp no.301 to 337.
‘SUBRAMANYAM.C.V.S’ , “A text book of physical
pharmaceutics” , pp no.-110 to 127.
The theory and practice of industrial pharmacy ,leo
lachmann ,heberta. Liberman ,joseph L. Kanio:3rd
edition ,pg no- 158 to 159.
Encyclopedia of pharmaceutical technology , 2 nd
edition ,volume -2: pg no -1246 to 1247 ; edited by james
swarbrick ,james C.Boylan.
www.phrmainfo.net
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