What is the Distribution

> Distribution refer to the reversible transfer of drugs

between the blood and the extra vascular fluid(EVF) and
tissues of the body

Distribution Volumes:
Three important physiological volumes—plasma water, extracellular
fluid, and total body water. In the table 1. volumes were explained.
1. Volume of plasma
In the systemic circulation, drugs distribute throughout the volume of
plasma
Where a drug goes beyond cellular elements of the blood, depends on the
physicochemical properties of the drug and the permeability
characteristics of individual membrane

1
 2. Volume of Extracellular Fluid:
The membranes of the capillary epithelial cells are generally very
loose in nature and permit the Para cellular passage of even
polar and/or large drug molecules, including the
aminoglycosides (logD7.4≈—10;MW450 to 1000 Da)
and protein molecules. Thus, most drugs are able to distribute
throughout the volume of extracellular fluid, a volume of about
19 L (Tab.l). However, the capillary membranes of certain
tissues, notably delicate tissues such as the central nervous
system, the placenta, and the testes, have much more tightly knit
membranes, which may limit the access of certain drugs,
particularly large and/or polar drugs

3.
Volume of Intracellular Fluid
Once in the extracellular fluid, drugs are exposed to the
individual cells of tissues. The ability of drugs to penetrate
the membrane of these cells is dependent on a drug’s
physicochemical properties ,Polar drugs and large molecular
mass drugs will be unable to pass cell membranes by passive
diffusion.
For example, the extremely polar aminoglycosides cannot
penetrate cell membranes and,as a result, distribute into a
volume that is approximately equal to that of extracellular
fluid.
Polar drugs may enter cells if they are substrates for
specialized uptake transporters.
The antidiabetic drug metformin is a small polar molecule
(MW 129 Da; log D7.4 ≈-3.4) that
would be expected to have difficulty diffusing through cell
membranes.

Table 1

Volumes of body fluids

Volume (liter) Fluid substances
r
Plasm

u Extracellular fluids

rr
Intracellular fluids

tr Total body water

v/.n/ir

Drug distribution patterns:.

The extent to which a drug distributes affects the half-life
of the drug and the fluctuation of the concentration at
Steady state.

Distribution can be thought of as following one of four

types of pattern

1-The drug may remain largely within the vascular system.

Plasma substitutes such as dextran are an example of this
type, but drugs which are strongly bound to plasma
protein may also approach this pattern.

Drug distribution patterns

2.Some low molecular weight water soluble compounds such as

ethanol and a few sulfonamides become uniformly distributed
throughout the body water
Afew drugs are concentrated specifically in one or more tissues
3.
that may or may not be the site of action.
■ Iodine is concentrated by the thyroid gland.
■ The antimalarial drug chloroquine may be present in the liver
at concentrations 1000 times those present in plasma
 Drug distribution patterns
•Tetracycline is almost irreversibly bound to bone and developing
teeth.
•Consequently tetracyclines should only be given to young
children or infants in extreme conditions as it can cause
discoloration of the developing second set of teeth.
•An other type of specific concentration may occur with highly
lipid soluble compounds which distribute into fat tissue like
thiopental

Most drugs exhibit anon-uniform distribution in the body

4.
with variations that are largely determined by the ability to
pass through membranes and their lipid/water solubility.
The highest concentrations are often present in the
kidney,liver,and intestine usually reflecting the amount of
drug being excreted
 v/^/tr

Diagram Representing Various Volumes Distribution

Patterns

Apparent Volume Distribution

• The concentration of drug in the plasma or tissues depends on the amount
of drug systemically absorbed and the volume in which the drug is
distributed. The apparent volume of distribution, V D in a model, is used to
estimate the extent of drug distribution in the body. Although the apparent
volume of distribution does not represent a true anatomical, or physiological
volume, the V D represents the result of dynamic drug distribution between
the plasma and the tissues and accounts for the mass balance of the drug in
the body.
amount of drug in the body (mg} ,
VD=------------------------------------------------------------ *
plasma concentrationafter equillibrium(mg /L(

n
Apparent volume of distribution(V) is a useful indicator
of the type of pattern that characterizes a particular
drug.
□ A value of V in the region of 3-51iter(in an adult)would
be compatible with patternl.This is approximately the
volume of plasma.
□ Pattern two would be expected to produce a V value of
30 to50 liter ,corresponding to total body water.
□ Agents or drugs exhibiting pattern 3 would exhibit
very large values of V. Chloroquine has aV value of
approximately 115L/kg.
□ Drugs following pattern4 may have aV value within
wide range of values.

• Redistribution
• Highly lipid soluble drug when given by i.v or by inhalation get
distributed to organs with high blood flow,e.g.. Brain ,heart,kidney
• Later. Less vascular but more bulky tissues (muscles ,fat) take up
the drug and plasma concentration falls and drug was withdrawn
from these sites.
• If the site of action of the drug was in one of highly perfused
organs Redistribution result in termination of the drug action .
• Greater the lipid solubility of the drug ,faster is its redistribution .

• For example ,thiopental produce anesthesia within seconds after

administration, why? Because rapid equilibrium between blood and
brain. The conc.of drug in brain rapid decline as a drug
redistributed to other tissue.
Factors Affecting Distribution

A-Rate of distribution
1. Membrane permeability
2. Blood perfusion
B-Extent of Distribution
1. Lipid Solubility
2. pH -pKa
3. Plasma protein binding
4. Tissue drug binding

A. Rate of distribution

1 .Membranepermeability:
□ Capillary walls are quite permeable.
□ Lipid soluble drugs pass through very rapidly.
□ Water soluble compounds penetrate more slowly at a rate more
dependent on their size.
□ Low molecular weight drugs pass through by simple diffusion.
For compounds with molecular diameter above 100A transfer is
slow.
□ For drugs which can be ionized the drug's pKa and the pH of
the blood will have a large effect on the transfer rate across the
capillary membrane
There are two deviations to the typical capillary structure which result
in variation from normal drug tissue permeability.
i)Permeability is greatly increased in the renal capillaries by pores in
the membrane of the endothelial cells ,and in specialized hepatic
capillaries, known assinusoids which may lack acomplete lining. This
results in more extension distribution of many drugs out of the
capillary bed

Sinusoid Capillary (Liver, spleen and bone marrow)

'Pencaplllary tissue r.v„?

Microvilli of hepatocyte
JI.•
bi1 .Lv istS&i cI( r-hil 'df icir

II) On the other hand ,brain capillaries seem to have

impermeable walls restricting the transfer of molecules
from blood to brain tissue.
-Lipid soluble compounds can be readily transferred but
the transfer of polar substance is severely restricted.
-This is the basis of the "blood-brain"barrier.
 Approaches to enhance crossing BBB

■ Use of permeation enhancer (e.g.DMS)

■ Infuse internal carotid artery with mannitol which cause the
content of artery to be hyperosmotic to the cell (Osmotic
disruption).
■ Water leaves the cell and enters the artery in order to recreate
osmotic equillibrium.This loss of water causes the cell to shrink
,stretching the tight junctions between cells.
■ Use of Dihydropyridine Redox System as drug carriers to the
brain

Penetration of drugs through placental barrier

■ Placenta is the membrane separating fetal blood from maternal

blood
■ It is made up of fetal trophoplast basement membrane and
endotheliumm Mean thickness in early pregnancy is (25p ) which
reduce to(2p) at full term.
■ Many drugs have M.Wt. less than 1000 Daltons and moderate to
high lipid solubility like ethanol,sulfonamides and barbiturates
cross the barrier by simple diffusion quit rapidly wherase large
molecular size, low lipid solubility and ionized drugs such as
tubocurarine need hours for equilibrium and may not detect in
fetUS.
■ Nutrients that essential for fetal growth are transported by
carrier mediated processes.
 2. Blood perfusion rate:
■ The delivery of drug to the tissue is controlled by the specific
blood flow to a given tissue.
■ This is expressed as tissue perfusion, the volume of blood
delivered per unit of time (mL/min/per unit of tissue)
■ Table 1.2 shows the perfusion of some tissues. Once at the
tissue site.
■ uptake or distribution from the blood is driven largely by the
passive across the epithelial membrane of the capillaries
diffusion of drug
■ Drug distribution is perfusion controlled. The rate of drug
distribution varies from one tissue to another, and generally,
drugs will distribute fastest to the tissues that have the
higher perfusion rates.

Table 2

Blood Perfusion Rate

■ Perfusion Rate Percent of
Organ (mL/min/mL cai'diac output
of tissue) (CO)
Bone O.25 5
Brain 0.5-0.55 14=15
Fat 0.01-0.03 2-4
Heart 0.6-o/z ' 4
Kidneys 4-O-4-5 22-24
..Liver, 25-27
Muscle 0.025-0.030 15
Skin - O.C4-C.O5 5-6
B.Extent of Distribution
■ 1.Lipid solubility
■ Will affect the ability of the drug to bind to plasma proteins and to
cross Epid membrane barriers.
■ -Very high Epid solubiEty can result in adrug partitioning into highly
vascular lipid-rich areas.Subsequendy these drugs slowly redistribute
into body fat where they may remain for long periods of time. E.g
thiopental
Effects
2. of pH: •
The rate of movement of a drug out of circulation will depend on its •
degree of ionization and therefore its pKa.
-Changes in pH occurring in disease may also affect drug distribution. •
.For example, blood becomes more acidic if respiration is inadequate

3.Plasma protein binding:

Extensive plasma protein binding will cause more drug to stay in the •
central blood compartment. Therefore drugs which bind strongly to
plasma protein tend to have lower volume .(↑protein binding=↓V).
Albumin comprises 50% of the total proteins binds the wide strange
of drugs. Acidic drugs commonly bind to albumin, while basic drugs
often bind to al-acid glycoproteins and Epoproteins.
Forces involved:-Groups on the protein molecules that are responsible •
for electrostatic interactions with drugs include.
 NH3+ of lysine
□ N-terminal amino acids
□ NH2+ of histidine
□ S-of cysteine
□ COO-of aspartic and glutamic acid residues
In order to achieve stable complexes, the initial electro static attraction
is reinforced by Vander Waal's forces and hydrogen bonding

1. Extensive plasma protein binding will decrease the amount of •

absorbed drug(decrease peak plasma level).
2. Elimination of a highly bound drug may be delayed. Since the •
concentration of free drug is low,drug elimination by metabolism and
excretion may be delayed. This effect is responsible for prolonging the
effect of tire drug digoxin.
3. Changes in the concentration of plasma proteins will influence the •
effect of a highly bound drug
• Y/ • k/S I

A low plasma protein level may occur in

old age
-malnutrition
-illness such as liver disease(remember that most plasma proteins are
made in the liver),or chronic renal failure where there is excessive
excretion of albumin.
In each case the result is a smaller proportion of drug in bound form
and more free drug in the plasma.
The greater amount of free drug is able to produce a greater
therapeutic effect and reduced drug dosages

4.
There may be competition between drugs, in which agents that are
bound very tightly, such as coumarin anticoagulants, are able to
displace less tightly bound compounds from their binding sites.
• Y/« A/tY

Other distribution considerations

1.Weight considerations: ♦
• A. Body composition of the very young and the very old may be quite
different from‘ normal', that is the average subject in whom the
parameter. —
B-Another group of patients in which body composition may be •
greatly altered from'normal‘ is the obese. These patients have a higher
proportion of adipose tissue and lower percentage of water.
Thus for drugs which are relatively polar, volume of distribution •
values may be lower than normal, values may have been originally
determined.

For example the apparent volume of distribution of antipyrine is •

0.621/kg in normal weight subjects but 0.461/kg in obese patients.
Other drugs such as digoxin and gentamicin are also quite polar and •
tend to distribute into water rather than adipose tissue.
2.Pregnancy •
During pregnancy the growth of the uterus, placenta and fetus •
increase the volume available for disrubtion of drug