Drug distribution

Drug distribution is the process by which a

drug reversibly leaves the blood stream and
enters into the interstitial and intracellular
fluids.

The delivery of a drug from the plasma

primarily depends on-
1. Blood flow
2. Capillary permeability
3. The degree of binding of the drug to
plasma & tissue proteins
4. The relative hydrophobicity of the drug
1. Blood flow
The rate of blood flow to the tissue
capillaries varies widely as a result of the
unequal distribution of cardiac output to the
various organs.
Organ % of cardiac output
Bone 5
Brain 14
Fat 4
Heart 4
Kidney 22
Liver 27
Muscle 15
Skin 6
 Heart, liver, kidney, brain and other well-
perfused organs receive most of the drug
during the first few minutes after absorption.
Delivery of drug to muscle, peripheral
organs, skin and fat is slower, and these tissues
may require several minutes to several hours
before steady state is attained.
Another phase of distribution is also
possible for some drugs where the drug slowly
accumulates in some tissues like fat tissue and
otherThe
tissues.
drug can be moved from the plasma to
the tissue until the equilibrium is established
(for unbound drug present in plasma).
 The differential blood flow partly explains
the short duration of hypnosis produced by a
bolus intravenous injection of thiopental.
The high blood flow together with the
superior lipid solubility of thiopental permit it to
rapidly move into and out of the CNS and
produce anesthesia.
Slower distribution to skeletal muscle and
adipose tissue lowers the plasma concentration
sufficiently so that the higher concentrations
within the CNS decrease and consciousness
Penicillin is quite polar and is thus slowly
regained.
permeable. Permeability limited transfer is
faster in muscle, as muscle capillaries are less
restrictive. Thus transfer of penicillin is faster in
Thiopental is an ultra-short-acting anesthesia.
Following intravenous injection the drug
rapidly reaches the brain and causes
unconsciousness within 30–45 seconds.
At one minute, the drug attains a peak
concentration of about 60% of the total dose in
the brain.
Thereafter, the drug distributes to the rest
of the body and in about 5–10 minutes the
concentration is low enough in the brain such
that consciousness returns.
2. Capillary permeability
Drug permeation occurs largely in the
capillary bed, where both surface area and time
available for exchange are maximal (extensive
vascular branching, low velocity of flow).
Drugs rapidly cross capillary membranes
into tissues because of passive diffusion and
hydrostatic pressure.
Capillary permeability is determined by-
2a. Capillary structure
2b. Chemical nature of the drug
Fig: Capillary
2a. Capillary structure:
The capillary wall consists of an
endothelial cell layer and a basement
membrane enveloping the endothelial cell
layer.
Capillary structure varies widely in terms
of the basement membrane that is exposed by
slit (tight) junctions between endothelial cells.
Endothelial
In the brain, the cell layer
capillary
Tight junction
structure is
continuous, and
there are no slit Basement
membrane
junctions.Capillary structure: CNS
The capillaries of the brain are surrounded by
glial cells that create the blood brain barrier that
acts as a thick lipid membrane. Polar and ionic
hydrophilic drugs cross this barrier slowly.
 In order to enter the brain, drugs must be
actively transported through the endothelial
cells or pass through the endothelial cells of the
capillaries of the central nervous system (brain
and spinal cord).
For example, the large neutral amino acid
carrier transports levodopa into the brain.
Lipid-soluble drugs readily penetrate into
the CNS, since they can dissolve in the
membrane of the endothelial cells.
Ionized or polar drugs generally fail to
enter the CNS, since they are unable to pass
through
Thisthe endothelial
selectivity of cells of the is
transport CNS.
known as
blood- brain barrier.
 In some capillary beds
(e.g., in the pancreas),
endothelial cells exhibit
fenestrations (an opening).
Although the cells are tightly
connected by continuous
junctions by diaphragms.
Capillary structure: Pancreas

Both the diaphragm and basement

membrane can be readily penetrated by
substances of low molecular weight— the
majority of drugs— but less so by
macromolecules, e.g., proteins such as insulin.
Fenestrated endothelia are found in the
 Drugs exchange freely
between blood and
interstitium in the liver,
where endothelial cells
exhibit large fenestrations
and where neither
diaphragms nor basement
membranes impede drug Capillary structure: Liver
movement.
2b. Chemical nature of the drug:
The chemical nature of the drug strongly
influences its ability to cross cell membranes.
Hydrophobic drugs (lipophilic drugs),
readily move across most biological
membranes. The major factor influencing the
hydrophobic drug's distribution is the blood flow
to theBy
area.
contrast, hydrophilic drugs, do not
readily penetrate cell membranes and must go
through the junctions of endothelial cells in
capillary beds.
Small drug molecules can freely diffuse
out of the blood vessel while large drug
molecules are confined to the plasma. Heparin
3. Binding of drugs to proteins
Having entered the blood, drugs may bind
to the protein molecules that are present in
abundance, resulting in the formation of drug-
protein complexes.
Reversible binding to plasma proteins
sequesters drugs in a non-diffusible form and
slows their transfer out of the vascular
compartment.
After absorption more than 90% phenytoin
(antiepileptic) bound to plasma protein.
 Protein binding involves albumin for acidic
drug and acidic glycoproteins for basic drug.
Nonspecific binding to other plasma proteins
generally occurs to a much smaller extent.
The degree of binding is governed by the
concentration of the drugs and the affinity of a
drug for a given protein.
As a rule, drugs exhibit much lower affinity
for plasma proteins than for their specific
binding sites (receptors).
Binding is relatively non-selective as to
chemical structure and takes place at sites on
the protein to which endogenous compounds
such as bilirubin, normally attach.
 Drug-binding protein may act as a drug
reservoir, as the concentration of the free drug
decreases due to elimination by metabolism or
excretion, the bound drug dissociates from the
protein.

This maintains the free drug concentration

as a constant fraction of the total drug in the
plasma.
Drug reservoirs
The body compartments in which a drug
accumulates are potential reservoirs for the
drug.
If stored drug is in equilibrium with that in
plasma and is released as the plasma
concentration declines, a concentration of the
drug in plasma and at its locus of action is
sustained, and pharmacological effects of the
drug are prolonged.
Fat as a reservoir:
Many lipid-soluble drugs are stored in fat.
In obese persons, the fat content of the
body may be as high as 50% and fat can serve
 Fat is a rather stable reservoir because it
has a relatively low blood flow.

Bones:
Tetracycline antibiotics (by forming
complex with calcium) and heavy metals may
accumulate in bone and bone can become a
reservoir for the slow release of toxic agents
such as lead or radium into the blood; their
effects can thus persist long after exposure has
ceased.
Placental transfer of drugs
The transfer of drugs across the placenta is of
critical importance because drugs may cause
anomalies in the developing fetus.
Lipid solubility, extent of plasma binding, and
degree of ionization of weak acids and bases are
important general determinants in drug transfer
across the placenta.
The fetal plasma is slightly more acidic than
that of the mother (pH 7.0 to 7.2 versus 7.4), so
that ion trapping of basic drugs occurs.
The placenta is a barrier to drugs, however, a
number of influx transporters are also present.
The fetus is to some extent exposed to all
drugs taken by the mother.
Volume of distribution
The actual volume in which drug molecules are
distributed within a patient’s body cannot be
measured.

However, volume of distribution (Vd) of drug

can be obtained and may be of some clinical
usefulness.

The volume of distribution (Vd) also known as

apparent volume of distribution. It is not a real
volume.
 Volume of distribution is the ratio of the
amount of a drug in the body to its
concentration in the plasma or blood.

The volume of distribution relates the amount

of drug in the body to the plasma concentration
according to the following equation:

Amount of drug in the body

Volume of distribution (Vd)=
Plasma drug concentration

(Units = volume)
- This volume does not necessarily refer to an
identifiable physiological volume but rather to
the fluid volume that would be required to
contain all the drug in the body at the same
concentration measured in the blood or
plasma.
- The plasma volume of a typical 70-kg man is
3 L, blood volume is about 5.5 L, extracellular
fluid volume outside the plasma is 12 L, and
the volume of total-body water is
approximately 42 L. Many drugs exhibit
volumes of distribution far in excess of these
The volume of distribution (Vd) may be defined
as the volume of fluid in which the drug
appears to distribute with a concentration
equal to that in plasma.

If a drug is highly tissue bound the plasma

concentration will be low and the Vd become
very large.

- Drug with large volume of distribution:

Digoxin (Approximately 420L).
- Drug with small volume of distribution:
Heparin (Approximately 5L).
For drugs that accumulate outside the plasma
compartment (e.g. in fat or by being bound to
tissues), Vd may exceed total body volume.
Relationship between the extent of distribution
and Vd in a 70 kg normal person (The numbers
are only rough approximation)

Vd, L % Body Extent of Distribution

Weight
5 7 Only in plasma
5-20 7-28 In extracellular fluids
20- 28-6 In total body fluids.
40
>40 >56 In deep tissues; bound to
peripheral tissues
Clinical importance of volume of distribution
In some clinical situations it is important to
achieve the target concentration
instantaneously.

A loading dose is often used and Vd is the

determinant of the size of the loading dose:
Loading dose (mg) =
(Vd, L) X (Desired plasma concentration,
mg/L)
Many acids including salicylates, sulfonamides
and penicillins are either too highly bound to
plasma proteins or too water soluble to enter
cells and adipose tissue in large amounts.
Therefore, their Vd is low (approximately 8-20
L).

In contrast, lipid soluble bases are taken up by

many tissues. Concentrations in plasma are
low, and Vd exceeds the volume of total body
fluids. For example, Vd for antihypertensive
drug propranolol is about 200L.