Drug Distribution
DR.SOBAN SADIQ
Definition

It is the process by which a drug reversibly
leaves the blood stream and enters the
interstitial fluid and/or the cells of the tissues
Apparent Volume of Distribution (Vd)

A hypothetical volume of fluid into which a
drug disseminates.
 Although the Vd has no physiologic or
physical basis,it is some times useful to
compare the distribution of a drug with the
volumes of the water compartments in the
body
Formula for Vd

It is calculated as the total amount of drug in
the body divided by the concentration of the
drug in plasma

Vd = total dose administered = D
plasma concentration
C
Distribution of Drugs in Various Body
Compartments





70kg Adult
Total Body Water = 42 Liters
ICF = 2/3 = 28 Liters
ECF = 1/3 = 14 Liters
Of the ECF:
Interstitial Volume = 10 Liters
Plasma Volume = 4 Liters
Plasma Compartment

If a drug has a very large molecular weight or
binds extensively to plasma proteins, it is too
large to move out through the endothelial slit
junctions of capillaries, thus restricted within
the vascular compartment e.g Warfarin
So Vd = 4L
Protein binding
Extracellular Fluid

If a drug has a low molecular weight but is
hydrophilic (lipid insoluble), it can move
through the endothelial slit junctions of
capillaries into the interstitial fluid but cannot
enter into the cells (e.g Mannitol)

Therefore Vd = ECF Volume (plasma volume
+ Interstitial fluid volume)
= 4+10 =14 L
Total Body Water

If a drug has a low molecular weight and is
hydrophobic (lipid soluble), it can move into
the interstitial fluid as well as can enter cells
 Thus it distributes into total body water = 42
Liters
 E.g. Alcohol
Factors
affecting
Distribution
Blood Flow

This is an important determinant of the rate of
uptake of drug.
 Drugs are first taken up by highly perfused
tissues (e.g. brain, heart) and these tissues
will often achieve high tissue concentrations
more rapidly than poorly perfused tissues
(e.g. fat, bone).
Size of the Organ

Organs of large size take up large amount of
drug driven by the concentration gradient

Organs of smaller size: distribution of only
small amount of drug into it will raise the
tissue concentration
Lipid: Water Partition Coefficient

Drugs that are highly lipid soluble will readily
cross cell membranes and thus be more
distributed
 And lipid soluble drugs also more readily
cross special barriers such as the blood brain
barrier as well as the placental barrier.
Binding

Binding of a drug to macromolecules in the
blood (plasma proteins) or a tissue
compartment will tend to increase the drug’s
concentration in that compartment.
Other Factors
Fat: Lean Body Mass Ratio:
Those people having high Fat:Lean body
mass ratio will have less distribution of the
drug
Pregnancy:
During pregnancy the fetus may take
up drugs and thus increase distribution of the
drug
Pathological States

Congestive Heart Failure: (alteration of body
water)

Cirrhosis of Liver: Decreased synthesis of
plasma proteins

Uremia: Accumulation of Metabolites that
displace drugs from binding sites
Plasma Protein Binding

After absorption, the drug circulates in the
blood either in the free form or bound to
plasma proteins. This binding is reversible.

These drugs are inert in
(Pharmacologically inactive)
bound
form

Only the free form is pharmacologically active

Bound form of the drug is not easily
metabolized or excreted

So plasma proteins act as a reservoir or
temporary storage place
Clinical Significance
1.
When TWO drugs are given, each with a
high affinity for plasma protein, they
compete for the available binding sites


If a patient who is taking 1 Drug e.g.
Tolbutamide which is normally 95% bound is
given II Drug e.g. Sulfonamide which has
higher affinity for the plasma protein
This II drug will now displace the I Drug
 This will lead to a rapid increase in
concentration of free drug (active drug) in the
plasma (Now 100% free)
2. In hypoalbuminemia, binding may be reduced
and high concentrations of free drug may be
attained e.g. Phenytoin and Frusemide
3. Drugs that are highly plasma protein bound
may have a longer duration of action and
hence longer half life because the drugs in
bound form cannot be metabolized or
excreted. Thus they require less frequent
dosing.


1-The following factor tends to reduce drug
distribution
A-High lipid solubility
 B-Low ionization at physiological ph values
 C-High plasma protein binding
 D-High tissue binding


2-The volume of distribution (Vd) relates:
A- Single to a daily dose of an administrated
drug
 B- An administrated dose to a body weight
 C- An uncharged drug reaching the systemic
circulation
 D-The amount of a drug in the body to the
concentration of a drug in plasma


3-For the calculation of the volume of
distribution (Vd) one must take into account:
A-Concentration of a substance in plasma
 B-Concentration of substance in urine
 C-Therapeutical width of drug action
 D- A daily dose of drug


4-Which of the following factor increases the
drug distribution
A-decrease blood flow
 B-decrease lipid –water partition coefficient
 C-decrease size of the organ
 D-decrease plasma protein binding


5-High plasma protein binding:
A-Increase Vd of the drug
 B-Facilitates glomerular filtration of the drug
 C-Minimises drug interactions
 D-Generally makes the drug long acting


6-The plasma protein bound fraction of a
drug:
A-contributes to the response at the given
moment
 B-remains constant irrespective of the total
drug concentration
 C-remains constant irrespective of the
disease state
 D-is not available for metabolism