Distribution of drugs

Reversible transfer of a drug between the blood and the extra vascular fluids and tissues of a body, eg. fat muscle and brain tissue.
Distribution is a Passive Process for which
the diving force is the concentration gradient
between the blood and extravascular
o
1.
2.
3.
4.
5.
6.
a)
b)
o

The process occurs by the diffusion of

free drug until equilibrium is established

Once a drug enters into systemic circulation by absorption or direct administration it has to be distributed into interstitial
and intracellular fluids
Lipid solubility
pH of compartment
Extent of binding with plasma protein and tissue proteins
Cardiac output
Regional blood flow
Capillary permeability
are associated for distribution of the drug through tissues
The drug I easily distributed in highly perfused organs like liver/heart/kidney, etc in large quantities
In small quantities it is distributed in low perfused organs like muscle, fat and peripheral organs
Drug can be moved from the plasma to the tissue until the equilibrium is established (for unbound drug present in plasma)

Body compartment

Body fluid = water + dissolved solvent

Around 45 75% of the body weight consist of water
It is gradually more in men (60%) then women (55%). Infants have the highest % of water up to 75% of body weight
Main body fluid is distributed into 2 compartments:
Intracellular fluid (ICF): It involves the fluid present in the cells of the body. 2/3 of the body weight
Extracellular fluid (ECF): Involves plasma, interstitial fluid and lymph. 1/3 of the body weight
Fluid also present as a transcellular form: present in the cavities made up of cells like CSF, Intra ocular fluid (IOF),

Pleural/Peritoneal/Synovial/digestive secretions etc.

This type of fluid is produced by the cells present nearby to that organ
The drug molecules that are present in this type of body compartment of fluid as free and bound form. If the body acts as

a single compartment, the volume that contains the drug present in the body is called apparent volume of distribution (Vd).
Volume of distribution
It is defined as the volume in which the amount of drug would be uniformly distributed to produce the observed blood
concentration

Vd =

total amount of drugthe body

drug blood concentration

Redistribution
o

Highly lipid soluble drugs when given intravenously or by inhalation and get distributed to organs with high blood flow eg.

brain/heart/kidney, etc
Later, less vascular but more bulky tissues (muscles/fat) takes up the drug and plasma concentration falls and drug is

withdrawn from these sites.

Greater the lipid solubility of the drug, the faster the redistribution.

Drug reservoirs: body compartments that a drug can accumulate in serve as reservoirs, have dynamic effects on drug availability.

Plasma reservoirs:
-

Albumin

a1-acid glycoprotein

Tissue or cellular reservoirs:

Adipose reservoirs

Bone reservoirs

Transcellular reservoirs

GI tract reservoirs

Pharmacokinetics
Protein binding:
o
o
o

Not only affects the activity of the drug bound = inactive

But also influences its distribution from one compartment to another
This is particularly true with respect to glomerular filtration and passive trans.
Free drug + protein

bound drug

Binding of drug to blood/plasma protein

-

The drug may bound with proteins like albumin/globulin/lipoprotein (very less or not bind with fibrinogen),

glycoprotein/transferrin etc. and it also can bind with red blood cell on the small extend with white blood cell
Drugs that are circulated in the body as bound/unbound form are in equilibrium. It means that drugs which bind with

plasma protein cannot diffuse through capillary wall to reach the site of action
At lower dose the drug can bind excessively to plasma protein or with other substances so free drug concentration is less

But with the same drug, during repeated dose or higher dose, the free drug concentration is increased but there is no

effect on binding because the binding sites are saturated

Increase in the free drug concentration and if the drug is having low therapeutic index it can cause toxic effect to the body

Plasma protein-drug binding

Protein

Molecular weight (Da)

Concentration

Drugs that bind

Albumin

65,000

3.5-5.0

Large variety of drug

alpha1-acid glycoprotein

44,000

0.04-0.1

Basic drug propanol; imipramine and lidocaine

Globulins (globulins corticosteroids)

Lipoproteins

200,000-3,400,000

0.003-0.007

Basic lipophilic drug eg. chlorpromazine

alpha1 globulin

59000

0.015-0.06

Steroid, thyroxine cynocobalamine

alpha2 globulin

13400

Vitamin A, D, E and K

Factors affecting drug distribution

1.
2.
3.
4.

Tissue permeability of the drug

Organ/tissue size and perfusion rate
Binding of drugs to tissue components
Miscellaneous factors

1. Tissue permeability of the drug

a)
b)

Rate of tissue permeability, and

Rate of blood perfusion
The rate of tissue permeability depends upon physicochemical properties of the drug as well as physiological barriers that
restrict the diffusion of drug into tissues

Physicochemical properties that influence drug distribution are:

i.
Molecular size:
- Small ions of size < 50 daltons enter the cell through aqueous filled channels whereas larger size ions are
ii.

iii.

restricted unless a specialized transport system exists for them

pKa index to express the acidity of weak acids
Ionisation:
- Drug that remains unionized at pH values of blood and extracellular fluid can permeate the cells more rapidly
- Blood and ECF pH normally remains constant at 7.4 unless altered in conditions like systemic alkalosis/acidosis
o/w Partition coefficient
Lipophilicity:
- Only unionized drugs that are lipophilic rapidly crosses the cell membrane
- eg. Thiopental, a lipophilic drug, largely unionized in blood and ECF pH readily diffuses the brain where as
Penicillins which are polar and ionized at plasma pH do not cross BBB
Effective Partition Coefficient for a drug is given by
Effective K o/w = Fraction unionized at pH 7.4 x K o/w of unionized drug

Physiological barriers
i.
Penetration of drugs through blood brain barrier
A stealth of endothelial cells lining the capillaries
-

It has tight junctions and lack large intracellular pores

Astrocytes: special cells/elements of supporting tissue are found at the base of endothelial membrane

Since BBB is a lipoidal barrier

o It only allows the drugs having high o/w partition coefficient to diffuse passively where as moderately

ii.

lipid soluble and partially ionized molecules penetrate at a slow rate

Endothelial cells restrict the diffusion of microscopic objects (eg. bacteria) and large or hydrophilic

molecules into the CSF while allowing diffusion of small hydrophobic molecules (O2, CO2, hormones)
Cells of the barrier actively transport metabolic products such as glucose across the barrier with specific

proteins
Penetration of drugs through placental barrier
o Placenta is the membrane separating foetal blood from the maternal blood
o Made up of foetal trophoblast basement membrane and endothelium
o Mean thickness in early pregnancy is 25 micro which reduces to 2 micro at full term
o Many drugs having mol. wt. < 1000 Daltons and moderate to high lipid solubility eg. ethanol,
sulphonamides, barbiturates, steroids, anticonvulsants and some antibiotics cross the barrier by simple
o

diffusion quite rapidly.

Nutrients essential for foetal growth are transported by carrier mediated processes

2. Organ/tissue size and perfusion rate

Perfusion rate is defined as the volume of blood that flows per unit time per unit volume of the tissue
Greater the blood flow, faster the distribution.
Highly perfused tissues such as lungs, kidneys, liver, heart and brain are rapidly equilibrated with lipid soluble drugs.
The extent to which a drug is distributed in a particular tissue or organ depends upon the size of the tissue i.e. tissue vol.

3. Tissue binding of drug

Majority of drug bind to extravascular tissue the order of binding: liver > kidney > lung > muscle
a.
b.
c.
d.
e.
f.
g.
h.

Liver epoxide of number of halogenated hydrocarbon: Paracetamol

Lung basic drug imipramine, chlorpromazine, antihistamine
Kidney heavy metals like lead, mercury and Cd
Skin Chloroquine and phenothiazine
Eye Chloroquine and phenothiazine
Hairs Arsenicals and chloroquine
Bone Tetracycline
Fats Thiopental, pesticide DDT

Plasma-drug concentration of drug

Plasma drug concentration is a function of absorption and elimination:

Typical plasma drug concentration as function of time after a single oral dose
The area under the plasma drug concentration-time curve (AUC) reflects the actual body exposure to drug after

administration of a particular dose of the drug

The plasma concentration is how much of a drug is in your blood

Bioavailability (F) is determined by comparing plasma levels of a drug after a particular route of administration (for example, oral
administration) with plasma drug level achieved by IV injection in which all of the agent rapidly enters the circulation.
By plotting plasma concentrations of the drug versus time, one can measure the area under the curve (AUC). This curve reflects
the extent of absorption of the drug.