Distribution
The processes of distribution of a drug from the systemic
circulation to organs and tissue involve its permeation
through membrane barriers and are dependent on its solubility
(recall that only nonionized drugs cross biomembranes), the
rate of blood flow to the tissues, and the binding of drug
molecules to plasma proteins.
Factors Affecting Distribution
a. Rate of Distribution
- Membrane permeability
- Capillary wall structure
- Drug’s pKa and blood pH
- Blood Perfusion
b. Extent of Distribution
- Lipid solubility
- pH-pKa
- Tissue localization
- Plasma-protein binding
Central Compartment
The central compartment includes the well-perfused
organs and tissues (heart, blood, liver, brain and kidney)
with which drug equilibrates rapidly.
Peripheral Compartment(s)
The peripheral compartments include those organs
which are less well-perfused, and with which drug
therefore equilibrates more slowly.
Special Compartments
These include cerebrospinal fluid (CSF) and central
nervous system (CNS) , the blood-brain barrier ,
pericardial fluid, bronchial secretions and fluid in the
middle ear
Special Barriers to Distribution
Placental: most small molecular weight drugs
cross the placental barrier, although fetal blood
levels are usually lower than maternal
Blood-brain: permeable only to lipid-soluble
drugs or those of very low molecular weight
Plasma Protein Binding
- Many drugs bind to plasma proteins,
including albumin, with an equilibrium between
bound and free molecules (recall that only
unbound drugs cross biomembranes).
- Competition between drugs for plasma
protein binding sites may increase the "free
fraction," possibly enhancing the effects of the
drug displaced.
PROTEIN BINDING
Albumin
◦ Major plasma protein component
◦ Reversible drug binding
◦ Acidic drugs
Alpha-1 Acid Glycoprotein (AAG) and Globulin
◦ Basic drugs
Lipoproteins
◦ macromolecular complexes of lipids + proteins
◦ Binds drugs when albumin sites become saturated
RBC
• May bind both endogenous and exogenous compounds.
Globulin:
• may be responsible for the transport of certain endogenous
substances such as corticosteroids
FACTORS AFFECTING PROTEIN BINDING
The drug
◦ Physicochemical nature
◦ Concentration in the body
◦ The protein
◦ Qty available for binding
◦ Quality of protein synthesized
◦ Affinity between drug & protein
◦ Drug Interaction
Competition at binding sites
Alteration of the protein by a substance that modifies the
affinity of a drug for the protein
Physiologic conditions of the patient
PROTEIN BINDING EQUILIBRIA
Fraction Unbound = free drug conc
total drug conc
≤ 0.1 (≤ 10% free) significant protein binding changes; adjust normal
therapeutic range
> 0.5 clinically insignificant
• Blood flow is an important factor in
determining the initial distribution of drugs
• PERFUSION OR FLOW LIMITED
• Drug diffuse rapidly across the
membrane
• Blood flow is the rate limiting step in
distribution
• DIFFUSION OR PERMEABILITY LIMITED
• Drug distribution is limited by slow
diffusion of drugs cross the membrane
• Volume of distribution (VD )
• Estimate the extent of drug distribution in
the body
• Relates the plasma conc to the amount of
drug present in the body
• theoretical volume in which the total
amount of drug would need to be uniformly
distributed to produce the desired blood
concentration of a drug
CIRCULATORY SYSTEM 5L
EXTRACELLULAR FLUID 10-20L
INTRACELLULAR FLUID 25-30L
WHOLE BODY FLUID 40L
Depends on
◦ blood and tissue affinity for the drug
(reversible)
Drugs with high tissue affinity tend
to accumulate or concentrate in the
tissue
Drugs with a high lipid/water
partition coefficient tend to
accumulate in lipid tissue
Drug molecules may bind to plasma
proteins
Bound drugs are pharmacologically inactive
free, unbound drug can act on target sites
in the tissues, elicit a biologic response,
and be available to the processes of
elimination
Apparent Volume of Distribution (Vd)
A kinetic parameter of a drug that correlates dose with
plasma level at zero time.
The higher the Vd, the lower the plasma concentration
and vice versa.
Vd is low when a high percentage of a drug is bound to
plasma proteins. This relationship can be used for
calculating Vd by using the dose only if one knows or
can calculate C0.
Tissue binding and accumulation of drugs with high Vd
values raise the possibility of displacement by other
agentschanges in pharmacologic activity
