Chemistry Reference
In-Depth Information
for the membrane,
A
is the surface area of membrane available for absorp-
tion,
C
2
and
C
1
are the concentrations of drug on the external and internal
surfaces, respectively, and
d
is the thickness of the cell membrane. Rate of
diffusion is favoured by high values of
P
, high membrane surface area and a
steep concentration gradient across a thin membrane.
Passive diffusion can only occur with small molecules (e.g. drugs with
relative molecular masses of approximately 1000 or less). This excludes
large macromolecules such as proteins, which are polyelectrolytes and do
not partition well across lipid membranes. This can be important for drugs
that are extensively bound to proteins in the bloodstream. These drugs are
effectively trapped in the blood plasma and cannot easily gain access into
and through cells. The effect is most noticeable for drugs that do not
distribute widely around the body and are highly bound to plasma proteins
(
90% of the given dose). Examples of these include the anticoagulant
warfarin, the antibacterial sulfonamides and oral hypoglycaemic drugs such
as tolbutamide.
The potential for serious drug interactions occurs with drugs bound to
plasma proteins. The binding sites on the protein molecules are relatively
non-specific, and a bound drug can easily be displaced by another drug with
affinity for the protein. The well-documented interaction between the anti-
coagulant warfarin and non-steroidal anti-inflammatory drugs (NSAIDs)
such as aspirin, indometacin and phenylbutazone arises in this way. When
warfarin is administered,
90% of the dose can circulate in the blood
bound to plasma proteins; this means that the patient is effectively stabilised
on the remaining 10% of the dose of drug. If aspirin is co-administered
with warfarin, the aspirin can displace warfarin from binding sites on the
protein and increase the 'effective' concentration of warfarin in the body,
leading to increases in clotting time and haemorrhage. This serious effect
is potentiated because NSAIDs can inhibit the metabolism of warfarin.
Treatment of warfarin overdose is by prompt intravenous administration
of vitamin K and clotting factors II, VII, IX and X.
The pH partition hypothesis
Biological membranes are, essentially, non-polar or hydrophobic, due to the
long hydrocarbon chains of the phospholipid molecules. For a drug to cross
a membrane of this type, the drug must pass from the aqueous solution of
the extracellular fluid, through the lipid membrane to the aqueous solution
of the intracellular fluid (see Figure 2.5), i.e. the drug must be sufficiently
soluble in both the aqueous and the lipid phases to succeed.
