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DRUG DISTRIBUTION
When a drug gets into the systemic circulation; it needs to be distributed
throughout the whole body. This depends on the blood circulation. If, for
example the person is in shock where there is reduced blood flow, it will take
longer for the drug to distribute itself throughout the body.
Distribution of drugs is rarely uniform.
Drugs are simultaneously being eliminated and distributed, but distribution
is usually faster.
Steps of drug distribution
1. Dilution in blood
The drug has to reach equilibrium with itself in the blood. You can’t have an
area of high concentration and low concentration. The concentration needs to
be uniform.
2. Movement into extracellular fluid surrounding cells
Drugs need to be able to get out of the vascular system, either between
endothelial cells or through them.
3. Uptake into cells
The drug must be able to cross the cell membrane
Factors affecting drug distribution
Is the drug bound to proteins or not? (Ability of the drug to cross vascular
endothelium)
Most of the vascular endothelium is porous to drugs; however some drugs
are bound to plasma proteins. These drugs will be unable to get out since the
proteins are so large.
Ability of the drug to cross cell membranes
Is the drug lipid soluble?
Extent of blood perfusion
If a tissue is well perfused, the drug is able to get there faster. e.g. Adipose
tissue has a low blood perfusion and so drugs will not be able to reach these
places very quickly.
Sequestration in lipid
Determine if the drug is lipid soluble
pH differences across membrane barriers
A drug will pass through the membrane better if it is unionized. The pH is
important regarding whether the drug is an acid or a base. An acid drug will be
unionized in an acid environment; a basic drug will be unionized in a basic
environment.
Binding of drugs to other tissue components
The blood brain barrier
Most endothelial cells of the body are leaky except for the brain capillaries.
These capillaries are special in that they have tight junctions between the
endothelial cells, so it is not easy for substances to pass between the cells.
The only way a drug can pass from a brain capillary into the brain is if it is
sufficiently lipid soluble to pass through the endothelium, rather than between
them.
Thus, water soluble drugs are immediately excluded as being used as a CNS
acting drug. Also are highly polar compounds and proteins.
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All this is a protective mechanism which effectively shields the brain from
all the ups and downs of the peripheral circulation. The brain wants to live in a
constant environment, not a hectic one. The blood brain barrier also protects to
a certain extent against some toxins.
Drug reservoirs
Drugs do not distribute themselves in an even manner, which leads to
pooling of drugs in some places.
A drug reservoir is a site in the body where drugs accumulate.
The reservoir is will be like a storage depot – as drug is cleared from the
system, the reservoir keeps on releasing drugs back into the plasma. This is
able to prolong the action of the drug because not the entire drug is cleared
from the plasma at once.
Examples of drug reservoirs are:
Plasma proteins
Acidic drugs are preferentially bound
Only the unbound drug is able to get out of the circulation and into the
tissues.
The binding is non selective
The bound drug may become displaced by a similar drug with similar
properties
Cells
Accumulation of drugs in cells occurs due to the active transport of drugs
into cells or due to the binding of the drug to cell membrane receptors.
e.g. long term treatment of quinacrine (an antimalarial drug) leads to it being
concentrated in the liver. Hence, when the concentration of the drug in the
circulation decreases, the liver is able to release the drug to keep the
circulating levels high.
Fat
Highly lipid soluble drugs are able to make their way to adipocytes and
become stored there. However, they are slow to get there because fat has low
blood perfusion. When the drug is stored there, it is generally stable because
of the low perfusion – the drug is slow to get out into the circulation.
Sometime lead can be stored in fat. If people go on crash diets, all the fat
goes, releasing a whole heap of Pb – you get lead poisoning.
Bone
Some drugs bind to the bone crystal surface and become incorporated into
the crystal lattice.
Example of the principles of drug distribution
e.g. Thiopental
This drug is a highly lipid soluble general anesthetic.
Because it is lipid soluble, it is able to get through the blood brain barrier
and gets there quickly due to the high brain perfusion.
It is administered intravenously because we want it to act quickly to put a
person to sleep.
It has a short duration of action because it redistributes quickly to muscle.
Muscle is acting as the reservoir, hence decreasing the concentration of the
drug in the body.
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If repeated doses are given; we can greatly lengthen the action by saturating
the “sponge” (the muscle). Because the muscle can no longer absorb any more
circulating drug, the drug is able to circulate. Only when the muscle starts to
break the drug down, will it be able to soak up more drugs from the
circulation.
Volume of distribution
“Volume of body water in which a drug appears to be dissolved in after it
has distributed throughout the body”
Vd = amount of the drug in whole body / concentration in plasma
Vd = X / C
We then divide the result (which is in litres) by the mass of the person (in
kg) to give a value in L/kg
Often, it is very difficult to measure X, unless you are given an IV infusion.
In that case, X can be approximated as being the amount of drug given (the
dose) at time = 0.
Vd = Xo / Co
Only applies to an IV infusion
The factors determining the volume of distribution are:
Binding to plasma proteins
If a drug binds to plasma proteins; Vd will be small and approach plasma
volume. This is
because most of the drug is found in the plasma (hence a high C, low X). Vd
will approach plasma volume (0.06 L/kg)
The amount of drug in the whole body is considered to be the amount of
free, unbound drug.
Binding to tissues
If a drug passes through the capillaries, but does not enter cell membranes,
the drug will
end up in the Extra Cellular Fluid . Hence the Vd will be close to ECF volume
(0.2L/kg)
A drug will can pass through the cell membrane but is not bound to tissue
will have a Vd close to total body water (0.6 L/kg).
e.g. Morphine has a Vd = 2.8L/kg because it is bound to sites outside the
circulation (X is large, C is small).
What does a pharmacokineticist sees:
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Kabs
amount of drug in the body
Kelim
amount of drug eliminated
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A pharmacokineticist only sees the amount of drugs. (i.e. what they can
measure)
The rate constants determine the speed of movement of the drug between the
different amounts (e.g. from amount administered to the amount in your
body).
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