Drug Distribution
After absorption into the bloodstream, drugs become
disseminated to all parts of the body. Compounds that permeate freely through
cell membranes become distributed, in time, throughout the body water, both
extracellular and intracellular. Substances that pass readily through and
between capillary endothelial cells, but do not penetrate other cell membranes,
are distributed into the extracellular fluid space. Occasionally, the drug
molecule may be so large (>65,000 daltons) or so highly bound to plasma
proteins that it remains in the intravascular space after IV administration.
Drugs may also undergo redistribution in the body after initial high levels are
achieved in tissues that have a rich vascular supply, e.g., the brain. As the
plasma concentration falls, the drug readily diffuses back into the circulation
to be quickly redistributed to other tissues with high blood-flow rates, such
as the muscles; then, over time, the drug also becomes deposited in lipid-rich
tissues with poor blood supplies, such as the fat depots. Most drugs are not
distributed equally throughout the body but tend to accumulate in certain
specific tissues or fluids. The general principles that govern the passage and
distribution of drugs across cellular membranes (see above) are
applicable. Basic drugs tend to accumulate in tissues and fluids with pH values
lower than the pKa of the drug; conversely, acidic drugs concentrate
in regions of higher pH, provided that the free drug is sufficiently lipid
soluble to be able to penetrate the membranes that separate the compartments.
Even small differences in pH across boundary membranes, such as those that
exist between CSF (pH 7.3) and plasma (pH 7.4), milk (pH 6.5-6.8) and plasma,
renal tubular fluid (pH 5.0-8.0) and plasma, and inflamed tissue (pH 6.0-7.0)
and healthy tissue (pH 7.0-7.4), can lead to unequal distribution of drugs with
pKa values close to those of the pH of the fluid. Only freely
diffusible and unbound drug molecules are able to pass from one compartment to
another. Binding to macromolecules such as protein components of cells or
fluids, dissolution in adipose tissue, formation of nondiffusible complexes in
tissues such as bone, incorporation into specific storage granules, or binding
to selective sites in tissues all impede movement of drugs in the body and
account for differences in the cellular and organ distribution of particular
drugs. Therapeutic agents may also be transported by carrier-mediated systems
across certain cellular membranes, which leads to higher concentrations on one
side than the other. Examples of such nonspecific transport mechanisms are
found in renal tubular epithelial cells, hepatocytes, and the choroid plexus.
Only the unbound or free fraction of a
drug can diffuse out of capillaries into tissues. The most important binding of
drugs in circulation is to plasma albumin, although the globulins and,
especially, α-1 acid glycoprotein (for bases) may also play a significant role.
A drug may become bound to plasma proteins to a greater or lesser degree,
depending on a number of factors, eg, plasma pH, concentration of plasma
proteins, concentration of the drug, the presence of another agent with a
greater affinity for the limited number of binding sites, and the presence of
acute-phase proteins during active inflammatory conditions. The degree of
plasma-protein binding and the affinity of a drug for the nonspecific
protein-binding sites is of great clinical significance in some instances and
much less so in others. For example, a potentially toxic compound (such as
dicumarol) may be 98% bound, but if for any reason it becomes only 96% bound,
then the concentration of the free active drug that becomes available in the
plasma is doubled, with potentially harmful consequences. The concentration of
a drug administered in overdose may exceed the binding capacity of the plasma
protein and lead to an excess of free drug, which can diffuse into various
target tissues and produce exaggerated effects. Of equal importance is the
readiness with which drugs dissociate from plasma proteins. Those that are more
tightly bound tend to have much longer elimination half-lives because they are
released gradually from the plasma protein reservoir. The long-acting
sulfonamides are good examples of this phenomenon. Most unbound drugs
distribute easily to extracellular fluid. All membranes are transversed only by
the more lipid-soluble drugs. During distribution and elimination from the
body, a drug may or may not penetrate certain “physiologic” (eg, blood-brain,
placental, and mammary) barriers. A drug may gain access to the CNS by 2
distinct routes—the capillary circulation and the CSF. Drugs penetrate into the
cortex more rapidly than into white matter, probably because of the greater
delivery rate of drug via the bloodstream to the tissue. The pharmacologic
factors and consequences of the diverse rates of entry of different drugs into
the CNS include the following: 1) water-soluble ionized drugs will not enter
the CNS; 2) low ionization, low plasma-protein binding, and a fairly high
lipid-water partition coefficient confer ready penetration; 3) direct
injections into the CSF often produce unexpected effects; and 4)
meningoencephalitis can substantially alter the permeability of the blood-brain
barrier.
The placental barrier should be considered when selecting
an agent to treat a pregnant animal. The potential teratogenicity of any drug
needs to be known before its administration; if it is to be used during late
gestation, its effects on the fetus and on the process of parturition should be
considered. Nutrients, such as glucose, amino acids, minerals, and even some
vitamins, are actively transported across the placenta. The passage of drugs
across the placenta is largely by lipid diffusion, and the factors discussed
above play a role. The distribution of drugs within the fetus follows
essentially the same pattern as in the adult, with some differences with respect
to the volumes of drug distribution, plasma-protein binding, blood circulation,
and greater permeability of interceding membranous barriers.
The mammary gland epithelium, like other biologic
membranes, acts as a lipid barrier, and many drugs readily diffuse from the
plasma into milk. The pH of milk varies somewhat, but in goats and cows it is
generally 6.5-6.8 if mastitis is not present. Weak bases tend to accumulate in
milk because the fraction of ionized, nondiffusible drug is higher. The
opposite is true for acidic drugs. Agents delivered by intramammary infusion
can diffuse into plasma to a greater or lesser degree by the same processes
noted earlier.
Pharmacokinetics - Distribution of drugs
Once
drugs have entered the circulation their distribution to other parts of the
body is dependent on number of factors. The equilibria involved are outlined
below.
|
Fate
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Administered
|
Absorbed
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Distributed
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Acted
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Location
|
Gut
|
Blood
|
ECF
|
Target
|
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Bound
Drug
Free
Drug
|
Formulation
  Ions Non Ionized |
Plasma
bound
 Ions Non Ionized |
Tissue
bound
 Ions
Non Ionized
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Site
of Action
 Ions
Non Ionized
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Barrier
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Mucosa Endothelium Cell wall
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In
practice drug distribution is a dynamic process and equilibria are often not
attained. The rate at which a drug is distributed and reaches its site of
action is also dependent on number of
factors. The pattern of distribution of drugs varies enormously, but can often
be predicted on the basis of certain physicochemical characteristics. It is
also important to realize that concentration of a drug in a particular tissue
does not necessarily correlate with its action.
Apparent volume of distribution -
In many cases, drugs are absorbed into the circulation and then distributed to
their site(s) of action. Plasma levels of drugs can usually be measured
relatively easily. However, these may be very different from the levels
elsewhere in the body. Apparent volume of distribution is the volume of the
fluid into which the drug appears to distribute with a concentration equal to
that in plasma. It is also defined as the volume of fluid that would be
necessary to contain the amount of drug in the body at a uniform concentration
equal to that in the plasma.
Amount of
drug in the body
Vd
=
--------------------------------------------------- expressed as L/Kg
Concentration of drug in the plasma
Since
Vd is often characteristic of a drug and constant over a wide range,
it is useful in calculating the amount of drug in the body when the plasma
concentration is known, or in predicting the concentration in plasma following
a given dose. Large volume of distribution means good tissue perfusion and
small volume of distribution means poor tissue penetration.
Dose
= Vd x Plasma concentration
Unless
the drug is administered intravenously, its bioavailability from the particular
dosage form and route must also be taken into account. The Vd does
not correspond to a physiological volume in an animal but is simply an
imaginary but nonetheless useful volume. The factors governing volume of drug
distribution include lipid : water partition coefficient of the drug, pKa value
of the drug, degree of plasma protein binding, affinity for different tissues,
fat : lean body mass ratio and diseases like congestive heart failure, uremia
and cirrhosis.
Factors affecting drug distribution
include 1. Blood flow, 2. Plasma protein binding, 3. Lipid solubility, 4. pH,
5. Capillary permeability, 6. Drug dilution in body water, 7. Accumulation at
other sites.
Blood flow -
The rate at which a drug reaches different organs and tissues will depend on
the blood flow to those regions. Equilibration is rapidly achieved with heart,
lungs, liver, kidneys and brain where blood flow is high, while skin, bone and
depot fat equilibrate much more slowly.
Plasma protein binding -
Drugs tend to become associated with several blood constituents. Binding to
plasma proteins or to components in RBC facilitates absorption into the blood
stream by lowering the concentration of free drug in the plasma. It is only the
unbound or free fraction of a drug that can diffuse out of capillaries into
tissues. Many drugs are bound to plasma proteins. Most drugs bind to albumin
although certain drugs bind to other plasma proteins like globulins. Factors affecting plasma protein binding
include a. Drug concentration, b. Number of drug binding sites on the protein,
c. Protein concentration, d. Lipid solubility - there is a good correlation
between this and the binding of penicillins and tetracyclines, e.Weak acids
like penicillins are bound more extensively than weak bases, f. Competing
molecules, g. Species variation, h. Disease
Albumin
and other plasma proteins are essentially contained within blood vessels and so
the distribution of drugs that are bound is restricted. When more than 70 - 80
% of the drug is bound to plasma protein, it acts as a circulating reservoir
for the drug.
When
two or more drugs bind to the same site of the plasma proteins, administration
of a second drug may significantly affect the binding of the first drug.
Changes in binding have the greatest effect on the proportion of free drug when
the percent bound is high. Reducing the binding from 98% to 96% will double the
amount of free drug from 2% to 4% and thus the halflife of the drug would be
reduced much. At its therapeutic concentration warfarin is 97.4% bound. If a
therapeutic dose of the non-steroidal anti-inflammatory drug phenylbutazone is
administered, bound warfarin decreases to 92%. Thus free warfarin increases
from 2.6 to 8%. This increases the anticoagulant effect of warfarin
considerably. It also reduces its halflife from 18.4 to 9.6 hours since it is
also more available for biotransformation and excretion.
The drug protein binding reaction is reversible and
obeys the laws of mass action.
Drug
(Free) + Protein Drug-Portein
(Bound)
Acidic drugs are bound primarily by albumin and
basic drugs are bound by α1 – acid glycoprotein.
Binding doesnot prevent a drug from reaching the
site of action but it slows the rate at which a drug reaches a concentration
sufficient to produce a pharmacologic effect.
Drug – protein binding limits glomerular filtration
as an elimination process, because bound drugs cannot be filtered. Binding does
not typically limit the elimination of drugs that are actively secreted by the
kidneys. Or metabolized by the liver, because the fraction of the drug that is
free is transported & metabolized. As the free drug concentration is
lowered, there is rapid dissociation of the drug-protein complex to maintain
the concentration of the drug in the free form.
Lipid solubility -
Lipid solubility will affect the ability of the drug to bind to plasma proteins
and to cross the lipid membrane barriers. Very high lipid solubility can result
in a drug initially partitioning preferentially into highly vascular lipid-rich
areas. Subsequently these drugs slowly redistribute into body fat where they
remain for long periods of time.
pH - Small differences
in pH have significant effects and acidic drugs will tend to accumulate where
the pH is higher, while bases do the reverse. The rate of movement of a drug
out of the circulation will depend on its degree of ionization and therefore on
its pKa, Changes in pH occurring in disease may also affect drug distribution.
Blood becomes more acidic if respiration is inadequate. In cases of mastitis,
the pH of milk may increase as much as 0.7 units affecting drug distribution.
Capillary permeability -
The ability of drugs to reach the various tissues depends on the permeability
of the capillaries at the site in question. Thus the capillaries in liver are
extremely permeable, while those at the blood-brain barrier are normally
impermeable. Drugs can pass through the epithelial cells or between them
through the gap junctions. Thus molecular size is the major factor affecting
the permeability of water soluble drugs across capillaries.
Passage of drugs into the CNS -
Drugs enter into the CNS by two routes namely capillary circulation and through
the cerebrospinal fluid. Capillaries in the brain are different from the
capillaries in the other tissues because the endothelial cells lie close
together and form tight junctions. Thus capillaries in the brain have no
opening through which drug molecules can pass. Only small lipid-soluble drugs
can enter into the CNS. Inflammation of the epithelial layer may increase the
permeability and allow charged and normally impermeable drugs to attain
therapeutic concentrations in the CNS. E.g., Penicillin and streptomycin can
achieve therapeutic concentrations in CNS in meningitis.
Blood brain barrier -
This barrier is highly effective against chemicals and blood constituents. It
is mainly formed by the endothelial cells of the CNS blood vessels. Its purpose
is to protect the brain from the chemical environment of the rest of the body
due to the delicate balance between excitation and inhibition maintained within
the CNS. It contains transporter proteins essential to maintain an
extracellular environment appropriate for the CNS neurons. Transporters are
available for the essential amino acids and for glucose. Ion gradients must be
maintained across a cell membrane to provide the energy needed to drive amino
acid transport. The blood brain barrier contains active transporters for Ca2+,
Na+ and K+. About l/5th of the glucose utilization of a healthy animal is
required to maintain activity of ATP dependent active transporters, which
maintain the ionic gradients that sustain resting membrane potential. The brain
capillaries do not contain fenestrations (holes). There are more tight
junctions in brain capillaries decreasing the rate of diffusion through
interstitial spaces. Glial cells ensheath the brain capillaries providing a
second set of cell membranes which must be traversed as well as a second
intracellular compartment where cellular metabolic processes can transform
entering substances. Highly lipophilic drugs enter easily because they cross
membranes. Unionized forms of drugs enter more easily than ionized forms. The
blood brain barrier is more leaky in neonates and young animals, in the
hypothalamic region of the median eminence and the pituitary, over the
chemoreceptor trigger zone where the vomiting center is organized and
triggered, in some diseases like meningitis, high fever and high plasma
bilirubin and also during hyperosmotic shock.
Cerebrospinal fluid barrier -
This barrier is formed by choroids plexus epithelial cells. These cells serve
both a barrier and a transport function. They are impermeable to most blood
solutes.
Passage of drugs across the placenta -
The placenta is not an effective barrier to most drugs and hence care must be
taken while administering drugs to pregnant animals. Only highly ionised drugs
and drugs with low lipid solubility are excluded from passing through the
placenta. Drugs such as oxytocin are vulnerable to placental enzymes and so do
not pose such a risk to the foetus.
Passage of drugs into the mammary tissue -
The mammary gland epithelium, like the other biological membranes act as a
lipid barrier and many drugs readily diffuse from the plasma into the milk. The
pH of milk varies somewhat; but in goats and cows it is generally 6.5 - 6.8 if
mastitis is not present. Weak bases tend to accumulate in milk because the
fraction of ionized, nondiffusible drug is higher. Agents delivered by
intramammary infusion can diffuse into the plasma to a greater or lesser degree
based on pH differences and the pKa of the drug.
Other
distribution barriers are the prostate, testicles & globe of the eye.
Drug
dilution in body water - Body water constitutes about 75% of
total body weight and the drug gets diluted in this body water including the
transcellular secretions like cerebrospinal fluid, aqueous humor of the eyes,
contents of renal tubules, urine in the bladder, milk, synovial fluid, pleural
fluid, peritoneal fluid, bile saliva and gastrointestinal secretions. Within
each of the aqueous compartments, drug molecules usually exist both in free
form and in bound form. Further, drugs that are weak acids or bases will exist
as an equilibrium mixture of the charged and uncharged forms, the position of
the equilibrium depending on the pH. The equilibrium pattern of distribution
between the various compartments will therefore depend on permeability across
the tissue barriers, binding within compartments, pH partition and fat : water
partition. To enter the transcellular compartments from the extracellular
compartment, a drug must cross a cellular barrier. The distribution between
these body water compartments will depend on their volume. The gastrointestinal
tract of ruminants and to a lesser extent in horses constitutes a huge aqueous
volume into which the drug may be distributed. Furthermore, these animals
produce very large amounts of saliva. Drugs administered parenterally may
distribute into the rumen. Weak bases will tend to become trapped there since
they become ionized at the lower pH they encounter in the rumen. Since the pH
of milk (~ 6.8) is lower than the plasma (7.4), weak bases will tend to
accumulate in milk. Trapping of basic drugs in milk is an advantage in the
treatment of mastitis, but is also a potential problem in milking dairy
animals.
Accumulation at other sites
Cells - Many drugs
accumulate in muscle and other cells. Since the pH difference between the
cytoplasm (~ 7.0) and the extracellular
space (~ 7.4) is small, there is little pH trapping.
Accumulation
is either due to active transport or more commonly to binding.
Fat - Highly lipid
soluble drugs accumulate in fat. E.g., chlorinated hydrocarbons. Larger doses
of lipid soluble drugs may be necessary in obese animals.
Bone - certain drugs are
deposited in the bone and teeth e.g., lead and other heavy metals, fluoride,
tetracyclines.
Drug reservoirs -
Sites other than the site of action can act as reservoirs for the drug if a
large enough amount of the drug is sequestered there. For example
1. Plasma proteins - digoxin, phenytoin
2. Fat - thiopental, organochlorine pesticides
3. Cells - quinacrine (liver cells)
4. Bone - tetracyclines, lead
5. GI tract - weak bases
6. Keratinous tissues - Arsenic, griseofulvin
The
existence of drug reservoirs and sites of prolonged sequestration is a major
concern in food animals. Drug residues can be found in muscle, milk, eggs,
liver etc. Hence, many drugs are not approved for use in food producing animals
or if used, sufficient withdrawal time should be allowed before the animals are
sent for slaughter.
Redistribution of drugs -
Highly lipid soluble drugs given intravenously or by inhalation initially get
distributed to organs with high blood flow like brain, heart, kidneys etc.
Later less vascular but more bulky tissues like muscle and fat take up the
drug. Plasma concentration falls and the drug is withdrawn from these sites. If
the site of action of the drug was in one of the highly perfused organs,
redistribution results in termination of the drug action. Greater the lipid
solubility of the drug, faster is its redistribution. Anaesthetic action of
thiopentone is terminated in few minutes due to redistribution. However, when
the drug is given repeatedly or continuously, over long periods, the low
perfusion high capacity sites get progressively filled up and the drug becomes
longer acting.
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