Download Organ Blood Flow

Distribution
The process of translocating drugs from the
bloodstream into the tissues
Most drugs are not
uniformly distributed
throughout total body
water.
Factors Affecting Distribution
Organ Blood Flow
Redistribution
Ion trapping
Tissue Binding
Plasma Protein Binding
Organ Blood Flow
The rate at which a drug is distributed to various
organs depends largely on the proportion of cardiac
output received by the organs.
Drugs are rapidly distributed to highly perfused
tissues and this enables a rapid onset of action of
drugs affecting these tissues.
Organ Blood Flow
Drugs are distributed more slowly to less
perfused tissues and even more slowly to
those with the lowest blood flow
Organ
Lung
Kidney
Liver
Brain
Fat
Muscle
Bone
Flow
(ml/min/g)
10
4
0.8
0.5
0.03
0.025
0.02
Highly
perfused
Poorly
perfused
Later, less vascular but more
bulky tissues take up the
drug.
If the site of action of the
drug was in one of the
highly perfused organs,
redistribution results in
termination of the drug
action.
Redistribution
100
blood
brain
muscle adipose
50
Thiopental conc
(as % of initial dose)
Highly lipid soluble drugs
are initially distributed to
organs with high blood flow.
0
1
10
100
minutes
1000
Redistribution
After injection is
concluded, the plasma
concentration falls as
thiopental diffuses into
other tissues.
The onset of anesthesia is
rapid, but so is its
termination.
Intravenous Anesthetic
Thiopental
100
blood
brain
muscle adipose
50
Thiopental conc
(as % of initial dose)
Reaches its maximal
concentration in brain
within a minute of its
intravenous injection.
0
1
10
100
minutes
1000
Plasma Protein Binding
Once a drug has been absorbed into the circulation
it may become attached to plasma proteins.
The extent of binding depends on the affinity of a
particular drug for protein-binding sites.
A drug in blood exists in two forms:
bound and unbound.
Plasma Protein Binding

Plasma Proteins that Bind Drugs
 Albumin (acidic drugs)
 Alpha-1 acid glycoprotein (basic drugs)
 Lipoproteins (acidic drugs)
Plasma Protein Binding
Binding is often reversible
protein + drug ⇌ protein-drug complex
If the concentration of the unbound drug is
reduced, some of the protein-drug complex
may split to release more of the compound,
maintaining the equilibrium.
Plasma Extracellular water
Protein-bound drug
can be thought of as
a reservoir—with
drug gradually
released from
nonspecific binding
sites when plasma
concentrations of the
drug decline.
Plasma protein
drug
Tissue protein
Protein-bound drugs are not bioactive
Paracellular movement generally is limited to unbound drug
Bound drugs
cannot be
metabolized
Locus of
action
“receptors”
Bound
Tissue
reservoirs
Free
Bound
Free
Systemic
circulation
Absorption
Free drug
Bound drug
Bound
drugs
cannot be
filtered
Excretion
Metabolites
Biotransformation
Plasma Protein Binding
Effects of plasma protein binding
Free fraction: active, excreted,
metabolized
the more binding, the less
active drug
the more binding, the less
excreted and metabolized:
“longer half-life”
The amount of free drug determines
how effective it is in the body.
Clinical sketch
A man takes phenytoin for his epilepsy.
Unknown to him, his plasma albumin falls
markedly over the next few weeks,
without the dose of phenytoin being
changed. He develops marked ataxia.
Clinical sketch
Comment：the patient’s ataxia has
resulted from an increases in the free
concentration of phenytoin.
The clinical relevance of plasma
protein binding is often much less
clear cut than in this example.
Plasma Protein Binding
Plasma protein binding is saturable.
 Drugs may compete for binding with plasma
proteins.
 A drug can be displaced from binding sites by
other drugs that have a high affinity for such
sites.
Drug interaction of plasma protein binding
warfarin
+
99% bound
aspirin
98% bound
1% free
2% free
The amount of free drug has doubled
Effective
TOXIC
Why basic drugs are
secreted into the stomach
where pH is acidic, and
Ion Trapping
acidic drugs are excreted
in urine when it is alkaline？
Ion Trapping
The build-up of a higher concentration of a drug
across a cell membrane due to the pKa value of the
drug and difference of pH across the cell
membrane.
Cells have a more acidic
pH inside the cell than
outside
A basic drug is
preferentially
unionized in the
outside
H+
NH3
PH 7.0
H+
H+
H+
H+
H+
NH3
PH 7.4
NH3
NH3
H+
NH3
NH3
NH3
Once the unionized basic drug
crosses the cell membrane to
enter the cell, it becomes
ionized and thus becomes
unable to cross back.
NH3 + H+ ⇌ NH4+
NH4+
PH 7.0
NH4+
NH4+
NH4+
PH 7.4
NH4+
NH4+
NH4+
AA-
A-
NH4+
NH4+
A-
PH 7.0
A-
NH4+
NH4+
NH4+
ANH4+
PH 7.4
Ion trapping
results in basic
drug’s
accumulating in
acidic bodily
fluids and acidic
drug’s
accumulating in
basic fluids.
Tissue Binding
Most drugs do not spread evenly throughout the
body.
The water-soluble drugs tend to stay within the
blood and interstitial space. The lipid-soluble
drugs tend to concentrate in adipose tissue.
Other drugs concentrate mainly in only one small
part of the body.
Tissue Binding
Some drugs accumulate in certain tissues,
which can also act as reservoirs of extra drug.
The tissues with the highest drug concentrations
are not always the sites of drug action.
The tetracycline
antibiotics and heavy
metals cause permanent
staining of teeth and weak
bones in the baby.
Tetracycline Stains on Teeth
Central Nervous System and
Cerebrospinal Fluid
The distribution of drugs into the CNS from
the blood is unique.
It was discovered that if blue dye was
injected into the bloodstream, that tissues of
the whole body EXCEPT the brain and spinal
cord would turn blue.
Blood-Brain Barrier (BBB)
BBB prevents materials from the blood from
entering the brain existed.
The capillary endothelial cells in brain have tight
junctions. Glial cells (astrocytes) form a layer
around brain blood vessels.
Drug penetration into the brain depends on
transcellular rather than paracellular transport.
Some molecules, such as glucose, are transported
out of the blood by specific uptake transporters.
General Properties :
Blood-Brain Barrier
Large
molecules do not pass through the BBB
easily, while allowing the diffusion of small
hydrophobic molecules
Low
lipid soluble molecules do not penetrate
into the brain.
High
lipid soluble molecules rapidly cross
through into the brain.
Blood-Brain Barrier
Protects
the brain from "foreign substances" in
the blood that may injure the brain
Protects
the brain from hormones and
neurotransmitters in the rest of the body

Maintains a constant environment for the brain.
Hinders
some helpful things, making the
administration of some medications to treat brain
and central nervous conditions rather challenging.
Clinical sketch
A patient with meningitis is treated with
gentamicin. The organism is very
sensitive to the antibiotic in vitro, but
the patient shows no improvement.
Comments： this would be very
unacceptable clinical practice and the
patient may well die. Gentamicin does
not readily cross the blood-brain barrier.
Placental Transfer of Drugs
Drugs administered to mothers have the potential
to cross the placenta and reach the fetus.
The fetus is to some extent exposed to all drugs
taken by the mother and drugs may cause
anomalies in the developing fetus.
Pregnancy Categories
The FDA has divided drugs into five
categories based on their safety in pregnant
women.
Drugs in Categories A and B are relatively
safe.
Drugs in Category X are contraindicated
during pregnancy.
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Pregnancy
Category
A
B
C
D
Description
Remote risk of fetal harm – controlled studies in
women have been done.
Slightly more risk than A – no risk in animals but
no studies in women
A lot of drugs fall into this category
Greater risk than B – Animal studies show risk but
no studies in women
Proven risk of fetal harm but possibility of
significant benefit. “Warning” label.
Usually this is not from a study, but from
observation
Proven risk of fetal harm which outweighs benefi
X
32