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Drug Fate
Removing substances from the
body
• Some substances are
very difficult to
eliminate – heavy
metals such as lead
and mercury
• The body very
efficient at removing
most unwanted
substances such as
drugs
Ways of drug elimination
•
Exhaling air – lungs function as
chemical exchange unit
•
Also perspiration, saliva, feces
and even mother’s milk
•
Major job of eliminating drugs and
other unwanted substances is
done by the liver and kidneys
– Liver responsible for breaking
down chemicals
– Kidney responsible for excreting
chemicals, but some water soluble
chemicals are directly filtered out
and excreted by kidneys
The liver
• Largest organ in the body after
skin
• Located high in the abdomen
next to the stomach
• Function is to take molecules
and modify them to new
molecules
– In this case, toxic chemicals
are modified into less harmful
substances
• The liver receives 2 blood
supplies
– One from the digestive system
– Second directly from the heart
Blood from the digestive system
• Drugs taken orally
(alcohol) begin to be
metabolized, or altered
prior to being distributed
to the sites of action
• Referred to as first-pass
metabolism – drugs taken
orally must be given at
higher dosages than
those injected
Metabolism in the liver
• Most lipid soluble
substances cannot be
filtered out and excreted
by the kidneys. They
pass through the kidneys
and back into the
bloodstream
• The liver must metabolize
these substances into a
form the kidneys can filter
out
Metabolism through oxidation
• The liver produces
enzymes that use oxygen
to alter molecule structure
• These enzymes are
called mixed function
enzymes because they
act on a variety of
chemicals
• Drug interaction and
mixed – function
enzymes
– Alcohol and barbiturates
Metabolism through conjugation
• Liver enzymes add
chemicals to a drug
molecule inactivating it by
preventing its ability to be
absorbed
• This is usually a second
step in the metabolism
process
• Oxidation occurs to alter
the molecule, then
conjugation inactivates
the resulting molecule
Metabolism of Alcohol
• Ethanol (CH3CH2OH) is oxidized by P450
or alcohol dehydrogenase into
acetaldehyde
• Acetaldehyde then conjugated by other
enzymes (mainly aldehyde hydrogenase)
into acetyl-coenzyme
• Acetyl-coenzyme conjugated into water,
citric acid, carbon dioxide, and energy
Action of disufiram or antabuse
• Used to discourage
alcoholics from drinking
• Acts during the
conjugation phase
• It competes with
acetaldehyde for the
aldehyde dehydrogenase
• Levels of acetaldehyde
rise because it isn’t being
broken down as quickly
• Acetaldehyde is a toxin
causing sickness and
discomfort
Factors that effect liver metabolism
• Slowing metabolism by
introducing a second drug
that competes for the
same enzyme
• Stimulating increased
enzyme production due to
past history
• Interspecies differences –
animal research has to
account for metabolic
differences
• Age- enzyme systems not
fully functional at birth –
can be a problem
Drugs given to mother at delivery
• Anesthesia given to mother
during birth; it crosses the
placental barrier
• Mother’s liver metabolizes
anesthesia – fetus can’t
• Umbilical cord cut; drug
remains in baby for a long time
• Theophyline, a stimulant used
to treat asthma
• Baby’s liver converts
theophyline to caffeine,
mother’s doesn’t
• Baby metabolizes caffeine very
slowly
Kidney function
• Filters out chemicals
metabolized by the
liver and water
soluble chemicals the
liver cannot
metabolize
• It does not act like a
sieve or a swimming
pool filter
Kidney function
•
•
•
•
•
Blood pumped through kidney at
high pressure
Most of the fluid in the flood and
substances in the fluid absorbed
by the cell membranes of the
kidneys
Blood cells and large proteins are
not absorbed
Most of the fluid and substances
reabsorbed back into the
bloodstream
Substances not absorbed are
excreted in urine
– All lipid soluble substances diffuse
back into the blood
– Needed non-lipid soluble
substances, like glucose, are
transported back into the blood
The role of diffusion in excretion
•
•
•
•
•
•
Water, drugs and other substances
diffuse through the pores in the kidney
cells out of the blood
Water is reabsorbed or diffuses back
into the bloodstream faster than other
substances
Concentrations of drugs increase in
the kidneys and decreases the
concentration in the blood
There now exists a concentration
gradient
If the drug has not been metabolized
and if it is lipid soluble, it diffuses back
into the bloodstream
This is critical for nutrients and other
needed substances to not be excreted
Reabsorption of alcohol
• One of alcohols effects is
dehydration- it inhibits
ADH or antidiuretic
hormone that signals the
kidneys to retain water
• Urination and dehydration
increases as less water is
reabsorbed and more
alcohol is returned to the
bloodstream
• Only reasonable way to
decrease period of
intoxication is drinking
large amounts of water
Interaction of absorption and
excretion
• Excretion curve
• Absorption curve
• Combine to form
“therapeutic window”
• Therapeutic window –
a constant level that
is high enough to be
therapeutic, but not
toxic