Download Bioavailablity student notes 08_lesson_bioavalailabilityStudent_2

BIOAVAILABILITY
When someone overdoses on a drug, even if they don’t die, they often end up with a failing liver.
Currently the only way to survive liver failure is to receive a liver transplant. In October, 2010,
researchers at the University of California at San Francisco received a grant in collaboration with
investigators at the University of California at Davis to find an alternative. Drs. Zern and Willenbring
will be looking for ways to use embryonic stem cells to regenerate lost liver cells necessary for reestablishing normal liver function to someone with liver failure.
In order for a drug to have an effect, to bind to a receptor, it must be present in the body at the same
location of that receptor and in a form that can bind. There are several parameters that influence that
availability in our bodies. Thus the "bioavailability" of a drug must be computed after consideration of
all these parameters.
Objectives
After successfully completing this lesson you will be able to:
 Understand factors that determine how long drug molecules will stay in the body
 Relate method of administration to the effect of a drug in terms of speed and intensity
 Use a diagram of the circulatory system to predict how fast a drug molecule could reach the
brain based on method of administration
 Name two reasons that the blood brain barrier restricts delivery to the brain (two reasons
HOW and two reasons WHY).
 Recognize names of metabolic enzymes
 Recognize metabolic changes to drug molecules
 Understand half life and relate it to fat solubility of drugs
Before you begin!
o Your ideas
 Which is more addictive, snorted cocaine or crack cocaine?
 Which vitamins are fat soluble?
 What category of molecules is responsible for drug metabolism?
 Where are these metabolic enzymes produced?
o Previously learned material
 What is the main difference between fats and other biological molecules
 What are glial cells?
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Lesson 8: Bioavailability
Guiding Questions
1. Among the ways that drug molecules can enter the body, what method is slowest (gives the
slowest onset of drug-related symptoms)?
2. Why are some medications made in time-release formulations?
3. In what ways is blood circulation different in the brain?
4. What is half life? How does fat solubility influence half life?
5. What kinds of chemical reactions are metabolic enzymes capable of?
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Key Terms
 Parenteral administration
 Blood brain barrier
 Half life
 Fat soluble/ solubility
 Cytochrome P450
Activity One: Laboratory Exercise – Reactive Hydrogen Peroxide
Read the directions for the second laboratory exercise – “Reactive Hydrogen Peroxide”. Perform this
laboratory activity and complete the laboratory homework that follows.
TEST OF CONTENT
Among the food types you tested, which had the MOST activity when mixed with hydrogen
peroxide?
When graphing “time to rise” vs. food type, what do you notice about the height of each bar in
comparison to the relative amount of activity found in each food?
Why do discs rise? To answer this, write out the chemical reaction that is occurring around the
food-dipped discs.
Activity Two: Presentation Review
Follow this link to a presentation that simulates the influences that determine how "available" a drug
can be for binding to a receptor.
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Medication Absorption, Distribution, Metabolism and Excretion
http://davisplus.fadavis.com/wilkinson/Animations/MedicationDistribution.swf
Guiding questions to consider while watching this presentation are:
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Why might the manner of drug INTAKE matter in terms of the availability of that drug to its
receptors, especially receptors in the brain?
What does the circulatory system have to contribute to drug availability to its receptor?
What is the physical connectivity diagram for the circulatory system. Can you trace the pathway
of molecules as they enter the circulatory system at different places?
What influences drug availability via the circulatory system with regard to the brain or a fetus?
How is blood flow to the brain (or a fetus) different with other organs?
What influences the "shelf life" of a drug? How long can a drug molecule stay in the body
unmodified?
When drugs are stored in the body, WHERE are they stored?
How are drugs eliminated from the body?
These YouTube videos may also be helpful
http://www.youtube.com/watch?v=07Tr__R_koE&feature=related
http://www.youtube.com/watch?v=xiuWdJYyIKs&feature=related
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http://www.youtube.com/watch?v=kLvYCOSnPDc&feature=related
http://www.youtube.com/watch?v=2uehdqZzKEM&feature=related
http://www.youtube.com/watch?v=8zYIEiXvSZY&feature=related
Activity Three: Entry into Body
Start at http://science-education.nih.gov/supplements/nih2/addiction/activities/lesson3_pathways.htm
. Click on the second animation – “Pathways to the Brain”. For each pathway, jot down a
representation of the result (concentration of drug in brain) and label the way in which the drug was
administered.
Consider first how drugs enter the body. This idea might evoke images of someone taking a pill, or
another person smoking a pipe. There are many different ways to get a drug into the body and even for
a single drug, there are alternative methods of intake. The method by which a drug enters the body can
have profound impact on its ability to work, to stay intact, its potency, and the speed with which it gets
to target tissues.
Start by examining this diagram 1of the circulatory system. You might find it convenient to print out a
copy of the diagram so you can trace along the connected parts.
Imagine your first drug is aspirin. It enters the body
through the mouth and travels down the esophagus to
the stomach. It doesn't enter the circulatory system until
after passing through the stomach into the liver and or
intestines. The oral medication therefore enters the
circulatory system at the hepatic vein. How far must it
travel to get to the brain to relieve your headache? You
might quantify this in terms of number of stops the blood
makes along the way where the lungs and the heart are
considered "stops".
Now imagine that your headache is so serious you must
go to the hospital and the doctors there decide you really
need morphine (a drastic choice for a headache!).
Morphine is administered through an intravenous needle
directly into the blood stream. From the IV inserted into
your arm, the drug molecules will go to the heart via the
jugular vein. What happens to the speed with which
morphine gets to the brain as compared to aspirin?
Careful, not only do you have to consider time in the
circulatory system, but you also have to consider time in
the digestive system. And while you might understand
that morphine will do far more to relieve your headache
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Source - Internet Encyclopedia of Science
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than aspirin, the route of administration is only a small part of the difference - they are entirely different
drugs.
For another comparison, consider snorted cocaine vs. smoked, crack cocaine. Snorted cocaine enters
the body through the mucous membranes of the nose. Although AIR in the nose goes to the lungs,
absorption through these nasal membranes brings the drug into the circulatory system via the jugular
vein. Track the number of stops snorted cocaine molecules make before getting to the brain. Compare
that answer to the pathway traveled by smoked, crack cocaine. When you smoke a drug, it enters the
blood in the lungs, and starts out in the pulmonary artery.
TEST OF CONTENT
Crack cocaine is far more intense and more addictive than snorted cocaine. Propose why
based only on this difference in administration. Phrase your answer in terms of the concentration of
drug molecules reaching the brain (at the same time).
Activity Four: Time Release Medication
Some medications can be obtained in "time released" or "extended release" forms. There are different
mechanisms for making a drug form that is slowly released into the body. Most involve interfering with
the ability of the drug to be absorbed. Mixing your drug molecules with other "inert" (non-active
ingredients) that interfere with it getting processed or slowing entry into the blood stream will cause the
drug to enter only when the drug is unwound from its inert companion. Alternatively, drugs can be
encapsulated into gelatin capsules that allow slow release that depends upon the acid environment of
the GI system.
Time release formulations of a drug enable people to take the drug less frequently. Because of issues
pertaining to dosing (next lesson), it is unwise to take too much of any drug at one time. Keeping to safe
doses might lead people to take their medications so frequently that it could interfere with their sleep or
work. Time release formulations enable a person to take a large dose at once, even a full day's dose, but
because the drug gets into the blood supply slowly, the dangers of overdosing are minimized.
Activity Five: Drug Circulation is not Uniform
Blood that enters capillaries will generally release its load of nutrients and oxygen to surrounding
tissues. This happens because capillaries are very small, thin walled, and porous. But this is not always
the case. The capillaries that nourish the brain are not porous. They readily give up glucose and oxygen
to brain tissues, but many other molecules have a hard time leaving the capillaries to enter the blood.
This is part of what causes us to have a “blood brain barrier”. It also means that many drugs have a hard
time getting into the brain. The body protects this essential organ from toxins and pathogens this way.
Another reason that we have a blood brain barrier is that glial cells surround the capillary vessels that
enter the brain. These cells wrap their fatty membranes around the capillary beds, insulating them even
more against exchange of materials.
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Visit NeuroScience for Kids page pertaining to the blood brain barrier.
http://faculty.washington.edu/chudler/bbb.html Can you spot an interesting “exception” to the blood
brain barrier that helps our bodies know when we have to purge unwanted or toxic materials?
The blood brain barrier is very helpful for us when it comes to avoiding brain injury from toxins or
pathogens. But there are some medications that become useless because they do not pass the blood
brain barrier. Recently, researchers have found that by injecting microbubbles into the blood and then
delivering precision-targeted ultrasound waves to the brain, the blood brain barrier can be temporarily
disrupted. Listen to the story about this research by visiting
http://www.nsf.gov/news/special_reports/science_nation/goodvibrations.jsp
Consider these questions while viewing the video:
 It might be dangerous to destroy the entire blood brain barrier. How precise can one be in
disrupting the blood brain barrier with micro bubbles?
 What side effects do the test animals experience when given drug mixed with microbubbles and
exposed to ultrasound?
Many people erroneously think there is a similar, protective barrier around the fetus that protects it
from receiving pathogens or toxins from the maternal blood. The “placental barrier” does help the fetal
and maternal blood supplies stay distinct, but drug molecules that are found in the maternal blood are
readily released from maternal blood into the placenta where they can then be absorbed by the fetal
blood supply. Any drugs that pass through the blood brain barrier have no trouble leaving maternal
blood and entering fetal blood supply.
Activity Six: Metabolism
You might imagine that drug molecules just float around the blood stream indefinitely, waiting for their
opportunity to find a receptor to which they can bind. But like any molecule, drug molecules have
limited shelf-lives. Molecules in our bodies all have non-infinite shelf-lives, or half-lives. A half-life for
a molecule is the length of time it takes for half of the molecules to be lost due to metabolism or
degradation. If the half life of a drug is 1 hour, then half of the drug is gone in the first hour and one
half of the remaining one half (1/4) of the drug is gone in the second hour. Because the drug
molecules are less and less concentrated in successive time intervals, the “decay” of these molecules
slows down over time. Molecules are lost/degraded in
a log rhythmic fashion.
TEST OF CONTENT
In the graph to the right, what is the half life of
the molecule illustrated?
150 days
50 days
25 days
10 days
The reason why drug molecules are metabolized is
enzymes. Enzymes are molecular catalysts that make,
break, or rearrange chemical bonds. In OUR bodies,
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enzymes for metabolizing drugs are made generally in the liver.
The diagram on the right shows the molecular structure of nicotine.
Nicotine is metabolized by an enzyme called CYP2A6. When CYP2A6
encounters a nicotine molecule, the two molecules interact and nicotine
gets converted into cotenine (below). What difference do you see
between nicotine and cotenine? It might help to flip one of the molecules
so they are oriented similarly. Cotenine has an additional, double-bonded
oxygen added on. There is NO change in the methyl group stuck onto the
nitrogen in the five-ring portion of the molecule. Remember, a stick
that ends in a molecular diagram ends with a carbon unless something
else is shown. And the carbon that is at the end of the stick has four
bonds, one to nitrogen and therefore three more with hydrogens.
It might seem that CYP2A6 is a funny name for an enzyme. Some drug-metabolizing enzymes are
named in a way that suggests how they work. For instance, ethanol (an alcohol) is metabolized by
alcohol dehydrogenase. That name suggests that hydrogen(s) are removed when ethanol is
metabolized. Here are the molecular structures of ethanol and acetyl aldehyde, its metabolite.
How are these molecules different from each other? Acetyl aldehyde has two less hydrogens.
Alcohol dehydrogenase
But many drug-metabolizing enzymes have names
more like
nicotine’s metabolic enzyme. The “CYP” part of the enzyme name (pronounced SIP), stands for
cytochrome P450. Cytochrome P450 is a family of very related enzymes, each encoded by related
genes (more on the relationship between genes and proteins in unit 3). Some enzymes in this family
are very specific and metabolize only one drug as far as we know.. Others are more general. CYP3A4 is
the metabolic enzyme responsible for metabolizing nearly half of all prescription drugs.
TEST OF CONTENT
Below you find the molecule considered to be the main active ingredient in marijuana –
-THC) on the right. This is HARD.
-THC?
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Activity Seven: Elimination
Drug molecules or their metabolites are eventually lost from the body. Nicotine gets metabolized into
cotenine, and in the process, becomes more water soluble. Thus this conversion helps the drug
metabolite to be eliminated in urine. Drug molecules and metabolites can also be eliminated in feces,
vomit, sweat, and even breath (you’ve certainly heard of a breathalyzer test – which tests for alcohol
vapors released by breath).
It is particularly important to talk about a few more ways that drug molecules can leave the body.
When a woman lactates, the milk she makes will contain many substances in addition to ones that are
nutrients for the baby. Drug molecules can be passed from mother to nursing baby in this way. A
physician who is deciding about what to prescribe to a woman will ask if she is (or will be) pregnant or
nursing.
Another thing to keep in mind in regard to drug elimination is that many drug tests have been designed
to determine if a person is using drugs. Some of these tests are designed to take advantage of the
substances we eliminate. For instance, some are tests that examine breath or urine. Others are blood
tests. But drug molecules or their metabolites can also be detected in almost any cell of fluid we could
collect from our body. This includes finger nails and hair!
TEST OF CONTENT
If the half life of cocaine is 1 hour, but its metabolite has a much longer half life (nearly 24
hours), how long after a person uses cocaine can they pass a drug test?
1 hour
2 hours
24 hours
48 hours
None of the above
Activity Eight: Storage
Some drugs do not get eliminated readily from the body due to the fact that they are fat soluble. A drug
molecule that associates with lipids will not associate as well with watery blood and cell contents and
instead hide out in our adipose cells. Fat soluble drugs are therefore almost ALWAYS associated with
long half lives compared to water soluble drugs. Not only will fat soluble drugs have longer half lives,
because of this their dosage is even more important to control.
As an example, let’s consider vitamins instead of drugs. This list comes from Wikipedia
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Vitamin A (retinol)
Vitamin Bp (choline)
Vitamin B1 (thiamin)
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Vitamin B2 (riboflavin, vitamin G)
Vitamin B3 (niacin, vitamin P, vitamin PP)
Vitamin B4 (adenine, epileptic biotin)
Vitamin B5 (pantothenic acid)
Vitamin B6 (pyridoxine, pyridoxamine, or pyridoxal)
Vitamin B7 (biotin, vitamin H)
Vitamin B9 (folic acid, folate, vitamin M)
Vitamin B12 (cobalamin)
Vitamin C (ascorbic acid)
Vitamin D (ergocalciferol, or cholecalciferol)
Vitamin E (tocopherol)
Vitamin K (naphthoquinoids)
Remember dogs? Vitamin C is not an essential nutrient for them because they can make their own.
These are biomolecules we MUST consume for optimal health. Some people think more is better when
it comes to vitamins. But four of these essential vitamins are fat soluble. Because of that, ingesting high
doses of these vitamins on a regular basis is dangerous. Some side effects (depending upon the
vitamin) include weakness, pain, irritability, lethargy, and reduction in the ability to form blood clots.
TEST OF CONTENT
Which drug, blue or red, do you think is more
likely to be fat soluble?
Activity Nine: Reading
Required Reading
Liska
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Liska, Sections on Routes of Administration (4.2
in 7th edition),
Metabolism of Drugs (4.5 in 7th edition),
Excretion of Drugs (4.10 in 7th edition)
Introductory Biology Textbook
 Section on enzyme function
 Section on circulatory system and gastrointestinal system (both – just overview)
Internet
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http://www.youtube.com/watch?v=2uehdqZzKEM&feature=related (metabolism)
Supplemental Reading
Liska
 Chapter on Personal Drug Testing (chapter 16 in 7th edition)
Internet
 http://en.wikipedia.org/wiki/Time_Release_Technology_%28medicine%29 (time release meds)
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