Download Lesson 9: Dosage student notes 9_lesson_dosageStudent

DOSAGE
Between 2006 and 2007, an estimated 100,000+ people overdosed on acetaminophen1, the active
ingredient in Tylenol. Approximately
half of those people were not aware that
they were taking a dangerously high
dose. And among those, a large
percentage of victims were children
whose well-intentioned care givers gave
them the wrong dose inadvertently.
Surprisingly, the concentration of infant
formula acetaminophen is higher than
that found in toddler.2 So using infantformulations for a toddler can be tricky
and is ill-advised. If you decide to use
the
TODDLER dose of the INFANT
formula, serious overdose related risks can result.
This lesson is about drug dosing. It is crucial to understand what goes in to considering how much of
a drug to take and what the consequences are for taking too much drug.
Objectives
After successfully completing this lesson you will be able to:
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to be compute drug dosage in metric
to understand many reasons that influence the effectiveness of a given dosage
to understand how dosages are determined and other aspects of clinical trials
to understand why drugs give some side effects
to use therapeutic index (TI) as a measure of safety
to relate tolerance to dosage and therapeutic index
Before you begin!
o Your ideas
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How many milliliters are in a liter? 1000
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An “average” human weighs 70 kilograms. How many pounds is that?
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Besides weight, what is one thing that can influence a person’s response to a given dosage
of drug? Indicate all that are correct.
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2
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Sex
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Health
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Other drugs taken
national electronic injury surveillance system - estimated from 3720 actual cases.
Infant is 100 mg/ ml, toddler is 32 mg/ml. It is harder to get large volumes into an infant as compared to a toddler.
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DOSAGE
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Expectations
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Setting
How do drugs get tested to determine the appropriate dosing? Clinical trials, in particular
phase 0 – animal testing, phase IIb – testing in people with condition to be treated.
o Previously learned material
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Based on your knowledge of tolerance, would someone who regularly uses caffeine need
more or less caffeine to feel alert? More
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How does the way in which a person administers drug influence the dosage needed to feel
the drug’s effect?
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Taking the drug orally requires lower dosage because it gets to the brain faster
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Taking the drug in time-release capsules lowers the dosage because the drug
can be administered slowly over time
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Taking the drug by inhalation raises the necessary dose because lungs-to-brain
time is longer than all other routes
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Taking the drug intravenously raises the necessary dose because metabolic
enzymes have more access to the drug prior to arrival in the brain
Lesson 9: Dosage
Guiding Questions
1.
2.
3.
4.
5.
What factors influence how much drug is needed/used?
What goes in to deciding the recommended dosage of a drug?
Why do drugs have side effects?
Why are high doses of drugs sometimes lethal?
What is learned by comparing the therapeutic dose and lethal dose?
Key Terms
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Metric units
Clinical trials (Phase 0 – Phase IV)
Effective dose (ED50)
Lethal dose (LD50)
Therapeutic index
Activity One: Dealing with Metric Units
Please review the Web sites below, to be reminded what the metric system is and why we use it in
science. http://www.visionlearning.com/library/module_viewer.php?mid=47
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DOSAGE
Next view the video that helps you think about how to convert within the metric system.
http://www.youtube.com/watch?v=oBVWG8wNFqo
Finally, view the video that helps you think about how to convert from metric to conventional (or
reverse) measurements.
http://www.youtube.com/watch?v=NwiOlDt3xtE&feature=channel
TEST OF CONTENT
If your physician tells you to take 10 milliliters (ml) of a drug prescribed as a fluid. But you
don't have a device that measures milliliters. How much will you take in units you CAN measure?
1 tsp (teaspoon US) equals approximately 5 ml.
Dosage is often given in milligrams (mg) per kilogram (kg) of body weight. For instance,
diphenhydramine (an antihistamine) is available at the concentration 12.5 mg/ 5 ml. According to
http://www.drugs.com/pro/diphenhydramine.html, physicians recommend 5 mg/ kg body weight
in children for a 24 hour period. The child you are taking care of weighs 25 pounds. How many
milliliters of diphenhydramine do you give them?
Activity Two: Individual Experiences May Vary
Before you start this activity, brain storm for a few minutes. Think about cola - a caffeinated
beverage. Think about how YOU respond to cola compared to another person (you can substitute
any substance you want here for cola). Think about how you might respond differently to cola today
as compared to a year ago or more. Try to come up with at least FIVE reasons a person might use a
different dose of a drug as compared to another person. Hint - one of the reasons is given in the test
of content question above.
Here are the reasons we came up with to explain this individual variation. If something was on your
list and not on ours - congratulations! (please send us an email and "brag").
Weight
Age
Sex
Previous experience with this drug (could result in tolerance, which we'll get to later)
Food in system (especially if drug is taken orally)
Other drugs in system
Health (mental health, malnutrition, illness)
Allergies to drugs
Expectations (placebo effect)
Setting (where and when a person is using the drug)
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TEST OF CONTENT
Consider what you learned in activity 1 and explain how it relates to an answer given for
activity 2.
Consider what you learned in the bioavailability lesson about oral administration and
explain how it relates to an answer given in this activity 2.
Activity Three: Clinical Trials (for safety and efficacy) Includes Dosing
Whenever a new drug is developed, it cannot come to public market until it has been tested
extensively. Part of this testing is about efficacy. Recall back to Lesson 1, and how important
placebos are in testing for drug efficacy. But even before a drug can be tested for efficacy, it must be
tested for safety and dosing.
“Clinical trials” are a series of tests performed on a drug (or procedure) that are meant to evaluate the
drug’s safety and efficacy. Clinical trials several progressive stages. These stages are:
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Stage 0 – animal testing
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Stage I – healthy human testing
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Stage II – small scale patient testing
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Stage III – large scale patient testing
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Stage IV – post-marketing surveillance
Activity Four: What is Effective Dose?
Because there are several problems associated with high doses of many drugs, it is extremely
important to know what dose is BEST for a given purpose. The dose that is needed to achieve the
effect desired is referred to as the effective dose. At low doses of a drug, the effect is also minimal
as described by the dose-response curve
shown below.
Imagine that the drug being tested will help
relieve head ache symptoms. At low doses,
one can experience very small relief from
head ache pain. At higher doses, more relief.
Consider the plateau on this curve, where the
dose increases, but effectiveness does not.
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DOSAGE
Based on the receptor-site theory of drug action (Liska section 1.6 in 7th edition), what might
explain why there is no additional effect for this drug at increasing doses?
So there are really MANY effective doses. In fact, considering all the different people who might
take a drug (different weights, different past experience with the drug, and so forth), there are
even many maximally effective doses.
Effective dose (50) or ED50 is the effective dose of a given drug that represents the average for a
population. This dose is derived by finding the dose that is effective for 50% of the people in that
population. The dosage given on an over-the-counter medication table usually represents the
ED50. Thus if you are a very large (or very petite) person, the ED50 may not be the best dose for
YOU.
Activity Five: Side Effects, including Death
Every drug has side effects. Some only result when a person takes high doses, but this is not always
the case. Desired effects result from the drug binding to receptors in the targeted area (head ache
pain relievers bind to pain receptors in the brain, perhaps). But because these same receptors may be
found in other areas of the brain or even other areas in the body, the drug may impact those other
areas. Additionally, the binding of your drug to the “intended” receptors may result in unintended
effects. It is possible to imagine that the head ache pain reliever might suppress pain receptors but
this might also suppress the ability of these receptors to keep us alert. A side effect of this drug might
therefore be to make us sleepy.
Here are some typical, and a few atypical side effects.
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Sleepiness. Drugs that suppress neuronal function can make neurons that keep us wakeful
from doing their jobs.
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Nausea. Many oral medications will result in stomach discomfort due to the interference of
the drug with normal gut function.
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Liver failure. The liver responds to drug intake by increasing its function so that more drugmetabolizing enzyme can be made. This extra “work” takes a lot out of the liver.
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Orgasm that results from sneezing (ok, you caught us, this is the atypical side effect). One
antibiotic - anafranil – has been known to cause some people to experience a spontaneous
orgasm when they sneeze. The reason for this odd side effect is unknown.
The idea that liver failure can result from drug use should make you think that some side effects are
quite dangerous indeed. Almost every drug, when taken at high enough dosage, can result in death.
Drug-related death can occur for several reasons. It’s possible that a person could behave foolishly
while under the influence of a drug and put herself in a dangerous position. Small doses of a muscle
relaxant can cause a person to be sleepy enough that “operating motor vehicles” is ill-advised. Some
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DOSAGE
drugs result in dire physical outcomes for other reasons. Moderate doses of heroin can result in lifethreatening conditions if one uses “tainted” needles. But we will mostly discuss overdose and death
in terms of a TOXIC reaction to high doses of a drug. Even if someone were to take the drug and lay
perfectly still in a bed afterward, the high doses taken would be toxic to the body and would subdue
vital functions. For instance, high doses of ethanol (alcohol found in beer or wine or martinis) will
result in reduced brain function to areas of the brain that are required to control respiration. Ethanol
overdose can result in respiratory depression – and a person will not breath frequently enough to get
the necessary amount of oxygen into the body.
Activity Six: What is Lethal Dose?
Toxic doses of a drug can be computed in a couple of unpleasant ways. One of the consequences of
clinical trials is to learn about unsafe doses. But these doses must be determined in phase 0, prior to
human testing. Accidental human overdoses do happen as well. The DAWN (Drug abuse warning
network - https://dawninfo.samhsa.gov/default.asp ) surveys regularly to determine any relationship
between drug dosing and emergency room visits. Because some emergency room visits do not end
well, one can use information obtained from these overdose deaths to acquire information about
lethal doses of a drug. The lethal dose 50 (LD50) is the dose that is lethal to 50% of the population.
See if you can find the LD50 of ethanol.
Activity Seven: ONE Measure of Drug Safety - Therapeutic Index
Accidental overdose results from taking more drug than is necessary for the effect desired. Going
back to our acetaminophen opening story, why are there so many accidental acetaminophen
overdoses? Perhaps one reason for this is that a person can perceive the drug as “safe” and their pain
as “severe”. So a person in a lot of pain might opt to take a particularly high dose of acetaminophen.
How much room is there for error? It depends upon the drug. For acetaminophen, the margin of
error is not particularly great. The ED50 for acetaminophen is 650 mg. The LD50 for this same drug
is 10 grams in a perfectly healthy adult. How many pills (if each pill is 325 mg) can a person take
before they get to the LD50?
Therapeutic index is a convenient measure of this margin of safety. To compute therapeutic index,
divide the LD50 by the ED50. Compute it now for acetaminophen.
Consider the therapeutic index to be a measure of the margin of safety. Large numbers for
therapeutic index mean that there is more room for error. Drugs with small therapeutic indexes (TI)
are particularly worrisome. Try to rank the relative TIs for the five drugs given from lowest to
highest. The drugs are LSD, Prozac, Ethanol, Tobacco, and Cocaine.
Rank the following drugs from your general understanding, from lowest TI to highest TI.
LSD
Prozac
Ethanol
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DOSAGE
Tobacco
Cocaine
TEST OF CONTENT
If a drug is listed as a narrow therapeutic index drug (small TI) is it considered particularly
safe or particularly unsafe?
Methadone is a drug used to “treat” heroin addiction. The ED50 of methadone is 4 – 100
mg. The ED50 of methadone is 100 – 200 mg. Why are there different doses? What is the range
of TI?
Activity Eight: Reading
Required Reading
Liska
Liska section on “Getting Used to Dosages in the Metric System” - section 1.13 in 7th edition
Liska section on “How People Can Respond Differently to Drugs” - section 4.6 in 7th edition
Internet
http://en.wikipedia.org/wiki/Therapeutic_index
Supplemental Reading
Internet
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On clinical trials http://en.wikipedia.org/wiki/Clinical_trial
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On DAWN – emergency room “mention” statistics https://dawninfo.samhsa.gov/default.asp
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