Download Combinations student notes 10_lesson_combinationsStudent

COMBINATIONS
In January 2008, Heath Ledger was just 28 years old and a very prominent film actor. He was
found his NYC apartment, dead from an apparent drug overdose. What actually caused Heath
Ledger's demise was in fact MULTIPLE drugs all used at the same time. Due to a variety of
problems, such as insomnia, Ledger was prescribed diazepam, temazepam, alprazolam,
doxyelamine, oxycodone, and hyrdocodone. While each can be dangerous in itself and can lead to
overdose, Ledger's death resulted from combining the drugs.
This lesson considers how some drugs, other things we consume, and even how activities can
influence the response we get from a drug. It may surprise you to learn that oral contraceptives are
not ALWAYS 100% effective. Their efficacy is influenced by both diet and what other drugs a
woman uses. When multiple drugs are used, they can interact in unexpected ways. This why a
physician's first question to a patient is about the drug that patient uses. It is essential to give YOUR
doctor a very thorough list, even including food supplements.
Objectives
After successfully completing this lesson you will be able to:




to consider the relative merits of taking drugs in some circumstances as compared to others
to understand WHY drug combinations result in changing efficacy of an individual drug
to relate what is known about drug absorption and drug metabolism to the study of drug
combinations and other influences
to strongly comprehend the importance of honestly answering the question every doctor
and pharmacist asks you - “Are you taking any other medications?”
Before you begin!
o Your ideas

Are birth control pills universally effective contraceptives

What happens when you combine caffeine and alcohol?

Using your understanding of antagonism (from earlier in the course or from literature)
predict how two antagonistic drugs will work if taken in combination.

By each drug being more effective in combination than alone

By each drug being less effective in combination than alone

By one drug being more effective while the other is less effective

There is no influence on efficacy
o Previously learned material

Relate what you know about oral vs. other forms of drug intake to what you think will happen
if you use an oral medication while fasting – or if you use a laxative at the same time as an oral
medication.

Both alcohol and sedatives like rohypnol reduce neuronal activity. If you take these drugs at
the same time, what will happen to the learning pathway?
1
COMBINATIONS
Guiding Questions
1.
2.
3.
4.
5.
6.
What influences the efficacy of a drug?
How do drug combinations influence individual drug efficacy?
How do activities influence drug efficacy?
How can you predict (when can you predict) the result of a particular combination?
How can you determine the type of interaction based on data pertaining to drug response?
How can you determine the type of interaction based on information about drug metabolism?
Key Terms





Incompatible
Antagonistic
Additive
Synergistic
Induction and inhibition (with regard to enzyme activity)
Activity One: Web Site Review
Please review the Web sites below, http://en.wikipedia.org/wiki/Combined_drug_intoxication
Guiding questions:

What kinds of drugs can be involved in polydrug intoxication? Can herbal drugs be involved?
Alcohol?
 How prevalent is polydrug overdose? What has happened to the rate over time?
 What are some risk factors for adverse reactions to drug combinations?
 With regard to acetaminophen (and other drugs) what organ is particularly vulnerable to
failure with use of simultaneous drugs?
Watch the video at http://www.msnbc.msn.com/id/39835017/ns/us_news-life/
Guiding questions:






What is different about this story as compared to the last (polydrug intoxication)?
Why do people use Four Loko?
What were the blood alcohol levels among the 9 affected students? How does this compare to
BAC for driving while intoxicated?
One can of Four Loco is equivalent to how many beers?
DHusion – the maker of Four Loko claims that responsible use of their product is no more
dangerous than any other alcoholic drink. Do you agree?
Why did the students reported in this story even live? (not given in this video – look it up
elsewhere)
2
COMBINATIONS
Activity Two: When Two Drugs are Used, What Types of Interactions are Seen?
When two drugs are used, they might have a neutral consequence. Each drug alone may work on a
particular symptom and the use of one drug does not influence the symptoms of the other. Or there
may be a positive interaction in which one or both drugs has MORE effect. Lastly, there may be a
negative interaction in which one or both drugs has LESS effect when taken in combination.
In both cases, negative as well as positive, the alteration of impact might be small or large. A small
negative effect is termed antagonism while a large negative effect is incompatability. A small
positive effect is termed additivity while a large positive effect is synergism.
More effect when taken with another drug
Effect of a drug taken alone
Less effect when taken with another drug
Activity Three: Drugs Can Act Incompatibly
Incompatability describes drug interactions in which one drug makes another nearly 100%
ineffective. In some cases, both drugs are nullified. There are a couple of reasons this could take
place.
Most drug molecules need to be soluble in blood to work. If instead, two drugs together interfere
with the solubility of each other, then these drugs in combination will not work. This is seen when
diamorphine (an analgesic related to morphine) is injected in the same syringe as a drug called
cyclizine (a drug used to treat nausea). People undergoing chemotherapy, for instance, may
experience both pain and nausea. But if one treats both symptoms by combining the drugs in the
same syringe, both will be ineffective.
Alternatively, one drug may inactivate another, but itself stay active. Any oral medication taken
along with a laxative will become far less effective because the laxative speeds up the passage of
that drug through the gut, interfering with its absorption into the blood stream.
3
COMBINATIONS
How will this interaction look graphically? First, since the drugs do not treat the same symptoms, it
will help if you choose one to focus on. Let’s focus on cyclizine’s ability to treat nausea. Cyclizine
Nausea
relief
(blue) has a positive effect on reducing nausea while diamorphine has virtually none (red).
cyclizine
Combination
diamorphine
If instead, we measure the ability of each to relieve pain and compare that to the drug combination,
the cyclizine and the combination are ineffective, while diamorphine taken alone is quite effective as
a pain reliever.
Activity Four: Drugs that Act Antagonistically
If two drugs interact in a way that reduces the impact of one or both drugs, but does so more subtly,
Symptom
s treated
by drug A
the interaction is described as antagonism. This interaction might look graphically like this:
Drug A
Combination
Drug B
This type of interaction is exemplified by St. John’s Wort (red) and oral contraceptives (blue). Oral
contraceptives are very effective in reducing conception. But if a woman uses St. John’s Wort (often
used as an herbal anti-depressant, and available in any supplement store) her birth control is no
longer nearly as effective. While many people do not think of herbal supplements as being at all
worthy of mention when interviewed about their drug use, describing ALL medications you use is
extremely important! St. John’s Wort decreases the efficacy of oral contraceptives because it induces
the production of the CYP enzyme that metabolizes oral contraceptives. More CYP means less drug
which means less drug effect.
Here is an abstract from a journal article that describes this interaction. An abstract is a summary of a
research article. Often we gather a lot of broad information just from reading abstracts in academia.
The interaction between St John's wort and an oral contraceptive.
Hall SD, Wang Z, Huang SM, Hamman MA, Vasavada N, Adigun AQ, Hilligoss JK, Miller M, Gorski
JC.
Clin Pharmacol Ther. 2003 Dec;74(6):525-35.
OBJECTIVES: The popular herbal remedy St John's wort is an inducer of cytochrome P450 (CYP)
3A enzymes and may reduce the efficacy of oral contraceptives. Therefore we evaluated the effect
4
COMBINATIONS
of St John's wort on the disposition and efficacy of Ortho-Novum 1/35 (Ortho-McNeil
Pharmaceutical, Inc, Raritan, NJ), a popular combination oral contraceptive pill containing ethinyl
estradiol (INN, ethinylestradiol) and norethindrone (INN, norethisterone).
METHODS: Twelve healthy premenopausal women who were using oral contraception (>3
months) received a combination oral contraceptive pill (Ortho-Novum 1/35) for 3 consecutive 28day menstrual cycles. During the second and third cycles, the participants received 300 mg St
John's wort 3 times a day. The serum concentrations of ethinyl estradiol (day 7), norethindrone
(day 7), follicle-stimulating hormone (days 12-16), luteinizing hormone (days 12-16), progesterone
(day 21), and intravenous and oral midazolam (days 22 and 23) were determined in serial blood
samples. The incidence of breakthrough bleeding was quantified during the first and third cycles.
RESULTS: Concomitant use of St John's wort was associated with a significant (P <.05) increase
in the oral clearance of norethindrone (8.2 +/- 2.7 L/h to 9.5 +/- 3.4 L/h, P =.042) and a significant
reduction in the half-life of ethinyl estradiol (23.4 +/- 19.5 hours to 12.2 +/- 7.1 hours, P =.023).
The oral clearance of midazolam was significantly increased (109.2 +/- 47.9 L/h to 166.7 +/- 81.3
L/h, P =.007) during St John's wort administration, but the systemic clearance of midazolam was
unchanged (37.7 +/- 11.3 L/h to 39.0 +/- 10.3 L/h, P =.567). Serum concentrations of folliclestimulating hormone, luteinizing hormone, and progesterone were not significantly affected by St
John's wort dosing (P >.05). Breakthrough bleeding occurred in 2 of 12 women in the control phase
compared with 7 of 12 women in the St John's wort phase. The oral clearance of midazolam after
St John's wort dosing was greater in women who had breakthrough bleeding (215.9 +/- 66.5 L/h)
than in those who did not (97.5 +/- 37.2 L/h) (P =.005).
CONCLUSION: St John's wort causes an induction of ethinyl estradiol-norethindrone metabolism
consistent with increased CYP3A activity. Women taking oral contraceptive pills should be
counseled to expect breakthrough bleeding and should consider adding a barrier method of
contraception when consuming St Johns wort.
TEST OF CONTENT
After reading the abstract, see if you can answer these questions:
1. What two types of data are reported that suggest an interaction between oral
contraceptives and St. John’s Wort?
2. What happens to metabolic enzymes in people who take St. John’s Wort?
What is the “control” group here. CAREFUL.
3. Prior to treatment, two women demonstrated break-through bleeding. What tests
on these women helped to add to this story and what did the data add?
Symptom
s treated
by drug A
Alternatively, and perhaps more commonly, antagonism looks like this:
Drug A
Combination
Drug B
5
COMBINATIONS
In this case, one drug has the opposite effect on a symptom compared to the other drug. This might
be the case for sedation. Caffeine stimulates wakefulness, while tranquilizers stimulate sleepiness.
The drugs oppose each other with regard to inducing sleep/alertness. In fact, any drug pair that has
opposite effects will exhibit antagonism.
The main features of antagonism are that one or both drug is less effective but the reduction is
modest in comparison to incompatibility.
The reason Four Loko combines caffeine and alcohol is that when a person uses alcohol, they get
sleepy. Thus a person under the influence of alcohol will have a limited time wherein to party,
eventually they will pass out. Caffeine opposes this effect and enables a drinking person to stay
wakeful (and drunk). Thus an alcohol dose that usually makes someone lose their ability to continue
to consume alcohol (because they have passed out) does not similarly keep a Four Loko user from
drinking more, increasing the amount of alcohol that can be consumed.
Activity Five: Drugs that Act Additively
In our previous examples – two drugs used together will lessen the effect of one or both drugs. It is
possible for one drug to INCREASE the effect of another as well. Of course! In fact, in the field of
drug development, combination drugs are a fast-growing research area. The idea is that the dosage
needed to treat a disease might be so high that many unpleasant side effects result. So if instead we
can find a combination of drugs that each can be taken at low doses (minimizing dosage-dependent
side effects) and if those drugs “help” each other, then our combination drug would be safer and
more effective. Some specific examples can be found at
http://www.ncbi.nlm.nih.gov/books/NBK1583/ .
But keep in mind, when we map the effectiveness of a drug when alone or in combination, we could
equally well measure the SIDE effects of the drug alone or in combination. Sometimes drugs in
combination might be poor choices because their SIDE effects are additive or even synergistic. For
these drugs, raising the dosage is preferable to making products that use such combinations.
Symptom
s treated
by drug A
How would additivity (for effect or side effect) look graphically?
Drug A
Combination
Drug B
If the effect of the combination can be estimated to be equal to the effect of one drug added to the
effect of the other (like stacking the bars one on top of the other), the effect is additive.
Additive interaction is seen often when two drugs work on the same symptom but work from a
different angle on that symptom. For instance, inflammation (increase blood flow to an injured area)
can be painful and can create further damage to the inflamed tissue. Anti-inflammatory drugs come
in two forms. Some are steroidal anti-inflammatories (Steroidal drugs are those that have a molecular
structure resembling steroids such as testosterone), others are non-steroidal anti-inflammatories
6
COMBINATIONS
(aspirin is a non-steroidal anti-inflammatory drug or NSAID). If one uses BOTH drugs together,
their ability to treat inflammation is additive.
Another case is vicodin. Vicodin is a pain reliever (analgesic) that puts together acetaminophen and
an opiate-type of analgesic. Acetaminophen influences pain by interfering with an enzyme that
makes a chemical that stimulates pain receptors. Opiate analgesics interfere with pain by blocking
substance P – a molecule that amplifies pain in the central nervous system. Both treat pain, but for
very different reasons. Vicodin combines these drugs to manage pain with a two-prong approach.
TEST OF CONTENT
Why has it been argued that drug combinations might be more beneficial in treating disease
as compared to single drugs?
Combinations will counteract each other’s effectiveness
Combinations will counteract each other’s side effects
Combinations will increase each other’s effectiveness
Combinations will increase each other’s side effects
Activity Six: Drugs that Act Synergistically
Drugs that interact positively, but whose interaction is far greater than additive, are synergistic.
While there are a number of reasons for two drugs to be synergistic, one of the main reasons is that
the drugs influence the SAME mechanism that underlies the treatment of symptoms. For instance,
both alcohol and tranquilizers make a person feel more sedate. If a person has trouble sleeping, she
might drink a glass of wine before bed. She might alternatively take a sedative, such as valium or
rohypnol. But if she takes the two together (rohypnol is nicknamed ruffies) she will have a profound
sense of sleepiness, more than additive. Synergism looks like this graphically:
Symptom
s treated
by drug A
Drug A
Combination
TEST OF CONTENT
Drug B
Symptom
s treated
by drug A
What type of interaction is shown by this graph?
Drug A
Combination
Drug B
Definitely additivity
7
COMBINATIONS
Could be additivity or synergism
Definitely antagonism
Could be antagonism or incompatibility
Could be antagonism or additivity
What kind of interaction would be predicted between two drugs, one of which INHIBITS
the metabolic enzyme of the other?
Definitely additivity
Could be additivity or synergism
Definitely antagonism
Could be antagonism or incompatibility
Could be antagonism or additivity
Activity Seven: Things that Interact with Drugs
Besides other drugs, what kind of things are known to interact with drugs and change the way a drug
will work? Think about this from the perspective of a drug advertisement. “Do not take this drug
with X, Y, or while doing Z.” Come up with a list of foods, drinks, and activities that might influence
a person’s response to a drug.
This is of course not an exhaustive list, but here are some of the things a physician or pharmacist is
interested to know about you when prescribing a drug. See if you can guess what the item listed
does or why it interacts with a drug. Submit at least one educated guess (drugs that are affected by
the item or WHY a drug would be affected by the item) before you look at the list of explanations.
Food
Drink
Activity
Dark leafy vegetables
Grapefruit juice
Fasting
Garlic
Cola
Exercise
Some aged cheeses
Chianti wines
Exposure to pollution
Food
Drink
Activity
Dark leafy vegetables
Grapefruit juice
Fasting
Garlic
Cola
Exercise
Some aged cheeses
Chianti wines
Exposure to pollution
8
COMBINATIONS
TEST OF CONTENT
Grapefruit juice is also acidic, like cola. Add this to the inhibition of prescription drug
metabolism and predict how the two effects will alter someone’s reaction to an oral medication.
Activity Eight: Reading
Required Reading
Liska
Liska Section “Drug Interactions Can Be Dangerous to Your Health” (section 4.7 in 7th edition)
Internet
 http://en.wikipedia.org/wiki/Enzyme “Control of Activity” section
 Abstract found at http://www.ncbi.nlm.nih.gov/pubmed/14663455
 http://www.ncbi.nlm.nih.gov/books/NBK1583/ on multidrug products or combination drugs
Supplemental Reading
Internet

http://www.drugs.com/drug_interactions.php# (Drug interaction checker – but you have to
agree to terms to check any pair of drugs)
9