GENA® Objective 16 excerpt: Pharmacogenetics (an excerpt from NACIs GENA® obj 16; used with...

GENA® Objective 16 excerpt:

Pharmacogenetics

(an excerpt from NACI’s GENA® obj 16; used with permission from Linda B)

Native American Cancer Initiatives, Incorporated (NACI) and Mayo Clinic’s “Spirit of EAGLES Community Network Programs 2” [P.I. Kaur; U54CA153605]

http://www.NativeAmericanPrograms.org / http://www.NatAmCancerInitiatives.org 2


http: NativeAmericanPrograms.org / http:///www.NatAmCancerInitiatives.org 2



QUESTION: What factors can influence how a person responds to medication?

WeightDietFood in stomachFatigueAgeSun exposurePhysical condition / lack of exerciseDrug interactions (i.e., Cross reactivity, synergism)Genetic make-up

Obviously, many factors affect people’s responses drugs other than genes.







Definition of “Pharmacogenetics”The study of how an individual’s genetic inheritance affects the body’s response to drugs.

Pharmacology + genomics = the interaction of medications and genetics... decoding drug responsiveness







Goal

Medications “tailor-made” for individuals

Medications adapted to each person’s own genetic makeup

How “close” is this research to making personalized medicine for most of us?







Goal

(Eventually) Resulting in ... Safer drugs (reduction of side effects) Increased drug effectiveness Alternative drugs for “standard treatments”Dosages based on an individual’s genetics More effective and safer vaccines

Cytochrome p-450 enzymes

contribute to the metabolism of ~ half of all medications







The Enzyme “Cytochrome P-450”

Examples of medicines ...

Codeine (opiate to treat pain or relieve cough)

Acetaminophen

Diazepam (dye az' e pam)

Cyclosporin A

Erythromycin

Acetaminophen: To relieve mild to moderate pain from headaches, muscle aches,

menstrual periods, colds and sore throats, toothaches,

backaches, and reactions to vaccinations (shots), and to

reduce fever.

Diazepam: To relieve anxiety, muscle

spasms, and seizures and to control agitation

caused by alcohol withdrawal)

Cyclosporin A: An immunosuppressive agent used with

recipients of kidney, liver, bone marrow and pancreas transplants,

and it may also have clinical application in the treatment of

autoimmune disorders.

Erythromycin: antibiotic used to treat certain infections

caused by bacteria, such as bronchitis; diphtheria; Legionnaires' disease;

pertussis (whooping cough); pneumonia; rheumatic fever; venereal disease (VD); and ear, intestine, lung, urinary tract, and skin infections.







Example CYP3A4

Located 7q22

Super-family of cytochrome p-450 enzymes

Enzyme = Cytochrome P-450 3A4

Gene = CYP3A4

Expressed in the liver and intestines (i.e., involved in detoxification)

3A4 is an essential enzyme







Codeine Metabolism - 2D6

Located 22q13

2D6 is one enzyme that is required for the metabolism of codeine to morphine

Most people are “extensive metabolizers” that allows them to effectively metabolism codeine to morphine







Codeine Metabolism – Balance of 3A4 and 2D6

You always have 3A4 .... but if the balance of 3A4 is too high compared to 2D6, then the bioavailability of codeine is reduced

If too much 3A4, codeine doesn’t metabolize to morphine

3A4 converts “codeine” to “norcodeine” which cannot be used by the body








2D63A4

converts -> norcodeine

norcodeine is not used by the body








2D63A4

converts -> morphine







Factors affecting Metabolism or the Balance of 2D6 and 3A4

Some medications that inhibit codeine metabolism

.... like Quinidine (Quinidine Gluconate, Quinidine Sulfate)

Medication that is used to correct disturbances in the rhythm of the heart (antiarrhythmic).Also used to treat malariaQuinidine inhibits 2D6







Example of how other factors can affect the balance of CYP3A4 and 2D6

Grapefruit juice before you take some drugs can reduce your 3A4.

QUESTION: How does reducing 3A4 (i.e., in comparison the 2D6 is higher) affect your ability to metabolize codeine?

ANS: you CAN convert the drug to codeine (and subsequently to morphine)

3A4 2D6

Grapefruit Juice Quinidine

Group A Group B

Group C

Grapefruit Juice

Quinidine

Interactive Activity

Please form groups of 4 people each

Each group represents one human body

Each group (body) receives a stack of cytochrome (CYP) cards

Distribute the cards equally

Your “body” is going to look for the CYP enzymes

Interactive Activity Dealing the enzymes (proteins made by base pairs) Based on the “summary” (below) can the liver with these enzymes convert codeine into morphine?

2D6

SUMMARYMore 2D6 than 3A4 = can convert codeine into morphineMore 3A4 than 2D6 = cannot convert codeine (makes norcodeine)Grapefruit Juice = reduces 3A4Quinidine = reduces 2D6

3A4

Grapefruit Juice

Quinidine

Alternative Pharmacogenetics

Participant Interactive Activity







Pharmacogenetics Case Study / Role Play

Please form groups of 3. Count off as number 1, 2, or 3. The number 1s are the patient, FrankThe number 2s are the nurse, Ms. AbbyThe number 3s are the doctor, Dr. Thomas. Please read each situation in sequence. When a “QUESTION” card appears, all 3 of you can work together (in your roles) to try to answer the question.







Case Study / Role Play: The situation

Frank had an abnormal cancer screening test. He came to the clinic for a stereotactic biopsy. The nurse (Ms. Abby) gave Frank a local anesthesia to reduce the discomfort of the biopsy procedure. However, as Dr. Thomas started to cut Frank to take a tissue sample for the biopsy, Frank yelled that he wasn’t numb yet and to stop. Ms. Abby showed Dr. Thomas what (medication) had been given to Frank. It should have been sufficient to numb his body for the biopsy. Frank continued to complain about the pain.







Case Study / Role Play: The situationFrank next had his surgery and is in the recovery room at the clinic. He is moaning and keeps asking Ms. Abby for pain relief (codeine). She gave him an IV of the codeine medication 30 minutes ago, but Frank is complaining about the pain. QUESTION: What are some reasons why Frank may not be benefiting from the codeine (to relieve his pain)?Dr. Thomas: Hummm, this should have had an effect on you by now. Tell me Frank, how much alcohol do you drink every day and what other drugs are you taking daily? Frank: Nothing. I haven’t had a drink for 10 years and I don’t do drugs. Why are you asking me that?







Case Study / Role Play: The situationQUESTION: How may alcohol and other legal and illegal drugs interact with codeine?

Dr. Thomas: Well alcohol and drugs can affect how you respond to a painkiller. It can interfere with the medication’s ability to reduce pain or it can interact with the alcohol or drugs and make the patient overdose.

Ms. Abby: The question the doctor was asking doesn’t only mean street drugs. Are you taking prescriptions that aren’t in your medical record?

Frank: How would I know what’s in the medical record. I get all of my care here. Wouldn’t everything be in there?








Ms. Abby: Yes it should be in here. [Dr. Thomas goes to the computer and both of them look at the medical record]

Dr. Thomas: I don’t see anything that would interfere with the painkillers working. These have codeine in them. Now, we need for you to be honest with us… it looks like you may have a very high tolerance for the codeine … that maybe you do take some other drugs that also have codeine. That is probably why you need more. You have a high tolerance.








Frank: Hey, I don’t do drugs. I told you. I’ve been preparing for ceremony. I drink a lot of water and a lot of juices. I am walking a lot so that I can be ready for ceremony. I don’t do drugs.

Ms. Abby: I am looking at your medical record. It says that you are taking quinidine because you have some irregular heart rhythm.

Frank: Yeah, I do. So what?

Dr. Thomas: Quinidine can lower an enzyme (2D6) in your body. If you have too little 2D6, your liver cannot metabolize codeine into morphine.







Case Study / Role Play: The situationFrank: so are you saying I either have an irregular heart beat or I have pain from surgery or procedures like today?

Ms. Abby: Not quite. We are just trying to figure out a way to help you. Do not quit taking your quinidine for your heart rhythm. [She turns to Dr. Thomas] I wonder if his 3A4 and 2D6 balance is off?

Frank: What the heck are you talking about? What does that (3A4, 2D6) mean?








Frank: so are you saying I either have an irregular heart beat or I have pain from surgery or procedures like today?Ms. Abby: Not quite. We are just trying to figure out a way to help you. Do not quit taking your quinidine for your heart rhythm. [She turns to Dr. Thomas] I wonder if his 3A4 and 2D6 balance is off?Frank: What the heck are you talking about? What does that (3A4, 2D6) mean?QUESTION: What are 3A4 and 2D6?







Case Study / Role Play: The situationMs. Abby: These are enzymes in your body. Everybody has 3A4. We all need 3A4 to stay alive. But we also have another enzyme, 2D6 that we need for certain things to happen in our liver (our bodies). We need 2D6 to change codeine into morphine. There needs to be less 2D6 than 3A4 for your liver/body to be able to metabolize or break down codeine into morphine. Morphine is why most people experience pain relief.Frank: So why not me?







Case Study / Role Play: The situationMs. Abby (talking to Dr. Thomas): Do you remember that other patient about 3 months ago who said she felt everything and that the codeine wasn’t helping her at all? We did another test to check the balance of 3A4 and 2D6 in her liver. She had too little 2D6 and her body was metabolizing the codeine too quickly for her to benefit from the codeine. Dr. Thomas: Hummm. We are going to need to run some tests. Ms. Abby: Wait a minute. Frank, you said that you drink a lot of juices as part of your preparation for ceremony. What types of juices do you drink?







Case Study / Role Play: The situationFrank: I drink orange juice, cranberry and sometimes grape juice … the unfermented type.Dr. Thomas: But wait, Frank, do you also drink grapefruit juice?Frank: Not really. It’s rarely sold in our market out here on the Rez.Dr. Thomas: This could be a fairly simple fix. Actually, if we can get you grapefruit juice, just 1-2 glasses a day, that may be enough to gradually reduce the 3A4 enzyme and would moderately elevate the 2D6. If you have more of a balance between these 2 enzymes, you may benefit from codeine as a painkiller.







Case Study / Role Play: The situationFrank: Well then, if a little is good, isn’t more better? How about if I drink a whole bunch of grapefruit juice then … like 6-8 glasses a day? Would that fix it so that the codeine would work?QUESTION: What is a likely outcome from Frank drinking 6-8 glasses of grapefruit juice a day?Ms. Abby: Well actually too much is just as bad as too little. With too much, you would be like that other patient. Too much grapefruit juice can reduce your 3A4 so that you have way too much 2D6 … and then you metabolize the medication too fast for your body to benefit from pain relief.







Case Study / Role Play: The situationFrank: Fine, but what can you do to lessen the pain now?Dr. Thomas: We will give you another medication that does not have codeine. It is not as good (effective) as codeine, but should help reduce the discomfort. Dr. Thomas: But I want to run those tests first. If there is an imbalance of your 3A4 and 2D6, then the clinic will provide you with 1-2 glasses of grapefruit juice … we won’t know the appropriate amount until we run the tests. It will take several weeks before your body is able to change the balance between these enzymes so that you can benefit from codeine drugs. We have another procedure to do in 6 weeks that will go better if you can benefit from the codeine.







Case Study / Role Play: The situationEnd Role playQUESTION: What types of pharmacogenetics, other than 3A4 and 2D6, are you aware of that are being used in health care today?QUESTION: If you could prioritize the types of drugs that can be tailored to the individual AIAN patient, what types of drugs would you like to see?

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