Chapter 17

Question 1

Pharmacogenomics (or pharmacogenetics)

Answer 1

Study of how inherited variations in DNA affect the ways people respond to medications.

Question 2

Pharmacogenomics

Answer 2

refers to the genome-wide effects, which include the impact of sequence variations, translocarions, epigenetics, and gene expression.

Question 3

Pharmacogenetics

Answer 3

more specific and refers to the impact of inherited or acquired DNA sequence variations on a person’s response to a drug. Although many people use the terms interchangeably, we are learning more and more about the complex pathways that lead to protein production and use, so pharmacogenomics (PGx) is usually the preferred term.

Question 4

personalized medicine,

Answer 4

tailoring the therapy to an individual patient’s needs.

Question 5

precision medicine

Answer 5

Sometimes precision medicine is used interchangeably with personalized medicine because people think they mean the same thing. The term precision carries with it ideas of accuracy, but it is used to mean that therapies could be tailored to treat people with subgroups of diseases that would be determined by genomics

Question 6

Table 17-1
Personal Factors Affecting Drug Metabolism

Question 7

Intended action or therapeutic effect

Answer 7

-A drug is prescribed to produce a patient response, a desired and expected change in the function of one or more tissues or organs,
-A drug is prescribed to produce a patient response, a desired and expected change in the function of one or more tissues or organs,

Question 8

Pharmacodynamics

Answer 8

-refers to the body responses induced by a drug.
-These responses include both the intended action and side effects of the drug. A person’s genetic differences can influence a drug’s pharmacodynamics by changing the way that individual person responds to that drug.

Question 9

Receptors

Question 10

Agonist

Answer 10

Any drug that binds to a cell’s receptor sites and causes the same response as the naturally occurring hormone or substance is known as an agonist

Question 11

Antagonists

Answer 11

Foradrugtostimulateacell’sfunction,itmustbindcorrectlyandtighclytothecell’sreceptors.Thisis known as afunctional fit or fimctional binding. Some drugs bind incorreccly to a cell’s receptors, blocking the cell’s function (a nonfunctional fit). These drugs are known as antagonists because they cause the opposite responses of an agonist and inhibit the expected cell function by preventing receptor interaction with agonist substances.

Question 12

Targets

Answer 12

-Cells with receptors that can bind with a drug (functionally or nonfunctionally) are the targets of the drug.
-For example, the targets of insulin are those cells that have insulin receptors. When insulin binds to insulin receptors, the membranes of those cells become more permeable (open) to glucose, allowing glucose in the blood to enter the cells

Question 13

Side effects

Answer 13

-drug effects rhar are nor rhe main purpose of the intended action.
-When a known side effect is present to an exaggerated degree in a patient, or an unusual response occurs, the reaction is called an idiosyncratic response

Question 14

pharmacokinetics

Answer 14

The actions of the body that change the physical and chemical properties of a drug are known as the process of pharmacokinetics
-Most drugs must enter the body to produce their intended actions. Once inside the human body, the drug is distributed to different body fluid compartments. As a result of a drug coming into contact with a variety of cells, it is changed or processed by some of these cells. Thus, at the same time a drug is exerting one or more effects on the body, body cells are affecting the drug’s chemistry.

Question 15

minimum effective concentra- tion (MEC),

Answer 15

Because most drugs exert their effects on body tissues and organs, drugs first have to enter the body and then enter the bloodstream so they can reach their targets. For the intended action to occur, the drug must reach and maintain a high enough constant level in the blood or target tissue to produce the action. The lowest blood or tissue level required to cause the intended action is known as the minimum effective concentra- tion (MEC),
- If the drug is eliminated faster than it is absorbed, the blood or tissue druglevelwillnorbesufficienttoproducetheintendedaction.Ifthedrugiseliminatedmoreslowlythanit is absorbed, the drug blood or tissue level may reach toxic concentrations and result in serious adverse reac- tions. For drugs to produce intended actions without becoming toxic, blood drug levels must be maintained at the MEC by balancing drug absorption with drug elimination, a condition known as a steady-state drug level

Question 16

Drug absorption

Answer 16

the entrance of a drug from its route of administration into the bloodstream. The amount of an administered drug dose that reaches the bloodstream, regardless of the method of administration, is its bioavailability.

Question 17

enterohepatic circulation

Answer 17

-Drugs absorbed through the small intestine into venous blood are quickly exposed to the liver before entering the rest of venous blood flow in the inferior vena cava back to the heart, where the drug is then distributed throughout the circulatory system.
-This circulatory derour, known as enterohepatic circulation, is a result of all the venous blood from the last half of the mouth, the esophagus, the stomach, the intestines, and the higher part of the rectum draining first into the portal vein and circulating to the liver before entering the systemic circulation.

Question 18

Metabolism

Answer 18

• a chemical reaction in the body that changes the chemical shape, size, content, and activity of the drug.
  -The liver enzyme systems, especially the cytochrome P450 (CYP, pronounced “sip”) systems of enzymes, are most responsible for metabolism.
  -These enzymes also are present in white blood cells, both those that circulate and those that are embedded within various body tissues. A few other organs, such as the adrenal glands, lungs, kidneys, intestinal mucosa, and skin also have enzymes that can participate in metabolizing drugs.
  -Drugs are considered foreign chemicals in the body, which triggers the normal response of processing the drug for elimination through metabolism.

Question 19

Cytochrome P450 System

Answer 19

-The cytochrome P450 system of enzymes is coded for by a gene family currently known to be composed of 57 main genes and hundreds of subfamilies.
-Each cytochrome P450 gene name begins with “CYP,” indicating that it is part of the cytochrome P450 gene family.
-The gene name also has a number indicating its assignment into a specific group within the main gene family and a letter that represents the gene’s specific subfamily. The last number in the name indicates the gene’s assignment to the specific gene within the subfamily.
-For example, the cytochrome P450 gene that is in group 2, subfamily D, gene 6 is written as CYP2D6 (National Library of Medicine, 2017).
-These genes are large and vary greatly in sequencing. These variations make some genes and gene products more active and others less active than “average.”
-This group of enzymes is extremely important in drug metabolism. Some specific enzymes, such as CYP2D6, metabolize thousands of different substances from within and outside of the body. Some, such as CYPI9A, metabolize JUSta few. Although these enzymes are present in several body sites, because the liver has the great- est concentration, it is the tissue in which drug metabolism is most active.

Question 20

Prodrug

Answer 20

it is ingested as an inactive parent compound and
cannot exert its intended action in this form. When
atorvastatin is metabolized by one of the CYP enzymes,
five separate active drug metabolites are formed, each of
which can help lower blood lipid levels. So, in this case,
first-phase metabolism activates this drug rather than
prepares it for elimination. For these active metabolites
to be eliminated, they must then undergo second-stage
metabolism, which then alters the chemical structure
further co add substances to the now-active drug metabo-
lites that enhance their excretion through the intestinal
tract or in the urine by the kidney. (These substances
include glucuronic acid, sulfuric acid, acetic acids, amide
groups, and methyl groups.)

Question 21

Elimination

Answer 21

-the inactivation and final removal of drugs from the body.
-Although many tissues and organs eliminate drugs to some degree after they have been prepared for elimination by metabolism, the most active elimination routes are the GI tract, the kidneys, and the lungs. Drugs can be eliminated in the feces, urine, exhaled air, sweat, tears, saliva, breast milk, and semen.

Question 22

first-pass loss

Answer 22

-When a drug is given orally, some of the drug is metabolized very quickly by the liver and rapidly eliminated from the body. This rapid inactivation and elimination of enteral drugs is called first-pass loss.

Question 23

GENETIC/GENOMIC VARIATIONS

Answer 23

Genomics influences the way drugs work in four ways:
(1) altering a drug’s pharmacodynamics,
(2) altering a drug’s pharmacokinetics,
(3) creating unique reactions such as hypersensitivity to a drug, and
(4) targeting specific factors in the pathogenesis of disease to alter disease severity.

Question 24

Table 17-2

Answer 24

Selected Clinically Relevant CYP450 Substrates

Question 25

Table 17-3

Some Inhibitors of CYP450 Enzymes

Question 26

Table 17-4

Some Inducers of CYP450 Enzymes

Question 27

Table 17-5

Estimated Ethnic Distribution of CYP2D6 Phenotype

Question 28

Summary

Answer 28

Drug response is a complex trait influenced by many genes and the environment. You have seen examples of increased or decreased drug metabolism in the CYP450s, acetylation, and TPMT enzyme systems.
We have also seen genetic variants cause unexpected responses such as the hemolytic anemia seen when a person with GGPD deficiency takes an antimalarial drug.
Despite some very promising studies, little improvement in clinical outcomes using PGx testing for drug administration has been reported. That means that our understanding of the impact genetic variations have on the way we use drugs is incomplete. Polymorphisrns in modifier genes or major genes that have not been identified probably have an as-yet-undiscovered impact on the ways that our patients process drugs such as warfarin.
Much must be learned before pharmacogenomics will be in use at every bedside, but that day will come.
• Pharmacogenetics and pharmacogenomics are similar concepts, but pharmacogenomlcs has a more in-depth scope.
• Precision medicine includes the idea that we can develop medications tailored to specific subgroups of disease.
• We know most about genetic/genomic differences in the way people metabolize drugs as compared to drug absorption or transport.
• Drugs often work in the same way the body hormones, enzymes, and other proteins do.
• Most drugs exert their effects by binding to a cell recepror.
• At the same time that a drug is changing the body’s activity, the body is processing the drug fur elimination.
• Drugs have to reach a high enough level in the blood to exert their effects.
• Taking more than one drug at the same time can change the effectiveness of each drug.
• Drug metabolism reduces its bioavailability.
• The most important organs for drug metabolism and elimination are the liver, kidneys, and white blood cells.
• The CYP450 enzyme system is responsible for the metabolism of many of the most commonly prescribed drugs.
• People can be classified as slow, intermediate, extensive, or ultrarapid metabolizers, depending on CYP450 enzyme activity.
• N-acetyltransferase (NAT) is required for phase II metabolism of many drugs.
• People can be classified as slow or fast acerylators.
• Genetic testing is available for some variations in the way people respond to drugs.
• The clinical efficacy of drug response genetic testing is controversial, but PGx testing is currently being used clinically.

Question 29

What drugs block a cell’s function by binding incorrectly (a nonfunctional fit) to a cell’s receptor?
a. Antagonists
b. Sympathetic drugs
c. Agonists
d. Colony-stimulating factors

Answer 29

A

Question 30

Which provides the best explanation of pharmacodynamics?
a. Distribution of a drug into the body’s compartments
b. How the body responds to drugs, including the drug’s mechanism of action
c. Drug metabolism by the body
d. Drug bioavailability

Answer 30

B

Question 31

Your patient has had direct-to-consumer genetic testing to determine her CYP2D6 status before she begins taking flecainide (formulated as an active compound) for her paroxysmal atrial fibrillation. What might she expect if she is found to be a poor metabolizer?
a. High enzyme activity
b. Drug elimination that is faster than drug absorption
c. Poor clinical efficacy
d. Possible toxic levels of drug when it is given at standard doses

Answer 31

D

Question 32

You find Out that your patient will be taking cimetidine (a CYP2D6 inhibitor) along with her flecainide. What might you expect from adding this drug?
a. It is likely to increase enzyme activity, making her drug metabolism more normal.
b. It may worsen her poor metabolism of the Aecainide.
c. It would increase first-pass loss.
d. It will have no clinical effect, due to CYP2C19 activiry.

Answer 32

B

Question 33

What might a drug that is a “targeted therapy” do?
a. Attack specific tumor cells
b. Be given along with another drug to counteract any CYP450 inhibition c . Increase acetylation
d. Promote effective drug elimination

Answer 33

A

Question 34

Genotyping consistently and accurately predicts whether a patient will have a therapeutic response to adrug.
a. True
b. False

Answer 34

B

Question 35

Your patient is a “fast acetylator.” What might happen when she takes procainamide, a drug that requires acetylation for phase II metabolism?
a. Higher blood level of the drug at a standard dose
b. Lower blood level of the drug at a standard dose
c. Tenfold increase in TPMT activity, resulting in toxicity
d. Eightfold decrease in TPMT activity, resulting in lack of therapeutic result

Answer 35

B

Question 36

1. What is different about the drugs that are being developed based on CTFR mutations that cause cystic fibrosis?
2. How do you think PGx will affect your nursing practice now and 5 years from now?
3. Why is the concept of precision medicine important, and how does it vary from the concept of
   personalized medicine?