PK, PD, Genomics

Question 1

Sources of variability drug exposure

Answer 1

renal/hepatic function 
gastric ph 
drug-drug interactions 
drug metabolism polymorphisms
medication compliance

Question 2

sources of variability drug response

Answer 2

placebo effect
drug receptor or enzyme polymorphisms
tolerance, tacyphylaxis
gender, race,

Question 3

Variables Determining Drug Response

Answer 3

affinity for site of action (phamacodynamics) x Drug concentration at site of action (pharmacokinetics) x underlying biology of patient (genetics, age, disease, enviornment)

Question 4

Pharmacodynamics

Answer 4

what the drug does to the body

Question 5

Pharmacokinetics

Answer 5

what the body does to the drug

Question 6

PD concepts

Answer 6

• Dose response curve (potency, slope, efficacy, variability)
• Receptor mechanisms (agonist, antagonist, partial agonist)
• Therapeutic index (median effective dose “ED50”, median
lethal dose “LD50”

Question 7

Dose-Response Cure

Answer 7

• Helps illustrate the relationship between the dose administered and the
degree of response it produces
• Usually an “S” shape when plot log dose vs intensity of effect
• Can help estimate response and safety, or compare profiles of drugs

Question 8

Many (not all!) drugs exert

Answer 8

t their pharmacologic actions via receptormediated mechanisms

Question 9

Agonist =

Answer 9

substance that interacts with a receptor and produces an
effect
- Indirect (Do not bind directly to a receptor. Affect formation,
release, inactivation, or reuptake of a neurotransmitter.)
- Direct

Question 10

Antagonist =

Answer 10

substance that interacts with a receptor, but has no action

of its own. Prevents agonists, such as neurotransmitters, from acting.

Question 11

Agonist are not

Answer 11

as perfect as a fit. It will interact with a receptor but not all sub types

Question 12

Most perfect fit is the

Answer 12

hormone or neurotransmitter these interact with all subtypes.

Question 13

Neurotransmitter Dopamine (DA) – a

Answer 13

D2 agonist

Question 14

Aripiprazole (APZ) – a

Answer 14

D2 partial agonist

Question 15

First Generation Antipsychotic (FGA) – a

Answer 15

D2 antagonist

Question 16

Overall effect of a

partial agonist may be as a

Answer 16

“functional” agonist or
“functional” antagonist
depending on surrounding
levels of naturally occurring
neurotransmitter

Question 17

increase in dopamine is related to

Answer 17

positive symptoms

Question 18

decrease in dopamine related to

Answer 18

negative symptoms

Question 19

Median effective dose (ED50)

Answer 19

Dose that would produce a therapeutic

response in 50% of the population

Question 20

Median lethal dose (LD50)

Answer 20

Dose that would be lethal in

= LD50 50% of the population

Question 21

The study of what happens to a drug in the body after it is administered.

Answer 21

PK

Question 22

PK elements

Answer 22

Absorption
Distribution
Metabolism
Excretion

Question 23

Therapeutic Index

Answer 23

= LD50/ED50

Question 24

Concentration-Time Curve

Answer 24

• Shows the plasma concentration of a drug over time

* Obtained after administration of a single dose

Question 25

Cmax

Answer 25

maximum concentration (absorption rate = elimination rate)

Question 26

Tmax

Answer 26

the time Cmax happens

Question 27

AUC

Answer 27

Area Under the Curve. Represents overall drug exposure

Question 28

MEC

Answer 28

minimum effective concentration

Question 29

minimum effective concentration

Answer 29

minimum effective concentration

Question 30

Absorption

Answer 30

``` • Process by which a drug moves from its site of administration into the circulatory system (blood) • Key step in drug disposition for all routes of administration – except IV ```

Question 31

Area between MEC and MTC is the

Answer 31

therapeutic range. anything above MTC is toxic or can cause side effects. Anything under MEC may not work.

Question 32

Distribution

Answer 32

• Process by which a drug reversibly leaves the circulatory system and is distributed throughout tissues of the body • Generally not even distribution throughout the entire body • Affected by many factors!

Question 33

example of something that could cause delay in absorption other than route

Answer 33

you eat food

Question 34

Protein Binding

Answer 34

Many drugs interact with and bind to plasma or tissue proteins (ex. albumin) • Protein bound drugs are not pharmacologically active • The less bound a drug is, the more efficiently it can cross cell membranes or diffuse • Does not affect “bioavailability” • Potential source of drug interactions

Question 35

___ are not pharmacologically active

Answer 35

protein bound

Question 36

Unbound drugs are

Answer 36

active and can cause effect. Example is unbound warfarin would result in an increased INR.

Question 37

Metabolism

Answer 37

The process in which drugs are chemically changed to other compounds

Question 38

New substance =

Answer 38

metabolite

Question 39

Metabolites generally

Answer 39

y less active than administered (or “parent”) drug

Question 40

metabolites may be more

Answer 40

active or have a longer duration of | action

Question 41

metabolism sites

Answer 41

Usually occurs in the liver (but can be other sites: lungs, skin, kidney, gut)

Question 42

Cytochrome P450 (CYP450)

Answer 42

• Superfamily of enzymes responsible for the metabolism of many drugs • Predominantly in the liver, but also in gut wall • At least 12 different “families” • CYP1, 2, 3 family involved in most drug metabolism • CYP3A4 involved in >60% • Limited amounts of each enzyme in the body • Best levels of evidence for pharmacogenetic clinical utility are with drug metabolism genes and variability in CYP450 activity • Drugs may compete for the same enzyme – may result in drug interactions!

Question 43

Elimination (Metabolism & Excretion)

Answer 43

``` Drugs most often excreted in urine or stool • In addition to kidneys and GI tract, may also involve lungs, skin, breast milk, etc. ```

Question 44

Bioavailability

Answer 44

``` The fraction of administered drug reaching systemic circulation in an unchanged form that can produce an effect • 100% after IV administration • Oral bioavailability depends on the amount absorbed and amount metabolized before reaching systemic circulation (first-pass metabolism) ```