PK, PD, Genomics Flashcards
Sources of variability drug exposure
renal/hepatic function gastric ph drug-drug interactions drug metabolism polymorphisms medication compliance
sources of variability drug response
placebo effect
drug receptor or enzyme polymorphisms
tolerance, tacyphylaxis
gender, race,
Variables Determining Drug Response
affinity for site of action (phamacodynamics) x Drug concentration at site of action (pharmacokinetics) x underlying biology of patient (genetics, age, disease, enviornment)
Pharmacodynamics
what the drug does to the body
Pharmacokinetics
what the body does to the drug
PD concepts
• Dose response curve (potency, slope, efficacy, variability)
• Receptor mechanisms (agonist, antagonist, partial agonist)
• Therapeutic index (median effective dose “ED50”, median
lethal dose “LD50”
Dose-Response Cure
• 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
Many (not all!) drugs exert
t their pharmacologic actions via receptormediated mechanisms
Agonist =
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
Antagonist =
substance that interacts with a receptor, but has no action
of its own. Prevents agonists, such as neurotransmitters, from acting.
Agonist are not
as perfect as a fit. It will interact with a receptor but not all sub types
Most perfect fit is the
hormone or neurotransmitter these interact with all subtypes.
Neurotransmitter Dopamine (DA) – a
D2 agonist
Aripiprazole (APZ) – a
D2 partial agonist
First Generation Antipsychotic (FGA) – a
D2 antagonist
Overall effect of a
partial agonist may be as a
“functional” agonist or “functional” antagonist depending on surrounding levels of naturally occurring neurotransmitter
increase in dopamine is related to
positive symptoms
decrease in dopamine related to
negative symptoms
Median effective dose (ED50)
Dose that would produce a therapeutic
response in 50% of the population
Median lethal dose (LD50)
Dose that would be lethal in
= LD50 50% of the population
The study of what happens to a drug in the body after it is administered.
PK
PK elements
Absorption
Distribution
Metabolism
Excretion
Therapeutic Index
= LD50/ED50
Concentration-Time Curve
- Shows the plasma concentration of a drug over time
* Obtained after administration of a single dose
Cmax
maximum concentration (absorption rate = elimination rate)
Tmax
the time Cmax happens
AUC
Area Under the Curve. Represents overall drug exposure
MEC
minimum effective concentration
minimum effective concentration
minimum effective concentration
Absorption
• 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
Area between MEC and MTC is the
therapeutic range. anything above MTC is toxic or can cause side effects. Anything under MEC may not work.
Distribution
• 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!
example of something that could cause delay in absorption other than route
you eat food
Protein Binding
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
___ are not pharmacologically active
protein bound
Unbound drugs are
active and can cause effect. Example is unbound warfarin would result in an increased INR.
Metabolism
The process in which drugs are chemically changed to other compounds
New substance =
metabolite
Metabolites generally
y less active than administered (or “parent”) drug
metabolites may be more
active or have a longer duration of
action
metabolism sites
Usually occurs in the liver (but can be other sites: lungs, skin, kidney, gut)
Cytochrome P450 (CYP450)
• 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!
Elimination (Metabolism & Excretion)
Drugs most often excreted in urine or stool • In addition to kidneys and GI tract, may also involve lungs, skin, breast milk, etc.
Bioavailability
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)
