Pharmacodynamics - part 1 Flashcards
Pharamcokinetics includes:
Absorption
Distribution
Metabolism
Excretion
These factors take a dose of drug and determine the drug concentration in target organ over time.
Pharmacodynamics includes:
Receptor binding
Signal transduction
Physiological effect
These factors use the drug concentration in target over time to determine the mechanism + magnitude of drug effect.
What is the therapeutic window?
The drug concentration above lack of effect (therapeutic failure) and below side effects (drug excess).
While over the counter drugs have a _________ therapeutic window, prescription drugs have a ________ therapeutic window.
Larger; narrow
The side effects/toxicity a drug can exert and pass the therapeutic window may be due to:
1) Same mechanism/action as the therapeutic effect but HIGHER INTENSITY
2) Same mechanism/action but NON-TARGET TISSUE
3) Different mechanism than the therapeutic effect
In simpler terms, PD is how the ________ affects the _________, while Pk is how the __________ affects the ________.
substance; organism
organism; substance
What are three methods a xenobiotic can make use of to induce changes in the organism?
1) Xenobiotic-receptor interactions (agonism, antagonism, inhibition, etc)
2) Physical actions (osmotic activity, effects of membrane)
3) Chemical actions (antacids, chelating agents, pro/antioxidants)
2/3 not as specific like 1.
As a mechanism of action, a drug typically exerts effects on the molecular level, which induces cellular changes, leading to tissue/organ changes that affect the whole organism (systemic).
Briefly use these terms to describe the effects of Nifedipine, Verapamil, Diltiazem (Ca2+ ion blockers).
Usually calcium ions go and bind to calmodulin which causes contraction in tissues/organs, leading to an increased blood pressure.
This xenobiotic:
Molecular: blocks calcium ion channels
Cellular: calcium can no longer bind to calmodulin
Tissue/organ: contraction is inhibited
Systemic: blood pressure decreases
What is a dose-response relationship?
The relationship between the concentration of a xenobiotic at the receptor site (in vitro) or in the dose/blood (clinic) and the magnitude of response.
Concentration is in reference to bioavailability (in blood or SOA).
What are the two types of dose response relationships?
1) Graded (continuous; describe the effect of various doses of a drug on an individual)
2) Quantal (all-or-none; respond or not - show the effect of various doses of a drug on a population of individuals)
A graded dose response is the relationship among dose/concentration, target/receptor “activation”, and the ____________ of the response.
The response elicited with each dose is plotted against the _____ dose/concentration and can be described as ______ _______________.
Magnitude
Log; % of Maximal Response
A quantal dose response is the relationship among dose/concentration and the ________ of the response.
The response elicited with each is plotted against the _____ dose and can be described as _________________.
Frequency
log; % of population
Responses generated with increasing dose of a drug/toxin described as the cumulative % of subjects exhibiting a defined all-or-none effect.
Match the following terms to their definition:
1) Emax
2) ED50
3) Tmax
4) TD50
5) LD50
A) MEDIAN EFFECTIVE DOSE the dose that produces 50% of the Emax
B) MEDIAN TOXIC DOSE - the dose that produces 50% of the Tmax
C) MEDIAN LETHAL DOSE - if the effect is death, ED50 is referred to as LD50.
D) the maximal response produced when the targeted interaction is saturated (all receptors occupied)
E) the maximum toxic response
Emax: the maximal response produced when the targeted interaction is saturated (all receptors occupied)
ED50: MEDIAN EFFECTIVE DOSE - the dose that produces 50% of the Emax
Tmax: the maximum toxic response
TD50: MEDIAN TOXIC DOSE - the dose that produces 50% of the Tmax
LD50: MEDIAN LETHAL DOSE - if the effect is death, ED50 is referred to as LD50.
(T/F) LD50s are calculated and expressed relative to a population; Quantal relationship (yes/no).
True!
What is NOEL? What is NOAEL?
NOEL: no observed effect level
NOAEL: no observed adverse effect level
In a graded dose response, first there is _______ and then a _________ and then the _______ effect.
Where is NOAEL?
NOEL; threshold, maximal
NOAEL is between the threshold and the maximum effect where ED50 is.
Some drugs can have a threshold and some do not. What is the difference between the two?
Having a threshold means that the patient can tolerate the drug for a little without a response. It is after crossing that threshold where the effects start showing.
Without a threshold, the patient is not able to tolerate without a response. The response is present right away.
Describe potency: how it is expressed, how it is determined, what it is related to, etc.
Potency is generally expressed as EC50 (dose that produces 50% of the maximal effect).
It is determined by the affinity of the xenobiotic for its target. A drug with high affinity requires lower dose to occupy more receptors.
Potency is inversely related to ED50; a drug with ED50 of 5 mg is 10x more potent than a drug with ED50 of 50mg.
Efficacy is the _________ response produced by a drug.
A full agonist has a ________ efficacy.
An antagonist has a ________ efficacy.
Maximal
Maximal; partial agonists have below 100-50%.
No
Drugs can have the ______ efficacy but a _______ potency or vice versa.
same; different
more potent drug; less dose needed to reach 50% of the max efficacy
less potent drug: more dose needed to reach 50% of the same max efficacy
What is IC50?
The concentration of an inhibitor where the response is reduced by half.
The smaller the IC50 (less drug to inhibit more), the greater the potency of the drug.
What is the slope in graded dose response curves?
High slope means ________ concentration sensitive; a ________ therapeutic window.
Low slope means _______ concentration sensitive; a _________ therapeutic window.
The change in response per unit dose/plasma concentration.
HIGHLY: narrow (small changes = big differences)
MIDLY; broader (OTC drugs)
(T/F) In the slopes of graded dose response curves, a high slope drug means individual variation is less important, while a low slope drug means individual variation more import.
False!
High slope: individual variation important; need for personalized dose titration
Low slope: individual variation less import; common dosing schedules
Suppose drug A has a slope of 1.0, drug B has a slope of 1.5, and drug C has a slope of 0.5 in a graded dose-response curve.
Which drug is most likely to be an OTC drug?
Which drug is least likely to be an OCT drug?
Drug C (lowest slope) most likely to be an OTC drug.
Drug B (highest slope) least likely to be an OTC drug.
The higher the slope, the higher the sensitive to dose. Less drug = more changes. Therapeutic window narrow.
What is the therapeutic index (TI)?
How is TI measured?
TI is the mathematical measure between the toxicity and therapeutic effect.
TI = TD50/ED50
The TI (therapeutic index) of a drug has to be _________ than 1 to be useable.
The larger the TI, the ________ the therapeutic window.
Greater (TI of 1 or lower = poison)
Larger
(T/F) Therapeutic index, therapeutic window and standard safety margin all mean the same thing.
False!
Therapeutic window: the range of blood level wherein the drug is producing the desired effect without the feared toxicity.
Therapeutic index: the ratio of the dose that produces the desired therapeutic effect to the dose that produces a toxic effect.
Standard Safety margin: the concentration of the drug that leads to 1% of the population dying relative to treating (LD1-ED99/ED99)
Therapeutic index (TI) and standard safety margins are based on ________ dose-response relationships.
Quantal
TI can be defined using a graded dose relationship curves but standard safety margin can only be quantal.
What are the effects of competitive antagonist and competitive agonist in graded dose-response curves?
Competitive antagonist:
- binds REVERSIBLY to receptor at an orthosteric site
- effects can be overcome with increasing doses of the agonist
- SHIFTS the agonist’s dose-response curve to the RIGHT
- does NOT REDUCE the MAXIMAL response
Competitive agonist:
- SHIFTS the agonist’s dose-response curve to the LEFT
- does NOT REDUCE the MAXIMAL response
*parallel shift
What are the effects of non-competitive antagonist in graded dose-response curves?
Non-competitive antagonist:
- binds to the receptor (reversible/irreversible) in a way that reduces the ability of the agonist to elicit a response at an ALLOSTERIC SITE
- CANNOT be OVERCOME with greater doses of an agonist
- REDUCES the agonist’s MAXIMAL response
- No change in EC50 (potency)
(T/F) Many bioactive xenobiotics exert multiple effects.
True!
What is the difference between frequency distribution and cumulative frequency distribution of a quantal dose response relationships?
Frequency tells you how often something happened; it is a non-cumulative response.
The cumulative frequency is calculated by adding each frequency from a frequency distribution table to the sum of its predecessors. The last value will always be equal to the total for all observation.
(T/F) A graded response can be represented/transformed to a quantal response by setting a specific endpoint along the graded response. Similarly, a quantal can become graded.
FALSE!
Graded can be quantal by setting a specific endpoint along the graded response but a QUANTAL CAN NOT BE GRADED.
What does a negative 17% standard safety margin value mean?
(LD1-ED99)/ED99 = -17%
If you continue with the treatment for the 99% of the population, 17 people will have died.
Dose predicted to induce therapeutic effect in 99% of individuals must be DECREASED by 17% to avoid the xenobiotic being lethal to 1% of the population.
If a drug has a ________ safety margin, they are often initiated at low dose and increased gradually. Alternative treatments are considered if the dose increases beyond _____.
Negative
EC50 (the concentration of a drug that is necessary to cause half of the maximum possible effect).
(T/F) While the therapeutic index and standard safety margin are ratios, therapeutic window is a range of numbers.
True!
For time/dose-response relationships,
Pharmacokinetics has _________ on the y-axis, _______ on the x-axis.
Pharmacodynamics has _________ on the y-axis, ______ on the x-axis.
PK/PD has __________ on the y-axis, __________ on the x-axis.
concentration; time
effect; concentration
effect; time
(dose response has concentration/dose on the x-axis)
(T/F) We can tell a lot about time in dose-response relationship models.
False! Dose-response relationship models do not tell us anything about time.
(T/F) Time response relationships and dose response relationships are both monotonic.
False, dose response curve is monotonic, while time response curve is non-monotonic.
In time-response relationships:
Bigger dose, _______ onset, _______ duration
Does the Tmax remain the same if you change doses in time-response relationships?
earlier; longer
Yes, Tmax remains the same (if absorption and elimination processes are unsaturated)
Out of the three routes of administration, which one would have the fastest Tmax + highest Cmax in the plasma? Which one would have the slowest Tmax + lowest Cmax?
1) Inhalation
2) Oral
3) Topical
Inhalation would have the fastest Tmax (time to reach Cmax) and the highest Cmax (maximum drug concentration). Strong response, early onset + long duration.
Topical would have the slowest Tmax and the lowest Cmax. Less intense effect, longer onset + short duration.
The higher the volume of distribution, the more time for ___________.
Elimination
When the rate of elimination is smaller than the rate of absorption, ______________ occurs.
Bioaccumulation
