Final L1 - PKD 1 Flashcards
Pharmacodynamics definition
A discipline that quantifies the relationship between drug concentration at the site of drug action and the drug’s pharmacologic effect
Pharmacodynamics
What the DRUG does to the BODY
Importance of PK/PD
-Relate temporal patterns of response (efficacy, harm) to drug admin following acute and chronic dosing
-Provide a rational basis for drug design, drug selection, and dosage regimen design
Exposure
Any dose or drug input to the body or various measures of acute or integrated drug concentrations in plasma or other biological fluid
Response
Direct measure of a pharmacologic observation
Desired response
Clinical response (quality of life, survival, organ survival, etc)
-Biomarker (LDL-cholesterol, blood glucose, blood pressure, etc.)
-Surrogate endpoint: biomarker that substitutes for a clinically meaningful endpoint
Harmful response
Mortality, hospitalization, etc.
-ADRs
-Change in biologic/pharmacologic observation from one time to another
Effect
Change in response from one time to another
response and effect will be used interchangeably
Exposure vs Effect
Exposure - measure of CMAX
Effect - measure of Rmax
Drug effect is mediated by (unbound/bound) drug concentration?
Unbound (free) drug concentration
Graded response
Continuous scale
Measured in a single biologic unit (person, animal, etc)
Relates dose (and concentration) to intensity of effect
(EC50, Emax, Kd)
Quantal response
All or none effect
Measured in more than one (large numbers of) individual
Relates dose (or concentration) to frequency of effect
Units for EMax are
100% (hematocrit units
Emax is the
maximal effect (max binding)
EC50 units
Concentration; (mg/L)
Concentration effect relationship
EMax, EC50 and Kd
Sigmoid shape (S shaped curve)
Looks like non-linear PK
Kd
Dissociation constant
EC50 is a measure of
Potency - sensitivity to the drug
Clinical correlation to heart failure: If an agonist is given, it will shift curve to (right/left) and make it (more/less) potent
Left; less potent
reason why we give naloxone in overdose cases
Disease states on ADME: CKD
When a patient has CKD:
-Diuretic is less potent, and causes about 1/2 of the max response
need an increase in dose, or same dose but given more often
Concentration response curve is steep
Most drugs, we are trying to achieve concentrations between (%range) of the max effect
20-80%
Response vs time
Predicts response will decline linearly
-One compartment model (monoexponential decline)
-Linear log-dose relationship
Decrease in effect is impact by both K (PK) and m (PD)
Changes in response profiles: What happens to the time course of response if k is increased
Start at the same point, but curve is shifted more to the left
-Eo is unchanged
-m is unchanged
-Time course changed due to a change in PK
-Declines more quickly
Given Dose, Vd, k and m, you could estimate/predict response at any given time
Direct effect model
Peak conc happens at the same time as peak response
CP = Exposure
-Max conc and response happen at roughly the same time
Response is directly related to concentration
Disequilibrium in concentration effect relationship
When conc and response do not happen at the same time
Max drug conc vs max response - displaced to the right (Takes more time) = delay
Hysteresis Loop
Counterclockwise
-S curve turns into this loop because there is a delay in drug reaching the effect side = takes longer to reach response
-Up slope: The effect is lower than that of the down slope
-Greater effect LATER in therapy as opposed to EARLIER in therapy
Potential reasons for delay in response: Increased effect as compared to earlier temporal effect at same CP
Delay in drug reaching the effect site/biophase
Production of an active metabolite that produces a response similar to parent
Up-regulation of receptor response or sensitization
Indirect effect
-Ex, steroids, have to get into system to trigger something else, takes more time = delayed response
Proteresis loop
Clockwise
-Greater effect EARLY in therapy as opposed to later in therapy
Potential reasons for Clockwise Proteresis: Decreased effect as compared earlier temporal effect at same Cp
-Alteration in distribution between venous and arterial concentrations
-Production of an “active” metabolite opposite of the parent
Down-regulation of receptor response or tolerance (desensitization)
Indirect effect
Biggest example of a tolerance drug
Opioids; keeps up max effect even at later doses
