L15. Time Course of Immediate Drug effects Flashcards
What are the principles of pharmacokinetics vs pharmacodynamics - PK vs PD
Pharmacokinetics: describes the time course of concentration- the linking factor between dose and effect. eg. Clearance and Volume of distribution
Pharmacodynamic: describes how effects change with concentration. eg. Emax: conc to make maximum effect and C50: conc producing 50% of max effect.
What is the Emax model equation, the assumptions behind it, and what does it look like on a graph- two transformations
Emax model helps to predict the effect of the drug at different concentrations. This is assuming that all biological responses must reach a maximum and that effect is proportional to drug binding to a receptor. eg. Theophylline
Drug effect= Emax x conc at the receptor / c50 + conc at receptor.
On a graph between effect and concentration, it is a hyperbolic curve with asymptote comes up to 100%. If conc is log transformed it helps to see the S shaped curve but don’t use it to predict values- can’t log 0, and it doesn’t approach max.
When concentrations are low in relation to C50, how can the conc vs effect relationship be approximated. Also how does C20 and C80 relate to C50
Low conc compared to C50: linear relationship
Effect: Slope x concentration
C20: 1/4 of C50, C80: 4 x C50
What is the Sigmoid Emax model and what is it used for
Sigmoid Emax model is the same Emax equation but with all the concentrations of drug increased by a Hill coefficient.
E= Emax x Conc (^ hill) / C50 (^hill) + conc (^hill)
The hill coefficient is used to change the slope of the graph, increasing the rate they reach the emax but not changing emax itself.
How does the graph of the sigmoid model vary with different Hill Coefficient
If hill exponent>1 then slow increase at low conc with steep increase to high effect at higher conc (above c50).
hill exponent = 1, same curve as emax.
hill exponent <1, then at lower conc big effect then doesn’t get much steeper.
hill exponent> 10 : demonstrates threshold “On or off”
How does the Pharmacokinetics and pharmacodynamics interact to show the relationship between concentration and effect of a drug over time with eg.
Over time the concentrations fall exponentially based on pharmacokinetics- half life of the drug, however the drug effect depends upon the initial conc + subsequent Pharmacokinetics of the drug.
Starting with:
peak Conc C50: time course of effect is almost parallel with time course of conc
peak Conc: 10 x C50: (90% emax) By one half life, effect only waned by 10% and starts to disappear more quickly as conc decreases more.
peak Conc 100 x C50: (~100% emax). After 5 half lives, effect only waned by 30%
Describe the time course of effect in 3 regions depending on >C80, C80-C20, < C20
> C80: Flat relationship: the exponential decrease in concentration, only results in a small decrease in effect (upside down exponential)
Between C80 and C20: there is a Linear loss of drug effect vs time
< C20: Time course of effect and concentration almost parallel in Exponential decline- so effect half-life can be used here but these conc are not v useful in clinical situation
What are the pharmacodynamic determinants of dosing interval to sustain the desired level of effect of a drug.
Not just half life of the drug.
- If you double the dose the duration of effect will increase by one half life for the whole range. However this will not double the effect
- Depends on the target concentration and its relation to C50- when dosing, to know the time course of the effect as this is different to the change in concentration throughout the day
What effect does doubling the dose of a drug on the duration of response
The time that the drug effect is above a pre-defined critical value will increase by one half life for the whole range
*The increase in the duration of response from doubling the dose is independent of the size of effect that is chosen to mark the end of the response,
What is the equation to predict target concentration from target effect
target Conc= C50 x effect/ (emax -effect)
