Time course of immediate drug effects Flashcards
What does pharmacokinetics describe and what does pharmacodynamics describe?
Pharmacokinetics = the time course of conc (CL and V) Pharmacodynamics = how effects change with conc (Emax and EC50)
What are 3 ways to think about the time course of effects of drugs?
- The immediate effect of drugs is related to the conc in the plasma directly after administration
- The drug effects are delayed in relation to observed drug conc
- The drug effects are determined by the cumulative effect of the action of the drug
Can you determine EC50 if given the half life of a drug?
No, you dont know what the max effect is. The starting concentration of the data used to determine half life might not be the conc that gives max effect.
Conc vs effect should be plotted on a hyperbolic curve. This assumes the effect is directly proportional to binding so EC50 (conc of 50% of max effect) is the same as Kd (conc of unbound drug at which 50% of binding sites are occupied). Is this was transformed into a log function (easily done on a calculator), why is this misleading?
The log transformation is just a mathematic transformation - the X axis is in log form so the relationship dosent show any biological relationship.
- It makes it look like effect increases very slowly at low conc then most rapidly at moderate conc however we know to be true that the conc increases most rapidly at the low concs
- The log of zero is undefined (not zero) and yet we know that when the drug conc is 0 there is 0 drug effect.
What are the benefits of a log transformation of conc vs effect?
- It expands the concentration axis - the scale is larger so we can see more concentrations (both low and high) and we can appreciate how close conc approaches Emax.
What is the C20 and C80 and why are these important data points to remember?
C20 is the conc at which 20% of max effect is produced (1/4 of C50) and C80 is the conc at which 80% of max effect is produced (4x the C50).
This then therefore predicts that there must be a 16x change in conc to change the effect from 20% to 80% of max.
What is the Hill coefficient?
A physiologist -“Hill” found that the bindings oxygen to haemoglobin is steeper than the simple predictions of the Emax model. By trial and error he found that adding a coefficient to the conc values in the Emax equation, the shape of the relationship could be made steeper.
What is the target conc of Theophylline?
10mg/L.
This is the EC50. Although it is only 50% of the maximum effect Theophylline can achieve, anything above this starts to cause adverse effects/is toxic so that is a good trade off conc-effect.
What is the time course of drug action of Theophylline after giving 1x, 10x and 100x the C50 for the drug.
Theophylline C50 is 10mg/L. Half life approx 9 hours.
After a bolus dose of initial conc 10mg/L the effect appears to decrease at a similar (not identical) rate to the concentration.
After a bolus dose of initial conc of 100mg/L the effect dosent decrease as quickly. After one half life the conc has halved but the effect has decreased by less than 10%.
After a bolus dose of initial conc of 1000mg/L the effect barely decreases at all compared to conc. After more than 5 half lives when nearly all of the inital dose will have been elimnated, the effect is still 70% of Emax. (note this would kill someone).
This shows how drugs with short half lives can have big effects, even when the dosing interval is many half lives. This is common for receptor antagonists such as beta blockers (Theophylline) and ACE inhibitors.
When is it somewhat reasonable to describe the effect as having a half life? (effect dosent have a half life, only conc)
Between C20 and C80 as this portion of the effect vs time graph is linear.
What does doubling the dose (doubling the conc) do to time course of effect?
Doubling dose will increase the duration of the drug effect by one half life.
Selection of dosing interval depends on both half life and the target conc and its relation to C50. Describe using Theophylline
Theophylline has a short half life (hours) but because the target conc in the body is about/above C50 then it can be given one a day and remain effective in the body despite its short half life.
