Time course of delayed and cumulative drug effects Flashcards
What are the three main mechanisms associated with delayed drug effects?
- Distribution to effect site (pharmacokinetics)
- Binding to receptor (receptor kinetics)
- Physiological intermediate (physiokinetics), physiological changes occur before effect is produced
What drug is an example of ‘distribution to effect site’ delayed drug response?
Thiopentone, a short acting anaesthetic that acts on the brain. (must cross BB barrier)
Time for drugs to go from the blood to the brain. (was measured using EEG thing)
What can be said about he effect compartment?
Like the plasma compartment, the time needed to reach steady state is dependent on the elimination half life. In this case it is called the equilibration half life.
What determines the equilibration half life?
how can this be applied to thiopentone?
The volume of the effect compartment ( organ size/ tissue binding) and the clearance of the effect compartment (blood flow/diffusion)
V: relatively small
C: rapid brian perfusion so reavches brain shortly and is then washed out
gives 1min half life of equilibration
What drug is an example of ‘binding to receptor. delayed drug response? Why?
Digoxin binding to the heart. Slows AV conduction and increases contractility
What is shown on the graph pg 109, plasma conc decreases and tissue conc increases. However effect compartment effect went up with a delay.
The equilibrium half life of digoxin is high due to the high V (despite rapid perfusion), the delay is attriubuted to the long dissociation half life, which makes digoxin potent
What drug is an example of ‘physiological intermediates’ delayed drug response?
Explain the delay by talking about clotting factors/ prothrombin complexes
Warfarin- will inhibit vitamin K recycing. This has a rapid effect. However the response is delayed and is measure by a prolonged clotting time, or INR.
It is delayed because any remaining clotting factors do not go away immediately due to the long half lives of elimination of them. (14hrs) This means a new steady state INR occurs after 2-3 days
Learning point is be careful when altering warfarin dose changes due to delayed effects
What can be said about frusemide diuretics and the affect
A large dose of drug causes great effect very quickly due to high hill coefficient. Then the effect goes away very quickly after a brief plateau.
However if we give a smaller dose (one third), can reach close to the Emax and produce a greater overall effect. this is because above certain concentrations, the drug doesn’t produce any more effect.
What is the concept of schedule dependence?
That a drug can be given of the same total dose, but over at different intervals to produce the desired effect/ more effect.
Is important the drug effect is reversible
What can be said about irreversible cancer drugs?
they do not show schedule dependence. They bind irreversibly to cell structures and cause cell death, giving a cumulative response.
busulfan
ablates bone marrow before BM transplants.
Need to see plasma concentration after first dose to adjust subsequent doses, as you don’t want to be wasting conc as it will kill the patient
